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Intranasal administration of stem cell-derived exosomes for central nervous system diseases

Neural Regeneration Research 2024年第6期19卷 1249-1255页

作者： Shuho Gotoh masahito kawabori Miki Fujimura Department of Neurosurgery Hokkaido University Graduate School of Medicine

Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including antiapoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

关键词： central nervous system disease exosome extracellular vesicle intranasal administration stem cell

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Non-Kramers doublet ground state in a quaternary cubic compound PrRu_(2)In_(2)Zn_(18) investigated by ultrasonic measurements

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Chinese Physics B 2024年第6期33卷 405-411页

作者：张化远 Kazuhei Wakiya Mitsuteru Nakamura masahito Yoshizawa Yoshiki Nakanish Graduate School of Science and Engineering Iwate UniversityMorioka 020-8551Japan

We performed ultrasonic measurements on a quaternary cubic compound PrRu_(2)In_(2)Zn_(18) to explore the ground state properties derived from non-Kramers Γ_(3) doublet of Pr^(3+).PrRu_(2)In_(2)Zn_(18) is a quaternary derivative of the ternary compound PrRu_(2)Zn_(20) that exhibits a structural phase transition at T_S=138 K.In PrRu_(2)In_(2)Zn_(18),the Zn atoms at the 16c site in PrRu_(2)Zn_(20) are selectively replaced by In atoms.A monotonic increase was observed in the temperature dependence of elastic constants C_L=(C_(11)+2C_(12)+4C_(44))/3 and C_(T)=(C_(11)-C_(12)+C_(44))/3 in the temperature range around T_(S) to which an elastic softening was observed in(C_(11)-C_(12))/2 for PrRu_(2)Zn_(20).The disappearance of the softening indicates that the structural transition in PrRu_(2)Zn_(20) is suppressed by the substitution of Zn ions by In ones with a larger ionic radius.Alternatively,the C_(T) of PrRu_(2)In_(2)Zn_(18) exhibits a precursor Curie-type elastic softening toward low temperatures being responsible for the non-Kramers Γ_(3) ground state.We discuss the ground state and the evolution of the elastic properties of the different single-crystal samples of PrRu_(2)In_(2)Zn_(18) grown under different conditions.

关键词： ultrasonic measurements non-Kramers doublet structural phase transition crystalline electric field effect

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Beam based alignment using a neural network

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Nuclear Science and Techniques 2024年第4期35卷 108-118页

作者： Guan-Liang Wang Ke-Min Chen Si-Wei Wang Zhe Wang Tao He masahito Hosaka Guang-Yao Feng Wei Xu National Synchrotron Radiation Laboratory University of Science and Technology of ChinaHefei 230029China Diamond Light Source Oxfordshire OX110DEUK

Beams typically do not travel through the magnet centers because of errors in storage rings.The beam deviating from the quadrupole centers is affected by additional dipole fields due to magnetic field feed-down.Beam-based alignment(BBA)is often performed to determine a golden orbit where the beam circulates around the quadrupole center axes.For storage rings with many quadrupoles,the conventional BBA procedure is time-consuming,particularly in the commissioning phase,because of the necessary iterative process.In addition,the conventional BBA method can be affected by strong coupling and the nonlinearity of the storage ring optics.In this study,a novel method based on a neural network was proposed to determine the golden orbit in a much shorter time with reasonable accuracy.This golden orbit can be used directly for operation or adopted as a starting point for conventional BBA.The method was demonstrated in the HLS-II storage ring for the first time through simulations and online experiments.The results of the experiments showed that the golden orbit obtained using this new method was consistent with that obtained using the conventional BBA.The development of this new method and the corresponding experiments are reported in this paper.

关键词： Golden orbit Beam-based alignment Neural network Storage ring

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Sphingolipids in cardiovascular and cerebrovascular systems:Pathological implications and potential therapeutic targets

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World Journal of Cardiology 2013年第4期5卷 75-86页

作者： masahito kawabori Rachid Kacimi Joel S Karliner Midori A Yenari Department of Neurology San Francisco and San Francisco Veterans Affairs Medical CenterUniversity of CaliforniaSan FranciscoCA 94121United States Department of Cardiology VA Medical CenterUniversity of California San FranciscoSan FranciscoCA 94121United States

The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.

关键词： Sphingolipids Sphingosine-1-phosphate Sphingosine kinase Ceramide kinase

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Real-world efficacy and safety of tofacitinib treatment in Asian patients with ulcerative colitis

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World Journal of Gastroenterology 2024年第13期30卷 1871-1886页

作者： Kentaro Kojima Kenji Watanabe Mikio Kawai Soichi Yagi Koji Kaku Maiko Ikenouchi Toshiyuki Sato Koji Kamikozuru Yoko Yokoyama Tetsuya Takagawa masahito Shimizu Shinichiro Shinzaki Department of Gastroenterology Hyogo Medical UniversityNishinomiya 663-8501Japan Department of Gastroenterology Gifu University Graduate School of MedicineGifu 501-1194Japan Department of Internal Medicine for Inflammatory Bowel Disease The University of ToyamaToyama 930-0194Japan Center for Clinical Research and Education Hyogo Medical UniversityNishinomiya 663-8501Japan

