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Bile acids and sphingolipids in non-alcoholic fatty liver disease

Chinese Medical Journal 2022年第10期135卷 1163-1171页

作者： Kaitlyn G.Jackson Grayson W.Way Huiping Zhou Department of Microbiology and Immunology Virginia Commonwealth University School of MedicineRichmondVA 23298USA center for Clinical and translational research Virginia Commonwealth University School of MedicineRichmondVA 23298USA Central Virginia Veterans Healthcare System RichmondVA 23249USA.

Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

关键词： Bile acids Sphingolipids Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis

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A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

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Neural Regeneration research 2023年第10期18卷 2141-2146页

作者： Angelina S.Bortoletto Ronald J.Parchem center for Cell and Gene Therapy Stem Cell and Regenerative Medicine CenterDepartment of NeuroscienceDepartment of Molecular and Cellular BiologyTranslational Biology and Molecular Medicine ProgramMedical Scientist Training ProgramBaylor College of MedicineHoustonTXUSA

Type 2 diabetes mellitus patients have a markedly higher risk of developing *** multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes *** amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are *** this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of *** discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced *** are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at ***,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating *** such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

关键词： Alzheimer’s disease amylin amyloid dementia diabetes human islet amyloid polypeptide islet amyloid polypeptide protofibrils type 2 diabetes mellitus vascular dementia

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Genome engineering technologies in rabbits

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The Journal of Biomedical research 2021年第2期35卷 135-147页

作者： Jun Song Jifeng Zhang Jie Xu Minerva Garcia-Barrio Y.Eugene Chen Dongshan Yang center for Advanced Models for translational Sciences and Therapeutics University of Michigan Medical CenterAnn ArborMI 48109USA

The rabbit has been recognized as a valuable model in various biomedical and biological research fields because of its intermediate size and phylogenetic proximity to ***,the technology for precise genome manipulations in rabbit has been stalled for decades,severely limiting its applications in biomedical *** genome editing technologies,especially CRISPR/Cas9,have remarkably enhanced precise genome manipulation in rabbits,and shown their superiority and promise for generating rabbit models of human genetic *** this review,we summarize the brief history of transgenic rabbit technology and the development of novel genome editing technologies in rabbits.

关键词： rabbit transgenic animal gene targeting genome editing base editing

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Signaling pathways in obesity:mechanisms and therapeutic interventions

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3405-3435页

作者： Xue Wen Bohan Zhang Beiyi Wu aitao Xiao Zehua Li Ruoyu Li Xuewen Xu Tao Li Department of Plastic and Burn Surgery National Clinical Research Center for GeriatricsWest China Hospital of Sichuan UniversityChengdu 610041China Laboratory of Mitochondria and Metabolism West China Hospital of Sichuan UniversityChengdu 610041China Department of Anesthesiology National-Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China Hospital of Sichuan UniversityChengdu 610041China

Obesity is a complex,chronic disease and global public health *** by excessive fat accumulation in the body,obesity sharply increases the risk of several diseases,such as type 2 diabetes,cardiovascular disease,and nonalcoholic fatty liver disease,and is linked to lower life *** lifestyle intervention(diet and exercise)has remarkable effects on weight management,achieving long-term success at weight loss is extremely challenging,and the prevalence of obesity continues to rise *** the past decades,the pathophysiology of obesity has been extensively investigated,and an increasing number of signal transduction pathways have been implicated in obesity,making it possible to fight obesity in a more effective and precise *** this review,we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies,focusing on signaling pathways and their roles in the regulation of food intake,glucose homeostasis,adipogenesis,thermogenesis,and chronic *** also discuss the current antiobesity drugs,as well as weight loss compounds in clinical trials,that target these *** evolving knowledge of signaling transduction may shed light on the future direction of obesity research,as we move into a new era of precision medicine.

