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Frontiers of Medicine 2022年第5期16卷 667-685页

作者： Yuqiu Han Lanjuan Li Baohong Wang State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Research Units of Infectious disease and Microecology Chinese Academy of Medical SciencesHangzhou 310003China Jinan Microecological Biomedicine Shandong Laboratory Jinan 250117China

Nonalcoholic fatty liver disease(NAFLD)is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer.Akkermansia muciniphila(A.muciniphila)is a next-generation probiotic that has been reported to improve metabolic disorders.Emerging evidence indicates the therapeutic potential of A.muciniphila for NAFLD,especially in the inflammatory stage,nonalcoholic steatohepatitis.Here,the current knowledge on the role of A.muciniphila in the progression of NAFLD was summarized.A.muciniphila abundancy is decreased in animals and humans with NAFLD.The recovery of A.muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD.The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed.The modulation mechanisms by which A.muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells(such as macrophages).This review provides insights into the roles of A.muciniphila in NAFLD,thereby providing a blueprint to facilitate clinical therapeutic applications.

关键词： Akkermansia muciniphila NAFLD NASH steatosis inflammation

Krüppel-like factor 10 (KLF10) as a critical signaling mediator: Versatile functions in physiological and pathophysiological processes

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Genes & Diseases 2023年第3期10卷 915-930页

作者： Hong-Yang Luo Jie-Ying Zhu Min Chen Wang-Jing Mu Liang Guo Shanghai Frontiers Science Research Base of Exercise and Metabolic Health Shanghai University of SportShanghai 200438China School of Kinesiology Shanghai University of SportShanghai 200438China

Krüppel-like factor 10 (KLF10), also known as TGFβ-inducible early gene-1 (TIEG1), was first found in human osteoblasts. Early studies show that KLF10 plays an important role in osteogenic differentiation. Through decades of research, KLF10 has been found to have complex functions in many different cell types, and its expression and function is regulated in multiple ways. As a downstream factor of transforming growth factor β (TGFβ)/SMAD signaling, KLF10 is involved in various biological functions, including glucose and lipid metabolism in liver and adipose tissue, the maintenance of mitochondrial structure and function of the skeletal muscle, cell proliferation and apoptosis, and plays roles in multiple disease processes, such as nonalcoholic steatohepatitis (NASH) and tumor. Besides, KLF10 shows gender-dependent difference of regulation and function in many aspects. In this review, the biological functions of KLF10 and its roles in disease states is updated and discussed, which would provide new insights into the functional roles of KLF10 and a clearer view of potential therapeutic strategies by targeting KLF10.

关键词： Adipose tissue Estrogen signaling Glucose and lipid metabolism NASH Obesity Skeletal muscle TGFβ/SMAD signaling Tumor

Tumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies

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Journal of Genetics and Genomics 2022年第4期49卷 269-278页

作者： Sijia Lu Yibing Wang Junli Liu Shanghai Diabetes Institute Department of Endocrinology and MetabolismShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai 200233China School of Kinesiology Shanghai University of SportsShanghai 200438China

Nonalcoholic steatohepatitis(NASH),an inflammatory subtype of nonalcoholic fatty liver disease,is featured by significantly elevated levels of various proinflammatory cytokines.Among numerous proinflammatory factors that contribute to NASH pathogenesis,the secreted protein,tumor necrosis factoralpha(TNF-α),plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target.In this review,we will first systematically describe the preclinical studies on the biochemical function of TNF-αand its intracellular downstream signaling mechanisms through its receptors.Moreover,we extensively discuss its functions in regulating inflammation,cell death,and fibrosis of liver cells in the pathogenesis of NASH,and the molecular mechanism that TNF-αexpression is regulated by NF-κB and other upstream master regulators during NASH progression.As TNF-αis one of the causal factors that remarkably contributes to NASH progression,combination of therapeutic modalities,including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits.For translational studies,we summarize recent advances in strategies targeting TNF-αand its signaling pathway,which paves the way for potential therapeutic treatments for NASH in the future.

