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Emerging mechanisms of non-alcoholic steatohepatitis and novel drug therapies

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Chinese Journal of Natural Medicines 2024年第8期22卷 724-745页

作者： CHEN hao ZHOU Yang hao haiping XIONG Jing Department of Pharmacology School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Non-alcoholic fatty liver disease(NAFLD)has become a leading cause of chronic liver disease *** initiates with simple steatosis(NAFL)and can progress to the more severe condition of non-alcoholic steatohepatitis(NASH).NASH often advances to end-stage liver diseases such as liver fibrosis,cirrhosis,and hepatocellular carcinoma(HCC).Notably,the transition from NASH to end-stage liver diseases is irreversible,and the precise mechanisms driving this progression are not yet fully ***,there is a critical need for the development of effective therapies to arrest or reverse this *** review provides a comprehensive overview of the pathogenesis of NASH,examines the current therapeutic targets and pharmacological treatments,and offers insights for future drug discovery and development strategies for NASH therapy.

关键词： Metabolic dysfunction Drug development Bile acids Liver-gut axis Inflammation Fibrosis

Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H:quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase

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Chinese Journal of Natural Medicines 2024年第1期22卷 75-88页

作者： SONG Jiangzhou ZOU Guiqing Zhao Zhou ZHU Ya XUE Jiayu AO Lanjia SUN Huiyong hao haiping ZHANG Bo XU Xiaowei State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer ***1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)*** ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell *** phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer *** concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+*** this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and *** these,compound T8 demonstrated potent antitumor ***,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and *** discovery offers a promising new molecular entity for advancing anticancer research.

关键词： NQO1 ROS NAMPT NAD^(+) T8

STING signaling in islet macrophages impairs insulin secretion in obesity

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Science China(Life Sciences) 2024年第2期67卷 345-359页

作者： Ze Hong Saihua Chen Jing Sun Dan Cheng Hanli Guo Jiahao Mei Xiang Zhang Munire Maimaiti haiping hao Peng Cao Haiyang Hu Chen Wang School of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Natural Medicines Department of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China School of Life Sciences Westlake UniversityHangzhou 310012China

The innate immune regulator stimulator of interferon genes(STING)mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines,which promotes the progression of various inflammatory and autoimmune *** immune system plays a critical role in regulating obesity-induced islet dysfunction,whereas the potential effect of STING signaling is not fully ***,we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet(HFD)***^(-/-)alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of ***,palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in ***,STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment ofβcell insulin secretory *** inhibiting STING activation enhances insulin secretion to control ***,our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

关键词： STING obesity type 2 diabetes insulin macrophages islet

场域理论视角下同行评议公平信度提升路径研究

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编辑学报 2024年第3期36卷 253-259页

作者：卢娜孙劲楠丁佐奇郝海平中国药科大学国际医药商学院中国药科大学《中国天然药物》期刊编辑部中国药科大学药学院南京211198

为了梳理和总结同行评议模式中的非公平性行为,在科研诚信视阈下为国内学术期刊和项目评审同行评议发展提供借鉴和参考。本文借鉴场域理论“场域”“资本”和“惯习”3个核心视角分析同行评议主体背后的实践逻辑,系统分析其产生机理并... 详细信息

为了梳理和总结同行评议模式中的非公平性行为,在科研诚信视阈下为国内学术期刊和项目评审同行评议发展提供借鉴和参考。本文借鉴场域理论“场域”“资本”和“惯习”3个核心视角分析同行评议主体背后的实践逻辑,系统分析其产生机理并对提升路径的多维角度进行研究。在场域理论背景下,科研诚信视阈下同行评议公平信度缺失是场域关系危机、学术资本争夺、惯习形塑共同作用的结果。在此基础上,可以从建立场域良好的学术共同体合作关系、规避权力资源不当使用、改善形塑惯习的制度环境等方面对同行评议公平信度提升路径进行矫正与提升。

关键词：场域理论同行评议科研诚信

Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2129-2149页

作者： Baoyi Guan Jinlin Tong haiping hao Zhixu Yang Keji Chen hao Xu Anlu Wang Xiyuan Hospital China Academy of Chinese Medical SciencesBeijing 100091China National Clinical Research Center for Chinese Medicine Cardiology Beijing 100091China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

Cardiometabolic disease(CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids(BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor(FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

关键词： Bile acid Nuclear receptors Cardiometabolic diseases Systemic immunometabolism Therapeutic opportunities

Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS

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Acta Pharmaceutica Sinica B 2023年第1期13卷 113-127页

作者： Xunxun Wu Lian Liu Qiuling Zheng Hui Ye Hua Yang haiping hao Ping Li State Key Laboratory of Natural Medicines Department of PharmacognosySchool of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China College of Pharmacy China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Jiangsu Provincial Key Laboratory of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China

Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is *** I(DT)is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of *** with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation(OGD),but the protection was prevented by a ROS *** addition,DT administration protected the heart against isoprenaline ***,PKM2 reacted to transient ROS via oxidization at Cys423/Cys424,leading to glutathionylation and nuclear translocation in dimer *** the nucleus,PKM2 served as a co-factor to promote HIF-1a-dependent gene induction,contributing to adaptive *** mice subjected to permanent coronary ligation,cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection,which was rescued by overexpression of wild-type Pkm2,rather than Cys423/424-mutated *** conclusion,PKM2 is sensitive to oxidation,and subsequent glutathionylation promotes its nuclear *** IPC has been viewed as a protective means against reperfusion injury,our study reveals its potential role in protection of the heart from no-reflow ischemia.