关键词： obesity homeostasis sharply

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Opening a window to skin biomarkers for diabetes stage with optoacoustic mesoscopy

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Light(Science & Applications) 2023年第11期12卷 2335-2349页

作者： Hailong He Nikolina-Alexia Fasoula Angelos Karlas Murad Omar Juan Aguirre Jessica Lutz Michael Kallmayer Martin Fuchtenbusch Hans-Henning Eckstein Annette Ziegler Vasilis Ntziachristos Institute of Biological and Medical Imaging Helmholtz Zentrum MunchenNeuherbergGermany Chair of Biological Imaging at the Central Institute for translational Cancer research(TranslaTUM) School of MedicineTechnical University of MunichMunichGermany Department for Vascular and Endovascular Surgery Klinikum rechts der IsarTechnical University of Munich(TUM)MunichGermany DZHK(German Centre for Cardiovascular research) partner site Munich Heart AllianceMunichGermany diabetes center at Marienplatz MunichGermany Forschergruppe diabetes e.V. Helmholtz Zentrum MunchenNeuherbergGermany Institute of diabetes research Helmholtz Zentrum MunchenNeuherbergGermany

Being the largest and most accessible organ of the human body,the skin could offer a window to diabetes-related complications on the ***,skin microvasculature is typically assessed by histological analysis,which is not suited for applications to large populations or longitudinal *** introduce ultra-wideband rasterscan optoacoustic mesoscopy(RSOM)for precise,non-invasive assessment of diabetes-related changes in the dermal microvasculature and skin micro-anatomy,resolved with unprecedented sensitivity and detail without the need for contrast *** unique imaging contrast,we explored a possible role for RSOM as an investigational tool in diabetes healthcare and offer the first comprehensive study investigating the relationship between different diabetes complications and microvascular features in *** applied RSOM to scan the pretibial area of 95 participants with diabetes mellitus and 48 age-matched volunteers without diabetes,grouped according to disease complications,and extracted six label-free optoacoustic biomarkers of human skin,including dermal microvasculature density and epidermal parameters,based on a novel image-processing *** then correlated these biomarkers to disease severity and found statistically significant effects on microvasculature parameters as a function of diabetes *** discuss how label-free RSOM biomarkers can lead to a quantitative assessment of the systemic effects of diabetes and its complications,complementing the qualitative assessment allowed by current clinical metrics,possibly leading to a precise scoring system that captures the gradual evolution of the disease.

关键词： diabetes anatomy precise

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A systematic review of metabolomic profiling of gastric cancer and esophageal cancer

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Cancer Biology & Medicine 2020年第1期17卷 181-198页

作者： Sha Huang Yang Guo Zhexuan Li Yang Zhang Tong Zhou Weicheng You Kaifeng Pan Wenqing Li Key Laboratory of Carcinogenesis and translational research(Ministry of Education/Beijing) Department of Cancer EpidemiologyPeking University Cancer Hospital&InstituteBeijing 100142China Joint International research center of translational and Clinical research Beijing 100142China

Objective:Upper gastrointestinal(UGI)cancers,predominantly gastric cancer(GC)and esophageal cancer(EC),are malignant tumor types with high morbidity and mortality *** studies have focused on metabolomic profiling of UGI cancers in recent *** this systematic review,we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with GC and ***:A systematic search of three databases(Embase,PubMed,and Web of Science)for molecular epidemiologic studies on the metabolomic profiles of GC and EC was *** Newcastle–Ottawa Scale(NOS)was used to assess the quality of the included ***:A total of 52 original studies were included for review.A number of metabolites were differentially distributed between GC and EC cases and non-cases,including those involved in glycolysis,anaerobic respiration,tricarboxylic acid cycle,and protein and lipid *** acid,glucose,citrate,and fumaric acid were among the most frequently reported metabolites of cellular respiration while glutamine,glutamate,and valine were among the most commonly reported amino *** lipid metabolites identified previously included saturated and unsaturated free fatty acids,aldehydes,and ***,the key findings across studies to date have been inconsistent,potentially due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication ***:Studies on metabolomics have thus far provided insights into etiological factors and biomarkers for UGI cancers,supporting the potential of applying metabolomic profiling in cancer prevention and management efforts.

