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Pathogenic contribution of cholesteryl ester accumulation in the brain to neurodegenerative disorders

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Neural Regeneration Research 2024年第10期19卷 2099-2100页

作者： michiko Shirane Department of Molecular Biology Graduate School of Pharmaceutical SciencesNagoya City UniversityNagoyaJapan

Cholesteryl esters(CEs) have been increasingly implicated in neurodegenerative disorders such as Alzheimer's disease(AD).Alois Alzheimer noted three prominent neuropathologic features in his original analysis of the AD brain:senile plaques,neurofibrillary tangles,and lipid granule accumulation.Senile plaques,which are aggregates of amyloid-beta(Aβ),and neurofibrillary tangles,which are aggregates of phosphorylated tau,have been regarded as more consistent characteristics of the AD brain compared with lipid granule accumulation and thus have been studied more intensively(Foley,2010).

关键词： esters ester cholesteryl

CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy

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Journal of Genetics and Genomics 2024年第2期51卷 184-196页

作者： Yan Shi Chunyan Cao Yiheng Zeng Yuanliang Ding Long Chen Fuze Zheng Xuejiao Chen Fanggui Zhou Xiefeng Yang Jinjing Li Liuqing Xu Guorong Xu Minting Lin Hiroyuki Ishiura Shoji tsuji Ning Wang Zhiqiang Wang Wan-Jin Chen Kang Yang Department of Neurology and Institute of Neurology of First Affiliated Hospital Institute of NeuroscienceFujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouFujian 350005China Department of Neurology National Regional Medical CenterBinhai Campus of the First Affiliated HospitalFujian Medical UniversityFuzhouFujian 350212China The First Affiliated Hospital College of Clinical Medicine of Henan University of Science and TechnologyLuoyangHenan 471000China Department of Neurology Zhangzhou Municipal Hospital of Fujian Province and Zhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhouFujian 363000China Department of Neurology Jian'ou Municipal Hospital of Fujian ProvinceJian'ouFujian 353100China Department of Radiology First Affiliated Hospital of Fujian Medical UniversityFuzhouFujian 350005China Department of Neurology Graduate School of MedicineThe University of TokyoTokyo 113-8655Japan Department of Neurology Okayama University Graduate School of MedicineDentistry and Pharmaceutical SciencesOkayama 700-8558Japan Institute of Medical Genomics International University of Health and WelfareChiba 286-0048Japan

CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy.However,since only three patients from a single family were reported,it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1.Here,using repeat-primed-polymerase chain reaction and long-read sequencing,we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1,typically presenting with oculopharyngodistal myopathy.The CGG repeat expansions range from 161 to 669 repeat units.Most of the patients present with ptosis,restricted eye movements,dysphagia,dysarthria,and diffuse limb muscle weakness.Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging.Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles.Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity,suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis.Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.

关键词： Oculopharyngeal myopathy with leukoencephalopathy Oculopharyngodistal myopathy CGG repeat expansion Rimmed vacuoles

Mesenchymal stem cells-derived extracellular vesicles as‘natural’drug delivery system for tissue regeneration

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BIOCELL 2022年第4期46卷 899-902页

作者： KENJI tsuji SHINJI KITAMURA JUN WADA Department of Nephrology RheumatologyEndocrinology and MetabolismOkayama University Academic Field of MedicineDentistry and Pharmaceutical SciencesOkayama700-8558Japan

Mesenchymal stem cells(MSCs)have abilities to mediate tissue protection through mechanisms of antiapoptosis,anti-oxidative stress and anti-fibrosis as well as tissue regeneration through mechanisms of cell proliferation,differentiation and angiogenesis.These effects by MSCs are mediated by a variety of factors,including growth factors,cytokines and extracellular vesicles(EVs).Among these factors,EVs,containing proteins,mRNA and microRNAs(miRNA),may carry their contents into distant tissues with high stability.Therefore,the treatment with MSC-derived EVs may be promising as‘natural’drug delivery systems(DDS).Especially,the treatment of MSCderived EVs with the manipulation of specific miRNAs expression has been reported to be beneficial under a variety of diseases and tissue injuries.The overexpression of specific miRNAs in the EVs might be through pre-loading method using the gene editing system by plasmid vector or post-loading method to load miRNA mimics into EVs by electroporation or calcium chloride-mediated transfection.Despite current several challenges for clinical use,it should open the next era of regenerative medicine for a variety of diseases.In this article,we highlight the therapeutic potential of MSC-derived EVs as‘natural’DDS and current challenges.

