MATSUDA Satoru
| Faculty Division of Human Life and Environmental Sciences Research Group of Food Science and Nutrition | Professor |
Last Updated :2025/04/27
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Name (Japanese)
MatsudaName (Kana)
Satoru
Research History
■Ⅱ．研究活動実績
Published Papers
- Biology, Behavioral Test Scores Could Be Linked to the Protein Expression Values of p62 and GLAST in the Brains of Mice with Neuropsychiatric Disorder-Related Behaviors, Yuka Ikeda; Moeka Nakashima; Sayuri Yoshikawa; Kurumi Taniguchi; Naoko Suga; Satoru Matsuda, Neuropsychiatric disorders are a public health concern, in which diagnosis and prognosis may be based on clinical symptoms that might often diverge across individuals. Schizophrenia is a major neuropsychiatric disorder, which may affect millions worldwide. However, the biochemical alterations of this disorder have not been comprehensively distinguished. In addition, there is less confidence in finding specific biomarkers for neuropsychiatric disorders, including schizophrenia, but rather a specific characteristic behavioral pattern. In general, maternal immune activation is considered to be one of the important factors in the development of neuropsychiatric disorders. Here, a mouse model of neuropsychiatric disorders was created, in which poly I:C, sodium dextran sulfate (DSS), and κ-carrageenan (CGN) were utilized for maternal immune activation during the pregnancies of mother mice. Subsequently, we examined the link between biochemical changes in p62 and/or glutamate aspartate transporter (GLAST) in the brains of offspring mice and the alteration in their experimental behavior scores. Furthermore, a therapeutic study was conducted on these neuropsychiatric disorder model mice using butyric acid, piceid, and metformin. It was found that some molecules could effectively improve the behavioral scores of neuropsychiatric model mice. Importantly, significant correlations between certain behavioral scores and p62 protein expression, as well as between the scores and GLAST expression, were recognized. This is the first report of a significant correlation between pathological behaviors and biochemical alterations in neuropsychiatric disorder model animals. This concept could contribute to the development of innovative treatments to at least ameliorate the symptoms of several psychiatric disorders., Dec. 2024, 13, 12, Scientific journal, 10.3390/biology13121039
- Discovery medicine, Exosomes, Endosomes, and Caveolae as Encouraging Targets with Favorable Gut Microbiota for the Innovative Treatment of Alzheimer's Diseases., Moeka Nakashima; Naoko Suga; Akari Fukumoto; Sayuri Yoshikawa; Satoru Matsuda, Neurodegenerative diseases are characterized by progressive damage to specific neuronal cells, resulting in cognitive impairments. Alzheimer's disease is one of the most common types of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained elusive. It has been suggested that oxidative stress, mitochondrial injury, and inflammation might lead to brain cell death in many neurological disorders. Therefore, the identification of effective neuroprotective agents is a research priority, and several autophagy-targeted bioactive compounds are promising candidate therapeutics for the prevention of brain cell damage. Some Alzheimer's disease risk genes expressed within the brain are linked to cholesterol metabolism, lipid transport, endocytosis, exocytosis, and/or caveolae formation, suggesting fruitful therapeutic targets for the treatment of cognitive impairments. Among them, a well-known genetic risk factor for late-onset Alzheimer's disease is allelic variation of the Apolipoprotein E (APOE) genes. APOE proteins may regulate aspects of cellular homeostasis, which is perturbed in the brain in Alzheimer's disease. Interestingly, the Apolipoprotein E ε4 allele (APOE4) protein is related to autophagy and to the biogenesis of caveolae, endosomes, and exosomes, processes which might consequently be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Recent research suggests that modification of the diet and/or gut-microbiota could be effective for treatment of various neurodegenerative diseases. Collectively, this research direction has the potential to improve clinical care through disease-modifying treatment strategies with benefits for patients with neurodegenerative diseases., Nov. 2024, 36, 190, 2132, 2142, Scientific journal, True, 10.24976/Discov.Med.202436190.196
- Nutrients, Hydroxyprolyl-Glycine in 24 H Urine Shows Higher Correlation with Meat Consumption than Prolyl-Hydroxyproline, a Major Collagen Peptide in Urine and Blood, Tomoko T. Asai; Satoshi Miyauchi; Sri Wijanarti; Ayaka Sekino; Akiko Suzuki; Sachiko Maruya; Takayo Mannari; Ai Tsuji; Kenji Toyama; Rieko Nakata; Yasunori Ogura; Hitoshi Takamura; Kenji Sato; Ribeka Takachi; Satoru Matsuda, 21 Oct. 2024, 16, 20, Scientific journal, 10.3390/nu16203574
- Molecules (Basel, Switzerland), Caveolae with GLP-1 and NMDA Receptors as Crossfire Points for the Innovative Treatment of Cognitive Dysfunction Associated with Neurodegenerative Diseases., Moeka Nakashima; Naoko Suga; Sayuri Yoshikawa; Satoru Matsuda, Some neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that encompasses memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative diseases that are characterized by deficits of cognition and alterations of behavior. Despite the huge efforts against Alzheimer's disease, there has yet been no successful treatment for this disease. Interestingly, several possible risk genes for cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes, and/or caveolae formation, suggesting that caveolae may be a therapeutic target for cognitive dysfunctions. Interestingly, the modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptor signaling may offer a novel approach to preventing and alleviating cognitive dysfunction. A paradigm showing that both GLP-1 and NMDA receptors at caveolae sites may be promising and crucial targets for the treatment of cognitive dysfunctions has been presented here, which may also be able to modify the progression of Alzheimer's disease. This research direction may create the potential to move clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases., 20 Aug. 2024, 29, 16, Scientific journal, True, 10.3390/molecules29163922
- International journal of molecular sciences, Caveolin and NOS in the Development of Muscular Dystrophy., Moeka Nakashima; Naoko Suga; Sayuri Yoshikawa; Satoru Matsuda, Caveolin is a structural protein within caveolae that may be involved in transmembrane molecular transport and/or various intercellular interactions within cells. Specific mutations of caveolin-3 in muscle fibers are well known to cause limb-girdle muscular dystrophy. Altered expression of caveolin-3 has also been detected in Duchenne muscular dystrophy, which may be a part of the pathological process leading to muscle weakness. Interestingly, it has been shown that the renovation of nitric oxide synthase (NOS) in sarcolemma with muscular dystrophy could improve muscle health, suggesting that NOS may be involved in the pathology of muscular dystrophy. Here, we summarize the notable function of caveolin and/or NOS in skeletal muscle fibers and discuss their involvement in the pathology as well as possible tactics for the innovative treatment of muscular dystrophies., 12 Aug. 2024, 25, 16, Scientific journal, True, 10.3390/ijms25168771
- Discovery medicine, Recent Progress of Chitosan Nanoparticles for the Development of Superior Delivery of Vaccines., Moeka Nakashima; Naoko Suga; Yuka Ikeda; Sayuri Yoshikawa; Satoru Matsuda, Chitosan seems to be an innovative biological material potentially utilized as a nanoparticle carrier for drug delivery, which could be low toxic, biocompatible, and easy to prepare. Chitosan nanoparticles have been employed in gene delivery. As a type of multifunctional adjuvant, chitosan nanoparticles could activate the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway to induce cell protection and/or proliferation via the modulation of autophagy within dendritic cells. In general, adjuvants may improve the innate and/or adaptive immune responses to a vaccine antigen by facilitating the antigen presentation of antigen presenting cells such as dendritic cells. The choice of a suitable adjuvant has become vital for improved safety and/or expanded application of vaccines. Fortunately, chitosan nanoparticles could be designed to target the dendritic cells to be enhanced by its adjuvant effect and for stimulating robust immune responses. Therefore, chitosan nanoparticles may be a good immune stimulant with encouraging properties for the development of superior vaccine delivery. Indeed, vaccines could play a key role in human health. In this review, we summarize the concept and/or recent progress in the field of chitosan nanoparticles, providing a valuable resource for investigating the molecular mechanisms of chitosan for the development of a greater vaccine., Mar. 2024, 36, 182, 457, 466, Scientific journal, True, 10.24976/Discov.Med.202436182.43
- International journal of physiology, pathophysiology and pharmacology, Caveolae with serotonin and NMDA receptors as promising targets for the treatment of Alzheimer's disease., Moeka Nakashima; Naoko Suga; Akari Fukumoto; Sayuri Yoshikawa; Satoru Matsuda, Alzheimer's disease is the most general type of cognitive impairments. Until recently, strategies that prevent its clinical progression have remained more elusive. Consequently, research direction should be for finding effective neuroprotective agents. It has been suggested oxidative stress, mitochondrial injury, and inflammation level might lead to brain cell death in many neurological disorders. Therefore, several autophagy-targeted bioactive compounds may be promising candidate therapeutics for the prevention of brain cell damage. Interestingly, some risk genes to Alzheimer's disease are expressed within brain cells, which may be linked to cholesterol metabolism, lipid transport, endocytosis, exocytosis and/or caveolae formation, suggesting that caveolae may be a fruitful therapeutic target to improve cognitive impairments. This review would highlight the latest advances in therapeutic technologies to improve the treatment of Alzheimer's disease. In particular, a paradigm that serotonin and N-methyl-d-aspartate (NMDA) receptors agonist/antagonist within caveolae structure might possibly improve the cognitive impairment. Consequently, cellular membrane biophysics should improve our understanding of the pathology of the cognitive dysfunction associated with Alzheimer's disease. Here, this research direction for the purpose of therapy may open the potential to move a clinical care toward disease-modifying treatment strategies with certain benefits for patients., 2024, 16, 5, 96, 110, Scientific journal, True, 10.62347/MTWV3745
- International journal of physiology, pathophysiology and pharmacology, Comprehension of gut microbiota and microRNAs may contribute to the development of innovative treatment tactics against metabolic disorders and psychiatric disorders., Moeka Nakashima; Naoko Suga; Akari Fukumoto; Sayuri Yoshikawa; Satoru Matsuda, Metabolic syndrome is a group of pathological disorders increasing the risk of serious diseases including cardiovascular disease, stroke, type 2 diabetes. Global widespread of the metabolic syndrome has put a heavy social burden. Interestingly, a crucial link between the metabolic syndrome and a psychiatric disorder may frequently coexist, in which certain shared mechanisms might play a role for the pathogenesis. In fact, some microRNAs (miRNAs) have been detected in the overlap pathology, suggesting a common molecular mechanism for the development of both disorders. Subsequent studies have revealed that these miRNAs and several metabolites of gut microbiota such as short chain fatty acids (SCFAs) might be involved in the development of both disorders, in which the association between gut and brain might play key roles with engram memory for the modulation of immune cells. Additionally, the correlation between brain and immunity might also influence the development of several diseases/disorders including metabolic syndrome. Brain could possess several inflammatory responses as an information of pathological images termed engrams. In other words, preservation of the engram memory might be achieved by a meta-plasticity mechanism that shapes the alteration of neuron linkages for the development of immune-related diseases. Therefore, it might be rational that metabolic syndrome and psychiatric disorders may belong to a group of immune-related diseases. Disrupting in gut microbiota may threaten the body homeostasis, leading to initiate a cascade of health problems. This concept may contribute to the development of superior therapeutic application with the usage of some functional components in food against metabolic and psychiatric disorders. This paper reviews advances in understanding the regulatory mechanisms of miRNAs with the impact to gut, liver and brain, deliberating the probable therapeutic techniques against these disorders., 2024, 16, 6, 111, 125, Scientific journal, True, 10.62347/WAZH2090
- Refereed, Microorganisms, MDPI AG, Efficacy of Life Protection Probably from Newly Isolated Bacteria against Cisplatin-Induced Lethal Toxicity, Yuka Ikeda; Naoko Suga; Satoru Matsuda, Cisplatin may be commonly used in chemotherapy against various solid tumors. However, cisplatin has a limited safety range with serious side effects, which may be one of the dose-restraining reasons for cisplatin. A favorable therapeutic approach is immediately required for ameliorating cisplatin-induced toxicity. In the present study, the potential protective effects of certain bacteria have been investigated at the lethal dosage of cisplatin in mice experimental models. Treated under the highest dosage of cisplatin, treatment of certain commensal bacteria could significantly increase the survival rate. In addition, our findings revealed that probiotic supplementation of these bacteria could result in the attenuation of the damage appearance on the kidney as well as the alteration of several antioxidant-related gene expressions, including SOD1, SOD2, SOD3, Nrf2, and/or HO-1 genes in the high dosage of cisplatin-treated mice. In short, acute kidney injury in mice was induced by a single dose of cisplatin 11 or 15 mg/kg intraperitoneally. Then, peroral administration of newly isolated bacteria could protect against the cisplatin-induced injury, probably by decreasing oxidative stress. Therefore, the data shown here might suggest that the usage of certain probiotic supplementation could contribute to the life protection of patients suffering from severe toxicity of cisplatin. However, the molecular mechanisms need to be further explored., 06 Sep. 2023, 11, 9, 2246, 2246, Scientific journal, 10.3390/microorganisms11092246
- Refereed, Epigenomes, MDPI AG, Integrated Multimodal Omics and Dietary Approaches for the Management of Neurodegeneration, Toshiyuki Murai; Satoru Matsuda, Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are caused by a combination of multiple events that damage neuronal function. A well-characterized biomarker of neurodegeneration is the accumulation of proteinaceous aggregates in the brain. However, the gradually worsening symptoms of neurodegenerative diseases are unlikely to be solely due to the result of a mutation in a single gene, but rather a multi-step process involving epigenetic changes. Recently, it has been suggested that a fraction of epigenetic alternations may be correlated to neurodegeneration in the brain. Unlike DNA mutations, epigenetic alterations are reversible, and therefore raise the possibilities for therapeutic intervention, including dietary modifications. Additionally, reactive oxygen species may contribute to the pathogenesis of Alzheimer’s disease and Parkinson’s disease through epigenetic alternation. Given that the antioxidant properties of plant-derived phytochemicals are likely to exhibit pleiotropic effects against ROS-mediated epigenetic alternation, dietary intervention may be promising for the management of neurodegeneration in these diseases. In this review, the state-of-the-art applications using single-cell multimodal omics approaches, including epigenetics, and dietary approaches for the identification of novel biomarkers and therapeutic approaches for the treatment of neurodegenerative diseases are discussed., 01 Sep. 2023, 7, 3, 20, 20, Scientific journal, 10.3390/epigenomes7030020
- Refereed, Genes, MDPI AG, Non-Coding RNAs and Gut Microbiota in the Pathogenesis of Cardiac Arrhythmias: The Latest Update, Naoko Suga; Yuka Ikeda; Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Satoru Matsuda, Non-coding RNAs (ncRNAs) are indispensable for adjusting gene expression and genetic programming throughout development and for health as well as cardiovascular diseases. Cardiac arrhythmia is a frequent cardiovascular disease that has a complex pathology. Recent studies have shown that ncRNAs are also associated with cardiac arrhythmias. Many non-coding RNAs and/or genomes have been reported as genetic background for cardiac arrhythmias. In general, arrhythmias may be affected by several functional and structural changes in the myocardium of the heart. Therefore, ncRNAs might be indispensable regulators of gene expression in cardiomyocytes, which could play a dynamic role in regulating the stability of cardiac conduction and/or in the remodeling process. Although it remains almost unclear how ncRNAs regulate the expression of molecules for controlling cardiac conduction and/or the remodeling process, the gut microbiota and immune system within the intricate networks might be involved in the regulatory mechanisms. This study would discuss them and provide a research basis for ncRNA modulation, which might support the development of emerging innovative therapies against cardiac arrhythmias., 30 Aug. 2023, 14, 9, 1736, 1736, Scientific journal, 10.3390/genes14091736
- Refereed, Exploration of Targeted Anti-tumor Therapy, Open Exploration Publishing, Potential tactics with certain gut microbiota for the treatment of unresectable hepatocellular carcinoma, Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Tomoko Asai; Ai Tsuji; Satoru Matsuda, Hepatocellular carcinoma (HCC) constitutes an extremely malignant form of primary liver cancer. Intricate connections linking to the immune system might be associated with the pathogenesis of HCC. Meanwhile, immunotherapy with immune checkpoint inhibitors has been established to be a favorable therapeutic possibility for advanced HCC. Although curative opportunities for advanced HCC are restricted, the immune checkpoint immunotherapy has developed as the main choice for treating HCC. However, patients with metabolic-associated fatty liver disease (MAFLD)-linked HCC might be less likely to benefit from the immunotherapy alone. The limitation of the effect of the immunotherapy might be owing to the impaired T cell activation in MAFLD patients, which could be well explained by a dysfunctional gut-liver axis. Gut microbiota and their metabolites including several bile acids could contribute to modulating the responses of the immune checkpoint immunotherapy. Roles of gut microbiota in the development of cancers have expected great interest in the latest studies. Here, an interplay between the gut and liver has been presented, which might suggest to affect the efficacy of immune checkpoint immunotherapy against HCC., 24 Aug. 2023, 556, 568, Scientific journal, 10.37349/etat.2023.00152
- Refereed, Neurology International, MDPI AG, In Search of a Function for the N6-Methyladenosine in Epitranscriptome, Autophagy and Neurodegenerative Diseases, Naoko Suga; Yuka Ikeda; Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Satoru Matsuda, Changes in epitranscriptome with N6-methyladenine (m6A) modification could be involved in the development of multiple diseases, which might be a prevalent modification of messenger RNAs (mRNAs) in eukaryotes. The m6A modification might be performed through the action of methyltransferases, demethylases, and methylation-binding proteins. Importantly, the m6A methylation may be associated with various neurological disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, aging-related diseases, and/or aging itself. In addition, the m6A methylation might functionally regulate the eukaryotic transcriptome by influencing the splicing, export, subcellular localization, translation, stability, and decay of mRNAs. Neurodegenerative diseases may possess a wide variety of phenotypes, depending on the neurons that degenerate on occasion. Interestingly, an increasing amount of evidence has indicated that m6A modification could modulate the expression of autophagy-related genes and promote autophagy in neuronal cells. Oxidative stresses such as reactive oxygen species (ROS) could stimulate the m6A RNA methylation, which may also be related to the regulation of autophagy and/or the development of neurodegenerative diseases. Both m6A modification and autophagy could also play critical roles in regulating the health condition of neurons. Therefore, a comprehensive understanding of the m6A and autophagy relationship in human diseases may benefit in developing therapeutic strategies in the future. This paper reviews advances in the understanding of the regulatory mechanisms of m6A modification in the occurrence and development of neurodegenerative diseases and/or aging, discussing the possible therapeutic procedures related to mechanisms of m6A RNA methylation and autophagy., 10 Aug. 2023, 15, 3, 967, 979, Scientific journal, 10.3390/neurolint15030062
- Refereed, Biology, MDPI AG, Metabolic Reprogramming toward Aerobic Glycolysis and the Gut Microbiota Involved in the Brain Amyloid Pathology, Toshiyuki Murai; Satoru Matsuda, Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of metabolic reprogramming in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method for the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in the near future., 03 Aug. 2023, 12, 8, 1081, 1081, Scientific journal, 10.3390/biology12081081
- Refereed, Microorganisms, MDPI AG, Gut Protective Effect from Newly Isolated Bacteria as Probiotics against Dextran Sulfate Sodium and Carrageenan-Induced Ulcerative Colitis, Yuka Ikeda; Ai Tsuji; Satoru Matsuda, Gut microbiome dysbiosis might be linked to certain diseases such as inflammatory bowel diseases (IBDs), which are categorized by vigorous inflammation of the gastrointestinal tract. Several studies have shown the favorable anti-inflammatory effect of certain probiotics in IBD therapy. In the present investigation, the possible gut protective effects of commensal bacteria were examined in an IBD model mouse that was cost-effectively induced with low molecular weight dextran sulfate sodium (DSS) and kappa carrageenan. Our conclusions show that certain probiotic supplementation could result in the attenuation of the disease condition in the IBD mouse, suggesting a favorable therapeutic capability for considerably improving symptoms of gut inflammation with an impact on the IBD therapy. However, the molecular mechanisms require further investigation., 23 Jul. 2023, 11, 7, 1858, 1858, Scientific journal, 10.3390/microorganisms11071858
- Refereed, Exploration of Targeted Anti-tumor Therapy, Open Exploration Publishing, Potential tactics with vitamin D and certain phytochemicals for enhancing the effectiveness of immune-checkpoint blockade therapies, Ai Tsuji; Sayuri Yoshikawa; Sae Morikawa; Yuka Ikeda; Kurumi Taniguchi; Haruka Sawamura; Tomoko Asai; Satoru Matsuda, Immunotherapy strategies targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are revolutionizing oncology. However, its effectiveness is limited in part due to the loss of effector cytotoxic T lymphocytes. Interestingly, supplementation of vitamin D could abolish the repressive effect of programmed cell death-ligand 1 (PD-L1) on CD8+ T cells, which might prevent the lymphocytopenia. In addition, vitamin D signaling could contribute to the differentiation of T-regulatory (Treg) cells associated with the expression of Treg markers such as forkhead box P3 (FOXP3) and CTLA-4. Furthermore, vitamin D may be associated with the stimulation of innate immunity. Peroxisome proliferator-activated receptor (PPAR) and estrogen receptor (ESR) signaling, and even the signaling from phosphoinositide-3 kinase (PI3K)/AKT pathway could have inhibitory roles in carcinogenesis possibly via the modulation of immune checkpoint molecules. In some cases, certain small molecules including vitamin D could be a novel therapeutic modality with a promising potential for the better performance of immune checkpoint blockade cancer therapies., 30 Jun. 2023, 460, 473, Scientific journal, 10.37349/etat.2023.00145