关键词： Dihydrotanshinone I Ischemic preconditioning PKM2 Glutathionylation Myocardial ischemia ROS Oxidation modification Nuclear translocation

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2022年第2期12卷 558-580页

作者： Danyu Du Chan Liu Mengyao Qin Xiao Zhang Tao Xi Shengtao Yuan haiping hao Jing Xiong Department of Pharmacology School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Research Center of Biotechnology School of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of Drug Screening China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical UniversityNanjing 210009China

Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence *** efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of ***,limitations exist in current strategies including chemoresistance for *** initiation and progression is driven by reprogramming of metabolism,in particular during HCC ***,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC *** this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical *** also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC ***,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

关键词： Metabolic dysregulation Hepatocellular carcinoma Glycolysis Tricarboxylic acid cycle Pentose phosphate pathway Fatty acidβ-oxidation Glutamine metabolism Cancer therapy

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不同细度石粉对胶砂性能的影响及碳排放分析

混凝土 2024年第7期 153-155,159页

作者：苏维维任龙芳夏京亮赫海平王晶冷发光刘文生平凉市新世纪建材有限责任公司甘肃平凉744024 中国建筑科学研究院有限公司北京100013

为实现平凉地区石灰石粉的高效资源化利用,探明不同细度石灰石粉对水泥基材料性能的影响,对平凉地区的机制砂石粉进行粉磨得到不同细度的石灰石粉,将不同细度的石粉以不同比例等质量取代水泥,对比研究石粉粒径、石粉掺量等对胶砂性能的... 详细信息

为实现平凉地区石灰石粉的高效资源化利用,探明不同细度石灰石粉对水泥基材料性能的影响,对平凉地区的机制砂石粉进行粉磨得到不同细度的石灰石粉,将不同细度的石粉以不同比例等质量取代水泥,对比研究石粉粒径、石粉掺量等对胶砂性能的影响,并基于碳排放计算标准计算分析了利用石粉制备混凝土带来的碳减排效益。结果表明:石灰石粉替代水泥可缩短胶砂凝结时间;随石粉掺量增加,胶砂流动度逐渐下降,抗压强度逐渐减小;石粉比表面积是水泥比表面积的1.5倍时,胶砂的流动性较好,石粉细度变细有利于胶砂抗压强度的增加;石灰石粉替代水泥可有效降低混凝土碳排放,不同强度等级的混凝土碳减排百分比与其掺量大致相等。

关键词：石灰石粉胶砂细度流动度碳排放

Super-sensitive bifunctional nanoprobe: Self-assembly of peptide-driven nanoparticles demonstrating tumor fluorescence imaging and therapy

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1473-1486页

作者： Han Xiao Rui Zhang Xiaobo Fan Xinglu Jiang Mingyuan Zou Xuejiao Yan haiping hao Guoqiu Wu Medical School Southeast UniversityNanjing 210009China Department of Clinical Laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityNanjing 210009China Department of Cardiology the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical UniversityNanjing 210009China State Key Laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityZhuhai 519000China Center of Clinical Laboratory Medicine Zhongda HospitalSoutheast UniversityNanjing 21009China Jiangsu Provincial Key Laboratory of Critical Care Medicine Southeast UniversityChangzhou 213000China

The development of nanomedicine has recently achieved several breakthroughs in the field of cancer treatment;however,biocompatibility and targeted penetration of these nanomaterials remain as limitations,which lead to serious side effects and significantly narrow the scope of their *** self-assembly of intermediate filaments with arginine-glycine-aspartate(RGD)peptide(RGDIFP)was triggered by the hydrophobic cationic molecule 7-amino actinomycin D(7-AAD)to synthesize a bifunctional nanoparticle that could serve as a fluorescent imaging probe to visualize tumor *** designed RGD-IFP peptide possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step *** fluorescent nanoprobe with RGD peptide could be targeted for delivery into tumor cells and released in acidic environments such as endosomes/lysosomes,ultimately inducing cytotoxicity by arresting tumor cell cycling with inserted *** is noteworthy that the RGD-IFP/7-AAD nanoprobe tail-vein injection approach demonstrated not only high tumor-targeted imaging potential,but also potent antitumor therapeutic effects in *** proposed strategy may be used in peptide-driven bifunctional nanoparticles for precise imaging and cancer therapy.

关键词： Nanoprobe 7-Amino actinomycin D Intermediate filament protein Tumor image Antitumor therapy Integrin avβ3