关键词： Gastric cancer esophageal cancer metabolomics Warburg effect biomarkers

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Bile acids and their effects on diabetes

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Frontiers of Medicine 2018年第6期12卷 608-623页

作者： Cynthia Rajani Wei Jia University of Hawaii Cancer center HonoluluHI 96813USA Shanghai Key Laboratory of diabetes Mellitus and center for translational Medicine Shanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai 200233China

diabetes is a widespread, rapidly increasing metabolic disease that is driven by hyperglycemia. Early glycemic control is of primary importance to avoid vascular complications including development of retinal disorders leading to blindness, end-stage renal disease, and accelerated atherosclerosis with a higher risk of myocardial infarction, stroke and limb amputations. Even after hyperglycemia has been brought under control, “metabolic memory,” a cluster of irreversible metabolic changes that allow diabetes to progress, may persist depending on the duration of hyperglycemia. Manipulation of bile acid (BA) receptors and the BA pool have been shown to be useful in establishing glycemic control in diabetes due to their ability to regulate energy metabolism by binding and activating nuclear transcription factors such as farnesoid X receptor (FXR) in liver and intestine as well as the G-protein coupled receptor, TGR5, in enteroendocrine cells and pancreatic -cells. The downstream targets of BA activated FXR, FGF15/21, are also important for glucose/insulin homeostasis. In this review we will discuss the effect of BAs on glucose and lipid metabolism and explore recent research on establishing glycemic control in diabetes through the manipulation of BAs and their receptors in the liver, intestine and pancreas, alteration of the enterohepatic circulation, bariatric surgery and alignment of circadian rhythms.

关键词： bile acids metabolic memory diabetes circadian rhythm bariatric surgery

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Gasdermin D Inhibitor Necrosulfonamide Alleviates Lipopolysaccharide/D-galactosamine-induced Acute Liver Failure in Mice

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Journal of Clinical and translational Hepatology 2022年第6期10卷 1148-1154页

作者： Yi-Long Wu Wei-Jie Ou Ming Zhong Su Lin Yue-Yong Zhu Endoscopy center the First Affiliated HospitalFujian Medical UniversityFuzhouFujianChina Department of Hepatol-ogy Hepatology Research Institutethe First Affiliated HospitalFujian Medical UniversityFuzhouFujianChina Endocri-nology Department Metabolic Diseases Research Institutethe First Affiliated HospitalFujian Medical UniversityFuzhouFujianChina Fujian diabetes research Institute the First Affiliated HospitalFujian Medical UniversityFuzhouFujianChina Clinical research center for Liver and Intestinal Diseases of Fujian Province FuzhouFujianChina

Background and Aims:Acute liver failure(ALF)is as-sociated with high *** D(GSDMD)is the executioner of pyroptosis and is involved in the patho-physiology of immune dysregulation This study investi-gated the role of the GSDMD inhibitor necrosulfonamide(NSA)in ***:An ALF model was established by lipopolysaccharide/D-galactosamine challenge in C57BL/6J *** were divided into four groups:normal controls(control group),ALF group(ALF group),dimethyl sulfoxide group(DMSO group),and NSA intervention group(NSA group).Survival was monitored,liver damage was de-termined by hematoxylin and eosin staining,and serum alanine aminotransferase(ALT).Underlying mechanisms were explored by quantitative real-time PCR,western blot-ting,and enzyme-linked immunosorbent ***:Pyroptosis was activated in ALF model *** treat-ed with GSDMD inhibitor NSA developed less severe liver *** reduced the expression of GSDMD,NLRP3,cleaved caspase-1,cleaved caspase-11,and secretion of interleukin-1 beta in ALF mice ***:Py-roptosis was activated in *** alleviated ALF via the pyroptosis pathway.