- Refereed, Life, MDPI AG, Therapeutic Implications of Probiotics in the Gut Microbe-Modulated Neuroinflammation and Progression of Alzheimer’s Disease, Toshiyuki Murai; Satoru Matsuda, Alzheimer’s disease (AD) is characterized by the accumulation of specific proteins in the brain. A recent study revealed that manipulating gut microbiota (GM) significantly reduced tau pathology and neurodegeneration in an apolipoprotein E isoform-dependent manner. The resilience of a healthy microbiota protects it from a variety of dysbiosis-related pathologies. Convincing evidence has demonstrated the roles of GM in the pathogenesis of AD, which are partly mediated by modified microglial activity in the brain. Therefore, modulation of GM may be a promising therapeutic option for AD prevention. In addition to providing the cells with energy and affecting microglial maturation, these microbial metabolites appear to influence neuronal function. One of the potential therapeutic approaches targeting GM may involve using probiotics. Additionally, human GM and its metabolites have also become potential therapeutic targets for developing interventions for the prevention of disorders. Synbiotics and postbiotics can also be used to treat AD by modulating GM. In addition, physical activity, exercise, and physical fitness are being considered as potential nonpharmacological therapies to reduce signaling pathways related to neuroinflammation. Therefore, interventions targeting GM might be promising strategies for health promotion., 28 Jun. 2023, 13, 7, 1466, 1466, Scientific journal, 10.3390/life13071466
- Refereed, Metabolites, MDPI AG, Fatty Acid Metabolites and the Tumor Microenvironment as Potent Regulators of Cancer Stem Cell Signaling, Toshiyuki Murai; Satoru Matsuda, Individual cancer cells are not equal but are organized into a cellular hierarchy in which only a rare few leukemia cells can self-renew in a manner reminiscent of the characteristic stem cell properties. The PI3K/AKT pathway functions in a variety of cancers and plays a critical role in the survival and proliferation of healthy cells under physiologic conditions. In addition, cancer stem cells might exhibit a variety of metabolic reprogramming phenotypes that cannot be completely attributed to the intrinsic heterogeneity of cancer. Given the heterogeneity of cancer stem cells, new strategies with single-cell resolution will become a powerful tool to eradicate the aggressive cell population harboring cancer stem cell phenotypes. Here, this article will provide an overview of the most important signaling pathways of cancer stem cells regarding their relevance to the tumor microenvironment and fatty acid metabolism, suggesting valuable strategies among cancer immunotherapies to inhibit the recurrence of tumors., 31 May 2023, 13, 6, 709, 709, Scientific journal, 10.3390/metabo13060709
- Refereed, Molecules, MDPI AG, Gut Protective Effect from D-Methionine or Butyric Acid against DSS and Carrageenan-Induced Ulcerative Colitis, Yuka Ikeda; Satoru Matsuda, Microbiome dysbiosis resulting in altered metabolite profiles may be associated with certain diseases, including inflammatory bowel diseases (IBD), which are characterized by active intestinal inflammation. Several studies have indicated the beneficial anti-inflammatory effect of metabolites from gut microbiota, such as short-chain fatty acids (SCFAs) and/or D-amino acids in IBD therapy, through orally administered dietary supplements. In the present study, the potential gut protective effects of d-methionine (D-Met) and/or butyric acid (BA) have been investigated in an IBD mouse model. We have also built an IBD mouse model, which was cost-effectively induced with low molecular weight DSS and kappa-carrageenan. Our findings revealed that D-Met and/or BA supplementation resulted in the attenuation of the disease condition as well as the suppression of several inflammation-related gene expressions in the IBD mouse model. The data shown here may suggest a promising therapeutic potential for improving symptoms of gut inflammation with an impact on IBD therapy. However, molecular metabolisms need to be further explored., 28 May 2023, 28, 11, 4392, 4392, Scientific journal, 10.3390/molecules28114392
- Refereed, Antioxidants, MDPI AG, Pleiotropic Signaling by Reactive Oxygen Species Concerted with Dietary Phytochemicals and Microbial-Derived Metabolites as Potent Therapeutic Regulators of the Tumor Microenvironment, Toshiyuki Murai; Satoru Matsuda, The excessive generation of reactive oxygen species (ROS) plays a pivotal role in the pathogenesis of diseases. ROS are central to cellular redox regulation and act as second messengers to activate redox-sensitive signals. Recent studies have revealed that certain sources of ROS can be beneficial or harmful to human health. Considering the essential and pleiotropic roles of ROS in basic physiological functions, future therapeutics should be designed to modulate the redox state. Dietary phytochemicals, microbiota, and metabolites derived from them can be expected to be developed as drugs to prevent or treat disorders in the tumor microenvironment., 06 May 2023, 12, 5, 1056, 1056, Scientific journal, 10.3390/antiox12051056
- Refereed, Non-coding RNA, CircRNAs and RNA-Binding Proteins Involved in the Pathogenesis of Cancers or Central Nervous System Disorders., Yuka Ikeda; Sae Morikawa; Moeka Nakashima; Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Naoko Suga; Ai Tsuji; Satoru Matsuda, Circular RNAs (circRNAs), a newly recognized group of noncoding RNA transcripts, have established widespread attention due to their regulatory role in cell signaling. They are covalently closed noncoding RNAs that form a loop, and are typically generated during the splicing of precursor RNAs. CircRNAs are key post-transcriptional and post-translational regulators of gene expression programs that might influence cellular response and/or function. In particular, circRNAs have been considered to function as sponges of specific miRNA, regulating cellular processes at the post-transcription stage. Accumulating evidence has shown that the aberrant expression of circRNAs could play a key role in the pathogenesis of several diseases. Notably, circRNAs, microRNAs, and several RNA-binding proteins, including the antiproliferative (APRO) family proteins, could be indispensable gene modulators, which might be strongly linked to the occurrence of diseases. In addition, circRNAs have attracted general interest for their stability, abundance in the brain, and their capability to cross the blood-brain barrier. Here, we present the current findings and theragnostic potentials of circRNAs in several diseases. With this, we aim to provide new insights to support the development of novel diagnostic and/or therapeutic strategies for these diseases., 31 Mar. 2023, 9, 2, Scientific journal, True, 10.3390/ncrna9020023
- Refereed, International journal of molecular sciences, The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases., Ai Tsuji; Yuka Ikeda; Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Sae Morikawa; Moeka Nakashima; Tomoko Asai; Satoru Matsuda, The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine, and immune systems, as well as in the development of inflammatory diseases. It has been documented that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective properties. Importantly, many of these kynurenine metabolites may possess immune-regulatory properties that could alleviate the inflammation response. The abnormal activation of the tryptophan and kynurenine pathway might be involved in the pathophysiological process of various immune-related diseases, such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine metabolites may be involved in the brain memory system and/or intricate immunity via the modulation of glial function. In the further deliberation of this concept with engram, the roles of gut microbiota could lead to the development of remarkable treatments for the prevention of and/or the therapeutics for various intractable immune-related diseases., 17 Mar. 2023, 24, 6, Scientific journal, True, 10.3390/ijms24065742
- Refereed, International journal of molecular sciences, Tactics with Prebiotics for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease via the Improvement of Mitophagy., Ai Tsuji; Sayuri Yoshikawa; Yuka Ikeda; Kurumi Taniguchi; Haruka Sawamura; Sae Morikawa; Moeka Nakashima; Tomoko Asai; Satoru Matsuda, Mitophagy/autophagy plays a protective role in various forms of liver damage, by renovating cellular metabolism linking to sustain liver homeostasis. A characterized pathway for mitophagy is the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin-dependent signaling pathway. In particular, PINK1-mediated mitophagy could play an indispensable role in improving the metabolic dysfunction-associated fatty liver disease (MAFLD) which could precede to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. In addition, the PI3K/AKT/mTOR pathway might regulate the various characteristics of cellular homeostasis including energy metabolism, cell proliferation, and/or cell protection. Therefore, targeting mitophagy with the alteration of PI3K/AKT/mTOR or PINK1/Parkin-dependent signaling to eliminate impaired mitochondria might be an attractive strategy for the treatment of MAFLD. In particular, the efficacy of prebiotics for the treatment of MAFLD has been suggested to be useful via the modulation of the PI3K/AKT/mTOR/AMPK pathway. Additionally, several edible phytochemicals could activate mitophagy for the improvement of mitochondrial damages, which could also be a promising option to treat MAFLD with providing liver protection. Here, the potential therapeutics with several phytochemicals has been discussed for the treatment of MAFLD. Tactics with a viewpoint of prospective probiotics might contribute to the development of therapeutic interventions., 13 Mar. 2023, 24, 6, Scientific journal, True, 10.3390/ijms24065465
- Refereed, Molecules, MDPI AG, The Chemopreventive Effects of Chlorogenic Acids, Phenolic Compounds in Coffee, against Inflammation, Cancer, and Neurological Diseases, Toshiyuki Murai; Satoru Matsuda, Coffee is one of the most widely consumed beverages, which has several effects on the human body. In particular, current evidence suggests that coffee consumption is associated with a reduced risk of inflammation, various types of cancers, and certain neurodegenerative diseases. Among the various constituents of coffee, phenolic phytochemicals, more specifically chlorogenic acids, are the most abundant, and there have been many attempts to utilize coffee chlorogenic acid for cancer prevention and therapy. Due to its beneficial biological effect on the human body, coffee is regarded as a functional food. In this review article, we summarize the recent advances and knowledge on the association of phytochemicals contained in coffee as nutraceuticals, with a particular focus on phenolic compounds, their intake, and nutritional biomarkers, with the reduction of disease risk, including inflammation, cancer, and neurological diseases., 04 Mar. 2023, 28, 5, 2381, 2381, Scientific journal, 10.3390/molecules28052381
- Refereed, Livers, MDPI AG, Metabolic Associated Fatty Liver Disease as a Risk Factor for the Development of Central Nervous System Disorders, Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Tomoko Asai; Ai Tsuji; Satoru Matsuda, MAFLD/NAFLD is the most ordinary liver disease categorized by hepatic steatosis with the increase of surplus fat in the liver and metabolic liver dysfunction, which is associated with bigger mortality and a high medical burden. An association between MAFLD/NAFLD and central nervous system disorders including psychological disorders has been demonstrated. Additionally, MAFLD/NAFLD has been correlated with various types of neurodegenerative disorders such as amyotrophic lateral sclerosis or Parkinson’s disease. Contrasted to healthy controls, patients with MAFLD/NAFLD have a greater prevalence risk of extrahepatic complications within multiple organs. Dietary interventions have emerged as effective strategies for MAFLD/NAFLD. The PI3K/AKT/mTOR signaling pathway involved in the regulation of Th17/Treg balance might promote the pathogenesis of several diseases including MAFLD/NAFLD. As extrahepatic complications may happen across various organs including CNS, cooperative care with individual experts is also necessary for managing patients with MAFLD/NAFLD., 05 Jan. 2023, 3, 1, 21, 32, Scientific journal, 10.3390/livers3010002
- Refereed, Exploration of Targeted Anti-tumor Therapy, Open Exploration Publishing, Encouraging probiotics for the prevention and treatment of immune-related adverse events in novel immunotherapies against malignant glioma, Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Ai Tsuji; Satoru Matsuda, Among the malignant tumors in the central nervous system (CNS), glioma is the most challenging tumor to the public society, which accounts for the majority of intracranial malignant tumors with impaired brain function. In general, conventional therapies are still unable to provide an effective cure. However, novel immunotherapies have changed the treatment scene giving patients a greater potential to attain long term survival, improved quality of life. Having shown favorable results in solid tumors, those therapies are now at a cancer research hotspot, which could even shrink the growth of glioma cells without causing severe complications. However, it is important to recognize that the therapy may be occasionally associated with noteworthy adverse action called immune-related adverse events (IRAEs) which have emerged as a potential limitation of the therapy. Multiple classes of mediators have been developed to enhance the ability of immune system to target malignant tumors including glioma but may also be associated with the IRAEs. In addition, it is probable that it would take long time after the therapy to exhibit severe immune-related disorders. Gut microbiota could play an integral role in optimal immune development and/or appropriate function for the cancer therapy, which is a vital component of the multidirectional communication between immune system, brain, and gut, also known as gut-brain-immune axis. Here, we show the potential effects of the gut-brain-immune axis based on an “engram theory” for the innovative treatment of IRAEs., 27 Dec. 2022, 3, 6, 817, 827, Scientific journal, True, 10.37349/etat.2022.00114
- Refereed, Biomolecules, MDPI AG, Encouraging Tactics with Genetically Modified Probiotics to Improve Immunity for the Prevention of Immune-Related Diseases including Cardio-Metabolic Disorders, Tomoko Asai; Sayuri Yoshikawa; Yuka Ikeda; Kurumi Taniguchi; Haruka Sawamura; Ai Tsuji; Satoru Matsuda, The PI3K/AKT/mTOR signaling pathway may play crucial roles in the pathogenesis of obesity and diabetes mellitus, as well as metabolic syndromes, which could also be risk factors for cardio-metabolic disorders. Consistently, it has been shown that beneficial effects may be convoyed by the modulation of the PI3K/AKT/mTOR pathway against the development of these diseases. Importantly, the PI3K/AKT/mTOR signaling pathway can be modulated by probiotics. Probiotics have a variety of beneficial properties, with the potential of treating specific diseases such as immune-related diseases, which are valuable to human health. In addition, an increasing body of work in the literature emphasized the contribution of genetically modified probiotics. There now seems to be a turning point in the research of probiotics. A better understanding of the interactions between microbiota, lifestyle, and host factors such as genetics and/or epigenetics might lead to a novel therapeutic approach with probiotics for these diseases. This study might provide a theoretical reference for the development of genetically modified probiotics in health products and/or in functional foods for the treatment of cardio-metabolic disorders., 21 Dec. 2022, 13, 1, 10, 10, Scientific journal, True, 10.3390/biom13010010
- Refereed, Diseases, MDPI AG, Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis, Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Ai Tsuji; Satoru Matsuda, Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, the pathogenesis of which is based on alternations in the mitochondria of motor neurons, causing their progressive death. A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. Mitophagy has been considered one of the main mechanisms responsible for mitochondrial quality control. Since ALS is characterized by enormous oxidative stress, several edible phytochemicals that can activate mitophagy to remove damaged mitochondria could be considered a promising option to treat ALS by providing neuroprotection. Therefore, it is of great significance to explore the mechanisms of mitophagy in ALS and to understand the effects and/or molecular mechanisms of phytochemical action, which could translate into a treatment for neurodegenerative diseases, including ALS., 01 Dec. 2022, 10, 4, 117, 117, Scientific journal, True, 10.3390/diseases10040117
- Refereed, Metabolites, MDPI AG, A New Concept of Associations between Gut Microbiota, Immunity and Central Nervous System for the Innovative Treatment of Neurodegenerative Disorders, Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Ai Tsuji; Satoru Matsuda, Nerve cell death accounts for various neurodegenerative disorders, in which altered immunity to the integrated central nervous system (CNS) might have destructive consequences. This undesirable immune response often affects the progressive neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and/or amyotrophic lateral sclerosis (ALS). It has been shown that commensal gut microbiota could influence the brain and/or several machineries of immune function. In other words, neurodegenerative disorders may be connected to the gut–brain–immune correlational system. The engrams in the brain could retain the information of a certain inflammation in the body which might be involved in the pathogenesis of neurodegenerative disorders. Tactics involving the use of probiotics and/or fecal microbiota transplantation (FMT) are now evolving as the most promising and/or valuable for the modification of the gut–brain–immune axis. More deliberation of this concept and the roles of gut microbiota would lead to the development of stupendous treatments for the prevention of, and/or therapeutics for, various intractable diseases including several neurodegenerative disorders., 01 Nov. 2022, 12, 11, 1052, 1052, Scientific journal, True, 10.3390/metabo12111052
- Refereed, Exploration of Medicine, Open Exploration Publishing, A budding concept with certain microbiota, anti-proliferative family proteins, and engram theory for the innovative treatment of colon cancer, Yuka Ikeda; Kurumi Taniguchi; Sayuri Yoshikawa; Haruka Sawamura; Ai Tsuji; Satoru Matsuda, Inflammatory bowel disease (IBD) is a multifactorial chronic disease. Patients with IBD have an increased risk of developing colorectal cancer which has become a major health concern. IBD might exert a role of engrams for making the condition of specific inflammation in the gut. Dysregulation of immune cells induced by the command of engrams might be crucial in the pathogenesis of damages in gut epithelium. The anti-proliferative (APRO) family of anti-proliferative proteins characterized by immediate early responsive gene-products that might be involved in the machinery of the carcinogenesis in IBD. Herein, it is suggested that some probiotics with specific bacteria could prevent the development and/or progression of the IBD related tumors. In addition, consideration regarding the application of studying APRO family proteins for the comprehension of IBD related tumors has been presented. It is hypothesized that overexpression of Tob1, a member of APRO family proteins, in the epithelium of IBD could suppress the function of adjacent cytotoxic immune cells possibly via the paracrine signaling., 27 Oct. 2022, 2, 3, 468, 478, Scientific journal, 10.37349/emed.2022.00108
- Refereed, Cancers, MDPI AG, Presumed Roles of APRO Family Proteins in Cancer Invasiveness, Yuka Ikeda; Kurumi Taniguchi; Haruka Sawamura; Sayuri Yoshikawa; Ai Tsuji; Satoru Matsuda, The APRO family members may be involved in the regulation of cell growth, migration, and/or invasion. Although an APRO protein could suppress the invasiveness of several cancer cells, it has been reported that overexpression of the same APRO protein could also promote the invasiveness and/or metastasis of the same cancer cells. In general, the invasiveness of cancer cells might be associated with the function of matrix metalloproteinases (MMPs) as well as with the function of certain exosomes. However, it has been shown that exosomes involving particular APRO proteins, MMPs, and/or microRNA could contribute to the regulation of invasiveness. Here, we discuss contradictory reports on invasiveness in relation to APRO family proteins on the basis of understanding the function of MMPs and/or various exosomes. A better understanding of those mechanisms could be of use to bring about innovative strategies for cancer treatment., 08 Oct. 2022, 14, 19, 4931, 4931, Scientific journal, True, 10.3390/cancers14194931
- Refereed, World Journal of Gastroenterology, Baishideng Publishing Group Inc., Promising role of D-amino acids in irritable bowel syndrome, Yuka Ikeda; Kurumi Taniguchi; Haruka Sawamura; Ai Tsuji; Satoru Matsuda, Irritable bowel syndrome (IBS) is an important health care concern. Alterations in the microbiota of the gut-brain axis may be linked to the pathophysiology of IBS. Some dietary intake could contribute to produce various metabolites including D-amino acids by the fermentation by the gut microbiota. D-amino acids are the enantiomeric counterparts of L-amino acids, in general, which could play key roles in cellular physiological processes against various oxidative stresses. Therefore, the presence of D-amino acids has been shown to be linked to the protection of several organs in the body. In particular, the gut microbiota could play significant roles in the stability of emotion via the action of D-amino acids. Here, we would like to shed light on the roles of D-amino acids, which could be used for the treatment of IBS., 21 Aug. 2022, 28, 31, 4471, 4474, Scientific journal, True, 10.3748/wjg.v28.i31.4471
- Refereed, Oxygen, MDPI AG, Roles of Reactive Oxygen Species and Autophagy in the Pathogenesis of Cisplatin-Induced Acute Kidney Injury, Sayuri Yoshikawa; Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Ai Tsuji; Satoru Matsuda, Cisplatin-induced acute kidney injury (AKI) is the main factor restraining the clinical application of cisplatin. The AKI is associated with high mortality and morbidity, but no effective pharmacological treatment is available at present. As increased levels of reactive oxygen species (ROS) may promote the progression of the injury, the elimination of ROS has been considered as an effective method to prevent the cisplatin-induced AKI. In addition, it has been revealed that an inducer of autophagy could protect kidney cells in the autophagy dependent manner. Induction of autophagy could also modulate the production of ROS in cases of renal injury. Therefore, kidney-targeted antioxidants and/or autophagy are urgently required for the better treatment of AKI. Accumulating evidence has indicated the important roles of gut microbiota in the pathogenesis of AKI. In addition, there is a scientific basis for considering future clinical applications of probiotics and/or prebiotics to treat cisplatin-induced AKI. Thus, gut microbiota might be a promising therapeutic target via the alteration of autophagy for the cancer therapy-induced nephrotoxicity., 05 Aug. 2022, 2, 3, 317, 326, Scientific journal, 10.3390/oxygen2030022
- Refereed, Exploration of Neuroprotective Therapy, Open Exploration Publishing, Gut microbiota could modulate the effects of neuro-immune responses and memory traces via the gut-brain-immune axis in schizophrenia, Haruka Sawamura; Kurumi Taniguchi; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Altered immunity may have destructive consequences for the integrated central nervous system. This immune response often affects progressive neurodegenerative diseases such as Parkinson’s disease and/or psychiatric disorders such as schizophrenia. In particular, schizophrenia pathogenesis may be mediated by multiple neuro-immune interaction pathways. Gut microbiota might affect the brain and/or immune function. Significant machineries of immunity are commonly affected by the commensal gut microbiota. Therefore, schizophrenia may be connected with the gut-immune system. In addition, the brain and immune systems cooperate on multiple levels. The brain could save several pieces of information about specific inflammation in a body. This immunological memory named “engrams”, also called memory traces, could restore the initial disease state, which may help to explain key features of schizophrenia. Based on this concept, therapeutic strategies for schizophrenia could be the modification of the gut microbiota. Probiotics and/or fecal microbiota transplantation are now emerging as the most promising treatments for the modification. More consideration of the roles of gut microbiota will conduct the further development of immune-based therapeutics for the prevention and/or treatments of psychiatric disorders., 24 Apr. 2022, 74, 86, Scientific journal, 10.37349/ent.2022.00019