关键词： Mesenchymal stem cells Extracellular vesicles Drug delivery system microRNA Regeneration

Promising role of D-amino acids in irritable bowel syndrome

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World Journal of Gastroenterology 2022年第31期28卷 4471-4474页

作者： Yuka Ikeda Kurumi Taniguchi Haruka Sawamura Ai tsuji Satoru Matsuda Department of Food Science and Nutrition Nara Women's UniversityNara 630-8506Japan

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 Damino 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.

关键词： Irritable bowel syndrome D-amino acid Gut microbiota Colitis Probiotics Fecal microbiota transplantation

Efficacy of probiotics on the modulation of gut microbiota in the treatment of diabetic nephropathy

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World Journal of Diabetes 2022年第3期13卷 150-160页

作者： Nozomi Nagase Yuka Ikeda Ai tsuji Yasuko Kitagishi Satoru Matsuda Department of Food Science and Nutrition Nara Women's UniversityNara 630-8506Japan

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.

关键词： Diabetic nephropathy Short chain fatty acids Superoxide dismutase Reactive oxygen species D-amino acids Gut microbiota Diabetes mellitus Renal disease

In-situ observation of twinning and detwinning in AZ31 alloy

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Journal of Magnesium and Alloys 2022年第12期10卷 3418-3432页

作者： Wu Gong Ruixiao Zheng Stefanus Harjo Takuro Kawasaki Kazuya Aizawa Nobuhiro tsuji J-PARC Center Japan Atomic Energy Agency2-4 Shirane ShirakataTokaiNakaIbaraki 319-1195Japan Center for Elements Strategy Initiative for Structural Materials Kyoto UniversityYoshidahonmachiSakyo-kuKyoto 606-8501Japan Department of Materials Science and Engineering Kyoto UniversityYoshida-honmachiSakyo-kuKyoto 606-8501Japan School of Materials Science and Engineering Beihang UniversityBeijing 100191China

Twinning and detwinning behavior of a commercial AZ31 magnesium alloy during cyclic compression–tension deformation with a total strain amplitude of 4%(±2%) was evaluated using the complementary techniques of in-situ neutron diffraction, identical area electron backscatter diffraction, and transmission electron microscopy. In-situ neutron diffraction demonstrates that the compressive deformation was dominated by twin nucleation, twin growth, and basal slip, while detwinning dominated the unloading of compressive stresses and subsequent tension stage. With increasing number of cycles from one to eight: the volume fraction of twins at-2% strain gradually increased from 26.3% to 43.5%;the residual twins were present after 2% tension stage and their volume fraction increased from zero to 3.7% as well as a significant increase in their number;and the twinning spread from coarse grains to fine grains involving more grains for twinning. The increase in volume fraction and number of residual twins led to a transition from twin nucleation to twin growth, resulting in a decrease in yield strength of compression deformation with increasing cycles. A large number of-component dislocations observed in twins and the detwinned regions were attributed to the dislocation transmutation during the twinning and detwinning. The accumulation of barriers including twin boundaries and various types of dislocations enhanced the interactions of migrating twin boundary with these barriers during twinning and detwinning, which is considered to be the origin for increasing the work hardening rate in cyclic deformation of the AZ31 alloy.

关键词： Magnesium Neutron diffraction Twinning Detwinning Dislocation transmutation

Insulin sensitivity and inhibition by forskolin,dipyridamole and pentobarbital of glucose transport in three L6 muscle cell lines

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Science China(Life Sciences) 2007年第6期50卷 739-747页

作者： Philip J BILAN michiko HAYASHI Programme in Cell Biology Hospital for Sick Children Toronto Canada M5G 1X8

L6 skeletal muscle myoblasts stably overexpressing glucose transporter GLUT1 or GLUT4 with exofa- cial myc-epitope tags were characterized for their response to insulin. In clonally selected cultures, 2-deoxyglucose uptake into L6-GLUT1myc myoblasts and myotubes was linear within the time of study. In L6-GLUT1myc and L6-GLUT4myc myoblasts, 100 nmol/L insulin treatment increased the GLUT1 content of the plasma membrane by 1.58±0.01 fold and the GLUT4 content 1.96±0.11 fold, as well as the 2-deoxyglucose uptake 1.53±0.09 and 1.86±0.17 fold respectively, all by a wortmannin-inhibitable manner. The phosphorylation of Akt in these two cell lines was increased by insulin. L6-GLUT1myc myoblasts showed a dose-dependent stimulation of glucose uptake by insulin, with unaltered sensitiv- ity and maximal responsiveness compared with wild type cells. By contrast, the improved insulin re- sponsiveness and sensitivity of glucose uptake were observed in L6-GLUT4myc myoblasts. Earlier studies indicated that forskolin might affect insulin-stimulated GLUT4 translocation. A 65% decrease of insulin-stimulated 2-deoxyglucose uptake in GLUT4myc cells was not due to an effect on GLUT4 mobi- lization to the plasma membrane, but instead on direct inhibition of GLUT4. Forskolin and dipyridamole are more potent inhibitors of GLUT4 than GLUT1. Alternatively, pentobarbital inhibits GLUT1 more than GLUT4. The use of these inhibitors confirmed that the overexpressed GLUT1 or GLUT4 are the major functional glucose transporters in unstimulated and insulin-stimulated L6 myoblasts. Therefore, L6-GLUT1myc and L6-GLUT4myc cells provide a platform to screen compounds that may have differ- ential effects on GLUT isoform activity or may influence GLUT isoform mobilization to the cell surface of muscle cells.