关键词： TNF-αsignaling NASH Inflammation Cell death Fibrosis

The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1071-1092页

作者： Minxuan Xu Jun Tan Liancai Zhu Chenxu Ge Wei Dong Xianling Dai Qin Kuang Shaoyu Zhong Lili Lai Chao Yi Qiang Li Deshuai Lou Linfeng Hu Xi Liu Gang Kuang Jing Luo Jing Feng Bochu Wang Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region School of Biological and Chemical EngineeringChongqing University of EducationChongqing 400067China College of Modern Health Industry Chongqing University of EducationChongqing 400067China Key Laboratory of Biorheological Science and Technology(Chongqing University) Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400030China Shandong Cancer Hospital and Institute Shandong First Medical University&Shandong Academy of Medical SciencesJinan 250117China

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis(NASH)have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated.Inactive rhomboid protein 2(IRHOM2),a promising target for treatment of inflammation-related diseases,contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis(NASH)progression.However,the molecular mechanism underlying Irhom2 regulation is still not completely understood.In this work,we identify the ubiquitin-specific protease 13(USP13)as a critical and novel endogenous blocker of IRHOM2,and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes.Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis,followed by glycometabolic disorder,lipid deposition,increased inflammation,and markedly promotes NASH development.Conversely,transgenic mice with Usp13 overexpression,lentivirus(LV)-or adeno-associated virus(AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent.Mechanistically,in response to metabolic stresses,USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N(UBC13),a ubiquitin E2 conjugating enzyme,and thus prevents its activation of downstream cascade pathway.USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

关键词： Usp13 Irhom2 NASH Hepatosteatosis Ubc13 NAFLD Ubiquitination Liver inflammation

Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs-EBP interaction recover NAFLD through enhancing mitochondrial function in mice

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Acta Pharmaceutica Sinica B 2023年第2期13卷 542-558页

作者： Nazi Song Hongjiao Xu Shuohan Wu Suijia Luo Jingyao Xu Qian Zhao Rui Wang Xianxing Jiang School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 511400China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China School of Life Sciences Key Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical Sciences&Research Unit of Peptide ScienceLanzhou UniversityLanzhou 730000China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China

Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.

关键词： NASH Liver fibrosis Combination therapy Mitochondrial function Mitophagy Mitochondrial biogenesis AMPK EDPs AdipoR1/2 agonist

Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3869-3878页

作者： Joseph L.Jilek Kayla L.Frost Kevyn A.Jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational Sciences Rutgers UniversityPiscatawayNJ 08901USA

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.

关键词： Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity

竹节参总皂苷通过调节miR-199/SIRT1/MFN2干预小鼠脂肪性肝炎

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中国药理学通报 2022年第6期38卷 898-903页

作者：袁丁罗芙娇王婷周志勇何毓敏刘朝奇张长城袁成福三峡大学医学院湖北宜昌443002 武汉科技大学医学院湖北武汉430081

目的研究竹节参总皂苷(total saponins of Panax japonicas,TSPJ)通过调节miR-199/SIRT1/MFN2信号通路改善非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)的作用及相关机制。方法45只BALB/c小鼠随机分为正常组、高脂饮食(high fat diet,HFD)组、TSPJ低剂量组、TSPJ高剂量组,正常组给予普通维持饲料,HFD组、TSPJ低、高剂量组给予高脂饲料。TSPJ低、高剂量组小鼠分别每天灌胃给予15、45 mg·kg^(-1)的TSPJ(溶于生理盐水),其他组每天灌胃等量的生理盐水。持续7个月后处死小鼠,进行血清收集及肝脏取材。结果HE染色显示,HFD组小鼠肝脏脂质变性明显,炎症反应明显,TSPJ组小鼠肝组织脂质变性缓解,炎症减轻。TSPJ明显上调MFN2、SIRT1表达水平,下调TNF-α、IL-1β、SREBP、ChREBP表达水平。同时在mRNA水平,miR-199与SIRT1显示良好的负调控关系,生物信息学提示miR-199靶向SIRT1。结论TSPJ可通过miR-199/SIRT1/MFN2信号通路改善高脂饮食所致的NASH的发生发展。

关键词： NASH miR-199/SIRT1/MFN2信号通路竹节参总皂苷白细胞介素1β 肿瘤坏死因子-α 炎症

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目的地品牌建设中的旅游供应链合作研究

运筹与管理 2023年第6期32卷 138-144页

作者：孙勇樊杰孙中瑞乔琴广州大学公共管理学院广东广州510006 中国科学院科技战略咨询研究院北京100190 中国环境科学研究院生态研究所北京100012

目的地品牌协作有利于增强一个区域的核心竞争力,已有研究关注了目的地的利益相关者协作问题,但较少关注目的地品牌建设的供应链协作。基于微分博弈理论,建立由旅游景区和旅游企业构成的旅游目的地供应链长期纵向品牌建设合作问题。结... 详细信息