- Refereed, World Journal of Diabetes, Baishideng Publishing Group Inc., Efficacy of probiotics on the modulation of gut microbiota in the treatment of diabetic nephropathy, Nozomi Nagase; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are insufficient. The number of patients with DN has been increasing in Asian countries because of westernization of dietary lifestyle, which may be associated with the following changes in gut microbiota. Alterations in the gut microbiota composition can lead to an imbalanced gastrointestinal environment that promotes abnormal production of metabolites and/or inflammatory status. Functional microenvironments of the gut could be changed in the different stages of DN. In particular, altered levels of short chain fatty acids, D-amino acids, and reactive oxygen species biosynthesis in the gut have been shown to be relevant to the pathogenesis of the DN. So far, evidence suggests that the gut microbiota may play a key role in determining networks in the development of DN. Interventions directing the gut microbiota deserve further investigation as a new protective therapy in DN. In this review, we discuss the potential roles of the gut microbiota and future perspectives in the protection and/or treatment of kidneys., 15 Mar. 2022, 13, 3, 150, 160, Scientific journal, True, 10.4239/wjd.v13.i3.150
- Refereed, Diseases, MDPI AG, D-Amino Acids as a Biomarker in Schizophrenia, Kurumi Taniguchi; Haruka Sawamura; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, D-amino acids may play key roles for specific physiological functions in different organs including the brain. Importantly, D-amino acids have been detected in several neurological disorders such as schizophrenia, amyotrophic lateral sclerosis, and age-related disorders, reflecting the disease conditions. Relationships between D-amino acids and neurophysiology may involve the significant contribution of D-Serine or D-Aspartate to the synaptic function, including neurotransmission and synaptic plasticity. Gut-microbiota could play important roles in the brain-function, since bacteria in the gut provide a significant contribution to the host pool of D-amino acids. In addition, the alteration of the composition of the gut microbiota might lead to schizophrenia. Furthermore, D-amino acids are known as a physiologically active substance, constituting useful biomarkers of several brain disorders including schizophrenia. In this review, we wish to provide an outline of the roles of D-amino acids in brain health and neuropsychiatric disorders with a focus on schizophrenia, which may shed light on some of the superior diagnoses and/or treatments of schizophrenia., 31 Jan. 2022, 10, 1, 9, 9, Scientific journal, True, 10.3390/diseases10010009
- Refereed, Journal of Translational Genetics and Genomics, OAE Publishing Inc., Roles of gut dysbiosis, anti-proliferative proteins, and post-transcriptional regulation in carcinogenesis, Haruka Sawamura; Kurumi Taniguchi; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, The potentially powerful impact of microbiota has attracted much attention. For example, dysbiosis of the gut microbiota could be linked to various cancers. It is probable that DNA damage and DNA repair impairment due to inflammation from gut dysbiosis would be of importance in carcinogenesis and/or preventing carcinogenesis. In fact, the signature of the gut microbiome has been shown to be associated with responses and/or successful survival rate to certain immune-blockade therapy in several cancers. Conversely, living cells have to cope with the danger of reactive oxygen species (ROS) disturbing the integrity of biomolecules, which can eventually lead to carcinogenesis if otherwise untreated. Gut microbiota could modulate considerable levels of ROS and oxidative damage. Interestingly, an anti-proliferative family (APRO) characterized by several immediate early responsive gene products might be deeply involved in the mechanism of carcinogenesis. It has been described that APRO proteins also participate in a variety of cellular processes including cell division, DNA repair, and mRNA stability. The biological function of APRO proteins seems to be quite complicated; however, they might be a key modulator of microRNAs (miRNAs) for post-transcriptional regulation. The next generation of therapy would likely contain strategies for modifying the redox background as well as the regulation of ROS in cells and/or for better DNA repair machinery with the APRO proteins via the modulation of miRNA-derived post-transcriptional regulation in a sustainable manner. Given the important function of the gut microbiota in balancing the immune network, carcinogenesis could therefore be prevented by suitable gut microbiota via the roles of APRO proteins. Consequently, probiotics might play a key role in the modulation of gut immune system in keeping healthy and/or preventing cancers., 2022, 6, 157, 168, Scientific journal, 10.20517/jtgg.2021.57
- Refereed, Nutrition Research and Practice, The Korean Nutrition Society and The Korean Society of Community Nutrition, Reduction of oocyte lipid droplets and meiotic failure due to biotin deficiency was not rescued by restoring the biotin nutritional status, Ai Tsuji; Yuka Ikeda; Mutsumi Murakami; Yasuko Kitagishi; Satoru Matsuda, BACKGROUND/OBJECTIVES: Oocyte lipid droplets play a crucial role in meiosis and embryo development. Biotin is associated with fatty acid synthesis and is the coenzyme for acetyl-CoA carboxylase (ACC). The effects of a biotin deficiency on the oocyte lipid metabolism remain unknown. This study examined the effects of a biotin deficiency and its replenishment on murine 1) oocyte lipid droplet levels, 2) ovary lipid metabolism, and 3) oocyte meiosis. MATERIALS/METHODS: Mice were divided into 3 groups: control, biotin deficient (BD), and recovery groups. The control and BD groups were fed a control diet or BD diet (0.004 or 0 g biotin/kg), respectively. The recovery group mice were fed a BD diet until day 21, and were then fed the control diet from days 22 to 64. This study then quantified the oocyte lipid droplet levels, assessed the oocyte mitochondrial function, and examined the ability of oocytes to undergo meiosis. Ovarian phosphorylated ACC (p-ACC), lipogenesis, β-oxidation, and ATP production-related genes were evaluated. RESULTS: The BD group showed a decrease in lipid droplets and mitochondrial membrane potential and increased p-ACC levels. In the recovery group, the hepatic biotin concentration, ovarian p-ACC levels, and mitochondrial membrane potential were restored to the control group levels. On the other hand, the quantity of lipid droplets in the recovery group was not restored to the control levels. Furthermore, the percentage of oocytes with meiotic abnormalities was higher in the recovery group than in the control group. CONCLUSIONS: A biotin deficiency reduced the oocyte lipid droplet levels by downregulating lipogenesis. The decreased lipid droplets and increased oocyte meiosis failure were not fully restored, even though the biotin nutrition status and gene expression of lipid metabolism was resumed. These results suggest that a biotin deficiency remains robust and can be long-lasting. Biotin might play a crucial role in maintaining the oocyte quality., 2022, 16, 3, 314, 314, Scientific journal, True, 10.4162/nrp.2022.16.3.314
- Refereed, World Journal of Biological Chemistry, Baishideng Publishing Group Inc., Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease, Yuka Ikeda; Nozomi Nagase; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Alzheimer's disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway., 27 Nov. 2021, 12, 6, 104, 113, Scientific journal, True, 10.4331/wjbc.v12.i6.104
- Refereed, Recent Progress in Nutrition, LIDSEN Publishing Inc, Gut Microbiota Potentiates the Effect of Immune Checkpoint Therapy against Cancers, Haruka Sawamura; Kurumi Taniguchi; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Immune checkpoints have been aggressively investigated for anti-cancer immunotherapy. The power of microbiota on the outcome of this immunotherapy has attracted much attention. For example, intestinal microorganisms play a key role in the effectiveness of programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. Additionally, short-chain fatty acids produced in the gut may modulate anti-CTLA4 and anti-PD1 stimulated immune responses and their anti-tumor efficacy. Enhancing the anti-tumor effects of CTLA4 blockade depends on specific Bacteroides sp. of the gut microbiota, suggesting novel approaches to improve such immunotherapies. However, the molecular mechanism of the immune-potentiation remains largely unknown. Changes in the microbiota are influenced by dietary and environmental factors. Here, we have suggested the molecular mechanism of action regarding the interplay between gut microbiota and the anti-cancer immune system with APRO family proteins, which might contribute to innovative cancer therapy in the future., 16 Nov. 2021, 2, 1, 1, 1, Scientific journal, 10.21926/rpn.2201007
- Refereed, Exploration of Medicine, Open Exploration Publishing, Reactive oxygen species may influence on the crossroads of stemness, senescence, and carcinogenesis in a cell via the roles of APRO family proteins, Yuka Ikeda; Kurumi Taniguchi; Nozomi Nagase; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Excessive reactive oxygen species (ROS) may cause oxidative stress which is involved in aging and in the pathogenesis of various human diseases. Whereas unregulated levels of the ROS may be harmful, regulated basal level of ROS are even necessary to support cellular functions as a second messenger for homeostasis under physiological conditions. Therefore, redox medicine could develop as a new therapeutic concept for human health-benefits. Here, we introduce the involvement of ROS on the crossroads of stemness, senescence, and carcinogenesis in a stem cell and cancer cell biology. Amazingly, the anti-proliferative (APRO) family anti-proliferative proteins characterized by immediate early growth responsive genes may also be involved in the crossroads machinery. The biological functions of APRO proteins (APROs) seem to be quite intricate, however, which might be a key modulator of microRNAs (miRNAs). Given the crucial roles of ROS and APROs for pathophysiological functions, upcoming novel therapeutics should include vigilant modulation of the redox state. Next generation of medicine including regenerative medicine and/or cancer therapy will likely comprise strategies for altering the redox environment with the APROs via the modulation of miRNAs as well as with the regulation of ROS of cells in a sustainable manner., 31 Oct. 2021, Scientific journal, 10.37349/emed.2021.00062
- Refereed, The American Journal of Pathology, Elsevier BV, A novel mouse model of non-alcoholic steatohepatitis suggests that liver fibrosis initiates around lipid-laden macrophages, Mayuko Ichimura-Shimizu; Yosuke Tsuchiyama; Yuki Morimoto; Minoru Matsumoto; Tomoko Kobayashi; Satoshi Sumida; Takumi Kakimoto; Takeshi Oya; Hirohisa Ogawa; Michiko Yamashita; Satoru Matsuda; Katsuhisa Omagari; Shu Taira; Koichi Tsuneyama, Various cells such as macrophages and hepatic stellate cells interact in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), but the mechanism remains unclear. We employed a high fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis and investigate the pathogenesis of fibrosis. Two mouse strains differing in susceptibility to obesity, the susceptible strain C57BL/6J (B6) and the relatively resistant strain A/J, developed hepatic histological features of NASH including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis after 9 weeks of HFCC diet feeding. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in B6 mice. A/J mice fed the HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light visualized the Maltese cross, namely cholesterol crystals within the aggregated macrophages. Moreover, fibrosis developed in a ring-shape from the periphery of the aggregated macrophages, i.e., the starting point of fibrosis could be visualized histologically. Furthermore, matrix assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine (P-18:1 (11Z)/18:0) and phosphatidylethanolamine (18:0/20:2 (11Z, 14Z)), in aggregated macrophages in adjacent to the fibrotic lesions. In conclusion, the present HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis., Oct. 2021, Scientific journal, True, 10.1016/j.ajpath.2021.10.002
- Refereed, Reproductive Medicine and Biology, Wiley, d‐Leucine protects oocytes from chronic psychological stress in mice, Ai Tsuji; Yuka Ikeda; Mutsumi Murakami; Yasuko Kitagishi; Satoru Matsuda, Purpose: Psychological stress could negatively influence female reproductive ability. d-Leucine (d-Leu) is a d-type amino acid found in foods and mammalian tissues. We have examined the protective effects of d-Leu on oocyte abnormality induced by psychological stress. Methods: Female mice (6-week-old) were divided into three groups: control, restraint stress (RS), and RS/d-Leu. The RS and RS/d-Leu mice were holed for 3 hours daily during 14 days. RS/d-Leu mice were fed 0.3% d-Leu diet. The oocyte maturation failure was analyzed by shapes of spindles and chromosomes. In addition, levels of heme-oxygenase-1 (HO-1) and superoxide dismutase (SOD) expression in the ovaries were also examined. Whether d-Leu reduces the generation of reactive oxygen species (ROS) in cultured cells, K562 cells were treated with d-Leu, and then ROS in K562 were analyzed. Results: Oocyte maturation failure was increased in RS mice. d-Leu reduced abnormal oocytes to control level. The expression levels of HO-1 and SOD2 increased in RS/d-Leu mice compared to those of RS mice. ROS levels were decreased in K562 cells with d-Leu in a dose-dependent manner. Conclusions: We concluded that d-Leu protects oocytes from psychological stress through the induction of HO-1 and SOD2 expression then by reducing oxidative stress., Oct. 2021, 20, 4, 477, 484, Scientific journal, False, 10.1002/rmb2.12396
- Refereed, Oxygen, MDPI AG, Comprehension of the Relationship between Autophagy and Reactive Oxygen Species for Superior Cancer Therapy with Histone Deacetylase Inhibitors, Yuka Ikeda; Nozomi Nagase; Ai Tsuji; Kurumi Taniguchi; Yasuko Kitagishi; Satoru Matsuda, Epigenetics contains various mechanisms by which cells employ to regulate the transcription of many DNAs. Histone acetylation is an obvious example of the epigenetic mechanism regulating the expression of several genes by changing chromatin accessibility. Histone deacetylases (HDACs) are a class of enzymes that play a critical role in the epigenetic regulation by deacetylation of histone proteins. Inhibitors of the histone deacetylase could result in hyperacetylation of histones, which eventually induce various cellular consequences such as generation of reactive oxygen species (ROS), activation of apoptotic pathways, and initiating autophagy. In particular, excessive levels of ROS have been proposed to contribute to the pathophysiology of various diseases including cancer. Cancers are, as it were, a class of redox diseases. Low levels of ROS are beneficial for cells, however, cancer cells generally have high levels of ROS, which makes them more susceptible than normal cells to the further increases of ROS levels. Cancer cells exhibit metabolic alterations for managing to sustain these oxidative stresses. There is a growing interest in the use of HDAC inhibitors as promising cancer therapeutics with potentiating the activity of established therapeutic applications. Therefore, it should be important to understand the underlying relationship between the regulation of HDACs, ROS production, and cancer cell biology., 25 Jul. 2021, 1, 1, 22, 31, Scientific journal, 10.3390/oxygen1010004
- Refereed, Academia Letters, Academia.edu, COVID-19 and Glaucoma, Satoru Matsuda; Nozomi Nagase; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi, 16 Jul. 2021, Scientific journal, 10.20935/al2171
- Refereed, Journal of Research in Medical Sciences, Medknow, COVID-19 cellular pathogenesis in brief, Yuka Ikeda; Ai Tsuji; Mutsumi Murakami; Satoru Matsuda, 2021, 26, 1, 129, 129, Scientific journal, True, 10.4103/jrms.jrms_471_20
- Refereed, AIMS Bioengineering, American Institute of Mathematical Sciences (AIMS), Implications of Gut-Brain axis in the pathogenesis of Psychiatric disorders, Kurumi Taniguchi; Yuka Ikeda; Nozomi Nagase; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda,
<abstract>
<p>Psychiatric disorders may extremely impair the quality of life with patients and are important reasons of social disability. Several data have shown that psychiatric disorders are associated with an altered composition of gut microbiota. Dietary intake could determine the microbiota, which contribute to produce various metabolites of fermentation such as short chain fatty acids. Some of the metabolites could result in epigenetic alterations leading to the disease susceptibility. Epigenetic dysfunction is in fact implicated in various psychiatric and neurologic disorders. For example, it has been shown that neuroepigenetic dysregulation occurs in psychiatric disorders including schizophrenia. Several studies have demonstrated that the intestinal microbiome may influence the function of central nervous system. Furthermore, it has been proved that the alterations in the gut microbiota-composition might affect in the bidirectional communication between gut and brain. Similarly, evidences demonstrating the association between psychiatric disorders and the gut microbiota have come from preclinical studies. It is clear that an intricate symbiotic relationship might exist between host and microbe, although the practical significance of the gut microbiota has not yet to be determined. In this review, we have summarized the function of gut microbiota in main psychiatric disorders with respect to the mental health. In addition, we would like to discuss the potential mechanisms of the disorders for the practical diagnosis and future treatment by using bioengineering of microbiota and their metabolites.</p>
</abstract>, 2021, 8, 4, 243, 256, Scientific journal, 10.3934/bioeng.2021021 - Refereed, Biomedical Journal of Scientific & Technical Research, Biomedical Research Network, LLC, Is Lockdown Effective Against Fatality of COVID-19?, Satoru Matsuda, 17 Jul. 2020, 28, 5, Scientific journal, 10.26717/bjstr.2020.28.004729
- Refereed, International journal of preventive medicine, Prevention in Daily Life against Progression of COVID-19., Murakami M; Ikeda Y; Tsuji A; Matsuda S, Jul. 2020, 11, 99, 99, Scientific journal, True, 10.4103/ijpvm.IJPVM_219_20
- Refereed, Biomedical Reports, Spandidos Publications, Role of tumor suppressor molecules in genomic perturbations and damaged DNA repair involved in the pathogenesis of cancer and neurodegeneration (Review), Satoru Matsuda; Mutsumi Murakami; Yuka Ikeda; Yukie Nakagawa; Ai Tsuji; Yasuko χ Yasuko kitagishi, Genomic perturbations due to inaccurate DNA replication, including inappropriate chromosomal segregation often underlie the development of cancer and neurodegenerative diseases. The incidence of these two diseases increases with age and exhibits an inverse association. Therefore, elderly subjects with cancer exhibit a reduced risk of a neurodegenerative disease, and vice versa. Both of these diseases are associated with aging and share several risk factors. Cells have multiple mechanisms to repair DNA damage and inaccurate replication. Previous studies have demonstrated that tumor suppressor proteins serve a critical role in the DNA damage response, which may result in genomic instability and thus induction of cellular apoptosis. Tumor suppressor genes, such as phosphatase and tensin homologue deleted on chromosome 10 (PTEN), breast cancer susceptibility gene 1 (BRCA1) and TP53 reduce genomic susceptibility to cancer by repairing the damaged DNA. In addition, these genes work cooperatively to ensure the inhibition of the development of several types of cancer. PTEN, BRCA1 and TP53 have been recognized as the most frequently deleted and/or mutated genes in various types of human cancer. Recently, tumor suppressor genes have also been shown to be involved in the development of neurodegenerative diseases. The present review summarizes the recent findings of the functions of these tumor suppressors that are associated with genomic stability, and are involved in carcinogenic and neurodegenerative cell signaling. A summary is presented regarding the interactions of these tumor suppressors with their partners which results in transduction of downstream signals. The implications of these functions for cancer and neurodegenerative disease-associated biology are also highlighted., 17 Jun. 2020, 13, 3, 10, 10, Scientific journal, True, 10.3892/br.2020.1317
- Refereed, Biomedical Reports, Spandidos Publications, Special bioactive compounds and functional foods may exhibit neuroprotective effects in patients with dementia (Review), Mutsumi Murakami; Yuka Ikeda; Yukie Nakagawa; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Dementia is a failure of cognitive ability characterized by severe neurodegeneration in select neural systems, and Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Although numerous studies have provided insights into the pathogenesis of AD, the underlying signaling and molecular pathways mediating the progressive decline of cognitive function remain poorly understood. Recent progress in molecular biology has provided an improved understanding of the importance of molecular pathogenesis of AD, and has proposed an association between DNA repair mechanisms and AD. In particular, the fundamental roles of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and breast cancer gene 1 (BRCA1) tumor suppressors have been shown to regulate the pathogenesis of neurodegeneration. Consequently, onset of neurodegenerative diseases may be deferred with the use of dietary neuroprotective agents which alter the signaling mediated by the aforementioned tumor suppressors. In a healthy neuron, homeostasis of key intracellular molecules is of great importance, and preventing neuronal apoptosis is one of the primary goals of treatments designed for dementia-associated diseases. In the present review, progress into the understanding of dietary regulation for preventing or limiting development of dementia is discussed with a focus on the modulatory roles of PTEN and BRCA1 signaling., 02 Jun. 2020, 13, 2, 1, 1, Scientific journal, True, 10.3892/br.2020.1310
- Refereed, Biomedical Reports, Spandidos Publications, Diet induces hepatocyte protection in fatty liver disease via modulation of PTEN signaling (Review), Yuka Ikeda; Mutsumi Murakami; Yukie Nakagawa; Ai Tsuji; Yasuko Kitagishi; Satoru Matsuda, Fatty liver disease (FLD) is characterized by accumulation of excess fat in the liver. The underlying molecular mechanism associated with the progression of the disease has been in elusive. Hepatocellular demise due to increased oxidative stress resulting in an inflammatory response may be a key feature in FLD. Recent advances in molecular biology have led to an improved understanding of the molecular pathogenesis, suggesting a critical association between the PI3K/AKT/PTEN signaling pathway and FLD. In particular, PTEN has been associated with regulating the pathogenesis of hepatocyte degeneration. Given the function of mitochondria in reactive oxygen species (ROS) generation and the initiation of oxidative stress, the mitochondrial antioxidant network is of interest. It is vital to balance the activity of intracellular key molecules to maintain a healthy liver. Consequently, onset of FLD may be delayed using dietary protective agents that alter PTEN signaling and reduce ROS levels. The advancement of research on dietary regulation with a focus on modulatory roles in ROS generation and PTEN associated signaling is summarized in the current study, supporting further preventive and therapeutic exploration., 22 Apr. 2020, 12, 6, 295, 302, Scientific journal, True, 10.3892/br.2020.1299
- Refereed, Clinical Obstetrics, Gynecology and Reproductive Medicine, Open Access Text Pvt, Ltd., COVID-19, an infertility risk?, Ai Tsuji; Yuka Ikeda; Mutsumi Murakami; Satoru Matsuda, 2020, 6, 3, Scientific journal, 10.15761/cogrm.1000291
