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Scaling Insulin-Producing Cells by Multiple Strategies
Eiji Yoshihara,Jinhyuk Choi,Fritz Cayabyab,Harvey Perez 대한내분비학회 2024 Endocrinology and metabolism Vol.39 No.2
In the quest to combat insulin-dependent diabetes mellitus (IDDM), allogenic pancreatic islet cell therapy sourced from deceased donors represents a significant therapeutic advance. However, the applicability of this approach is hampered by donor scarcity and the demand for sustained immunosuppression. Human induced pluripotent stem cells are a game-changing resource for generating synthetic functional insulin-producing β cells. In addition, novel methodologies allow the direct expansion of pancreatic progenitors and mature β cells, thereby circumventing prolonged differentiation. Nevertheless, achieving practical reproducibility and scalability presents a substantial challenge for this technology. As these innovative approaches become more prominent, it is crucial to thoroughly evaluate existing expansion techniques with an emphasis on their optimization and scalability. This manuscript delineates these cutting-edge advancements, offers a critical analysis of the prevailing strategies, and underscores pivotal challenges, including cost-efficiency and logistical issues. Our insights provide a roadmap, elucidating both the promises and the imperatives in harnessing the potential of these cellular therapies for IDDM.
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FXR Regulates Intestinal Cancer Stem Cell Proliferation
Fu, Ting,Coulter, Sally,Yoshihara, Eiji,Oh, Tae Gyu,Fang, Sungsoon,Cayabyab, Fritz,Zhu, Qiyun,Zhang, Tong,Leblanc, Mathias,Liu, Sihao,He, Mingxiao,Waizenegger, Wanda,Gasser, Emanuel,Schnabl, Bernd,Atk Elsevier 2019 Cell Vol.176 No.5
<P><B>Summary</B></P> <P>Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5<SUP>+</SUP>) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5<SUP>+</SUP> cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5<SUP>+</SUP> cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Genetic and dietary risk factors for colorectal cancer converge on the BA-FXR axis </LI> <LI> FXR controls proliferating Lgr5<SUP>+</SUP> intestinal stem cells </LI> <LI> FXR agonists curtail colorectal cancer progression </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
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Shin Narita,Kazutaka Ikeda,Daisuke Nishizawa,Eiji Yoshihara,Maki Numajiri,Yuuya Onozawa,Nobuyo Ohtani,Kazuhiko Iwahashi 대한신경정신의학회 2017 PSYCHIATRY INVESTIGATION Vol.14 No.5
Objective: The autism susceptibility candidate 2 (AUTS2) gene has been implicated in multiple neurological disorders. Several recent studies have revealed that the polymorphism rs6943555 in the AUTS2 gene is broadly associated with human mental function and behavior. Therefore, in the present study we investigated whether the polymorphism rs6943555 is associated with human personality traits in Japanese university students. In addition, our previous study reported that the AUTS2 rs6943555-rs9886351 haplotype is associated with alcohol dependence. As a preliminary analysis, we also examined whether the AUTS2 haplotypes are related to personality traits. Methods: After written informed consent had been obtained from the participants, two AUTS2 polymorphisms were analyzed, and personality was assessed using the Temperament and Character Inventory (TCI) in 190 university students. In addition, in order to exclude the influence of the results for students with mental health problems, we gave the Patient Health Questionnaire-9 (PHQ-9) to all subjects. Results: In all the subjects, there was a main effect of the polymorphism rs6943555 genotype on reward dependence (p=0.038) and cooperativeness (p=0.031), although the significance was lost on Bonferroni correction. Similarly, on analysis that excluded the subjects with PHQ-9 scores≥10, no significant association with any TCI dimension score among the rs6943555 genotypes was seen. There was no effect of the rs6943555-rs9886351 haplotypes on the TCI dimension scores. Conclusion: This study suggests that the polymorphism AUTS2 rs6943555 is not associated with personality traits. Further large-scale studies with more subjects using other self-report questionnaires are needed.
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Shin Narita,Kazuhiko Iwahashi,Kenta Nagahori,Maki Numajiri,Eiji Yoshihara,Nobuyo Ohtani,Jun Ishigooka 대한신경정신의학회 2015 PSYCHIATRY INVESTIGATION Vol.12 No.3
ObjectiveaaNorepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger’s theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger’s personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model. MethodsaaAfter written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students. ResultsaaA significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms. ConclusionaaWe conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence- related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.
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