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Pathogenesis of nash and Promising Natural Products

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Chinese Journal of Natural Medicines 2021年第1期19卷 12-27页

作者： LENG Ying-Rong ZHANG Mei-Hui LUO Jian-Guang ZHANG Hao State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 210009China

Nonalcoholic steatohepatitis(nash)is a common clinical condition that can lead to advanced liver *** mechanism of the diaease progression,which is lacking effective therapy,remains ***,there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative *** accomplish this goal,experimental animal models that recapitulate the human disease are ***,an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for *** review summarized the pathogenesis of nash,animal models commonly used,and the promising targets for *** also reviewed the natural constituents as potential nash therapeutic agents.

关键词： nash Natural medicine Animal model Target Pathogenesis

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced nash mice

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Cellular & Molecular Immunology 2019年第11期16卷 878-886页

作者： Xianhong Du Zhuanchang Wu Yong Xu Yuan Liu Wen Liu Tixiao Wang Chunyang Li Cuijuan Zhang Fan Yi Lifen Gao Xiaohong Liang Chunhong Ma Key Laboratory for Experimental Teratology of Ministry of Education Department of ImmunologyShandong University School of Basic Medical ScienceJinanShandong 250012PR China Department of Radiation Oncology Qilu Hospital of Shandong UniversityJinanShandongPR China Key Laboratory for Experimental Teratology of Ministry of Education Department of Histology and EmbryologyShandong University School of Basic Medical ScienceJinanShandongPR China Institute of Pathology and Pathophysiology Shandong University School of MedicineJinanPR China Key Laboratory of Infection and Immunity of Shandong Province School of Basic Medical SciencesShandong UniversityJinanChina

As an immune checkpoint,Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver ***,the precise roles of Tim-3 in nonalcoholic steatohepatitis(nash)remain *** the current study,we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet(MCD)-induced nash *** results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice,including F4/80^(+)CD11b^(+),F4/80^(+)CD68^(+),and F4/80^(+)CD169^(+)***,Tim-3 knockout(KO)significantly accelerated MCD-induced liver steatosis,displaying higher serum ALT,larger hepatic vacuolation,more liver lipid deposition,and more severe liver ***,compared with wild-type C57BL/6 mice,Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2,NLRP3,and caspase-1 p20 together with increased generation of IL-1βand IL-18 in *** vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species(ROS)and related downstream pro-inflammatory cytokine secretion of IL-1βand IL-18 in *** administration of N-Acetyl-L-cysteine(NAC),a small molecular inhibitor of ROS,remarkably suppressed caspase-1 p20 expression and IL-1βand IL-18 production in livers of Tim-3 KO mice,thus significantly reducing the severity of steatohepatitis induced by *** conclusion,Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

关键词： macrophage nash ROS Tim-3

DNA methylation of SMPD3-based diagnostic biomarkers of nash and mild fibrosis

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Genes & Diseases 2024年第1期11卷 99-102页

作者： Na Wu Mofan Feng Siran Yue Xinyu Shi Nan Tang Yalan Xiong Jianying Wang Lei Zhang Hualing Song Yi Shi Guang He Guang Ji Baocheng Liu Shanghai Innovation Center of Traditional Chinese Medicine Health Service School of Public HealthShanghai University of Traditional Chinese MedicineShanghai 201203China Institute of Digestive Diseases Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersShanghai Jiao Tong UniversityShanghai 200030China Institute for Advancing Translational Medicine in Bone and Joint Diseases School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China

Non-alcoholic fatty liver disease(NAFLD)is a liver condition that is widely prevalent across the world.A considerable number of people with NAFLD have the potential to progress to a more severe form of the condition known as nonalcoholic steatohepatitis(nash),accompanied by bridging *** advancement is more likely if the patient has metabolic risk factors such as obesity or type 2 diabetes that deteriorate over ***,even slight inflammation or fibrosis in NAFLD can significantly increase the likelihood of progression compared to steatosis *** underscores the importance of revising the present methods of monitoring NAFLD patients to ensure early detection and effective management of the disease.