- Refereed, Diseases (Basel, Switzerland), Roles of PI3K/AKT/GSK3 Pathway Involved in Psychiatric Illnesses., Satoru Matsuda; Yuka Ikeda; Mutsumi Murakami; Yukie Nakagawa; Ai Tsuji; Yasuko Kitagishi, Psychiatric illnesses may be qualified to the cellular impairments of the function for survival or death in neurons, which may consequently appear as abnormalities in the neuroplasticity. The molecular mechanism has not been well understood, however, it seems that PI3K, AKT, GSK3, and their downstream molecules have crucial roles in the pathogenesis. Through transducing cell surviving signal, the PI3K/AKT/GSK3 pathway may organize an intracellular central network for the action of the synaptic neuroplasticity. In addition, the pathways may also regulate cell proliferation, cell migration, and apoptosis. Several lines of evidence have supported a role for this signaling network underlying the development and treatment for psychiatric illnesses. Indeed, the discovery of molecular biochemical phenotypes would represent a breakthrough in the research for effective treatment. In this review, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells. This study may provide novel insights on the mechanism of mental disorder involved in psychiatric illnesses and would open future opportunity for contributions suggesting new targets for diagnostic and/or therapeutic procedures., 13 Feb. 2019, 7, 1, Scientific journal, True, 10.3390/diseases7010022
- Refereed, Neural regeneration research, By using either endogenous or transplanted stem cells, which could you prefer for neural regeneration?, Satoru Matsuda; Yukie Nakagawa; Kumi Amano; Yuka Ikeda; Ai Tsuji; Yasuko Kitagishi, Oct. 2018, 13, 10, 1731, 1732, Scientific journal, True, 10.4103/1673-5374.238609
- Refereed, Cells, Reactive Oxygen Species, Superoxide Dimutases, and PTEN-p53-AKT-MDM2 Signaling Loop Network in Mesenchymal Stem/Stromal Cells Regulation., Matsuda S; Nakagawa Y; Kitagishi Y; Nakanishi A; Murai T, May 2018, 7, 5, 10.3390/cells7050036
- Refereed, Diseases (Basel, Switzerland), Implications of PI3K/AKT/PTEN Signaling on Superoxide Dismutases Expression and in the Pathogenesis of Alzheimer's Disease., Satoru Matsuda; Yukie Nakagawa; Ai Tsuji; Yasuko Kitagishi; Atsuko Nakanishi; Toshiyuki Murai, Alzheimer’s disease is a neurodegenerative sickness, where the speed of personal disease progression differs prominently due to genetic and environmental factors such as life style. Alzheimer’s disease is described by the construction of neuronal plaques and neurofibrillary tangles composed of phosphorylated tau protein. Mitochondrial dysfunction may be a noticeable feature of Alzheimer’s disease and increased production of reactive oxygen species has long been described. Superoxide dismutases (SODs) protect from excess reactive oxygen species to form less reactive hydrogen peroxide. It is suggested that SODs can play a protective role in neurodegeneration. In addition, PI3K/AKT pathway has been shown to play a critical role on the neuroprotection and inhibiting apoptosis via the enhancing expression of the SODs. This pathway appears to be crucial in Alzheimer’s disease because it is related to the tau protein hyper-phosphorylation. Dietary supplementation of several ordinary compounds may provide a novel therapeutic approach to brain disorders by modulating the function of the PI3K/AKT pathway. Understanding these systems may offer a better efficacy of new therapeutic approaches. In this review, we summarize recent progresses on the involvement of the SODs and PI3K/AKT pathway in neuroprotective signaling against Alzheimer’s disease., 20 Apr. 2018, 6, 2, Scientific journal, True, 10.3390/diseases6020028
- Refereed, JOURNAL OF NUTRITIONAL BIOCHEMISTRY, ELSEVIER SCIENCE INC, A diet-induced Sprague-Dawley rat model of nonalcoholic steatohepatitis-related cirrhosis, Mayuko Ichimura; Miki Masuzumi; Miku Kawase; Mika Sakaki; Shizuka Tamaru; Yasuo Nagata; Kazunari Tanaka; Kazuhito Suruga; Koichi Tsuneyama; Satoru Matsuda; Katsuhisa Omagari, Certain modified diets containing saturated fatty acids, cholesterol or fructose lead to the development of nonalcoholic steatohepatitis (NASH)-related fibrosis in rodents; however, progression to cirrhosis is rare. Experimental liver cirrhosis models have relied on genetic manipulation or administration of hepatotoxins. This study aimed to establish a reliable dietary model of NASH-related cirrhosis in a relatively short period. Male Sprague-Dawley rats (9 weeks of age) were randomly assigned to normal, high-fat (HF), or two types (1.25% or 2.5% cholesterol) of high-fat and high-cholesterol (HFC) diets for 18 weeks. All HFC diets contained 2% cholic acid by weight. Histopathological analysis revealed that the HFC diets induced obvious hepatic steatosis, inflammation with hepatocyte ballooning and advanced fibrosis (stage 3-4) in all 12 rats at 27 weeks of age. In contrast, all five rats given the HF diet developed mild steatosis and inflammation without fibrosis. The amount of cholesterol in the liver and hepatocellular mitochondria( and microsomal fractions was significantly higher in rats fed the HFC diets than the normal or HF diets. The HFC diets significantly suppressed mRNA levels of microsomal triglyceride transfer protein, adenosine triphosphate binding cassette transporter G5, bile acid CoA: amino acid N-acyltransferase and bile salt export pump, as well as the enzymatic activity of carnitine palmitoyltransferase in the liver. In conclusion, the HFC diets induced liver cirrhosis in conjunction with hepatic features of NASH in Sprague-Dawley rats within 18 weeks, and altered gene expression and enzyme activity to accumulate lipid and bile acid in the liver. (C) 2016 Elsevier Inc. All rights reserved., Feb. 2017, 40, 62, 69, Scientific journal, 10.1016/j.jnutbio.2016.10.007
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, PI3K/AKT signaling mediated by G protein-coupled receptors is involved in neurodegenerative Parkinson's disease, Noriko Nakano; Satoru Matsuda; Mayuko Ichimura; Akari Minami; Mako Ogino; Toshiyuki Murai; Yasuko Kitagishi, Parkinson's disease (PD) is a common progressive and multifactorial neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons. Numerous pathological processes including, inflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalance, and apoptosis as well as genetic factors may lead to neuronal degeneration. Motor deficits in PD are due mostly to the progressive loss of nigrostriatal dopaminergic neurons. Neuroprotection of functional neurons is of significance in the treatment of PD. G protein-coupled receptors (GPCRs) have been implicated in the neuroprotection against PD through the survival of dopaminergic neurons. In addition, phosphatidyl-inositol-3-kinase (PI3K)/AKT signaling has also been demonstrated to be neuroprotective. Knowledge of the mechanisms involved in this cellular protection could be critical for developing treatments to prevent this neurodegenerative disorder. In this review, we highlight the protective roles of the PI3K/AKT signaling pathway in the function of representative serotonin GPCRs. Particular attention is given to the molecular mechanisms of this pathway proposed to explain the favorable effects of food ingredients against neurodegenerative disease., Feb. 2017, 39, 2, 253, 260, 10.3892/ijmm.2016.2833
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Roles of oncogenes and tumor-suppressor genes in osteoclastogenesis, Akari Minami; Mako Ogino; Noriko Nakano; Mayuko Ichimura; Atsuko Nakanishi; Toshiyuki Murai; Yasuko Kitagishi; Satoru Matsuda, Osteoporosis is a bone disease that poses a tremendous burden to health care. The receptor activator of nuclear factor-KB (RANK) and its ligand (RANKL) have been a major focus of this research field. RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also adjusts bone homeostasis both in normal physiology and in bone disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various bone diseases such as osteoporosis. Osteoclasts are the exclusive cells involved in bone resorption. Abnormal activation of osteoclasts can lead to reduced bone density, resulting in osteopenia, osteoporosis and other bone disorders. To date, the mechanism of how osteoclast precursors differentiate into mature osteoclasts remains elusive. Cell proliferation and cell death may be key processes in the progression as well as other cell types. Oncogene products and tumor-suppressor molecules play a pivotal role in regulating the processes, which are important in regulating the configuration of bone disorders. Based on the understanding of these processes, promising alternatives to the use of medications against osteoporosis include specific diets with plant-derived supplements to modulate the expression and/or activity of these molecules. In this review, we summarize the progress of research with a focus on the modulatory roles of oncogene products and tumor-suppressor molecules and suggest the scope of further research concerning the prevention of osteoporosis in this field., Feb. 2017, 39, 2, 261, 267, 10.3892/ijmm.2017.2847
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, PINK1 signaling in mitochondrial homeostasis and in aging (Review), Yasuko Kitagishi; Noriko Nakano; Mako Ogino; Mayuko Ichimura; Akari Minami; Satoru Matsuda, Mitochondrial dysfunction is involved in the pathology of Parkinson's disease, an age-associated neurodegenerative disorder. Phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1) is responsible for the most common form of recessive Parkinson's disease. PINK1 is a mitochondrial kinase that is involved in mitrochondrial quality control and promotes cell survival. PINK1 has been shown to protect against neuronal cell death induced by oxidative stress. Accordingly, PINK1 deficiency is associated with mitochondrial dysfunction as well as increased oxidative cellular stress and subsequent neuronal cell death. In addition, several mitochondrial chaperone proteins have been shown to be substrates of the PINK1 kinase. In this review, we discuss recent studies concerning the signaling cascades and molecular mechanisms involved in the process of mitophagy, which is implicated in neurodegeneration and in related aging associated with oxidative stress. Particular attention will be given to the molecular mechanisms proposed to explain the effects of natural compounds and/or food ingredients against oxidative stress. Knowledge of the molecular mechanisms involved in this cellular protection could be critical for developing treatments to prevent and control excessive progression of neurodegenerative disorders., Jan. 2017, 39, 1, 3, 8, 10.3892/ijmm.2016.2827
- Refereed, INTERNATIONAL JOURNAL OF ONCOLOGY, SPANDIDOS PUBL LTD, Effective PI3K modulators for improved therapy against malignant tumors and for neuroprotection of brain damage after tumor therapy (Review), Satoru Matsuda; Mayuko Ichimura; Mako Ogino; Noriko Nakano; Akari Minami; Toshiyuki Murai; Yasuko Kitagishi, Due to the key role in various cellular processes including cell proliferation and cell survival on many cell types, dysregulation of the PI3K/AKT pathway represents a crucial step of the pathogenesis in many diseases. Furthermore, the tumor suppressor PTEN negatively regulates the PI3K/AKT pathway through its lipid phosphatase activity, which is recognized as one of the most frequently deleted and/or mutated genes in human cancer. Given the pervasive involvement of this pathway, the development of the molecules that modulate this PI3K/AKT signaling has been initiated in studies which focus on the extensive effective drug discovery. Consequently, the PI3K/AKT pathway appears to be an attractive pharmacological target both for cancer therapy and for neurological protection necessary after the therapy. A better understanding of the molecular relations could reveal new targets for treatment development. We review recent studies on the features of PI3K/AKT and PTEN, and their pleiotropic functions relevant to the signaling pathways involved in cancer progress and in neuronal damage by the therapy., Nov. 2016, 49, 5, 1785, 1790, 10.3892/ijo.2016.3710
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, MDPI AG, Roles of PTEN with DNA Repair in Parkinson's Disease, Mako Ogino; Mayuko Ichimura; Noriko Nakano; Akari Minami; Yasuko Kitagishi; Satoru Matsuda, Oxidative stress is considered to play key roles in aging and pathogenesis of many neurodegenerative diseases such as Parkinson's disease, which could bring DNA damage by cells. The DNA damage may lead to the cell apoptosis, which could contribute to the degeneration of neuronal tissues. Recent evidence suggests that PTEN (phosphatase and tensin homolog on chromosome 10) may be involved in the pathophysiology of the neurodegenerative disorders. Since PTEN expression appears to be one dominant determinant of the neuronal cell death, PTEN should be a potential molecular target of novel therapeutic strategies against Parkinson's disease. In addition, defects in DNA damage response and DNA repair are often associated with modulation of hormone signaling pathways. Especially, many observations imply a role for estrogen in a regulation of the DNA repair action. In the present review, we have attempted to summarize the function of DNA repair molecules at a viewpoint of the PTEN signaling pathway and the hormone related functional modulation of cells, providing a broad interpretation on the molecular mechanisms for treatment of Parkinson's disease. Particular attention will be paid to the mechanisms proposed to explain the health effects of food ingredients against Parkinson's disease related to reduce oxidative stress for an efficient therapeutic intervention., Jun. 2016, 17, 6, E954, 10.3390/ijms17060954
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, MDPI AG, BRCA1 and p53 Tumor Suppressor Molecules in Alzheimer's Disease, Atsuko Nakanishi; Akari Minami; Yasuko Kitagishi; Yasunori Ogura; Satoru Matsuda, Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer's disease. Alzheimer's disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer's disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer's disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer's disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field., Feb. 2015, 16, 2, 2879, 2892, 10.3390/ijms16022879
- Refereed, AIMS Molecular Science, American Institute of Mathematical Sciences (AIMS), Cigarette smoke may be an exacerbation factor in nonalcoholic fatty liver disease via modulation of the PI3K/AKT pathway, Mayuko Ichimura; Akari Minami; Noriko Nakano; Yasuko Kitagishi; Toshiyuki Murai; Satoru Matsuda, 2015, 2, 4, 427, 439, Scientific journal, 10.3934/molsci.2015.4.427
- Refereed, FRONTIERS IN BIOSCIENCE-LANDMARK, FRONTIERS IN BIOSCIENCE INC, Functions and characteristics of PINK1 and Parkin in cancer, Satoru Matsuda; Atsuko Nakanishi; Akari Minami; Yoko Wada; Yasuko Kitagishi, Most of the Parkinson disease (PD) linked genes are also associated with cancers. In particular, phosphatase and tensin homologue-induced kinase 1 (PINK1) and Parkin, both of which are involved in recessively inherited familial forms of PD linked to mitochondrial dysfunction, appear to be abnormally expressed in cancers. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. Although PD and cancer are obviously disparate human disorders, there is an evidence for low cancer rates in patients with PD. The relationship between cancer rates and PD might be related to the involvement of common pathways in both diseases. This paper provides a concise overview on the cellular functions of the PINK1 and Parkin., Jan. 2015, 20, 491, 501, Scientific journal, 10.2741/4321
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Function of alpha-synuclein and PINK1 in Lewy body dementia, Akari Minami; Atsuko Nakanishi; Satoru Matsuda; Yasuko Kitagishi; Yasunori Ogura, alpha-synuclein (-syn) is the major protein component of Lewy bodies, a key pathological characteristic of the degenerating brain. The misfolding and aggregation of -syn is associated with both the idiopathic and familial forms of Parkinson's disease (PD) and Lewy body dementia (LBD). However, the function of -syn is poorly understood, as it shows both neurotoxic and neuroprotective activities. Mutations in phosphatase and tensin homologue-induced putative kinase 1 (PINK1) also cause recessively inherited PD. Studies support the notion of neuroprotective roles for PINK1, as it protects cells from damage-induced mitochondrial dysfunction, oxidative stress and cell apoptosis. PINK1 plays an essential role in mitochondrial quality control and its homeostasis is maintained through mitochondrial stabilization. The -syn aggregation is linked to various aspects of mitochondrial dysfunction and PINK1-related mitophagy. Determination of the molecular pathways that lead to -syn oligomerization and further aggregation may be the basis for the successful design and development of treatments for these neurodegenerative diseases. The present review summarizes the function of PINK1 underlying -syn aggregation and the mechanisms through which mitochondrial dysfunction plays a role in this process., Jan. 2015, 35, 1, 3, 9, Scientific journal, 10.3892/ijmm.2014.1980
- Refereed, Open Biochem J, Certain Diet and Lifestyle May Contribute to Islet β-cells Protection in Type-2 Diabetes via the Modulation of Cellular PI3K/AKT Pathway., MATSUDA Satoru; Matsuda S, Nov. 2014, 8, 74-82, 10.2174/1874091X01408010074
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Atherosclerosis and tumor suppressor molecules (Review), Miho Suzuki; Aicari Minami; Atsuko Nakanishi; Keiko Kobayashi; Satoru Matsuda; Yasunori Ogura; Yasuko Kitagishi, Atherosclerosis, the major cause of heart attack and stroke, is a chronic inflammatory disease characterized by the formation of atherosclerotic plaque. Oxidized low-density lipoprotein through increased oxidative stress has been identified as one of the primary factors responsible for atherogenesis. Cell proliferation and death are key processes in the progression of atherosclerosis. The oxidative environment in areas of lipid accumulation is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage and levels of DNA repair are reduced during dietary lipid lowering. The tumor suppressor molecules play a pivotal role in regulating cell proliferation, DNA repair and cell death, which are important processes in regulating the composition of atherosclerotic plaque. Accordingly, in this review, we discuss the fundamental role of tumor suppressor molecules in regulating atherogenesis. In particular, we discuss how tumor suppressor molecules are activated in the complex environment of atherosclerotic plaque, and regulate growth arrest, cell senescence and the apoptosis of vascular smooth muscle cells, which may protect against the progression of atherosclerosis. In addition, we discuss promising alternatives to the use of medications (such as statin) against atherosclerosis, namely diet, with the use of plant-derived supplements to modulate the expression and/or activity of tumor suppressor molecules. We also summarize the progress of research made on herbs with a focus on the modulatory roles of tumor suppressors, and on the molecular mechanisms underlying the prevention if atherosclerosis, supporting designs for further research in this field., Oct. 2014, 34, 4, 934, 940, Scientific journal, 10.3892/ijmm.2014.1866
- Refereed, INTERNATIONAL JOURNAL OF ONCOLOGY, SPANDIDOS PUBL LTD, The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review), Atsuko Nakanishi; Yasuko Kitagishi; Yasunori Ogura; Satoru Matsuda, Numerous hereditary syndromes caused by mutations in multiple tumor suppressor genes can cause cancers. Germ line mutations in PTEN and p53 tumor suppressor cause Cowden syndrome and Li-Fraumeni syndrome, respectively. There exists some phenotypic overlap in these syndromes, and they are associated with high risks of breast cancer. The tumor suppressor protein PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream targets. PTEN gene is recognized as one of the most frequently mutated or mutated in many human cancers. Li-Fraumeni syndrome results from germline mutations of the tumor suppressor p53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. The p53 protein cooperates with PTEN and might be an essential blockage in development of mammary tumors. Many findings have demonstrated that PTEN as well as p53 plays a critical role in DNA damage response. This review summarizes the function of PTEN and p53 in carcinogenic cell signaling. In addition, we will discuss the role of PTEN signaling through its interaction with p53 and MDM2 pathways for the potential implications in hereditary cancer prevention and therapeutic intervention., Jun. 2014, 44, 6, 1813, 1819, 10.3892/ijo.2014.2377
- Refereed, AGING AND DISEASE, INT SOC AGING & DISEASE, Link between PI3K/AKT/PTEN Pathway and NOX Protein in Diseases, Atsuko Nakanishi; Yoko Wada; Yasuko Kitagishi; Satoru Matsuda, Accumulating evidence has revealed that the PI3K/AKT/PTEN pathway acts as a pivotal determinant of cell fate regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. NADPH oxidase (NOX) family of enzymes generates the ROS. The regulation of NOX enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. Cells are continuously exposed to the ROS, which represent mutagens and are thought to be a major contributor to several diseases including cancer and aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, the roles of oxidative stress in PI3K/AKT/PTEN signaling are summarized with a focus on the links between the pathways and NOX protein in several diseases including cancer and aging., Jun. 2014, 5, 3, 203, 211, 10.14336/AD.2014.0500203
- Refereed, ALZHEIMERS RESEARCH & THERAPY, BIOMED CENTRAL LTD, Dietary regulation of PI3K/AKT/GSK-3 beta pathway in Alzheimer's disease, Yasuko Kitagishi; Atsuko Nakanishi; Yasunori Ogura; Satoru Matsuda, Alzheimer's disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles composed of phosphorylated Tau. Several findings suggest that correcting signal dysregulation for Tau phosphorylation in AD may offer a potential therapeutic approach. The PI3K/AKT/GSK-3 beta pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. This pathway appears to be crucial in AD because it promotes protein hyper-phosphorylation in Tau. Understanding those regulations may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances in the involvement of the PI3K/AKT/GSK-3 beta pathways in cell signaling of neuronal cells. We also review recent studies on the features of several diets and the signaling pathway involved in AD., 2014, 6, 3, 35, 10.1186/alzrt265
- Refereed, Frontiers in Oncology, Frontiers Media S.A., Connection between tumor suppressor BRCA1 and PTEN in damaged DNA repair, Akari Minami; Atsuko Nakanishi; Yasunori Ogura; Yasuko Kitagishi; Satoru Matsuda, Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling., 2014, 4, 318, 10.3389/fonc.2014.00318
- Refereed, International Journal of Molecular Sciences, RUFY, rab and rap family proteins involved in a regulation of cell polarity and membrane trafficking, Yasuko Kitagishi; Satoru Matsuda, Cell survival, homeostasis and cell polarity rely on the control of membrane trafficking pathways. The RUN domain (comprised of the RPIP8, UNC-14, and NESCA proteins) has been suggested to be implicated in small GTPase-mediated membrane trafficking and cell polarity. Accumulating evidence supports the hypothesis that the RUN domain-containing proteins might be responsible for an interaction with a filamentous network linked to actin cytoskeleton and/or microtubules. In addition, several downstream molecules of PI3K are involved in regulation of the membrane trafficking by interacting with vesicle-associated RUN proteins such as RUFY family proteins. In this review, we summarize the background of RUN domain research with an emphasis on the interaction between RUN domain proteins including RUFY proteins (designated as RUN and FYVE domain-containing proteins) and several small GTPases with respect to the regulation of cell polarity and membrane trafficking on filamentous network. © 2013 by the authors
licensee MDPI, Basel, Switzerland., Mar. 2013, 14, 3, 6487, 6498, 10.3390/ijms14036487 - Abstracts of Annual Congress of The Japan Society of Home Economics, The Japan Society of Home Economics, Effects of some food ingredients on AKT and/or p38MAPK phosphorylation, Kitagishi Yasuko; Matsuda Satoru, 2013, 65, 7, 7, 10.11428/kasei.65.0_7
- Refereed, Int J Mol Med, Redox regulation of tumor suppressor PTEN in cancer and aging, MATSUDA Satoru; Matsuda S, Jan. 2013, 31, 3, 511
- Refereed, ISRN Endocrinol, Roles for PI3K/AKT/PTEN Pathway in Cell Signaling of Nonalcoholic Fatty Liver Disease., MATSUDA Satoru; Matsuda S, Jan. 2013, 3013, 472432