关键词： L6 muscle cells, glucose transporter (GLUT), insulin, 2-deoxyglucose uptake

Secretome-microRNA and anti-proliferative APRO family proteins as cancer prevention and stem cell research strategies

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BIOCELL 2022年第5期46卷 1163-1167页

作者： YUKA IKEDA NOZOMI NAGASE AI tsuji KURUMI TANIGUCHI YASUKO KITAGISHI SATORU MATSUDA Department of Food Science and Nutrition Nara Women’s UniversityNara630-8506Japan

Stemness of cancer cells contains limitless self-renewal proliferation.For the purpose of proliferation,secretome might exert its effects via the paracrine signaling.Specific microRNAs enclosed in the secretome of cancer stem cells could regulate the expression of anti-proliferative APRO family proteins.The biological functions of APRO family proteins seems to be quite intricate,however,which might be a key modulator of microRNAs,then could regulate the proliferation of cancer cells.In addition to affecting proliferation/differentiation during cellular development,APRO family proteins might also play an imperious role on keeping homeostasis in healthy stem cells under a physiological condition.Therefore,relationship between the microRNAs and the APRO family proteins has attracted much attention in the field of cancer research and regenerative medicine.Here,we have described the molecular mechanism behind this interplay that have a potential role in the future promising tools with targeting APRO family proteins for the medical applications.

关键词： Cancer Stem cell Secretome Proliferation APRO family microRNA

Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury: a single-arm study

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Neural Regeneration Research 2022年第2期17卷 427-432页

作者： Hiroki Okawara Syoichi Tashiro Tomonori Sawada Keiko Sugai Kohei Matsubayashi Michiyuki Kawakami Satoshi Nori Osahiko tsuji Narihito Nagoshi Morio Matsumoto Masaya Nakamura Department of Orthopaedic Surgery Keio University School of MedicineTokyoJapan Department of Rehabilitation Medicine Keio University School of MedicineTokyoJapan Department of Orthopedic Surgery National Hospital OrganizationMurayama Medical CenterTokyoJapan

Body weight-supported treadmill training with the voluntary driven exoskeleton(VDE-BWSTT) has been shown to improve the gait function of patients with chronic spinal cord injury. However, little is known whether VDE-BWSTT can effectively improve the trunk function of patients with chronic spinal cord injury. In this open-label, single-arm study, nine patients with chronic spinal cord injury at the cervical or thoracic level(six males and three females, aged 37.8 ± 15.6 years, and time since injury 51.1 ± 31.8 months) who underwent outpatient VDE-BWSTT training program at Keio University Hospital, Japan from September 2017 to March 2019 were included. All patients underwent twenty 60-minute gait training sessions using VDE. Trunk muscular strength, i.e., the maximum force against which patient could maintain a sitting posture without any support, was evaluated in four directions: anterior, posterior, and lateral(right and left) after 10 and 20 training sessions. After intervention, lateral muscular strength significantly improved. In addition, a significant positive correlation was detected between the change in lateral trunk muscular strength after 20 training sessions relative to baseline and gait speed. The change in trunk muscular strength after 20 training sessions relative to baseline was greatly correlated with patient age. This suggests that older adult patients with chronic spinal cord injury achieved a greater improvement in trunk muscle strength following VDE-BWSTT. All these findings suggest that VDE-BWSTT can improve the trunk function of patients with chronic spinal cord injury and the effect might be greater in older adult patients. The study was approved by the Keio University of Medicine Ethics Committee(IRB No. 20150355-3) on September 26, 2017.

关键词： body weight-supported treadmill training gait disorders hybrid assistive limb neurologic neurophysiotherapy postural balance precision medicine robot-assisted gait training robotics spinal cord injury trunk