关键词： NAFLD inflammation nash

On Dynamics and nash Equilibriums of Networked Games

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IEEE/CAA Journal of Automatica Sinica 2014年第1期1卷 10-18页

作者： Daizhan Cheng Tingting Xu Fenghua He Hongsheng Qi the Institute of Systems Science Chinese Academy of Sciences the Institute of Sstronautics Harbin Institute of Technology

Networked noncooperative games are investigated,where each player(or agent) plays with all other players in its neighborhood. Assume the evolution is based on the fact that each player uses its neighbors current information to decide its next strategy. By using sub-neighborhood, the dynamics of the evolution is obtained. Then a method for calculating nash equilibriums from mixed strategies of multi-players is *** relationship between local nash equilibriums based on individual neighborhoods and global nash equilibriums of overall network is revealed. Then a technique is proposed to construct nash equilibriums of an evolutionary game from its one step static nash equilibriums. The basic tool of this approach is the semi-tensor product of matrices, which converts strategies into logical matrices and payoffs into pseudo-Boolean functions, then networked evolutionary games become discrete time dynamic systems.

关键词： Networked non-cooperative game local infor-mation sub-neighborhood fundamental evolutionary equation nash equilibrium

Drugs for Non-alcoholic Steatohepatitis (nash): Quest for the Holy Grail

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Journal of Clinical and Translational Hepatology 2021年第1期9卷 40-50页

作者： Mithun Sharma Madhumita Premkumar Anand V Kulkarni Pramod Kumar D Nageshwar Reddy Nagaraja Padaki Rao Department of Hepatology Asian Institute of GastroenterologyHyderabadIndia Department of Hepatology PGIMERChandigarhIndia Department of Gastroenterology Asian Institute of GastroenterologyHyderabadIndia

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (nash). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic nash patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of nash. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of nash;moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or ‘Holy Grail’ within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for nash which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.

关键词： Fatty liver NAFLD nash Obeticholic acid Saroglitazar

Monocyte-derived KCs(MoKCs)contribute to the KC pool in nash

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Cellular & Molecular Immunology 2021年第3期18卷 518-519页

作者： Yingchun Wang Lifen Gao Key Laboratory for Experimental Teratology of Ministry of Education Shandong Key Laboratory of Infection and Immunityand Department of ImmunologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanShandong 250012P.R.China

Nonalcoholic fatty liver disease(NAFLD)is now recognized as the most common liver disease worldwide and has increasingly become a serious hazard to human *** consists of a spectrum of disease states ranging from simple steatosis to more severe disease termed nonalcoholic steatohepatitis(nash),fibrosis,cirrhosis,and even hepatocellular carcinoma.

关键词： NAFLD liver nash

The hepatic macrophage pool in nash

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Cellular & Molecular Immunology 2021年第8期18卷 2059-2060页

作者： Tixiao Wang Chunhong Ma Key Laboratory for Experimental Teratology of Ministry of Education Key Laboratory of Infection and Immunity of Shandong Provinceand Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical College of Shandong UniversityJinanShandongChina Advanced Medical Research Institute Shandong UniversityJinanShandongChina

Nonalcoholic fatty liver disease(NAFLD)and its inflammatory subtype nonalcoholic steatohepatitis(nash)are currently the most common chronic liver diseases worldwide and emerging risk factors for hepatocellular carcinoma.1 Numerous studies have demonstrated the critical involvement of hepatic macrophages,including resident Kupffer cells(KCs)and recruited monocyte-derived macrophages(MoMFs).