- Refereed, PPAR Research, Hindawi Publishing Corporation, Expression and function of PPARs in placenta, Satoru Matsuda; Mayumi Kobayashi; Yasuko Kitagishi, Peroxisome proliferator-activated receptors (PPAR) are members of the superfamily of nuclear hormone receptors involved in embryonic development and differentiation of several tissues including placenta, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. The PPARs also control a variety of target genes involved in lipid homeostasis. Similar to other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation but also by crosstalk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, several mechanisms underlying negative regulation of gene expression by PPARs have been shown. It is suggested that PPARs are key messengers responsible for the translation of nutritional stimuli into changes in gene expression pathways for placental development. © 2013 Satoru Matsuda et al., 2013, 2013, 256508, 10.1155/2013/256508
- Refereed, OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, HINDAWI PUBLISHING CORPORATION, Function and Characteristics of PINK1 in Mitochondria, Satoru Matsuda; Yasuko Kitagishi; Mayumi Kobayashi, Mutations in phosphatase and tensin homologue-induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease, a neurodegenerative disorder linked to mitochondrial dysfunction. Studies support the notion of neuroprotective roles for the PINK1, as it protects cells from damage-mediated mitochondrial dysfunction, oxidative stress, and cell apoptosis. PARL is a mitochondrial resident rhomboid serine protease, and it has been reported to mediate the cleavage of the PINK1. Interestingly, impaired mitophagy, an important autophagic quality control mechanism that clears the cells of damaged mitochondria, may also be an underlying mechanism of disease pathogenesis in patients for Parkinson's disease with the PARL mutations. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate the mitophagy. PINK1 is posttranslationally processed, whose level is definitely regulated in healthy steady state of mitochondria. As a consequence, PINK1 plays a pivotal role in mitochondrial healthy homeostasis., 2013, 2013, 601587, 10.1155/2013/601587
- Refereed, ALZHEIMERS RESEARCH & THERAPY, BIOMED CENTRAL LTD, Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury, Yasuko Kitagishi; Satoru Matsuda, Traumatic encephalopathy has emerged as a significant public health problem. It is believed that traumatic encephalopathy is caused by exposure to repetitive brain trauma prior to the initial symptoms of neurodegenerative disease. Therefore, prevention is important for the disease. The PI3K/AKT/PTEN (phosphoinositide-3 kinase/AKT/phosphatase and tensin homologue deleted on chromosome 10) pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Although PTEN has been discovered as a tumor suppressor, PTEN is also involved in several other diseases, including diabetes and Alzheimer's disease. Dietary fish oil rich in polyunsaturated fatty acids may induce the PTEN expression by activation of peroxisome proliferator-activated receptor. Supplementation of these natural compounds may provide a new therapeutic approach to the brain disorder. We review recent studies on the features of several diets and the signaling pathways involved in traumatic encephalopathy., 2013, 5, 5, 42, 10.1186/1758-9193-5-42
- Refereed, Cancers, MDPI AG, Peroxisome proliferator-activated receptor and vitamin D receptor signaling pathways in cancer cells, Satoru Matsuda; Yasuko Kitagishi, Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer., 2013, 5, 4, 1261, 1270, 10.3390/cancers5041261
- Refereed, Open Medicinal Chemistry Journal, Roles of PI3K/AKT/PTEN pathway as a target for Pharmaceutical therapy, Satoru Matsuda; Atsuko Nakanishi; Yoko Wada; Yasuko Kitagishi, Multiple enzymes participate in the phosphorylation of a group of phosphoinositide lipids. Because of their important role in signal transduction, the dysregulated metabolism of phosphoinositides represents a key step in many disease settings. Loss of their function has been demonstrated to occur as an early event a wide variety of carcinogenesis and has therefore been suggested as a biomarker for the premalignant disease. In addition, genetic alterations at multiple nodes in the pathway have been implicated in several other diseases. Accordingly, given this pervasive involvement in many diseases, the development of molecules that modulates this pathway has been initiated in studies. They have been the focus of extensive research and drug discovery activities. A better understanding of the molecular connections could uncover new targets for drug development. © Matsuda et al., 2013, 7, 1, 23, 29, Scientific journal, 10.2174/1874104501307010023
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Elucidating the regulation of T cell subsets (Review), Yasuko Kitagishi; Mayumi Kobayashi; Yurie Yamashina; Satoru Matsuda, CD4-positive T lymphocytes mainly direct immune as well as autoimmune responses against a variety of pathogens or allergens. This is achieved through the acquisition of specialized functions followed by differentiation into various T cell subsets. The differentiation process of naive T cells into effector subsets is regulated by dendritic cells and secreted cytokines. Signal transducer and activator of transcription proteins play critical roles in transmitting cytokine-mediated signals and specifying T cell differentiation. Epigenetic changes such as historic acetylation and methylation along with DNA methylation also regulate expression of differentiation-specific genes. Defining, exactly how extrinsic signals control the specification of T cells will provide important insights and therapeutic opportunities., Dec. 2012, 30, 6, 1255, 1260, Scientific journal, 10.3892/ijmm.2012.1152
- Refereed, ONCOLOGY LETTERS, SPANDIDOS PUBL LTD, Terpinolene, a component of herbal sage, downregulates AKT1 expression in K562 cells, Naoko Okumura; Hitomi Yoshida; Yuri Nishimura; Yasuko Kitagishi; Satoru Matsuda, Protein kinase AKT mediates cell proliferation and survival signals, and also contributes to cancer progression. Increased expression and/or activation of AKT is involved in a variety of human cancers. In cells treated with sage or rosemary extract, mRNA and protein expression levels of AKT1 were reduced compared with those of the control cells 48 h after the herbal treatments. We found that terpinolene, a common component of sage and rosemary, markedly reduced the protein expression of AKT1 in K562 cells and inhibited cell proliferation., Feb. 2012, 3, 2, 321, 324, Scientific journal, 10.3892/ol.2011.491
- Refereed, MOLECULAR MEDICINE REPORTS, SPANDIDOS PUBL LTD, Clobetasol synergistically diminishes Ciz1 expression with genistein in U937 cells, Naoko Okumura; Hitomi Yoshida; Yuri Nishimura; Yasuko Kitagishi; Satoru Matsuda, Cip-interacting zinc finger protein 1 (Ciz1) stimulates DNA replication and has been implicated in the tumorigenesis of breast cancer cells. In order to investigate the possibility of using medicinal glucocorticoids against breast cancer, we studied whether certain glucocorticoids affect the expression of Ciz1. The in vitro effect of clobetasol treatment on the reduction of Ciz1 expression was detected by reverse transcriptase-polymerase chain reaction. Western blotting also confirmed the down-regulation of the protein in a dose-dependent manner upon clobetasol treatment in U937 monocytoid cells. Furthermore, we found that Ciz1 protein expression was decreased after pre-treatment of the cells with clobetasol and genistein. An extract of Lens culinaris also had a synergistic effect on the repression of Ciz1 protein expression., Feb. 2012, 5, 2, 567, 569, Scientific journal, 10.3892/mmr.2011.665
- Refereed, MOLECULAR MEDICINE REPORTS, SPANDIDOS PUBL LTD, Genistein downregulates presenilin 1 and ubiquilin 1 expression, Naoko Okumura; Hitomi Yoshida; Yuri Nishimura; Mutsumi Murakami; Yasuko Kitagishi; Satoru Matsuda, The aim of this study was to determine the effects of several food ingredients and chemical inhibitors on the expression of presenilin, a molecule involved in gamma-secretase activity and the generation of amyloid-beta peptide in Alzheimer's disease. Western blotting revealed the downregulation of presenilin 1 protein expression by stimulation with genistein in vitro, while the effects on presenilin 1 gene expression examined by reverse transcriptase-polymerase chain reaction (RT-PCR) were unaltered in Daudi cells. Genistein likely downregulates presenilin via the inhibition of ubiquilin 1 expression in lymphoid cells. Our findings provide new insights that may help to establish preventive strategies against Alzheimer's disease., Feb. 2012, 5, 2, 559, 561, Scientific journal, 10.3892/mmr.2011.648
- Refereed, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBL LTD, Clobetasol down-regulates SLPI expression in U937 monocytoid cells, Naoko Okumura; Hitomi Yoshida; Yasuko Kitagishi; Yuri Nishimura; Satoru Matsuda, In order to investigate how glucocorticoids affect the expression of secretory leukocyte peptidase inhibitor (SLPI), which is overexpressed in a variety of cancers, clobetasol was added to cell culture medium of U937 cells and the SLPI mRNA levels were examined. The in vitro effect of the treatment on SLPI expression was detected by reverse transcriptase-polymerase chain reaction. Clobetasol treatment of U937 cells induced an up- and down-regulation of SLPI expression in a dose-dependent manner. Western blotting confirmed the down-regulation of SLPI protein expression. We hypothesized a loop formation in the SLPI genome domain, in which the glucocorticoid receptor regulates bi-directional transcriptional activity., Feb. 2012, 29, 2, 324, 326, Scientific journal
- Refereed, Advances in Hematology, PI3K/AKT/PTEN signaling as a molecular target in leukemia angiogenesis, Naoko Okumura; Hitomi Yoshida; Yasuko Kitagishi; Mutsumi Murakami; Yuri Nishimura; Satoru Matsuda, PI3K/AKT/PTEN pathway is important in the regulation of angiogenesis mediated by vascular endothelial growth factor in many tumors including leukemia. The signaling pathway is activated in leukemia patients as well as leukemia cell lines together with a decrease in the expression of PTEN gene. The mechanism by which the signaling pathway regulates angiogenesis remains to be further elucidated. However, it has become an attractive target for drug therapy against leukemia, because angiogenesis is a key process in malignant cell growth. In this paper, we will focus on the roles and mechanisms of PI3K/AKT/PTEN pathway in regulating angiogenesis. © 2012 Naoko Okumura et al., 2012, 2012, 843085, 10.1155/2012/843085
- Refereed, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC ELSEVIER SCIENCE, Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer, Naoko Okumura; Hitomi Yoshida; Yasuko Kitagishi; Yuri Nishimura; Satoru Matsuda, Alternative splicing is a major contributor to transcriptome and proteome diversity, which can lead to the deregulation of crucial cellular processes and have been associated with a variety of human diseases including cancer. As p53, BRCA1, and PTEN proteins have a key role in preventing breast cancer formation, cancer-associated splicing variants of these tumor suppressor genes are potential molecular markers and may contribute to the development of diagnostic and prognostic methods. In the present review, we summarize these tumor suppressor genes at a viewpoint of alternative splicing involved in breast cancer. (C) 2011 Elsevier Inc. All rights reserved., Sep. 2011, 413, 3, 395, 399, 10.1016/j.bbrc.2011.08.098
- Refereed, IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL, SPRINGER, Long-term cultivation of in vitro Apis mellifera cells by gene transfer of human c-myc proto-oncogene, Yasuko Kitagishi; Naoko Okumura; Hitomi Yoshida; Yuri Nishimura; Jun-ichi Takahashi; Satoru Matsuda, Establishment of cell lines representative of honeybee character would greatly assist in their analysis. Here, we show that immortalized cell line, designated as MYN9, has been generated from honeybee embryo by the gene transfer of human c-myc proto-oncogene. The morphology of the cell is characteristic of embryonic stem cell, although the cell is stable and does not spontaneously differentiate. Polymerase chain reaction analyses show that the cell is originated from authentic honeybee cell. It is proposed that the integration of human c-myc gene into honeybee precursor populations results in the establishment of stable cell line suitable for cellular and molecular studies., Aug. 2011, 47, 7, 451, 453, Scientific journal, 10.1007/s11626-011-9431-6
- Refereed, MOLECULAR MEDICINE REPORTS, SPANDIDOS PUBL LTD, Ethanol extracts of black pepper or turmeric down-regulated SIRT1 protein expression in Daudi culture cells, Yuri Nishimura; Yasuko Kitagishi; Hitomi Yoshida; Naoko Okumura; Satoru Matsuda, SIRT1 is a mammalian candidate molecule involved in longevity and diverse metabolic processes. The present study aimed to determine the effects of certain herbs and spices on SIRT1 expression. Human cell lines Daudi, Jurkat, U937 and K562 were cultured in RPMI-1640. Herb and spice powders were prepared and the supernatants were collected. RT-PCR was used to quantify the expression level of the gene. Protein samples were then analyzed by Western blotting. Western blotting revealed the down-regulation of SIRT1 protein expression in Daudi cells treated with extracts of black pepper or turmeric. On the other hand, the effect on the SIRT1 gene expression examined by reverse transcription polymerase chain reaction was unaltered. In conclusion, component(s) of certain herbs and spices may induce the down-regulation of SIRT1 protein., Jul. 2011, 4, 4, 727, 730, Scientific journal, 10.3892/mmr.2011.487
- Refereed, EXPERIMENTAL AND THERAPEUTIC MEDICINE, SPANDIDOS PUBL LTD, Turmeric and curcumin suppress presenilin 1 protein expression in Jurkat cells, Hitomi Yoshida; Naoko Okumura; Yuri Nishimura; Yasuko Kitagishi; Satoru Matsuda, In the present study, we aimed to determine the effects of herbs or spices on the expression of presenilin 1, a molecule involved in gamma-secretase activity and the generation of amyloid-beta peptide in Alzheimer's disease. Western blot analysis revealed that presenilin 1 protein expression was down-regulated by stimulation with turmeric or cinnamon extracts in vitro, while the effects on presenilin 1 gene expression examined by reverse transcriptase-polymerase chain reaction were unaltered. Our results showed that curcumin, a component of turmeric, induced the down-regulation of presenilin 1 protein in Jurkat and K562 cell lines., Jul. 2011, 2, 4, 629, 632, Scientific journal, 10.3892/etm.2011.246
- Refereed, FEBS LETTERS, ELSEVIER SCIENCE BV, How do you RUN on?, Hitomi Yoshida; Yasuko Kitagishi; Naoko Okumura; Mutsumi Murakami; Yuri Nishimura; Satoru Matsuda, RUN domain is present in several proteins related to the functions of Rap and Rab family GTPases. Accumulating evidence supports the hypothesis that RUN domain-containing proteins act as a component of vesicle traffic and might be responsible for an interaction with a filamentous network linked to actin cytoskeleton or microtubules. That is to say, on one hand, RUN domains associate with Rab or Rap family proteins, on the other hand, they also might interact with motor proteins such as kinesin or myosin via intervention molecules. In this review, we summarize the background and current status of RUN domain research with an emphasis on the interaction between RUN domain and motor proteins with respect to the vesicle traffic on filamentous network. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved., Jun. 2011, 585, 12, 1707, 1710, 10.1016/j.febslet.2011.05.011
- Refereed, Int J appl Biol pharm Technol, Ethanol extract of Rosemary repressed PTEN expression in K562 culture cells., MATSUDA Satoru; Hitomi Yoshida; Naoko Okumura; Yasuko Kitagishi; Yuri Nishimura; Satoru Matsuda, 2011, 2, 316-322
- Refereed, J amino acids, Dicer functions in aquatic species., MATSUDA Satoru; Yasuko Kitagishi; Naoko Okumura; Hitomi Yoshida; Chika Tateishi; Yuri Nishimura; Satoru Matsuda, 2011, 2011, 782187
- Refereed, Journal of home economics of Japan, 奈良近郊で販売された野菜などに含まれる硝酸態窒素量測定および簡便で効果的な除去法の検討, MATSUDA Satoru, Dec. 2010, 61, 12, 813-817, 817
- Refereed, INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, IVYSPRING INT PUBL, Rab5(Q79L) interacts with the carboxyl terminus of RUFY3, Hitomi Yoshida; Naoko Okumura; Yasuko Kitagishi; Naoki Shirafuji; Satoru Matsuda, 2010, 6, 2, 187, 189
- Refereed, Int J Curr Res, Ubiquitin and proteasomes are involved in the degradation of cytosolic Doppel protein., MATSUDA Satoru; Okumura N; Yoshida H; Nagata Y; Nishimura Y; Kitagishi Y; Matsuda S, 2010, 5, 38-40
- Not Refereed, BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, Tumor growth suppression by adenovirus-mediated introduction of a cell growth suppressing gene tob in a pancreatic cancer model, Hironobu Yanagie; Tuyoshi Tanabe; Hidetoshi Sumimoto; Hirotaka Sugiyama; Satoru Matsuda; Yasumasa Nonaka; Naoko Ogiwara; Katsunori Sasaki; Kensaburo Tani; Shinichi Takamoto; Hiroyuki Takahashi; Masazumi Eriguchi, TOB (transducer of ErbB-2) is a tumor suppressor that interacts with protein-tyrosine kinase receptors, including ErbB-2. Introduction of the tob gene into NIH3T3 cells results in cell growth suppression. In this study, we evaluated the effect of tob expression in pancreatic cell lines (AsPC-1, BxPC-3, SOJ) and discuss the tumor-suppressing effects of adenoviral vector expressing tob cDNA. We first measured the levels of endogenous tob mRNA being expressed in all pancreatic cancer cell lines. Then, we examined the effect of adenoviral vector containing tob cDNA (Ad-tob vector) on cancer cell lines. The viral vector was expanded with transfection in 293 cells. The titer of the vector was 350 x 10(6) pfu/ml. These cancer cells were able to be transfected with MOI 20 without adenoviral toxicity. The transfection of Ad-tob vector results in growth suppression of SOJ and AsPC-1 cell lines. The magnitude of the expression of the Ad-tob gene in cancer is correlated to tumor suppressive activity. We prepared pancreatic cancer peritonitis models using a peritoneal injection of AsPC-1 cells. In this model, bloody ascites and multiple tumor nodules were seen at the mesentery after 16 days. AdCAtob (50 x 10(6) pfu/day) was administered from day 5 to day 9 after 4 days of peritoneal injection of 2 x 106 AsPC-1 cells. Tumor growth suppression occurred 10 days after peritoneal injection of AdCAtob compared with the control group. There were no tumor nodules in the abdomen and no bloody ascites. These results suggest that the peritoneal injection of AdCAtob has potential to suppress the formation of pancreatic cancer peritonitis, and can be applied for chemotherapy-resistant cancer peritonitis. (C) 2008 Elsevier Masson SAS. All rights reserved., May 2009, 63, 4, 275, 286, Scientific journal, 10.1016/j.biopha.2008.04.010
- Refereed, ANNALS OF ONCOLOGY, OXFORD UNIV PRESS, Insulin receptor substrate protein 53 (IRSp53) as a binding partner of antimetastasis molecule NESH, a member of Abelson interactor protein family, S. Matsuda; S. Yokozaki; H. Yoshida; Y. Kitagishi; N. Shirafuji; N. Okumura, Jul. 2008, 19, 7, 1356, U2, 10.1093/annonc/mdn293
- Refereed, MOLECULAR ONCOLOGY, ELSEVIER SCI LTD, NESH protein expression switches to the adverse effect of imatinib mesylate, Satoru Matsuda; Yasukatu Ichigotani; Naoko Okumura; Hitomi Yoshida; Yuka Kajiya; Yasuko Kitagishi; Naoki Shirafuji, Jun. 2008, 2, 1, 16, 19, 10.1016/j.molonc.2008.03.003
- Refereed, FEBS LETTERS, ELSEVIER SCIENCE BV, NESH (Abi-3) is pre-sent in the Abi/WAVE complex but does not promote c-Abl-mediated phosphorylation, Noriko Hirao; Seiichi Sato; Tetsuya Gotoh; Masahiro Maruoka; Jun Suzuki; Satoru Matsuda; Tornoyuki Shishido; Katsuko Tani, Abl interactor (Abi) was identified as an Abl tyrosine kinase-binding protein and subsequently shown to be a component of the macromolecular Abi/WAVE complex, which is a key regulator of Rae-dependent actin polymerization. Previous studies showed that Abi-1 promotes c-Ab1-mediated phosphorylation of Mammalian Enabled (Mena) and WAVE2. In addition to Abi-1, mammals possess Abi-2 and NESH (Abi-3). In this study, we compared the three Abi proteins in terms of the promotion of c-Abl-mediated phosphorylation and the formation of Abi/WAVE complex. Although Abi-2, like Abi-1, promoted the c-Abl-mediated phosphorylation of Mena and WAVE2, NESH (Abi-3) had no such effect. This difference was likely due to their binding abilities as to c-Abl. Immunoprecipitation revealed that NESH (Abi-3) is present in the Abi/WAVE complex. Our results suggest that NESH (Abi-3), like Abi-1 and Abi-2, is a component of the Abi/WAVE complex, but likely plays a different role in the regulation of c-Abl. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved., Nov. 2006, 580, 27, 6464, 6470, Scientific journal, 10.1016/j.febslet.2006.10.065
- Refereed, GENES TO CELLS, BLACKWELL PUBLISHING LTD, Interaction of anti-proliferative protein Tob with poly(A)-binding protein and inducible poly(A)-binding protein: implication of Tob in translational control, K Okochi; T Suzuki; J Inoue; S Matsuda; T Yamamoto, Tob is a member of an emerging family of anti-proliferative proteins that suppress cell growth when over-expressed. tob mRNA is highly expressed in anergic T cells and over-expression of Tob suppresses transcription of interleukin-2 (IL-2) through its interaction with Smads. Here, we identified two types of cDNA clones coding for poly(A)-binding protein (PABP) and inducible PABP (iPABP) by screening an expression cDNA library with the GST-Tob probe. Co-immunoprecipitation and GST-pull down experiments showed that Tob associated with the carboxyl-terminal region of iPABP. We then found that iPABP, like PABP, was involved in regulation of translation: iPABP enhanced translation of IL-2 mRNA in vitro. The enhanced translation of IL-2 mRNA required the 3'UTR and poly(A) sequences. Tob abrogated the enhancement of translation through its interaction with carboxyl-terminal region of iPABP in vitro. Consistently, over-expression of Tob in NIH3T3 cells, in which exogenous iPABP was stably expressed, resulted in suppression of IL-2 production from the simultaneously transfected IL-2 expression plasmid. Finally, Tob, whose expression was induced by anergic stimulation, was co-immunoprecipitated with iPABP in human T cells. These findings suggest that Tob is involved in the translational suppression of IL-2 mRNA in anergic T cells through its interaction with iPABP., Feb. 2005, 10, 2, 151, 163, Scientific journal, 10.1111/j.1365-2443.2005.00826.x
- Refereed, Oncogene, Springer Science and Business Media LLC, A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling, Ali Reja Mohammad Ruhul Amin; Kazuya Machida; Kumi Oshima; Myat Lin Oo; Aye Aye Thant; Takeshi Senga; Satoru Matsuda; Anwarul Azim Akhand; Akito Maeda; Tomohiro Kurosaki; Michinari Hamaguchi, Dec. 2002, 21, 57, 8871, 8878, Scientific journal, 10.1038/sj.onc.1206018
- Refereed, Oncol Rep ., Expression of p73 gene, cell proliferation and apoptosis in breast cancer: Immunohistochemical and clinicopathological study, Tatsuyoshi Yamamoto; Koji Oda; Tomoyuki Kubota; Kou Miyazaki; Yasushi Takenouti; Yuji Nimura; Michinari Hamaguchi; Satoru Matsuda, Aug. 2002, 9, 4, 729, 735
- Refereed, Cancer Res., SHPS-1: a budding molecule against cancer dissemination., Oshima K; Machida K; Ichigotani Y; Nimura Y; Shirafuji N; Hamaguchi M; Matsuda S, Jul. 2002, 62, 14, 3929, 3933
- Refereed, Cancer Res., Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90, Zhang Y; Thant AA; Machida K; Ichigotani Y; Naito Y; Hiraiwa Y; Senga T; Sohara Y; Matsuda S; Hamaguchi M, Jul. 2002, 62, 14, 3962, 3965
- Refereed, In search of a function for the E3B1/Abi2/Argbp1/NESH family, Ichigotani Y; Fujii K; Hamaguchi M; Matsuda S, Jun. 2002, 9, 6, 591, 595
- Refereed, Cancer Res., Forced expression of NESH suppresses motility and metastatic dissemination of malignant cells, Ichigotani Y; Yokozaki S; Fukuda Y; Hamaguchi M; Matsuda S, Apr. 2002, 62, 8, 2215, 2219
- Refereed, Biochemical and Biophysical Research Communications, Elsevier BV, A Role for Focal Adhesion Kinase in Hyluronan-Dependent MMP-2 Secretion in a Human Small-Cell Lung Carcinoma Cell Line, QG90, Yanying Zhang; Aye Aye Thant; Yukiko Hiraiwa; Yuko Naito; Thet Thet Sein; Yasuyoshi Sohara; Satoru Matsuda; Michinari Hamaguchi, Jan. 2002, 290, 3, 1123, 1127, Scientific journal, 10.1006/bbrc.2001.6321
- Refereed, Histol Histopathol., STAT and SMAD signaling in cancer., Iwamoto T; Oshima K; Seng T; Feng X; Oo ML; Hamaguchi M; Matsuda S, 2002, 17, 3, 887, 895
- Refereed, Oncogene, Springer Science and Business Media LLC, Suppression of cell spreading by v-Crk requires Ras-MEK-MAP kinase signaling, Yuzhen Liu; Yukiko Hiraiwa; Enbo Liu; Hisashi Kurata; Aye Aye Thant; Satoru Matsuda; Michinari Hamaguchi, Sep. 2001, 20, 41, 5908, 5912, Scientific journal, 10.1038/sj.onc.1204738