BACKGROUND Real-world data on tofacitinib(TOF)covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis(UC)are scarce.AIM To investigate the long-term efficacy and safety of TOF treatment for UC,including clinical issues.METHODS We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center.All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled.Patients were followed up until August 2020.The primary outcome was the clinical response rate at week 8.Secondary outcomes included clinical remission at week 8,cumulative persistence rate of TOF administration,colectomy-free survival,relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.RESULTS The clinical response and remission rates were 66.3%and 50.5%at week 8,and 47.1%and 43.5%at week 48,respectively.The overall cumulative clinical remission rate was 61.7%at week 48 and history of anti-tumor necrosis factor-alpha(TNF-α)agents use had no influence(P=0.25).The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8(30.9%vs 88.1%;P<0.001).Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8(odds ratio:0.61,95%confidence interval:0.45-0.82,P=0.001).Relapse occurred in 45.7%of patients after TOF tapering,and 85.7%of patients responded within 4 wk after re-increase.All 6 patients with herpes zoster(HZ)developed the infection after achieving remission by TOF.CONCLUSION TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-αagents.Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF.Special attention is needed for tapering and HZ.

关键词： Ulcerative colitis Tofacitinib Janus kinase inhibitor Real-world Biologics

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River system in Japan from a landscape ecological aspect

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Journal of Environmental Sciences 2003年第2期15卷 160-166页

作者： Nobukazu NAKAGOSHI masahito INOUE Graduate School for International Development and Cooperation Hiroshima UniversityGraduate School for International Development and Cooperation Hiroshima University 1-5-1 Kagamiyama Higashi-Hiroshima 739-8529 Japan1-5-1 Kagamiyama Higashi-Hiroshima 739-8529 Japan

The objective of this study was to elucidate characteristics associated with rivers by classification of major rivers in Japan into several types based on riparian conditions. As the results of principal component analysis (PCA) with use of parameters reflecting forms and artificial alterations of respective rivers, four major components such as “comprehensive riparian size', “intactness of water front', “continuity of streams' and “simplicity of landform in river basin' were extracted. Subsequently, cluster analysis was performed based on principal component scores, leading to successful classification of major rivers into 6 types. These findings disclosed that (1) the extracted principal components provide effective viewpoint for classification of rivers; (2) distribution of respective classes indicates area properties; and (3) the employed quantitative procedures were found effective for classification of major rivers.

关键词： river system landscape ecological aspect Japan

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CRISPR/Cas9-mediated genome editing reveals 12 testis-enriched genes dispensable for male fertility in mice

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Asian Journal of Andrology 2022年第3期24卷 266-272页

作者： Yuki Oyama Haruhiko Miyata Keisuke Shimada Yoshitaka Fujihara Keizo Tokuhiro Thomas X Garcia Martin M Matzuk masahito Ikawa Graduate School of Pharmaceutical Sciences Osaka UniversitySuitaOsaka 565-0871Japan Department of Experimental Genome Research Research Institute for Microbial DiseasesOsaka UniversitySuitaOsaka 565-0871Japan Department of Bioscience and Genetics National Cerebral and Cardiovascular CenterSuitaOsaka 564-8565Japan Department of Genome Editing Institute of Biomedical ScienceKansai Medical UniversityHirakataOsaka 573-1191Japan Center for Drug Discovery Baylor College of MedicineHoustonTX 77030USA Department of Pathology and Immunology Baylor College of MedicineHoustonTX 77030USA Department of Biology and Biotechnology University of Houston-Clear LakeHoustonTX 77058USA The Institute of Medical Science The University of TokyoMinato-kuTokyo 108-8639Japan

Gene expression analyses suggest that more than 1000–2000 genes are expressed predominantly in mouse and human testes.Although functional analyses of hundreds of these genes have been performed,there are still many testis-enriched genes whose functions remain unexplored.Analyzing gene function using knockout(KO)mice is a powerful tool to discern if the gene of interest is essential for sperm formation,function,and male fertility in vivo.In this study,we generated KO mice for 12 testis-enriched genes,1700057G04Rik,4921539E11Rik,4930558C23Rik,Cby2,Ldhal6b,Rasef,Slc25a2,Slc25a41,Smim8,Smim9,Tmem210,and Tomm20l,using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9(CRISPR/Cas9)system.We designed two gRNAs for each gene to excise almost all the protein-coding regions to ensure that the deletions in these genes result in a null mutation.Mating tests of KO mice reveal that these 12 genes are not essential for male fertility,at least when individually ablated,and not together with other potentially compensatory paralogous genes.Our results could prevent other laboratories from expending duplicative effort generating KO mice,for which no apparent phenotype exists.