关键词： liver NAFLD nash

Hepatic CDP-diacylglycerol synthase 2 deficiency causes mitochondrial dysfunction and promotes rapid progression of nash and fibrosis

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Science Bulletin 2022年第3期67卷 299-314页

作者： iesi Xu Siyu Chen Wei Wang Sin Man Lam Yang Xu Shaohua Zhang Huimin Pan Jingjing Liang Xiahe Huang Yu Wang Ting Li Yuqiang Jiang Yingchun Wang Mei Ding Guanghou Shui Hongyuan Yang Xun Huang State Key Laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute of Medicinal Biotechnology Chinese Academy of Medical SciencesBeijing 100050China School of Biotechnology and Biomolecular Sciences University of New South WalesSydneyNew South Wales 2052Australia

Nonalcoholic fatty liver disease(NAFLD)encompasses a spectrum of pathologies,ranging from steatosis to nonalcoholic steatohepatitis(nash).The factors promoting the progression of steatosis to nash are still *** studies suggest that mitochondrial lipid composition is critical in nash ***,we showed that CDP-DAG synthase 2(Cds2)was downregulated in genetic or diet-induced NAFLD mouse ***-specific deficiency of Cds2 provoked hepatic steatosis,inflammation and fibrosis in five-week-old ***2 is enriched in mitochondria-associated membranes(MAMs),and hepatic Cds2 deficiency impaired mitochondrial function and decreased mitochondrial PE *** of phosphatidylserine decarboxylase(PISD)alleviated the nash-like phenotype in Cds2^(f/f);AlbCre mice and abnormal mitochondrial morphology and function caused by CDS2 deficiency in ***,dietary supplementation with an agonist of peroxisome proliferator-activated receptor alpha(PPARa)attenuated mitochondrial defects and ameliorated the nash-like phe-notype in Cds2^(f/f);AlbCre ***,Cds2 overexpression protected against high-fat diet-induced hepatic steatosis and ***,Cds2 modulates mitochondrial function and nash development.

关键词： nash CDP-diacylglycerol synthase Mitochondria Mitochondria-associated membranes Phospholipid

nash Embedding of Witten’s M-Theory and the Hawking-Hartle Quantum Wave of Dark Energy

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Journal of Modern Physics 2013年第10期4卷 1417-1428页

作者： Mohamed S. El Naschie Department of Physics Alexandria University Alexandria Egypt

Euclidean embedding of the 11-dimensional M-theory turned out to require a very large space leaving lavish amounts of 242 dimensional pseudo truly empty “regions” devoid of space and time and consequently of anything resembling ordinary physical energy density. It is shown here using nash embedding that the ratio of “solid” M-theory spacetime to its required embedding “non-spacetime” is 1/22 for a classical theory and 1/22.18033989 for an analogous fractal theory. This then leads to a maximal ordinary energy density equation equal to that of Einstein’s famous formula E=mc2 but multiplied with in full agreement with previous results obtained using relatively more conventional methods including running the electromagnetic fine structure constant in the exact solution of the hydrogen atom. Consequently, the new equation corresponds to a quantum relativity theory which unlike Einstein’s original equation gives quantitative predictions which agree perfectly with the cosmological measurements of WMAP and the analysis of certain supernova events. Never the less in our view dark energy also exists being the energy of the quantum wave amounting to 95.5 present of the total Einstein theoretical energy which is blind to any distinction between ordinary energy of the quantum particle and the dark energy of the quantum wave. However, since measurement leads to the collapse of the Hawking-Hartle quantum wave, dark energy being a quantum wave non-ordinary energy could not possibly be measured in the usual way unless highly refined quantum wave non-demolition technology is developed if possible. It is a further reason that dark energy having a different sign to ordinary energy is the cause behind the anti gravity force which is pushing the universe apart and accelerating cosmic expansion. Consequently it can be seen as the result of anticlastic Cartan-like curvature caused by extra compactified dimensions of spacetime. A simple toy model demonstration of the effect of curvature in

关键词： nash Euclidean Embedding Quantum Entanglement Dark Energy of the Quantum Wave Quantum Gravity Ordinary Energy of the Quantum Particle Hawking-Hartle Wave of the Cosmos Quantum Wave Non-Demolition Witten’s M-Theory