- Refereed, International Journal of Oncology, Spandidos Publications, p73 is highly expressed in myoepithelial cells and in carcinomas with metaplasia, Tatsuyoshi Yamamoto; Koji Oda; Kou Miyazaki; Yasukatu Ichigotani; Yasushi Takenouchi; Tomotaka Kamei; Naoki Shirafuji; Yuji Nimura; Michinari Hamaguchi; Satoru Matsuda, 01 Aug. 2001, Scientific journal, 10.3892/ijo.19.2.271
- Refereed, Journal of Human Genetics, Springer Science and Business Media LLC, Cloning and sequencing of a novel human gene that encodes a putative target protein of Nesh-SH3, S. Matsuda; C. Iriyama; S. Yokozaki; Y. Ichigotani; N. Shirafuji; K. Yamaki; T. Hayakawa; M. Hamaguchi, Aug. 2001, 46, 8, 483, 486, Scientific journal, 10.1007/s100380170049
- Refereed, Molecular Biology of the Cell, American Society for Cell Biology (ASCB), Hyaluronan Activates Cell Motility of v-Src-transformed Cells via Ras-Mitogen–activated Protein Kinase and Phosphoinositide 3-Kinase-Akt in a Tumor-specific Manner, Yasuyoshi Sohara; Naoki Ishiguro; Kazuya Machida; Hisashi Kurata; Aye Aye Thant; Takeshi Senga; Satoru Matsuda; Koji Kimata; Hisashi Iwata; Michinari Hamaguchi, We investigated the production of hyaluronan (HA) and its effect on cell motility in cells expressing the v-src mutants. Transformation of 3Y1 by v-src virtually activated HA secretion, whereas G2A v-src, a nonmyristoylated form of v-src defective in cell transformation, had no effect. In cells expressing the temperature-sensitive mutant of v-Src, HA secretion was temperature dependent. In addition, HA as small as 1 nM, on the other side, activated cell motility in a tumor-specific manner. HA treatment strongly activated the motility of v-Src–transformed 3Y1, whereas it showed no effect on 3Y1- and 3Y1-expressing G2A v-src. HA-dependent cell locomotion was strongly blocked by either expression of dominant-negative Ras or treatment with a Ras farnesyltransferase inhibitor. Similarly, both the MEK1 inhibitor and the kinase inhibitor clearly inhibited HA-dependent cell locomotion. In contrast, cells transformed with an active MEK1 did not respond to the HA. Finally, an anti-CD44–neutralizing antibody could block the activation of cell motility by HA as well as the HA-dependent phosphorylation of mitogen-activated protein kinase and Akt. Taken together, these results suggest that simultaneous activation of the Ras-mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase pathway by the HA-CD44 interaction is required for the activation of HA-dependent cell locomotion in v-Src–transformed cells., Jun. 2001, 12, 6, 1859, 1868, Scientific journal, 10.1091/mbc.12.6.1859
- Refereed, Genes to Cells, Wiley, A serine/threonine kinase p90rsk1 phosphorylates the anti-proliferative protein Tob, Toru Suzuki; Satoru Matsuda; Junko K. Tsuzuku; Yutaka Yoshida; Tadashi Yamamoto, BACKGROUND: tob is a member of a gene family with anti-proliferative function. Over-expression of Tob in NIH3T3 cells results in the suppression of cell proliferation. The growth suppression is hampered by the presence of activated ErbB2 kinase. The molecular mechanisms by which Tob suppresses cell growth and by which ErbB2 abrogates Tob function remain to be elucidated. RESULTS: We show that Tob is phosphorylated on serines and threonines, but not tyrosines, by a kinase(s) that associates with Tob in the lysates of various cells, including ErbB2-over-expressed cells. We also show that a 95 kDa kinase associates with Tob in vitro. The autophosphorylation activity of this kinase co-chromatographes with Tob-phosphorylating activity, suggesting that the 95 kDa kinase phosphorylates Tob. Among the known kinases with molecular mass around 95 kDa, p90rsk1 associates with Tob in vitro and in vivo, and phosphorylates Tob at least in vitro. Therefore, it is likely that p90rsk1 represents the 95 kDa kinase and is involved in the regulation of Tob function through phosphorylation. CONCLUSION: p90rsk1 associates with and phosphorylates Tob. Because p90rsk1 is activated downstream of receptor tyrosine kinases, we propose that Tob function is at least in part under the control of growth factor-stimulated tyrosine kinases through its phosphorylation by p90rsk1., Feb. 2001, 6, 2, 131, 138, Scientific journal, True, 10.1046/j.1365-2443.2001.00406.x
- Refereed, Oncogene, Springer Science and Business Media LLC, A role for FAK in the Concanavalin A-dependent secretion of matrix metalloproteinase-2 and -9, Thet Thet Sein; Aye Aye Thant; Yukiko Hiraiwa; ARM Ruhul Amin; Yasuyoshi Sohara; Yuzhen Liu; Satoru Matsuda; Tadashi Yamamoto; Michinari Hamaguchi, Nov. 2000, 19, 48, 5539, 5542, Scientific journal, 10.1038/sj.onc.1203932
- Refereed, Journal of Human Genetics, Springer Science and Business Media LLC, Molecular cloning of a novel human gene (SIRP-B2) which encodes a new member of the SIRP/SHPS-1 protein family, Y. Ichigotani; S. Matsuda; K. Machida; K. Oshima; T. Iwamoto; K. Yamaki; T. Hayakawa; M. Hamaguchi, Nov. 2000, 45, 6, 378, 382, Scientific journal, 10.1007/s100380070013
- Refereed, Journal of Biological Chemistry, Elsevier BV, Constitutive Tyrosine Phosphorylation of ErbB-2 via Jak2 by Autocrine Secretion of Prolactin in Human Breast Cancer, Toshimasa Yamauchi; Naoko Yamauchi; Kohjiro Ueki; Takuya Sugiyama; Hironori Waki; Hiroshi Miki; Kazuyuki Tobe; Satoru Matsuda; Toshio Tsushima; Tadashi Yamamoto; Toshiro Fujita; Yuji Taketani; Masashi Fukayama; Satoshi Kimura; Yoshio Yazaki; Ryozo Nagai; Takashi Kadowaki, Oct. 2000, 275, 43, 33937, 33944, Scientific journal, 10.1074/jbc.m000743200
- Refereed, Oncogene, Springer Science and Business Media LLC, The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK–STAT activation, Takashi Iwamoto; Takeshi Senga; Yuko Naito; Satoru Matsuda; Yozo Miyake; Akihiko Yoshimura; Michinari Hamaguchi, Sep. 2000, 19, 41, 4795, 4801, Scientific journal, 10.1038/sj.onc.1203829
- Refereed, International Journal of Oncology, Spandidos Publications, C-Cbl protein in human cancer tissues is frequently tyrosine phosphorylated in a tumor-specific manner., T Kamei; K Machida; Y Nimura; T Senga; I Yamada; S Yoshii; S Matsuda; M Hamaguchi, 01 Aug. 2000, Scientific journal, 10.3892/ijo.17.2.335
- Refereed, Cancer Res., The Ras-mitogen-activated protein kinase pathway is critical for the activation of matrix metalloproteinase secretion and the invasiveness in v-crk-transformed 3Y1., Liu E; Thant AA; Kikkawa F; Kurata H; Tanaka S; Nawa A; Mizutani S; Matsuda S; Hanafusa H; Hamaguchi M, May 2000, 60, 9, 2361, 2364
- Biochimica et biophysica acta, Molecular cloning and characterization of a novel human gene (NESCA) which encodes a putative adapter protein containing SH3., S Matsuda; K Miyazaki; Y Ichigotani; H Kurata; Y Takenouchi; T Yamamoto; Y Nimura; T Irimura; S Nakatsugawa; M Hamaguchi, A full-length cDNA encoding a novel protein was isolated and sequenced from a human placental cDNA library. This cDNA consists of 1990 bp and has a predicted open reading frame encoding 433 amino acids. It possesses an Src homology 3 (SH3) motif, a leucine zipper motif and no catalytic domain, suggesting that it seems to be an adapter protein. PCR-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to human chromosome 1q21-22., 25 Apr. 2000, 1491, 1-3, 321, 6, Scientific journal, True
- Biochimica et biophysica acta, Molecular cloning and characterization of a novel human gene (HERNA) which encodes a putative RNA-helicase., S Matsuda; Y Ichigotani; T Okuda; T Irimura; S Nakatsugawa; M Hamaguchi, A full-length cDNA encoding a novel protein was isolated and sequenced from a human hepatocellular cDNA library. This cDNA consists of 7037 base pairs and has a predicted open reading frame encoding 1924 amino acids. It possesses an RNA-helicase motif containing a DEXH-box in its amino-terminus and an RNase motif in the carboxy-terminus. From a striking homology to Caenorhabditis elegans K12H4.8, it might be a human homolog of the K12H4.8. PCR-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to human chromosome 14q31 near the marker D14S605., 31 Jan. 2000, 1490, 1-2, 163, 9, Scientific journal, True
- Refereed, Oncogene, Springer Science and Business Media LLC, Clustered cysteine residues in the kinase domain of v-Src: critical role for protein stability, cell transformation and sensitivity to herbimycin A, Takeshi Senga; Kou Miyazaki; Kazuya Machida; Hiroyuki Iwata; Satoru Matsuda; Izumi Nakashima; Michinari Hamaguchi, Jan. 2000, 19, 2, 273, 279, Scientific journal, 10.1038/sj.onc.1203296
- Refereed, Applied Biochemistry and Biotechnology - Part B Molecular Biotechnology, Intercept-PCR, an improvement for elevating performance to find a new member of a certain gene family, S. Matsuda; Y. Ichigotani; T. Okuda; K. Miyazaki; T. Yamamoto; Y. Nimura; T. Irimura; S. Nakatsugawa; M. Hamaguchi, We have established a method by which the performance of reverse transcriptase coupled polymerase chain reaction (RT-PCR) for seeking a new gene is improved. The actual procedure is quite easy: it is only to add several specific oligonucleotides into the reaction mixture of the usual RT-PCR. To verify the effectiveness of this method is also easy: it is only to detect the PCR products in the preliminary experiment. The finding in the present study provides valuable information for gene cloning tactics., 2000, 16, 1, 1, 4, Scientific journal
- Refereed, Oncogene, Springer Science and Business Media LLC, Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1, Aye Aye Thant; Thet Thet Sein; Enbo Liu; Kazuya Machida; Fumitaka Kikkawa; Teruhiko Koike; Motoharu Seiki; Satoru Matsuda; Michinari Hamaguchi, Nov. 1999, 18, 47, 6555, 6563, Scientific journal, 10.1038/sj.onc.1203049
- Refereed, Biochemical and Biophysical Research Communications, Elsevier BV, Critical Amino Acid Substitutions in the Src SH3 Domain That Convert c-Src to Be Oncogenic, Kou Miyazaki; Takeshi Senga; Satoru Matsuda; Miho Tanaka; Kazuya Machida; Yasushi Takenouchi; Yuji Nimura; Michinari Hamaguchi, Oct. 1999, 263, 3, 759, 764, Scientific journal, 10.1006/bbrc.1999.1464
- Refereed, Biochemical and Biophysical Research Communications, Elsevier BV, Molecular Cloning of Macrophin, a Human Homologue of Drosophila Kakapo with a Close Structural Similarity to Plectin and Dystrophin, Takahito Okuda; Satoru Matsuda; Shigekazu Nakatsugawa; Yasukatu Ichigotani; Naoko Iwahashi; Masahide Takahashi; Takeo Ishigaki; Michinari Hamaguchi, Oct. 1999, 264, 2, 568, 574, Scientific journal, 10.1006/bbrc.1999.1538
- Refereed, Oncogene, Springer Science and Business Media LLC, ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system, Yutaka Yoshida; Satoru Matsuda; Naoko Ikematsu; Junko Kawamura-Tsuzuku; Johji Inazawa; Hisashi Umemori; Tadashi Yamamoto, May 1998, 16, 20, 2687, 2693, Scientific journal, 10.1038/sj.onc.1201805
- Refereed, Genes, Chromosomes and Cancer, Wiley, Homozygous deletion and frequent allelic loss of the 21q11.1-q21.1 region including theANA gene in human lung carcinoma, Takashi Kohno; Masashi Kawanishi; Satoru Matsuda; Hitoshi Ichikawa; Minoru Takada; Misao Ohki; Tadashi Yamamoto; Jun Yokota, Mar. 1998, 21, 3, 236, 243, Scientific journal, 10.1002/(sici)1098-2264(199803)21:3<236::aid-gcc8>3.0.co;2-0
- Refereed, Advances in Experimental Medicine and Biology, Springer US, Inhibition of Human Pancreatic Cancer Growth by the Adenovirus-Mediated Introduction of a Novel Growth Suppressing Gene, tob, In Vitro, Hironobu Yanagie; H. Sumimoto; Y. Nonaka; S. Matsuda; I. Hirose; S. Hanada; H. Sugiyama; S. Mikamo; Y. Takeda; I. Yoshizaki; K. Nakazawa; K. Tani; T. Yamamoto; S. Asano; M. Eriguchi; T. Muto, 1998, 91, 96, In book, 10.1007/978-1-4615-5357-1_15
- Refereed, Journal of Biological Chemistry, Elsevier BV, Molecular Cloning and Characterization of a Novel Cytoplasmic Protein-tyrosine Phosphatase That Is Specifically Expressed in Spermatocytes, Miho Ohsugi; Satomi Kuramochi; Satoru Matsuda; Tadashi Yamamoto, Dec. 1997, 272, 52, 33092, 33099, Scientific journal, 10.1074/jbc.272.52.33092
- Refereed, Mitochondrial antisense RNA for cytochrome C oxidase (MARCO) can induce morphologic changes and cell death in human hematopoietic cell lines, Shirafuji N; Takahashi S; Matsuda S; Asano S, Dec. 1997, 90, 11, 4567, 4577
- Refereed, Gene, Elsevier BV, A novel zinc finger protein, Finb, is a transcriptional activator and localized in nuclear bodies, Akiko Fujimoto-Nishiyama; Shunsuke Ishii; Satoru Matsuda; Jun-ichiro Inoue; Tadashi Yamamoto, Aug. 1997, 195, 2, 267, 275, Scientific journal, 10.1016/s0378-1119(97)00172-8
- Refereed, Gene, Elsevier BV, Cloning and characterization of the mouse tob gene, Yutaka Yoshida; Satoru Matsuda; Tadashi Yamamoto, May 1997, 191, 1, 109, 113, Scientific journal, 10.1016/s0378-1119(97)00049-8
- Refereed, JOURNAL OF IMMUNOLOGY, AMER ASSOC IMMUNOLOGISTS, Physical and functional interactions of protein tyrosine kinases, p59(fyn) and ZAP-70, in T cell signaling, Noemi Fusaki; Satoru Matsuda; Hirofumi Nishizumi; Hisashi Umemori; Tadashi Yamamoto, The src family protein tyrosine kinases participate in signaling through cell surface receptors that lack intrinsic tyrosine kinase domains, One of the src family kinases, p59(fyn)(Fyn), plays an important role in the TCR-mediated signaling, Here we report that Fyn becomes associated with the zeta-associated tyrosine kinase, ZAP-70, in a T cell hybridoma upon stimulation, The association was transient; it occurred as early as 10 s after stimulation and disappeared after 10 min. The two proteins were also associated with each other when coexpressed in COS cells, Coexpression of the zeta-chain was not required for their interaction, Mutational analysis of Fyn and ZAP-70 revealed that their kinase activities were relevant to the association, Deletion of both the SH2 and SH3 domains of Fyn resulted in the decrease of the association with ZAP-70, Consistently, Fyn-SH2 and Fyn-SH3 fused to glutathione S-transferase were able to bind to ZAP-70, These data suggest that multiple sites of Fyn and ZAP-70 are involved in the association, Furthermore, coexpression of the wild-type of both kinases in COS cells enhanced tyrosine phosphorylation of the helix-turn-helix-containing protein, HS1, HS1 was also tyrosine phosphorylated upon TCR stimulation, Thus, we propose that Fyn phosphorylates and activates ZAP-70 and that both kinases cooperate in TCR signaling., Feb. 1996, 156, 4, 1369, 1377, Scientific journal
- Refereed, FEBS Letters, Wiley, Molecular cloning and characterization of Byp, a murine receptor-type tyrosine phosphatase similar to human DEP-1, Satomi Kuramochi; Satoru Matsuda; Yoichi Matsuda; Toshiyuki Saitoh; Miho Ohsugi; Tadashi Yamamoto, 02 Jan. 1996, 378, 1, 7, 14, Scientific journal, 10.1016/0014-5793(95)01415-2
- Refereed, International Immunology, Oxford University Press (OUP), Characterization of p59fyn-mediated signal transduction on T cell activation, Noemi Fusaki; Kentaro Semba; Takuya Katagiri; Gen Suzuki; Satoru Matsuda; Tadashi Yamamoto, 1994, 6, 8, 1245, 1255, Scientific journal, 10.1093/intimm/6.8.1245
- Refereed, Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, 17 beta-estradiol mimics ligand activity of the c-erbB2 protooncogene product., S. Matsuda; Y. Kadowaki; M. Ichino; T. Akiyama; K. Toyoshima; T. Yamamoto, 15 Nov. 1993, 90, 22, 10803, 10807, Scientific journal, 10.1073/pnas.90.22.10803
- Refereed, Biochemical and Biophysical Research Communications, Elsevier BV, Active c-erbB-2 induces short-term growth of FDC-P2 cells after IL-3 depletion, Budsaba Wongsasant; Satoru Matsuda; Tadashi Yamamoto, Dec. 1991, 181, 3, 981, 988, Scientific journal, 10.1016/0006-291x(91)92033-g
- Nippon rinsho. Japanese journal of clinical medicine, Regulation of the c-erb B-2 transforming ability, S. Matsuda; T. Yamamoto, 1990, 48, 8, 71, 76, Scientific journal
- Refereed, Granulocyte colony-stimulating factor stimulates human mature neutrophilic granulocytes to produce interferon-alpha, Shirafuji N; Matsuda S; Ogura H; Tani K; Kodo H; Ozawa K; Nagata S; Asano S; Takaku F, Jan. 1990, 75, 1, 17, 19
- Refereed, Human granulocyte colony-stimulating factor specifically binds to murine myeloblastic NFS-60 cells and activates their guanosine triphosphate binding proteins/adenylate cyclase system, Matsuda S; Shirafuji N; Asano S, Nov. 1989, 74, 7, 2343, 2348
- Refereed, Journal of Biological Chemistry, Elsevier BV, A new bioassay for human granulocyte colony-stimulating factor (hG-CSF) using murine myeloblastic NFS-60 cells as targets and estimation of its levels in sera from normal healthy persons and patients with infectious and hematological disorders., Shirafuji N; Asano S; Matsuda S; Watari K; Takaku F; Nagata S, Feb. 1989, 17, 2, 116, 119, Scientific journal, 10.1074/jbc.272.28.17668
- Refereed, Experimental Hematology, CARDEN JENNINGS PUBL CO LTD, A new bioassay for human granulocyte colony-stimulating factor (hG-CSF) using murine myeloblastic NFS-60 cells as targets and estimation of its levels in sera from normal healthy persons and patients with infectious and hematological disorders, Shirafuji, N.; Asano, S.; Matsuda, S.; Watari, K.; Takaku, F.; Nagata, S., 1989, 17, 2, 116, 119, Scientific journal
- Refereed, Leukemia Research, Elsevier BV, Production of granulocyte colony-stimulating factor by acute myelomonocytic leukemia cells, Naoki Shirafuji; Shigetaka Asano; Koji Kozai; Satoshi Takahashi; Satoru Matsuda; Fumimaro Takaku; Shigekazu Nagata, Jan. 1988, 12, 9, 745, 750, Scientific journal, 10.1016/0145-2126(88)90007-0
MISC
- International Journal of Molecular Sciences, Caveolin and NOS in the Development of Muscular Dystrophy, Moeka Nakashima; Naoko Suga; Sayuri Yoshikawa; Satoru Matsuda, Caveolin is a structural protein within caveolae that may be involved in transmembrane molecular transport and/or various intercellular interactions within cells. Specific mutations of caveolin-3 in muscle fibers are well known to cause limb–girdle muscular dystrophy. Altered expression of caveolin-3 has also been detected in Duchenne muscular dystrophy, which may be a part of the pathological process leading to muscle weakness. Interestingly, it has been shown that the renovation of nitric oxide synthase (NOS) in sarcolemma with muscular dystrophy could improve muscle health, suggesting that NOS may be involved in the pathology of muscular dystrophy. Here, we summarize the notable function of caveolin and/or NOS in skeletal muscle fibers and discuss their involvement in the pathology as well as possible tactics for the innovative treatment of muscular dystrophies., Aug. 2024, 25, 16, Book review, 10.3390/ijms25168771
- Molecules, Caveolae with GLP-1 and NMDA Receptors as Crossfire Points for the Innovative Treatment of Cognitive Dysfunction Associated with Neurodegenerative Diseases, Moeka Nakashima; Naoko Suga; Sayuri Yoshikawa; Satoru Matsuda, Some neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that encompasses memory loss and/or apathy. Alzheimer’s disease is the most typical type of such neurodegenerative diseases that are characterized by deficits of cognition and alterations of behavior. Despite the huge efforts against Alzheimer’s disease, there has yet been no successful treatment for this disease. Interestingly, several possible risk genes for cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes, and/or caveolae formation, suggesting that caveolae may be a therapeutic target for cognitive dysfunctions. Interestingly, the modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptor signaling may offer a novel approach to preventing and alleviating cognitive dysfunction. A paradigm showing that both GLP-1 and NMDA receptors at caveolae sites may be promising and crucial targets for the treatment of cognitive dysfunctions has been presented here, which may also be able to modify the progression of Alzheimer’s disease. This research direction may create the potential to move clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases., Aug. 2024, 29, 16, Book review, 10.3390/molecules29163922
- Refereed, International Journal of Molecular Sciences, MDPI AG, Neuron membrane trafficking and protein kinases involved in autism and ADHD, Yasuko Kitagishi; Akari Minami; Atsuko Nakanishi; Yasunori Ogura; Satoru Matsuda, A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention., 30 Jan. 2015, 16, 2, 3095, 3115, Book review, 10.3390/ijms16023095
- Refereed, International Journal of Molecular Medicine, Spandidos Publications, PI3K/AKT/PTEN pathway as a target for Crohn's disease therapy (Review), Nana Tokuhira; Yasuko Kitagishi; Miho Suzuki; Akari Minami; Atsuko Nakanishi; Yuna Ono; Keiko Kobayashi; Satoru Matsuda; Yasunori Ogura, The pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease, is a subject of increasing interest. Loss-of-function mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) are strong genetic factors linked to Crohn's disease, which eventually leads to an excessive mucosal inflammatory response directed against components of normal gut microbiota. Reactive oxygen species (ROS) play an important role in inflammation processes, as well as in transduction of signals from receptors for several cytokines, such as tumor necrosis factor α (TNFα). ROS activate nuclear factor-κB (NF-κB) via IκB kinase (IKK) through the PI3K/AKT/PTEN pathway. Therefore, this pathway is recognized to play a key role in Crohn's disease. Loss of function has been demonstrated to occur as an early event in a wide variety of diseases. Given this prevalent involvement in a number of diseases, the molecular development that modulates this pathway has been the subject of several studies. In addition, it has been the focus of extensive research and drug discovery activities. A better understanding of the molecular assemblies may reveal novel targets for the therapeutic development against Crohn's disease., 01 Jan. 2015, 35, 1, 10, 16, Book review, 10.3892/ijmm.2014.1981
- Refereed, International Journal of Oncology, Defective DNA repair systems and the development of breast and prostate cancer (Review), Yasuko Kitagishi; Mayumi Kobayashi; Satoru Matsuda, Genetic defects in DNA repair and DNA damage response genes often lead to an increase in cancer incidence. The role of defects is also associated with the modulation of hormone signaling pathways. A number of studies have suggested a role for estrogen in the regulation of DNA repair activity. Furthermore, mutations or epigenetic silencing in DNA repair genes have been associated with the sensitivity of cancers to hormonal therapy. The molecular basis for the progression of cancers from hormone-dependent to hormone-independent remains a critical issue in the management of these types of cancer. In the present review, we aimed to summarize the function of DNA repair molecules from the viewpoint of carcinogenesis and hormone-related cell modulation, providing a comprehensive view of the molecular mechanisms by which hormones may exert their effects on the regulation of tumor progression., Jan. 2013, 42, 1, 29, 34, Book review, 10.3892/ijo.2012.1696
- Not Refereed, VITAMINS, THE VITAMIN SOCIETY OF JAPAN, Expression of glutamate decarboxylase in human leukocyte cell lines, Kikuta Kanae; Tohyama Yumi; Matsukawa Satoko; Matsuda Satoru; Akagiri Satomi; Ueno Hiroshi, Expression of GAD65, an isoform of glutamate decarboxylase, was examined on peripheral blood mononuclear leukocyte (PBMC) and on three kinds of mononuclear leukocyte cell lines, Jurkat, Ramos and HL-60. RT-PCR was performed for mRNA isolated from each cells with the probes specific to GAD65. PBMC and mononuclear leukocyte cell lines were found to give an mRNA corresponding to the full length of GAD65. Western blot analysis was carried out for each cell extracts by using GAD specific antibodies. Protein band at 80 kDa was found for PBMC that was different from 60 kDa found for each cell lines, where those protein bands were recognized by different antibodies. Results show that PBMC and mononuclear leukocyte cell lines express full length mRNA of GAD65 and GAD65 of mononuclear leukocytes differ in pattern of expression., 2013, 87, 3, 147, 151, 10.20632/vso.87.3_147
- Not Refereed, 日本生化学会大会(Web), (公社)日本生化学会, ヒト白血球とその培養細胞におけるグルタミン酸デカルボキシラーゼに関する研究, 菊田香苗; 通山由美; 松川聡子; 松田覚; 赤桐里美; 植野洋志, Dec. 2012, 85th, 3P-291 (WEB ONLY), 291
- 25 Apr. 2012, 86, 4, 269, 269
- Refereed, Journal of Oncology, Protection against cancer with medicinal herbs via activation of tumor suppressor, Yasuko Kitagishi; Mayumi Kobayashi; Satoru Matsuda, Cancer remains a major cause of death, although research is ongoing for the development of more effective drugs. Some herbs have shown potential in preventing the occurrence and/or progression of cancer and other chronic diseases. They are being screened comprehensively to explore the possibility of development of feasible anticancer drugs. However, more information is required about the response to and the molecular target for specific herbs. It seems that there is a relationship between some medicinal herbs and tumor suppressor molecules which protect a cell from cancer. In this paper, we summarize the progress of recent research on herbs, with a particular focus on its anticancer role and molecular mechanisms underlying the cancer prevention property, supporting design for further research in this field. © 2012 Yasuko Kitagishi et al., 2012, Book review, 10.1155/2012/236530
