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Large animal models for Huntington's disease research

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Zoological Research 2024年第2期45卷 275-283页

作者： Bofeng Han Weien Liang Xiao-Jiang Li Shihua Li Sen Yan Zhuchi Tu Guangdong-Hongkong-Macao CNS Regeneration Institute of Jinan University Key Laboratory of CNS Regeneration(Jinan University)-Ministry of EducationGuangdong Key Laboratory of Non-Human Primate ResearchGuangzhouGuangdong 510632China Department of pathophysiology School of MedicineJinan UniversityGuangzhouGuangdong 510632China

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no ***,the development of appropriate disease models is critical to thoroughly investigate disease *** genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT *** HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain *** models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic *** to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD *** models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment *** have explored the advantages of utilizing large animal models,particularly pigs,in previous *** then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of *** the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic *** also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and *** objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

关键词： Huntington's disease Large animal models Sheep Non-human primates Transgenic pigs

Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

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Neural Regeneration Research 2024年第9期19卷 1973-1980页

作者： Yumei Yue Xiaodan Zhang Wen Lv Hsin-Yi Lai Ting Shen Department of Neurology of Sir Run Run Shaw Hospital Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina Department of Emergency Medicine The University of Hong KongHong Kong Special Administrative RegionChina Department of Neurology of the Second Affiliated Hospital and School of Brain Science and Brain Medicine Interdisciplinary Institute of Neuroscience and TechnologyKey Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouZhejiang ProvinceChina College of Biomedical Engineering and Instrument Science Zhejiang UniversityHangzhouZhejiang ProvinceChina MOE Frontier Science Center for Brain Science and Brain-Machine Integration State Key Laboratory of Brain-machine IntelligenceSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic *** parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related *** glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial *** of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal ***,impairment of the glymphatic system could be considered as the final common pathway to *** evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions *** review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related *** focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and *** review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

关键词： atypical parkinsonism glymphatic system magnetic resonance imaging neurotoxic proteins Parkinson’s disease

LncRNA HCP5-encoded protein contributes to adriamycin resistance through ERK/mTOR pathway-mediated autophagy in breast cancer cells

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Genes & Diseases 2024年第4期11卷 69-72页

作者： Jia-Ni Xing Yi-Ni Shang Zheng-Ling Yu Shun-Heng Zhou Wang-Yang Chen Li-Hong Wang Department of pathophysiology Medical College of Southeast UniversityNanjingJiangsu 210009China Department of Biomedical Engineering Nanjing University of Aeronautics and AstronauticsNanjingJiangsu 211106China School of Medicine Taizhou UniversityTaizhouZhejiang 318000China Jiangsu Provincial key laboratory of Critical Care Medicine NanjingJiangsu 210009China

Adriamycin(ADR),also known as doxorubicin,is an anthracycline anticancer drug and a chemotherapeutic drug commonly used in breast cancer treatments.1 However,breast cancer patients can gradually become tolerant to ***,improving the curative effect of ADR remains an urgent problem to be *** is a complex catabolic process;normal living cells break down damaged organelles or aggregated molecules and absorb energy to maintain homeostasis through autophagy.

关键词： breast cancer homeostasis

Gut microbial-host-isozymes are new targets for diseases

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Science China(Life Sciences) 2024年第7期67卷 1525-1527页

作者： Zhiwei Zhang Kai Wang Changtao Jiang Department of Physiology and pathophysiology School of Basic Medical SciencesState Key Laboratory of Female Fertility PromotionCenter for Reproductive MedicinePeking UniversityBeijing 100191China Center for Obesity and Metabolic Disease Research School of Basic Medical SciencesState Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijing 100191China

Gut microbiota can interact with the host through lots of media including small molecular metabolites and proteins(Cani,2019;Fan and Pedersen,2021;Krautkramer et al.,2021).Recently,a new interaction pattern was identified,i.e.,gut microbiota can mimic the function of the host by producing a variety of enzymes with functions homologous to host enzymes.

关键词： diseases pattern

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A Novel Poly(3-hexylthiophene) Engineered Interface for Electrochemical Monitoring of Ascorbic Acid During the Occurrence of Glutamate-Induced Brain Cytotoxic Edemas

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Research 2024年第1期2023卷 301-313页

作者： Zexuan Meng Yuchan Zhang Lu Yang Shuang Zhao Qiang Zhou Jiajia Chen Jiuxi Sui Jian Wang Lizhong Guo Luyue Chang Jialing He Guixue Wang Guangchao Zang Institute of Life Science and Laboratory of Tissue and Cell BiologyLab Teaching and Management CenterChongqing Medical UniversityChongqing 400016China key laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular ImplantsBioengineering College of Chongqing UniversityChongqing 400030China Jinfeng laboratory Chongqing 401329China Department of pathophysiology Chongqing Medical UniversityChongqingChina