目的地品牌协作有利于增强一个区域的核心竞争力,已有研究关注了目的地的利益相关者协作问题,但较少关注目的地品牌建设的供应链协作。基于微分博弈理论,建立由旅游景区和旅游企业构成的旅游目的地供应链长期纵向品牌建设合作问题。结果表明:集中决策模式下旅游目的地品牌竞争力和供应链整体利润均显著高于同时决策和主从决策,旅游供应链上下游之间的协作是有效提高品牌竞争力的方式;景区和旅游企业之间的利润分成对集中决策情形下供应链总体利润无影响,但对同时决策和主从决策的影响较大;不同决策模式均显示,品牌竞争力的自然衰减率对品牌竞争力具有负向影响,品牌竞争力的初始值变化不会影响目的地品牌竞争力的稳定值,伴随消费升级,品牌竞争力对供应链利润的影响系数不断增大,对目的地旅游供应链整体利润的促进作用越来越大。

关键词：目的地品牌 NASH Stackelberg 成本分担契约决策

Hyperbenzones A and B,two 1,2-seco and rearranged polycyclic polyprenylated acylphloroglucinols from Hypericum beanii

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Chinese Chemical Letters 2022年第8期33卷 4121-4125页

作者： Weijia Lu Yanqiu Zhang Yawei Li Shengtao Ye Jun Luo Lingyi Kong Wenjun Xu Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China

Two novel seco-polycyclic polyprenylated acylphloroglucinols(PPAPs),hyperbenzones A(1)and B(2),were isolated from the roots of Hypericum beanii,together with one known biosynthetic congener 3.Compound 1 incorporates a 6/5/5 ring system with an unprecedented spiro[bicyclo[3.3.0]octane-3,1'-cyclohexane]-2,2'-dione motif.The structures of 1 and 2 were determined by a combination of high resolution electrospray ionization mass spectroscopy(HRESIMS),nuclear magnetic resonance(NMR)spectroscopic analyses,gage-independent atomic orbital(GIAO)NMR chemical shift calculation with DP4+analyses,electronic circular dichroism(ECD)calculation,and X-ray diffraction analysis.A 1,2-seco retroClaisen rearrangement from a bicyclo[3.3.1]nonane PPAP precursor and following chemodivergent radical cascade cyclizations are proposed as the key steps in the biosynthetic pathway to yield compounds 1 and2.Biological investigations indicated that compounds 1 and 3 could decrease intracellular lipid accumulation in a palmitic acid-induced nonalcoholic steatohepatitis(NASH)cell model.

关键词： seco-PPAPs Hypericum beanii Hyperbenzones A and B NASH 1 2-seco-Bicyclic derivatives

cGAS-STING signaling and function in metabolism and kidney diseases

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Journal of Molecular Cell Biology 2021年第10期13卷 728-738页

作者： Juli Bai Feng Liu Department of Pharmacology University of Texas Health at San AntonioSan AntonioTX 78229USA National Clinical Research Center for Metabolic Diseases Metabolic Syndrome Research CenterKey Laboratory of Diabetes ImmunologyMinistry of Educationand Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangsha 410011China

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway senses the presence of cytosolic DNA and,in turn,triggers downstream signaling to induce the expression of inflammatory and type I interferon genes in immune cells.Whereas the innate immune function of the cGAS-STING pathway is well studied over the past years,emerging evidence suggests that this signaling pathway may have additional functions beyond innate immune surveillance.Consistent with this notion,dysregulation of the cGAS-STING signaling pathway in adipocytes,hepatocytes,and renal proximal tubule epithelial cells are associated with metabolic dysfunction,impaired energy homeostasis,and kidney diseases.In this review,we summarize current understanding of the cGAS-STING pathway in several metabolic diseases such as obesity,insulin resistance,alcoholic and nonalcoholic fatty liver diseases,as well as acute kidney injury and chronic kidney disease.We also review the interaction between the cGAS-STING pathway and lipid metabolism.Lastly,we discuss potential mechanisms by which cGAS-STING signaling regulates metabolism and point toward future avenues of research targeting the cGAS-STING pathway as possible means to treat common metabolic disorders.

关键词： cGAS STING obesity NAFLD NASH AKI CDK