- Not Refereed, 生化学, (公社)日本生化学会, グルタミン酸デカルボキシラーゼ(GAD)の選択的スプライシング機構の解明, 菊田香苗; 松川聡子; 通山由美; 松田覚; 赤桐里美; 植野洋志, Sep. 2011, 84回, ROMBUNNO.4P-0409, 0409
- Refereed, FEBS LETTERS, ELSEVIER SCIENCE BV, In search of a function for the TIS21/PC3/BTG1/TOB family, S Matsuda; JP Rouault; JP Magaud; C Berthet, The Btg family of anti-proliferative gene products includes Pc3/Tis21/Btg2, Btg1, Tob, Tob2, Ana/Btg3, Pc3k and others. These proteins are characterized by similarities in their amino-terminal region: the Btg1 homology domain. However, the pleiotropic nature of these family proteins has been observed and no common physiological function among family members was suggested from the history of their identification. Recent progress in the search for Btg family functions has come from the analysis of cell regulation and of cell differentiation. It is now emerging that every member of this family has a potential to regulate cell growth. We would like to propose here to use a nomenclature APRO as a new term for the family. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B,V, All rights reserved., May 2001, 497, 2-3, 67, 72, Book review
- Not Refereed, CANCER RESEARCH, AMER ASSOC CANCER RESEARCH, Invasion activating caveolin-1 mutation in human scirrhous breast cancers, K Hayashi; S Matsuda; K Machida; T Yamamoto; Y Fukuda; Y Nimura; T Hayakawa; M Hamaguchi, We looked for mutations in the caveolin-1 gene, encoding a critical molecule for membrane signaling to cell growth, in 92 primary human breast cancers, and we report here the identification of a mutation in caveolin-1 at codon 132 (P132L) in 16% of cases. The mutation-positive cases were mostly invasive scirrhous carcinomas. In cell lines expressing the same mutant of caveolin-1, we observed that the mutant Caveolin-1 expression seemed to induce cellular transformation and activation of mitogen-activated protein kinase-signaling pathway and to promote invasion-ability as well as altered actin networks in the cells, These results provide, for the first time, genetic evidence that a functioning Caveolin-1 mutation may have a role in the malignant progression of human breast cancer., Mar. 2001, 61, 6, 2361, 2364
- Not Refereed, BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, ELSEVIER SCIENCE BV, Isolation and characterization of a novel human gene (NESH) which encodes a putative signaling molecule similar to e3B1 protein, K Miyazaki; S Matsuda; Y Ichigotani; Y Takenouchi; K Hayashi; Y Fukuda; Y Nimura; M Hamaguchi, Using a conventional cloning technique, a novel full-length cDNA was isolated and sequenced from a human placental cDNA library. This cDNA consists of 2129 bp and has a predicted open reading frame encoding 366 amino acids. It possesses a Src homology 3 (SH3) motif, proline-rich region, serine-rich region and no catalytic domain, suggesting that it seems to be a signaling protein most similar to e3B1, an eps8 SH3 binding protein. PCR-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to human chromosome 17q21.3 near the marker D17S1795. (C) 2000 Elsevier Science B.V. All rights reserved., Sep. 2000, 1493, 1-2, 237, 241, 10.1016/S0167-4781(00)00158-5
- Refereed, BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, ELSEVIER SCIENCE BV, Molecular cloning and characterization of a novel human gene (NESCA) which encodes a putative adapter protein containing SH3, S Matsuda; K Miyazaki; Y Ichigotani; H Kurata; Y Takenouchi; T Yamamoto; Y Nimura; T Irimura; S Nakatsugawa; M Hamaguchi, A full-length cDNA encoding a novel protein was isolated and sequenced from a human placental cDNA library. This cDNA consists of 1990 bp and has a predicted open reading frame encoding 433 amino acids. It possesses an Src homology 3 (SH3) motif, a leucine zipper motif and no catalytic domain, suggesting that it seems to be an adapter protein. PCR-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to human chromosome 1q21-22. (C) 2000 Elsevier Science B.V. All rights reserved., Apr. 2000, 1491, 1-3, 321, 326
- Not Refereed, ONCOGENE, STOCKTON PRESS, v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells, K Machida; S Matsuda; K Yamaki; T Senga; AA Thant; H Kurata; K Miyazaki; K Hayashi; T Okuda; T Kitamura; T Hayakawa; M Hamaguchi, We investigated the effect of cell transformation by v-src on the expression and tyrosine phosphorylation of SHPS-1, a putative docking protein for SHP-1 and SHP-2. We found that transformation by v-sle virtually inhibited the SHPS-1 expression at mRNA level. While nontransforming Src kinases including c-Src, nonmyristoylated forms of v-Src had no inhibitory effect on SHPS-1 expression, transforming Src kinases including wild-type v-Src and chimeric mutant of c-Src bearing v-Src SH3 substantially suppressed the SHPS-1 expression. In cells expressing temperature sensitive mutant of v-Src, suppression of the SHPS-1 expression was temperature-dependent. In contrast, tyrosine phosphorylation of SHPS-1 was rather activated in cells expressing c-Src or nonmyristoylated forms of v-Src, SHPS-1 expression in SR3Y1 was restored by treatment with herbimycin A, a potent inhibitor of tyrosine kinase, or by the expression of dominant negative form of Ras. Contrary, active form of Mek1 markedly suppressed SHPS-1 expression. Finally, overexpression of SHPS-1 in SR3Y1 led to the drastic reduction of anchorage independent growth of the cells. Taken together, our results suggest that the suppression of SHPS-1 expression is a pivotal event for cell transformation by v-src, and the Ras-MAP kinase cascade plays a critical role in the suppression., Mar. 2000, 19, 13, 1710, 1718, 10.1038/sj.onc.1203497
- Refereed, CANCER RESEARCH, AMER ASSOC CANCER RESEARCH, Molecular cloning and characterization of human MAWD, a novel protein containing WD-40 repeats frequently overexpressed in breast cancer, S Matsuda; R Katsumata; T Okuda; T Yamamoto; K Miyazaki; T Senga; K Machida; AA Thant; S Nakatsugawa; M Hamaguchi, A full-length cDNA clone encoding a novel protein containing WD-40 repeats, which were frequently involved in protein-protein interactions, was isolated and-sequenced. This clone had a predicted open reading frame (ORF) encoding 350 amino acids possessing six repeats of WD-40 motif, It was most closely homologous to TRIP-1, a phosphorylation substrate of the transforming growth factor-beta type II receptor. In the process of characterizing the function of the new gene product, we found that overexpression of the gene seemed to activate mitogen-activated protein kinase and to promote anchorage-independent growth of the cells, Moreover, the gene product was frequently overexpressed in human tumor breast tissues compared with their normal breast tissues, suggesting that the gene might be involved in the tumor progression, Radiation hybrid mapping placed the gene into human chromosome 12q11-12 near the marker D12S1593., Jan. 2000, 60, 1, 13, 17
- Refereed, BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, ELSEVIER SCIENCE BV, Molecular cloning and characterization of a novel human gene (HERNA) which encodes a putative RNA-helicase, S Matsuda; Y Ichigotani; T Okuda; T Irimura; S Nakatsugawa; M Hamaguchi, A full-length cDNA encoding a novel protein was isolated and sequenced from a human hepatocellular cDNA library. This cDNA consists of 7037 base pairs and has a predicted open reading frame encoding 1924 amino acids. It possesses an RNA-helicase motif containing a DEXH-box in its amino-terminus and an RNase motif in the carboxy-terminus. From a striking homology to Caenorhabditis elegans K12H4.8, it might be a human homolog of the K12H4.8. PCR-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to human chromosome 14q31 near the marker D14S605. (C) 2000 Elsevier Science B.V. All rights reserved., Jan. 2000, 1490, 1-2, 163, 169
- Not Refereed, 日本癌学会総会記事, c‐Src及びv‐SrcのSH3ドメイン 癌化能・基質特異性の比較, MIYAZAKI KO; MATSUDA SATORU; NIMURA YUJI; HAMAGUCHI MICHINARI, 30 Aug. 1999, 58th, 521, 521
- Not Refereed, 臨床検査, Gene diagnosis. Src tyrosine kinase., MATSUDA SATORU; MIYAZAKI KO; HAMAGUCHI MICHINARI, Jan. 1999, 43, 1, 75, 80, 10.11477/mf.1542903986
- Refereed, MOLECULAR BIOLOGY OF THE CELL, AMER SOC CELL BIOLOGY, Regulation of the biochemical properties of Tob by means of its phosphorylation, T Suzuki; J Tsuzuku; Y Yoshida; S Matsuda; T Yamamoto, Nov. 1998, 9, 360A, 360A, Introduction scientific journal
- Oct. 1997, 1, 2, 186, 191
- Not Refereed, EUROPEAN JOURNAL OF CANCER, PERGAMON-ELSEVIER SCIENCE LTD, Application of a novel growth suppressing gene, tob, for gene therapy of pancreatic cancer in vitro, H Yanagie; H Sumimoto; S Matsuda; Hirose, I; S Hanada; M Eriguchi; K Tani; T Yamamoto; S Asano; T Muto, Sep. 1997, 33, 382, 382, Summary international conference
- Not Refereed, CANCER GENE THERAPY, APPLETON & LANGE, Inhibition of human pancreatic cancer growth by a novel growth suppressing gene, tob, in vitro, H Yanagie; H Sumimoto; Y Nonaka; S Matsuda; K Tani; T Yamamoto; S Asano; T Muto; M Eriguchi, Sep. 1997, 4, 5, 300, 300, Summary international conference
- Not Refereed, 環境科学会年会一般講演・シンポジウム・プログラム, The role of tyrosine kinases in intracellular signaling triggered by the enviromental stimuli such as UV and heavy metal., MATSUDA SATORU; HAMAGUCHI MICHINARI, 1997, 1997, 224, 225
- Refereed, ONCOGENE, STOCKTON PRESS, Tob, a novel protein that interacts with p185(erbB2), is associated with antiproliferative activity, S Matsuda; J KawamuraTsuzuku; M Ohsugi; M Yoshida; M Emi; Y Nakamura; M Onda; Y Yoshida; A Nishiyama; T Yamamoto, We have molecularly cloned a cDNA for a novel protein termed Tob (Transducer of ErbB-2) that interacts with the c-erbB-2 gene product p185(erbB2). Nucleotide sequencing reveals that the Tob protein is a 45 kDa protein that does not contain either SH2 (Src Homology 2) or SH3 domain but is homologous to the previously characterized anti-proliferative gene product BTG-1 at its amino-terminal half. The carboxyl-terminal half of Tob is characterized by the presence of a sequence rich in proline and glutamine and shows no homology to known proteins. Like BTG-1, exogenously expressed Tob is able to suppress growth of NIH3T3 cells, but the growth suppression is hampered by the presence of kinase-active p185(erbB2). By using the GST-Tob protein that contains either full length or amino-terminal half of Tob, we show that the carboxyl-terminal half of Tob is relevant to its interaction with p185(erbB2). Furthermore, we could co-immunoprecipitate the Tob protein with anti-ErbB-2 antibody, and reciprocally the p185(erbB2). With anti-Tob antibodies. These data suggest that p185(erbB2) negatively regulates the Tob-mediated anti-proliferative pathway through its interaction with Tob, resulting possibly in growth stimulation by p185(erbB2). Finally, expression of the Tob mRNA is observed in various cell types and is not correlated with expression of c-erbB-2, suggesting that other receptor-type protein-tyrosine kinases are also involved in the Tob-mediated regulation of cell growth., Feb. 1996, 12, 4, 705, 713
- Estradiol mimics ligand activity of the c-erbB-2 protooncogene product., MATSUDA Satoru, 01 May 1995, 43, 5, 49, 52
Books etc
Research Projects
- Grant-in-Aid for Scientific Research (A), 01 Apr. 2012 - 31 Mar. 2017, 24240098, Interaction of DNA repair epigenetics and Nutrition, MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nara Women's University, 47450000, 36500000, 10950000, Because p53 plays an important role in the transcriptional regulation of genes encoding proteins involved in DNA repair and apoptosis, the modification of p53 may appear to be a pivotal determinant of cells fate. During carcinogenic progression, p53 is mutated or deleted in nearly half of all human cancers and fails to function normally. Both PTEN and BRCA1 also regulate the expression of several genes identified as key roles in affecting breast and ovarian cancer risk. They also participate in DNA repair and recombination processes related to maintenance of genomic integrity and control of cell proliferation. Genetic defects in DNA repair and DNA damage response genes often lead to an increase in cancer incidence. The role of defects is also associated with modulation of signaling pathways. Furthermore, mutations or epigenetic silencing in DNA repair genes have been associated with a phenotype of sensitivity of cancers to the therapy., kaken
- Grant-in-Aid for Challenging Exploratory Research, 01 Apr. 2013 - 31 Mar. 2016, 25560050, Diets may contribute to the improved cellular function via the modulation of AKT signaling, MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nara Women's University, 3770000, 2900000, 870000, Reactive oxygen species (ROS) play an important role in the inflammation processes as well as in transduction of signals from receptors for several cytokines such as tumor necrosis factor α (TNFα). ROS activate nuclear factor kB (NF-kB) via IkB kinase (IKK) through PI3K/AKT/PTEN pathway. Regulation of the PI3K/AKT pathways may also constitute an important signaling center in the subcellular integration of the synaptic neurotransmission. The pathways modulate cell proliferation, migration, and plasticity. The PI3K/AKT/PTEN pathway has been shown to play a pivotal role in several disease protections. Although PTEN has been discovered as a tumor suppressor, PTEN is also involved in several other diseases, including diabetes and Alzheimer's disease. Dietary fish oil rich in polyunsaturated fatty acids may induce the PTEN expression by activation of peroxisome proliferator-activated receptor., kaken
- Grant-in-Aid for Challenging Exploratory Research, 2010 - 2012, 22650179, Expressional and regulatory characterization of mRNA and miRNA for food-intake related molecules, MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nara Women's University, 3320000, 2900000, 420000, Some of herbs and spices have shown potential in preventing the occurrence and/or progression of cancer and other chronic diseases including anorexia. They are being screened to explore the possibility of development of feasible medical drugs by analyzing the expression of mRNA and miRNA. For example, mRNA and protein expression levels of AKT1 were reduced compared with the control cells 48 hours after these herbal treatments in cells treated with sage or rosemary extract., kaken
- Grant-in-Aid for Scientific Research (B), 2007 - 2008, 19300251, Analysis of prion and prion related protein for the purpose of food safety, MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nara Women's University, 18330000, 14100000, 4230000, アポトーシスや細胞膜抗酸化作用との関連を追究するために、プリオン及びドッペルの発現ベクターを作製して、リンパ系細胞に強制発現させ、紫外線照射時や血清除去時のアポトーシスに対する細胞の挙動変化を解析した。プリオン関連蛋白質と微小RNAとの結合の有無を検討したが、特定のRNAとは結合していない。ドッペル蛋白質ではプリオン蛋白質と異なる機能が報告されており、Bcl2関連アポトーシスカスケードの中で機能していることが示唆された。アダプター蛋白質NESHとの相互作用を免疫沈降やウエスタン法で確認した。SOD活性については、WAT1を用いて測定し、ドッペル蛋白質がSOD活性を阻害していることが判明した。, kaken
- 萌芽研究, 2005 - 2005, 17650224, 食生活要因からアプローチするプリオン関連遺伝子産物の機能解析と疾患予防, 松田 覚, 日本学術振興会, 科学研究費助成事業, 奈良女子大学, 3400000, 3400000, 狂牛病の発症機構や診断法の開発に貢献するため、原因に関与するプリオン遺伝子とドッペル遺伝子に着目してその正常機能を追究した。特に、ドッペル遺伝子の機能解析はプリオンの機能解析よりも格段に遅れているがドッペルの解析によってこれらファミリー遺伝子の正常機能が正確に推測されると考え注力した。まずドッペルの遺伝子をヒトリンパ球ライブラリーより単離して、その一部を利用してGST融合蛋白質を精製し、ウサギポリクローナル抗体を作製した。また各種欠失型ドッペル遺伝子発現プラスミッドを構築して、遺伝子発現細胞をクローン化した。これらのシグナル伝達系に関わる分子として以前Tobを発見していたが、その機能解析をRNA結合蛋白質との機能的結合性から追究し論文にした。ドッペルの機能解析過程では、アポトーシス関連のp38やTobとの相互作用の検討は不可欠であると考えている。さて、RNAiや新生ペプチドによる高効率シグナル制御システムを用いれば、細胞外から細胞内シグナル伝達系を制御し得ることから、プリオンやドッペルの遺伝子に対するsiRNA生成システムを構築した。作製したsiRNAが実際に培養細胞系で機能することも確認した。一方、ドッペルやプリオンはカヴェオリンとの関連が強いことの傍証を得たため、現在コレステロール代謝系におけるプリオンとドッペルの機能を、作製したツールを用いて解析している。食生活要因についての検討として、どのような食習慣の改善が望ましいのかについても科学的な研究を行いつつ考察した。その一部を中高生の啓蒙を図るために食育の一環として出版した。, kaken
- 萌芽研究, 2004 - 2004, 16650182, 腸内細菌が健康に与える影響とRNAiを利用した疾患予防, 松田 覚, 日本学術振興会, 科学研究費助成事業, 奈良女子大学, 3500000, 3500000, 最近話題になっているRNAiや新生ペプチドによる高効率シグナル制御システムを用いれば、細胞外からそれらのシグナル伝達系を制御し癌の浸潤・転移を完全に阻止することは充分に期待できる。このRNAiの細胞内のメカニズムの中で中心的役割を果たしているのがHERNA/DICERである。この分子を申請者は最初にクローニングしたので、ひとつにはRNAiのin vivo応用を目指して生体内で有効に働くシステムを構築している。解析への応用として例えば、NESHをこのRNAiを用いて発現抑制をかけると、それに応じて細胞浸潤・転移能が上昇する。SNPs解析結果を踏まえると、CaveolinとNESHにおいて癌に対する効果的なRNAiのデザインが考えられる。このため、これらの分子を標的とした2重鎖RNAの発現ベクターを作製している。また、人工的に合成した2重鎖RNAを用いて細胞内の発現が効果的に抑制されることを確認し、同時に細胞内の2重鎖RNAを効率よく細胞外へ放出させるペプチドを発現するベクターを現在作成中である。これらが有効に働けば癌の効果的な予防に貢献する。そして、RNAiを効率よく無害に働かせるためには、腸内細菌を利用することが考えられたため、腸内細菌の生物的動態をチェックした。まず、腸内細菌と常在菌の増殖抑制をUV照射下と電子レンジを用いて検討した。この結果、UVやマイクロウエーブは相乗効果的に細菌増殖を抑制した。さらに、比較的これらの照射に弱い菌を用いて、菌外に放出するRNAiの合成システムを構築している。, kaken
- 特定領域研究, 2004 - 2004, 16021238, アダプター分子を中心とした発がん及びがん悪性化機構の解析, 松田 覚, 日本学術振興会, 科学研究費助成事業, 奈良女子大学, 6800000, 6800000, 癌の悪性化阻止の目的で、癌の浸潤・転移能に関連する分子の解析を行った。NESHはSH3領域を有する新しいアダプター蛋白質であるが、Ablチロシンキナーゼに結合し下流へのシグナルを調節しながら細胞運動や浸潤能を負に制御していることを明らかにした。SNPs解析として、主として乳癌の症例90例と肝内結石の症例20例についてCaveolinとNESHについて検討した。乳癌の中のスキルスタイプなど特に悪性例においてCaveolin132プロリンからロイシンへの点突然変異例が見つかったが、これはCaveolinのスカフォールドドメイン領域内であり、シグナル伝達に影響していることが予想されたが、事実この変異をもたらしたカベオリンを発現する細胞膜カベオラ構造は著明に変化することが示された。また、NESHにおいても乳癌の一部にNESH334バリンからアラニンへの点突然変異例が見つかった。この部位はNESHのSH3領域内であり。蛋白質間の結合に影響していることが予想された。外来性のNESHの発現は癌細胞転移を著明に抑制するが、癌細胞増殖には影響しないという結果を得た。中程度の発現が認められる癌細胞のNESH発現をRNAiによって抑制すると顕著な細胞浸潤能の増加が認められた。NESH結合蛋白質の検索により新規分子Tarshを同定していたが、生理的な条件下でin vivoでの結合はほとんど認められなかった。本研究結果から、NESHは細胞運動の制御系で役割を担っていることが明らかになり、NESH・SHPS-1・Caveolin-1など細胞接着や細胞運動に関わる分子の特異的な阻害が癌の浸潤・転移を劇的に抑えることも強く示唆された。, kaken
- 特定領域研究, 2003 - 2003, 15023225, アダプター分子を中心としたがん悪性化機構の解析, 松田 覚, 日本学術振興会, 科学研究費助成事業, 奈良女子大学, 3500000, 3500000, Two-hybrid screening法を用いてNESH結合蛋白質を同定した。この分子は新規分子でありNESHのSH3領域と結合する。この分子TarshとNESHとの結合を検討したが、in vitroでの結合が認められるもののin vivoではその結合は検出されなかった。NESHの発現をサーベイし、多くの高転移性の癌細胞ではNESHがほとんど発現していないことを見い出した。高転移性の癌細胞4種類にNESHを発現させた細胞株を樹立し、その細胞運動能能についてボイデンチャンバー法と金コロイド法を用いて検討した。その結果NESH発現による細胞運動能の抑制が観察された。またヌードマウスを用いたin vivoにおける細胞転移能に対しても同様にNESHは著明にがん転移を抑制した。NESH発現細胞内におけるPAKのリン酸化は著明に減弱しており、NESHとPACの共発現やNESHとPAKとの生化学的な会合が示された。NESHのRNAiを導入した結果、その細胞の浸潤能や運動の亢進が認められ、癌細胞では明らかな転移能の上昇が確認された。本研究結果から、NESHは細胞運動の制御系で役割を担っていることが明らかになった。正常組織の血管内皮細胞や神経細胞でのNESHの発現が比較的高いため、これらの細胞運動や神経突起誘導に関与していることが予想される。事実NESHの発現により細胞増殖因子刺激後の細胞膜ラップリング形成も阻害される。NESHを強制発現させた場合、癌細胞ではその増殖には全く影響しないが、転移能を著明に抑制する。つまり、NESH発現により癌細胞が転移することを抑える。マウスの転移モデルでもNESHのSH3領域の変異はNESHの転移抑制機能を解除した。さらに解析を進めるためにはNESH遺伝子欠損マウスの作製と解析は今後絶対不可欠な課題である。, kaken
- Grant-in-Aid for Scientific Research (B), 1999 - 2002, 11470207, Feasibility of MARCO(Mitochondrial antisense RNA for cytochrome C Oxidase) for the treatment of leukerniaz, SHIRATUJI Naoki; GOTO Moritaka; MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, 14500000, 14500000, The plasmid which expressed MARCO: mitochondrial antisense RNA for cytochrome C oxidase was constructed with CMV promoter, and was introduced into murine leukemia cell line MOPC (B cell), EL-4 (T cell), and WEHI-3B (myelomonocytic) with liposomal delivery. The efficiency of the introduction of MARCO to each cell line was approximately 10 %. Cell-death was observed significantly in a time dependent manner in in vitro system. In in vivo system there were also observed elongated survival for 4 weeks when MARCO was administered to the tumor-burden mice for 3 days intra peritoneally, and intra venously. When MARCO was administered to the tumor-burden mice for 14 days with liposomal delivery, there were observed 3 months' elongated survival compared with the mock-transfected mice. There were also observed dose-dependency on the amount of the administered MARCO. The adverse effects were observed leukocytopenia for a transient period ( after 12 to 24 hours after the administration), and no other effects were observed to main organs which was determined with pathological findings. Also, recombinant Adenovirus which expressed MARCO was constructed with cosmid shattle vector originated from Adenovirus. The efficiency of the introduction to MOPC, EL-4, and WEHI-3B cells was approximately 50%. However, in in vitro, and in vivo study, cell-death effects were less than that observed with liposomal administration of MARCO. These data indicated that gene therapy using MARCO is feasible against leukemias, especially with liposomal delively. On the next step, we intend to use RNAi for the gene therapy against leukemias., kaken
- 特定領域研究(C), 2001 - 2001, 13214045, 新規アダプター型分子を中心とした発がん機構の解析, 松田 覚, 日本学術振興会, 科学研究費助成事業, 名古屋大学, 1800000, 1800000, 細胞仮足形成への関与が示唆される新規アダプター分子NESHを発見し癌研究の視点から申請者らは解析を加えてきた。NESHはSH3領域を有する新しいアダプター蛋白質である。本研究では特にNESHアダプター分子がどのように細胞運動や癌転移の調節に関わっているのかについて解明することを目的としている。NESH類似分子(E3B1/Abi-1,Abi-2,Argbp1)のこれまでの解析結果と一致して、NESHもAblチロシンキナーゼに結合し下流へのシグナルを調節していることや、Racを介したシグナル伝達にも関与していることが明らかになった。NESHの発現は種々の高転移性癌細胞ではほとんど検出されない。また、ヒト染色体上のNESH遺伝子局在領域に一致して癌転移抑制遺伝子の存在が推測された。従ってNESHも癌化や細胞運動調節系で機能を果たしていることが予想され、NESH発現による癌細胞の運動能や転移能への影響について検討した。そして、NESHの発現は癌細胞転移を著明に抑制するが、癌細胞増殖には影響しないという結果を得た。またNESHによる細胞運動能の調節は、PAKキナーゼとの相互作用を介していることが示唆された。Two-hybrid法を用いたNESH結合蛋白質の検索により新たな分子(Tarsh)を同定した。しかし、Tarsh自体の細胞運動に対する影響やNESHとの相互作用について詳細は不明である。正常組織の血管内皮細胞や神経細胞でのNESHの発現が比較的高いため、これら細胞の運動や神経突起誘導にNESHは関与しているのかもしれない。予備的解析によれば、NESHの発現により細胞増殖因子刺激後の細胞膜ラッフリング形成は阻害された。今後は、転移能を持つ癌と持たない癌との比較で、NESHに突然変異や遺伝子欠失が見出されるのか否かを明らかにする必要がある。, kaken
- Grant-in-Aid for Scientific Research (C), 2000 - 2001, 12671152, FUNCTIONAL ANALYSIS OF P73 GENE AND P51/P63 GENE IN HUMAN MAMMARY TISSUE AND MAMMARY CARCINOMA, ODA Koji; NAGINO Masato; KAMIYA Junichi; NIMURA Yuji; MATSUDA Satoru; HAMAGUCHI Michinari, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nagoya University, 3200000, 3200000, In the present study, expression of p73 in mammary carcinoma was studied immunohistochemically to avoid the contamination of the cells expressing p73. The aim of this study is to evaluate usefulness of p73 protein as a parameter of high-grade malignant potential in mammary carcinoma.Design : We developed anti-p73 polyclonal antibody by standard techniques. Rabbit was immunized with glutattjione S-transferase (GST) -p73 (ammo acids from TQWKRCPNH to YEPPQVGTEF) for the production of anti-p73 antibody. Tissue specimens of invasive mammary carcinomas and nonneoplastic mammary tissue were Obtained from 75 patients with mammary carcinoma undergoing mastectomies. Immunohistochemical expression of p53 (DO-7, PharMingen International), the apoptotic index (AI) and the mitotic index (MI) were also examined.Results : Immunohistochemical expression of p73 was evident in 20 mammary carcinomas (20%, p73 (+)), while myoepithelium showed immunohistochemical expression of p73protein in all 75cases (100%). The apoptotic index (AI) (medium, range) of p73 (+) cases (2.01, 1.14-6.56%) was significantly higher than those of 73 (-) cases (0.48, 0.06-4.90%)(p < 0.05). The mitotic index (MI) (medium, range) of p73 (+) cases (2.00, 1.08-3.42%) was significantly higher than those of p73 (-) cases (0.37, 0.01-2.41%)(p < 0.05). All 4 cases with distant metastases in this series showed high MI (>1%) and P73 (-). 22 cases (29.3%) showed overexpression of p53 (p53 (+)). The AI (median, range) of P73(+)/p53 (+)(2.17% (0.1-3.41%)) was interestingly higher than P73(-)/p53 (+) (1.12%, 0.25-2.40%) (p<0.05).Conclusion : Results of the present study.suggest : 1. P73 protein expressed in myoepithelium.2. P73 protein expressed in mammary carcinoma showing high MI may play a role in the induction of apoptosis.3. The loss of p73 expression may be associated with advanced carcinogenesis and metastatic potential.4. P73 protein may functions even in cases showing p53 overexpression., kaken
- 2001, RNA干渉を応用したヒト疾患の予防と治療, 0, 0, 0, Competitive research funding
- 2001, Medical application of RNAi to the human health, 0, 0, 0, Competitive research funding
- 特定領域研究(C), 2000 - 2000, 12215063, v-Src癌化細胞の浸潤・転移に決定的なシグナル伝達系の研究, 浜口 道成; 岩本 隆司; 松田 覚, 日本学術振興会, 科学研究費助成事業, 名古屋大学, 4300000, 4300000, 我々の主な研究対象とする癌遺伝子srcは、元々ラウス肉腫ウイルスの癌遺伝子として同定されたが、最近その癌原遺伝子c-srcの産物c-Srcキナーゼがヒト大腸癌や乳癌で高率に活性化される事、悪性の臨床症状を示す大腸癌症例で、その活性化を生じる欠損変異が高率に見い出され、ヒト癌の浸潤転移に関与するシグナル伝達系を同定する為に、重要なモデル系であると言える。
我々はまずv-Srcキナーゼによるマトリックスメタロプロテイナーゼ(MMP)の分泌活性化機構に関して研究を進めた。その結果、v-Src癌化細胞では、MEK1-MAPKシグナル伝達系がMMPの分泌と活性化に決定的なシグナルである事を、ドミナントネガティブMEK1遺伝子を用いて同定した。更に、同様の系が、v-Crk癌化細胞や、ConA刺激細胞においてもMMPの分泌活性化に必須である事を証明した。v-Srcによって転写抑制を受ける遺伝子を調べ、その内のSHPS-1がMAPキナーゼを介して転写抑制され、その強制発現がv-Src癌化細胞の足場非依存増殖を特異的に抑制する事を見い出した。ヒト癌におけるMEK1-MAPKシグナル伝達系と癌化の相関を調べた結果、乳癌細胞、乳癌組織においてMAPキナーゼを活性化させ、細胞の足場非依存増殖を活性化する新規の因子MAWDを同定した。現在その詳細を解析中である。, kaken - Grant-in-Aid for Scientific Research (B), 1998 - 2000, 10557086, Identification of genes determining radiosentivities of tumors in vitro and in vivo., NAKATSUGASA Shigekazu; MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nagoya University, 12400000, 12400000, During 1998-2000, we have investigated on the identification of genes determining radiosensitivities of tumors in hi vitro and in vivo based on the observation that the radiosensitivity of two tumors had shown the dessociation between in vitro and in vivo. In order to clone novel human genomes responsible for the radiosensitivities of tumors, we adopted novel methodology, that is,modified degenerative primer technique. Using this, we have successsfully cloned 4 novel human genomes which might be associated with cell cycle or cell adgesion.