关键词： Liver failure Acute Pyroptosis GSDMD GSDMD-NT Necrosul-fonamide

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Neutrophils as key regulators of tumor immunity that restrict immune checkpoint blockade in liver cancer

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Cancer Biology & Medicine 2023年第6期20卷 421-437页

作者： Mei Feng Fangyanni Wang Xinyu Liu Tingting Hao Ning Zhang Mi Deng Yisheng Pan Ruirui Kong translational Cancer research center Peking University First HospitalBeijing 100034China Division of General Surgery Peking University First HospitalBeijing 100034China International Cancer Institute Peking University Health Science CenterBeijing 100191China Yunnan Baiyao Group Kunming 650500ChinaDivision of General SurgeryPeking University First HospitalBeijing 100034China

Objective:Liver cancer is a deadly malignancy associated with high mortality and *** than 20%of patients with advanced liver cancer respond to a single anti-PD-1 *** high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade(ICB).However,the underlying mechanism remains largely ***:We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12Dinto the genome in liver cells from conditional Trp53 null/null mice(pTMK/Trp53^(-/-)).Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor *** ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils(TANs)on CD8^(+)T *** roles of neutrophils,T cells,and NK cells were validated through antibody-mediated *** efficacy of the combination of neutrophil depletion and ICB was ***:Orthotropic pTMK/Trp53^(-/-)mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 *** of neutrophils increased the infiltration of CD8^(+)T cells and decreased the number of exhausted T cells in the tumor ***,depletion of either CD8^(+)T or NK cells abrogated the antitumor efficacy of anti-Ly6G ***,the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8^(+)T cells and thereafter resulted in a significantly greater decrease in tumor ***:Our data suggest that TANs may contribute to the resistance of liver cancer to ICB,and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.

关键词： Liver cancer neutrophil PD-1,CD8^(+)T cell exhaustion

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Protein ubiquitination in plant peroxisomes

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Journal of Integrative Plant Biology 2023年第2期65卷 371-380页

作者： Delara Akhter Yuchan Zhang Jianping Hu Ronghui Pan State Key Laboratory of Rice Biology Zhejiang Provincial Key Laboratory of Crop Genetic ResourcesCollege of Agriculture and Biotechnology&ZJU-Hangzhou Global Scientific and Technological Innovation CenterZhejiang UniversityHangzhou 310058/311200China Zhejiang Laboratory Hangzhou 311121China Department of Genetics and Plant Breeding Sylhet Agricultural UniversitySylhet 3100Bangladesh Department of Energy Plant research Laboratory and Plant Biology Department Michigan State UniversityEast LansingMichiganUSA Department of Plant Biology Michigan State UniversityEast LansingMichiganUSA

Protein ubiquitination regulates diverse cellular processes in eukaryotic organisms,from growth and development to stress *** subjected to ubiquitination can be found in virtually all subcellular locations and organelles,including peroxisomes,singlemembrane and highly dynamic organelles ubiquitous in *** contain metabolic functions essential to plants and animals such as lipid catabolism,detoxification of reactive oxygen species(ROS),biosynthesis of vital hormones and cofactors,and *** peroxisomes possess a complex proteome with functions varying among different tissue types and developmental stages,and during plant response to distinct environmental ***,how these diverse functions are regulated at the post-translational level is poorly understood,especially in *** this review,we summarized current knowledge of the involvement of protein ubiquitination in peroxisome protein import,remodeling,pexophagy,and metabolism,focusing on plants,and referencing discoveries from other eukaryotic systems when *** on previous ubiquitinomics studies,we compiled a list of 56 ubiquitinated Arabidopsis peroxisomal proteins whose functions are associated with all the major plant peroxisomal metabolic *** discovery suggests a broad impact of protein ubiquitination on plant peroxisome functions,therefore substantiating the need to investigate this significant regulatory mechanism in peroxisomes at more depths.

关键词： peroxins peroxisome peroxisome biogenesis peroxisome metabolism pexophagy ubiquitination

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