关键词： CRISPR/Cas9 knockout mice male infertility spermatozoa testis

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Validation of the Japan Coma Scale for the prediction of mortality in children:analysis of a nationwide trauma database

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World Journal of Pediatric Surgery 2022年第2期5卷 23-28页

作者： Yuki Enomoto Yusuke Tsutsumi Asuka Tsuchiya Takahiro Kido Koji Ishigami masahito Togo Susumu Yasuda Yoshiaki Inoue Department of Emergency and Critical Care Medicine University of TsukubaTsukubaIbarakiJapan Department of Emergency and Critical Care Medicine Mito Medical CenterMitoIbarakiJapan Department of Emergency and Critical Care Medicine Tokai University School of Medicine Graduate School of MedicineIseharaKanagawaJapan Department of Clinical Epidemiology and Health Economics The University of TokyoBunkyo-kuTokyoJapan Department of Pediatrics University of Tsukuba HospitalTsukubaIbarakiJapan

Objective The Japan Coma Scale(JCS)is widely used in clinical practice to evaluate levels of consciousness in Japan.There have been several studies on the usefulness of JCS in adults.However,its usefulness in evaluating children has not been reported.Therefore,this study aimed to assess the usefulness of the JCS for the prediction of mortality in children.Methods This is a multicenter cohort study which used data from a national trauma registry(Japan Trauma Data Bank).This study included patients under 16 years of age who were treated between 2004 and 2015.The primary outcome measure was in-hospital mortality.Two models were used to examine each item of the Glasgow Coma Scale(GCS)and the JCS.Model A included the discrete levels of each index.In model B,data regarding age,sex,vital signs on arrival to hospital,the Injury Severity Score,and blunt trauma were added to each index.The effectivity of the JCS score was then evaluated using the area under the curve(AUC)for discrimination,a calibration plot,and the Hosmer-Lemeshow test for calibration.Results A total of 9045 patients were identified.The AUCs of the GCS and JCS were 0.929(95%confidence interval(CI)0.904 to 0.954)and 0.930(95%CI 0.906 to 0.954)in model A and 0.975(95%CI 0.963 to 0.987)and 0.974(95%CI 0.963 to 0.985)in model B,respectively.The results of the Hosmer-Lemeshow test were 0.00(p=1.00)and 0.00(p=1.00)in model A and 4.14(p=0.84)and 8.55(p=0.38)in model B for the GCS and JCS,respectively.Conclusions We demonstrated that the JCS is as valid as the GCS for predicting mortality.The findings of this study indicate that the JCS is a useful and relevant tool for pediatric trauma care and future research.

关键词： Glasgow prediction nationwide

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The mechanism of sperm-egg interaction and the involvement of IZUMO1 in fusion

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Asian Journal of Andrology 2011年第1期13卷 81-87页

作者： Naokazu Inoue masahito Ikawa Masaru Okabe Research Institute for Microbial Diseases Osaka University Yamadaoka 3-1 Suita Osaka 565-0871 Japan

An average human ejaculate contains over 100 million sperm, but only a few succeed in accomplishing the journey to an egg by migration through the female reproductive tract. Among these few sperm, only one participates in fertilization. There might be an ingenious molecular mechanism to ensure that the very best sperm fertilize an egg. However, recent gene disruption experiments in mice have revealed that many factors previously described as important for fertilization are largely dispensable. One could argue that the fertilization mechanism is made robust against gene disruptions. However, this is not likely, as there are already six different gene-disrupted mouse lines （Calmegin, Adam Ia, Adam2, Adam3, Ace and Pgapl）, all of which result in male sterility. The sperm from these animals are known to have defective zona-binding ability and at the same time lose oviduct-migrating ability. Concerning spermzona binding, the widely accepted involvement of sugar moiety on zona pellucida 3 （ZP3） is indicated to be dispensable by gene disruption experiments. Thus, the landscape of the mechanism of fertilization is revolving considerably. In the sperm-egg fusion process, CD9 on egg and IZUMO1 on sperm have emerged as essential factors. This review focuses on the mechanism of fertilization elucidated by gene-manipulated animals.

关键词： egg fusion gene-manipulation interaction IZUMO1 sperm zona pellucida

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Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents

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World Journal of Gastroenterology 2016年第1期22卷 394-406页

作者： Hiroyasu Sakai Yohei Shirakami masahito Shimizu Department of Gastroenterology/Internal Medicine Gifu University Graduate School of Medicine

Obesity and its related metabolic disorders are serious health problems worldwide,and lead to various healthrelated complications,including cancer.Among human cancers,hepatocellular carcinoma(HCC)is one of the most common malignancies affected by obesity.Therefore,obesity and its related disorders might be a key target for the prevention of HCC.Recently,new research indicates that the molecular abnormalities associated with obesity,including insulin resistance/hyperinsulinemia,chronic inflammation,adipokine imbalance,and oxidative stress,are possible molecular mechanisms underlying the pathogenesis of obesityrelated hepatocarcinogenesis.Green tea catechins and branched-chain amino acids,both of which are classified as nutraceutical agents,have been reported to prevent obesity-related HCC development by improving metabolic abnormalities.The administration of acyclic retinoid,a pharmaceutical agent,reduced the incidence of HCC in obese and diabetic mice,and was also associated with improvements in insulin resistance and chronic inflammation.In this article,we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals.We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents,and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC.

关键词： Hepatocellular carcinoma Obesity Greentea catechins Branched-chain amino acids Acyclicretinoid

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