On the other hand, we have found that the cellular radiosensitivities of tumor cells which are not equivalent to the ones of original histologies may not differ from each other irrespective of p53 status. Then, weinvestigated the oxygen tension in 10 different human malignancies xenografts. Successfully we have demonstrated the correlation between the tumor radiosensitivities and their oxygen tension. As for the molecular mechanisms of the hypoxia issue, we adopted RT-PCR methods using primers of coagulation/fibrinolytic and angiogenesis factors such as PAI-1. Successfully we have demonstrated that the mRNA expression of these factors at the tissue level are more relevant to the tumor hypoxia rather than those at the cellualr level. In conclusion, the radiosensitivities of tumors in in vitro and in vivo may be determined by the different mechanisms, that is, the gene expression of different genes., kaken - 特定領域研究(A), 1999 - 1999, 06283203, 癌遺伝子産物の生理機能に基づく発癌機構の解析, 山本 雅; 藤元 次郎; 梅森 久視; 松田 覚; 椎尾 譲, 日本学術振興会, 科学研究費助成事業, 東京大学, 150000000, 150000000, チロシンりん酸化をはじめとする蛋白質りん酸化反応に着目して、細胞の増殖制御に関する解析を進め、以下の知見を得た。
1.ショウジョウバエがん抑制遺伝子のヒトホモローグLATS2の産物が、細胞周期のG2/M期でキナーゼ活性が高いことを示し、細胞周期制御に関わっている可能性を示唆した。
2.細胞増殖抑制性蛋白質TobはPDGF刺激により、Ras,MAPK経路を介してりん酸化され、そのことで増殖抑制活性が調節される。従ってTobは細胞周期のG0あるいはearly G1で機能していると考えられた。
3.TobはBMP2シグナル伝達に関わり、Tob欠損骨芽細胞ではBMP2反応性が亢進している。その結果、Tob欠損マウスは骨の過形成を示す。
4.Tob2をβ-galに置換したTob2欠損マウスを作成した。Tob2は種々の組織で普遍的に発現するものの、特に小腸細胞、生殖組織で顕著に発現している。
5.B細胞で抗原刺激依存的にLynでりん酸化されるCblは、BLNKとPLCγの会合を阻害し、結果としてPLCγの活性を負に制御している。一方Cbl類似Cbl-b蛋白質はPLCγの活性を正に制御している。
6.Cblに類似するCbl-cを新規にクローニングした。Cbl-cは他のCblファミリーメンバー同様受容体型チロシンキナーゼやSrcファミリーチロシンキナーゼと会合する。
7.ショウジョウバエFakの発現様式の解析から、Fakがインテグリンシグナル伝達系に関わる事を示唆した。, kaken - Grant-in-Aid for Scientific Research (C), 1998 - 1999, 10670137, c-Src Signaling that regulates Cell Adhesion, HAMAGUCHI Michinari; MATSUDA Satoru, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nagoya University, 3300000, 3300000, The aim of this study is to clarify the critical signaling pathway for the regulation of cell adhesion that depends on reversible biochemical reaction regulated by c-Src. Based on our previous report that Src kinase can regulate cell adhesion, we planned to clarify the regulation of cell adhesion dependent on cell cycle and NO-signaling.
In this study we found that Crk, an adopter molecule that binds c-Src to activate it, suppressed cadherin-dependent cell adhesion via Ras-MEK pathway. In addition we found NO produced by e-NOS could directly activate c-Src kinase., kaken - Grant-in-Aid for Scientific Research (B)., 1998 - 1999, 10044261, Signaling Pathways for Cell Cycle & Growth, HAMAGUCHI Michiaki; MATSDA Satoru; HANAFUSA Hidesaburo, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Nagoya University, 3900000, 3900000, The aim of this study is to clarify signaling pathway for the regulation of cell cycle that depends on protein-protein interactions regulated by SH2-phosphotyrosine binding or SH3-proline bindings, under the international collaborative study. Advance of recent study revealed that cell growth cycle is regulated by a variety of intracellular signaling pathway that activated by tyrosine phosphorylation of cellular proteins. Up to date, two types of signaling pathway, positive and negative ones, that regulate cell growth were identified.
In this study we mainly focused on a transmembrane glycoprotein, SHPS-1. SHPS-1 appears to have a function as a docking protein that reclutes the tyrosine phosphatase, SHP-2 which seems to be required for the cell growth. Despite for its unique structure, however, the function of SHPS-1 in cell growth remains largely unclear. in this study, we showed that cell transformation by v-src substantially suppresses the expression of SHPS-1 protein. In contrast, overexpression of exogenous SHIPS-1 in v-src-transformed cells virtually suppresses anchorage-independent growth of the cells., kaken - 特定領域研究(A), 1998 - 1998, 10169228, チロシンキナーセを標的とした生体機能制御, 浜口 道成; 岩田 啓之; 松田 覚, 日本学術振興会, 科学研究費助成事業, 名古屋大学, 1600000, 1600000, 我々は、受容体型チロシンキナーゼTrk、非受容体型チロシンキナーゼSrcを題材として、新規のキナーゼ活性の制御機構を世界に先駆けて発見すると共に、そのシグナル伝達系について系統的な研究を展開してきた。本研究は、TrkキナーゼとSrcキナーゼを標的に、われわれの見い出したキナーゼ活性制御機構の詳細を明らかにし、新しい概念の機能探索子による腫瘍の分化誘導療法、遺伝子療法の開発を目指すものである。本年度は、レドックス依存の新規のSrc活性化機構に焦点を絞り実験を進めた。我々は、Srcキナーゼがシステイン残基に依存して、塩化第二水銀やNOによる酸化還元反応によってキナーゼの括性化を受ける事を見い出した。そこでSrcキナーセのシステイン残基を点突然変異させ、キナーゼ活性や細胞癌化能に対する影響を調べた。v-Srcキナーゼの場合、全長526アミノ酸残基中に10個のシステイン残基を含む。本年は、これらすべてのシステインをアラニンに点突然変異た。その結果、8、9番に突然変異を導入したものは癌化能が温度感受性となり、Src蛋白質の崩壊が起きることが示唆された。この結果は、キナーゼ活性ドメイン中のシステイン残基が、Srcキナーゼの安定性に重要であることを示唆する。そこで、これらの変異型Srcキナーゼの、塩化第二水銀、NO等に対する反応にって解析する予定である。, kaken
- 重点領域研究, 1996 - 1996, 08264107, 転写制御遺伝子群の発癌への関与, 林 健志; 中別府 雄作; 松田 覚; 森下 和弘; 濱田 文彦; 恒吉 正澄, 日本学術振興会, 科学研究費助成事業, 九州大学, 13900000, 13900000, 1.hMTH1は、8-oxo-GTP分解酵素であり、突然変異頻度を抑制している。同酵素の遺伝子構造を決定し、択一的スプライシング機構によって数種類の酵素蛋白質が作られること、また、肺癌患者に、スプライシング異常を引き起こす生殖細胞突然変異を見い出した。2.がん抑制遺伝子であるWT1を、トランスフェクション後に強制的に発現誘導させたところ、細胞種によってその帰結が多様であることを見い出した。3.がん遺伝子c-erbB-2の発現調節に関与する転写因子様の蛋白質のcDNA2個を得た。このうちの一個、Kidは、セントロメア領域DNAとも結合し、染色体分配に深く関与していることを明らかにした。今一つのcDNA、tobは細胞増殖を抑制し、細胞周期にも関与することを示した。4.白血病原因遺伝子EVI-1のコードする蛋白質EVI-1のDrosophilahomologueを同定し、その機能を検索したところ、同蛋白質は神経系ニューロン形成の初期過程に関係していることが支唆された。5.平滑筋肉腫組織のp53遺伝子DNAを増幅し、変異配列を検索し、予後因子としての可能性を見い出した。尿路腫瘍の同時性および異時性多発例についての同様の解析では、多発例間で変異が一致するものとしないものがあり、多発性の原因には、モノクローナル、ポリクローナル2種のものがあると結論された。6.高分解能・高度自動化キャピラリー電気泳動装置による効率の良い蛍光PCR-SSCP法を確立した。この方法は、変異の判定を、コンピュータにより統計的根拠によって行うものであり、全過程における人的ミスの排除、検出感度の飛躍的向上を達成した。7.多剤耐性遺伝子の転写因子YB-1のc-DNAおよびゲノムDNAのクローニングを行い、シスプラチン耐性細胞におけるはYB-1の高発現、発現抑制によるシスプラチン感受性の増加を証明した。, kaken
- 重点領域研究, 1995 - 1995, 07272108, 転写制御遺伝子群の発癌への関与, 林 健志; 中別府 雄作; 松田 覚; 森下 和弘; 濱田 文彦; 常吉 正澄, 日本学術振興会, 科学研究費助成事業, 九州大学, 14700000, 14700000, 発癌に関与する転写遺伝子群の作用機構に関わる数多くの遺伝子群を同定した。またこれらの遺伝子群の臨床的な癌における構造異常検索を行い、かつより多くの遺伝子構造異常検索のための実験系の確立に着実な成果をあげた。浜田は、転写関連の遺伝子で、かつがん抑制遺伝子であるWT1と相互作用する蛋白質のcDNAを酵母two hybrid法を用いて単離し、その性質を明らかにし、またWT1の白血病細胞増殖抑制作用を見いだした。中別府は、核内がん遺伝子産物△FosBがmRNAの安定化という新しいメカニズムによってサイクリンEとそのパートナーであるCDK2の発現を増加させ、細胞周期の回転、すなわち細胞増殖を引き起こし、これが細胞癌化を引き起こしうることを見いだした。松田は、がん遺伝子c-erbB-2の発現調節に関与すると思われる転写因子様の蛋白質のcDNA2個をサウスウェスタン法によってクローニングした。このうちの一個(toblと命名した)は細胞増殖抑制遺伝子btglと相同性を示すものであった。これ自身、細胞の増殖を抑制したが、この阻害は細胞周期依存的であり、CDK4等との相互作用によることを見い出した。森下は白血病原因遺伝子EVI-1の持つ2個のDNA結合領域はGATA/ETS結合領域と類似しており、これらの転写因子と相互作用することにより癌化を引き起こすと結論した。恒吉はホルマリン固定パラフィン包埋標本から効率よく標的DNAを増幅し、変異配列を検索する実験法を確立し、これを利用して平滑筋肉腫、大腸癌各数十例でのp53の異常を検索した。またこの結果と臨床病理学的データ、およびp53蛋白質の免疫染色の結果を総合し、診断への応用について検討した。林は遺伝子構造異常の大規模検索法として、PCRチューブ内での極めて単純な操作のみで行える増幅産物のポストPCR蛍光標識法を開発し、さらにキャピラリー電気泳動式DNAシークエンサーを用いた高度に自動化された非RIのPCR-SSCP法を確立した。さらに白血病細胞におけるp53遺伝子の突然変異検出に極めて有効であることを示し、今後臨床診断としてのDNA診断の実現にとって極めて重要な技術革新である。, kaken
- Grant-in-Aid for international Scientific Research, 1994 - 1995, 06044068, Joint Research on the signal transduction to the nucleus. -from the membrane receptors to the nuclear transcription factors-, INOUE Junichiro; VERMA Inder M.; OTSUKA Masami; UMEMORI Hisashi; MATSUDA Satoru; YAMAMOTO Tadashi, Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, The University of Tokyo, 7000000, 7000000, 1. CD40 signalings are linked to induction of the Bcl-xL,Cdk4 and Cdk6 proteins whose expression was significantly suppressed by the apoptotic signal through sIgM.Mutational analyzes of CD40 revealed taht the domain of human CD40 required for blocking apoptosis coincides with that required for Bcl-xL induction. sIgM signalings arrest cells in G_1 followed by apoptosis, while constitutive expression of Bcl-xL leads to the inhibition of apoptosis. Bcl-xL fails to induce S phase entry. By CD40 signalings, both Cdk4 and Cdk6 resume their normal expression levels which are sufficient for passing the restriction point in G_1 even in the presence of the apoptotic signals. These results suggest that co-operation of Bcl-xL,Cdk4 and Cdk6 induced by CD 40 signalings plays a key role in CD40-mediated selective growth of B cells. CD40 signalings activate Rel, but the role of Rel activation in blocking apoptosis remains to be elucidated.
2. Yeast two-hybrid system has been performed to identify proteins which interact with cytoplasmic tail of CD40. Two candidates have been analyzed.
3. IkappaBalpha is rapidly phosphorylated and degraded in response to the stimulation. We have delineated the domain in IkappaBalpha required for TNFalpha-induced phosphorylation and rapid degradation. In contrast to the previous reports, the PEST-like sequences are dispensable for TNFalpha-induced degradation. The ankyrin repeats, essential for forming a complex with RelA,are required for TNFalpha-induced degradation suggesting that the putative IkappaB protease could interact with IkappaBalpha in complex with RelA.Our data also indicate that neither the ankyrin repeats nor the PEST-like sequences, are essential for TNFalpha-induced phosphorylation.
4. Phosphorylation activity which associates with amino-terminus of IkappaB has been identified.
5. Novel heterocyclic compounds which inhibit the DNA binding activity of Rel have been synthesized. (298 words), kaken - 重点領域研究, 1994 - 1994, 06280115, 転写制御遺伝子群の発癌への関与, 林 健志; 恒吉 正澄; 森下 和弘; 松田 覚; 佐藤 明; 中別府 雄作, 日本学術振興会, 科学研究費助成事業, 九州大学, 13500000, 13500000, 各班員はそれぞれの実験系を用いて、発癌に関与する転写遺伝子群の作用機構を解明し、これに関わる他の遺伝子群を数多く同定した。またこれらの遺伝子群の癌化における構造異常検索のための実験系の確立に着実な成果をあげた。即ち、中別府は、核内がん遺伝子fosBの産物の一つである△FosBがサイクリンEとそのパートナーであるCDK2の発現をmRNA安定化によって増加させ、細胞増殖を引き起こすことを見いだした。佐藤は、がん抑制遺伝子WT1が細胞のG1/S移行を阻害し、またEC細胞の分化に抑制的に働き、血球系幹細胞と急性白血病細胞で異常発現していることを見いだした。松田はがん遺伝子c-erbB-2の発現調節に関与すると思われる転写因子様の蛋白質のcDNA2個をサウスウェスタン法によってクローニングした。一個はZink fingerを15個含む転写因子様蛋白質をコードし、今一個は細胞増殖抑制遺伝子btg1と相同性を示し、核移行シグナルと、PQの繰り返しを含むもので、これ自身、導入細胞の増殖を抑制した。森下は白血病原因遺伝子EVI-1の持つ2個のDNA結合領域の結合配列特異性を詳細に検討し、転写の活性化と抑制の両側面にそれぞれ関与していることを明らかにした。さらにこの蛋白質によって発現制御を受ける遺伝子の同定を進めている。恒吉は軟部悪性腫瘍(肉腫)における遺伝子構造異常を検索するためにホルマリン固定パラフィン包埋標本からの標的DNAの効率よいPCR増幅条件の検討を行ない、PCR-SSCP法によってすでに2例のp53点突然変異を同定している。またこれらの異常と、病理学的知見との相関に関して多くの知見を得ている。林は遺伝子構造異常の大規模検索法として、ポストラベル法による蛍光標識PCR-SSCP法の開発を行い、従来法の欠点であった蛍光標識プライマーの合成を経由しない実験法を確立した。, kaken
- 重点領域研究, 1993 - 1993, 04253203, がん遺伝子の機能解析, 山本 雅; 梅森 久視; 松田 覚, 日本学術振興会, 科学研究費助成事業, 東京大学, 42000000, 42000000, 我々は、チロシンキナーゼの生理機能を明らかにすることが細胞がん化の機構を解明する上で重要であると考えて以下の研究を行なった。
1.lyn遺伝子を欠損する細胞株等に遺伝子を導入する実験から、Bリンパ球の抗原受容体と会合するLynキナーゼがSykキナーゼと共存することにより、細胞内蛋白質のチロシンリン酸化反応を促進することを示した。又fynを過剰発現するT細胞ハイブリドーマでは、Fynの活性化がZAP-70キナーゼの活性制御に関わっていることを示唆する結果を得た。一方、CD30陽性リンパ腫でチロシンリン酸化が亢進しているp80蛋白質を同定し、その分子生物学的解析を進めると共に、リンパ腫発症に於けるp80の意義を検討している。
2.脳で発現する新規チロシンキナーゼ遺伝子fakとbrtのcDNAをクローニングした。fakは同時期に外国のグループによって細胞接着に関わることが示されたが、我々はfakの脳特異的産物を見いだしており、fak欠損マウスの作成や、免疫生化学的手法を用いてその機能解析を進めている。又Fynがミエリン形成に関わることを示し、更にfyn欠損マウスでミエリン形成が不完全であることを示した。
3.受容体型チロシンキナーゼErbB-2の標的蛋白質としてTob-1ならびにTob-2を同定し、そのcDNAクローニングを行なった。tob-1遺伝子はヒト染色体17q22にマップされること、そしてTob-1蛋白質が細胞増殖抑制活性を有することを示した。又、エストロゲンがErbB-2チロシンキナーゼ活性を促進するという昨年度の成果に基づいて、エストロゲンに抗がん剤を結合させ、ErbB-2過剰発現細胞を選択的に殺傷することに成功した。, kaken - がん特別研究, 1991 - 1993, 05151042, 細胞がん化における蛋白質リン酸化, 秋山 徹; 入江 賢児; 西田 栄介; 月田 早智子; 松田 覚; 野島 博, 日本学術振興会, 科学研究費助成事業, 大阪大学, 24000000, 24000000, 1)MAPキナーゼキナーゼ(MAPKK)が、MAPKK-Kによってリン酸化されて活性化すること、MAPキナーゼによってもリン酸化されることを明らかにした。MAPKKに対する中和抗体を用いてMAPキナーゼの活性化が卵成熟過程におけるMPFの活性化に重要な役割を担っていることを示した。2)酵母のシグナル伝達系においてプロテインキナーゼCの下流で機能する因子を同定しBck1-Mkk1/Mkk2-Mpk1の順序で機能することを明らかにした。これはそれぞれ動物細胞におけるMAPKK-K,MAPKK,MAPキナーゼと対応する。3)各種インスリン受容体の解析より、IRS-1チロシンリン酸化とRas活性化、細胞増殖作用とが並行することを見いだした。IRS-1欠損マウスの作製に成功し、prenatalおよびpostnatalの個体の発育の傷害を認めた。4)CskがFynやLckからの細胞内情報伝達を抑制することを明らかにした。5)ErbB-2にエストロジェンが作用してそのキナーゼ活性を上昇させることを明らかにした。6)好中球においてFgrがIgGFc受容体IIと複合体を形成し、IgGFc受容体IIを介したシグナル伝達路上に存在すると考えられた。7)CotはC末端部分の欠失によりキナーゼ活性が亢進して細胞トランスフォーミング能を獲得したことを明らかにした。8)CrkのSH3領域に結合する蛋白質としてRasグアニンヌクレオチド交換因子C3GのcDNAをクローニングした。9)アンチセンスDNAを用いてERMファミリーが細胞間と細胞基質間の接着および微絨毛の形成に重要な役割をしていることを明らかにした。ERMがCD44に結合していることを見いだした。, kaken
- がん特別研究, 1991 - 1993, 04151039, 細胞癌における蛋白質リン酸化, 秋山 徹; 野島 博; 月田 早智子; 高橋 雅英; 松田 覚; 西田 栄介, 日本学術振興会, 科学研究費助成事業, 大阪大学, 24000000, 24000000, 1)MAPキナーゼキナーゼの精製・cDNAクローニングに成功し、MAPキナーゼキナーゼ/MAPキナーゼカスケードが酵母からヒトまで保存されたシグナル伝達システムであることを明らかにした。さらにMAPキナーゼキナーゼが存在することを示した。また、ras p21の下流でMAPキナーゼキナーゼ/MAPキナーゼが活性化することを示した。2)β-カテニンがチロシンキナーゼの基質となり、この蛋白質がリン酸化されると細胞接着能が低下することを見出した。また、スキラスタイプの胃癌では、高率(2/3以上)でαカテニンの発現が見られないことを明らかにした。3)Src型チロシンキナーゼFynからの情報がT細胞においてIL-2プロモーター及びc-fosプロモーターを活性化することを明かにした。この情報伝達にFyn蛋白質構造の中のSH2領域が重要であること、CSKの存在により活性が負に調節されていることを明らかにした。4)ヒトCRK遺伝子のクローニングを行ない、そのmRNAが2種類あること、その産物はp28CRK-Iとp40/p42CRK-IIであることを明らかにした。CRK遺伝子産物をmicroinjectするとPC12細胞の分化を誘導することが明らかになった。5)癌抑制遺伝子Rbの産物(RB蛋白質)のリン酸化に細胞周期のG1→Sの移行を制御するキナーゼcdk2が関与していることが示唆された。6)分裂酵母の温度感受性細胞周期変異株のうちcdc2.cdc10.cdc13を宿主とした用い、それらの変異を機能相補するcDNAを多数単離した。各々の変異遺伝子のホモログ以外にResl.Resl/Cdc10.Reml.RNA結合蛋白質などが単離された。7)膀胱癌の予後因子の多変量解析の結果、ErbB2過剰発現は独立した重要な予後因子であることが判明した。, kaken