Although neuroelectrochemical sensing technology offers unique benefits for neuroscience research,its application is limited by substantial interference in complex brain environments while ensuring biosafety *** this study,we introduced poly(3-hexylthiophene)(P3HT)and nitrogen-doped multiwalled carbon nanotubes(N-MWCNTs)to construct a composite membrane-modified carbon fiber microelectrode(CFME/P3HT-N-MWCNTs)for ascorbic acid(AA)*** microelectrode presented good linearity,selectivity,stability,antifouling,and biocompatibility and exhibited great performance for application in neuroelectrochemical ***,we applied CFME/P3HT-N-MWCNTs to monitor AA release from in vitro nerve cells,ex vivo brain slices,and in vivo living rat brains and determined that glutamate can induce cell edema and AA *** also found that glutamate activated the N-methyl-d-aspartic acid receptor,which enhanced Na^(+) and Cl^(−) inflow to induce osmotic stress,resulting in cytotoxic edema and ultimately AA *** study is the first to observe the process of glutamate-induced brain cytotoxic edema with AA release and to reveal the *** work can benefit the application of P3HT in in vivo implant microelectrode construction to monitor neurochemicals,understand the molecular basis of nervous system diseases,and discover certain biomarkers of brain diseases.

关键词： release microelectrode Engine

The non-canonical poly(A)polymerase FAM46C promotes erythropoiesis

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Journal of Genetics and Genomics 2024年第6期51卷 594-607页

作者： Ke Yang Tiangi Zhu Jiaying Yin Qiaoli Zhangg Jing Li Hong Fan Gajing Han Weiyin Xu Nan Liu Xiang Lv d.e:a Bone Marrow Transplantation Center The First Affliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China Liangzhu laboratory Zhejang UniversityHangzhouZhejang 311121China Institute of HematologyZhejiang UniversityHangzhouZhejiang 311121China The State key laboratory for Complex Severeand Rare DiseasesHaihe Laboratory of Cell EcosystemDepartment of PathophysiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China Medical Epigenetics Research Center Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China

The post-transcriptional regulation of mRNA is a crucial component of gene *** disruption of this process has detrimental effects on the normal development and gives rise to various *** for novel post-transcriptional regulators and exploring their roles are essential for understanding development and *** a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell ***46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific *** demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent ***,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox *** conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.

关键词： FAM46C TENT5C Poly(A)polymerase Erythroblasts Post-transcriptional regulation Erythroid-specific enhancer

Genomic characterization of peritoneal lavage cytology-positive gastric cancer

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Chinese Journal of Cancer Research 2024年第1期36卷 66-77页

作者： Zhouqiao Wu Tingfei Gu Changxian Xiong Jinyao Shi Jingpu Wang Ting Guo Xiaofang Xing Fei Pang Ning He Rulin Miao Fei Shan Yuan Zhou Ziyu Li Jiafu Ji key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China Department of Biomedical Informatics Department of Physiology and PathophysiologyCenter for Noncoding RNA MedicineMOE Key Lab of Cardiovascular SciencesSchool of Basic Medical SciencesPeking UniversityBeijing 100191China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric ***: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric ***: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

关键词： Cytology gastric carcinoma peritoneal metastasis whole exome sequencing

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2992-3008页

作者： Shicheng Fan Yue Gao Pengfei Zhao Guomin Xie Yanying Zhou Xiao Yang Xuan Li Shuaishuai Zhang Frank JGonzalez Aijuan Qu Min Huangb Huichang Bi NMPA key laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial key laboratory of New Drug Screening&Guangdong-Hongkong-Macao Joint laboratory for New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Provincial key laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Physiology and pathophysiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA The State key laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyShenzhen Graduate School of Peking UniversityShenzhen 518055China

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia *** studies also showed that it has therapeutic potential in various liver ***,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain ***,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and *** further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD *** inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced *** factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver *** studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

关键词： Fenofibrate PPARa Hepatomegaly Partial hepatectomy Liver regeneration YAP TEAD Ubiquitination

Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 766-781页

作者： Lei Zhang Jiabing Chen Xiaoying Yang Chuangpeng Shen Jiawen Huang Dong Zhang Naihua Liu Chaonan Liu Yadi Zhong Yingjian Chen Kaijia Tang Jingyi Guo Tianqi Cui Siwei Duan Jiayu Li Shangyi Huang Huafeng Pan Huabing Zhang Xiaoqiang Tang Yongsheng Chang Yong Gao State key laboratory of Traditional Chinese Medicine Syndrome Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina key laboratory of Immune Microenvironment and Disease(Ministry of Education) Tianjin Key Laboratory of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical UniversityTianjinChina Jiangsu key laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina Department of Endocrinology The First Clinical CollegeGuangzhou University of Chinese MedicineGuangdongChina The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine ShenzhenChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor Nanjing University of Chinese MedicineNanjingChina Department of Biochemistry and Molecular Biology Metabolic Disease Research CenterSchool of Basic MedicineAnhui Medical UniversityHefeiChina key laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengduChina

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin *** the details of the underlying mechanisms are not fully ***,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of *** Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin ***,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic ***,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome *** key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in ***,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.

关键词： hepatic Hepatic impaired