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Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer

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Acta Pharmaceutica Sinica B 2020年第3期10卷 399-413页

作者： Puvanesswaray Ramakrishnan Wei Mee Loh Subash CBGopinath Srinivasa Reddy Bonam Ismail M.Fareez Rhanye Mac Guad Maw Shin Sim Yuan Seng Wu Ageing and Age-Associated Disorders Research Group Faculty of MedicineUniversity of MalayaKuala Lumpur 50603Malaysia Depanment of Pharmacology Faculty of MedicineUniversity of MalayaKuala Lumpur 50603Malaysia School of Bioprocess Engineering Universiti Malaysia PerlisArau 02600Malaysia Institute of Nano Electronic Engineering Universiti Malaysia PerlisKangar 01000Malaysia UMR 7242 CNRS-University of StrasbourgBiotechnology and Cell Signaling/Laboratory of Excellence MedalisIllkirch 67400France Department of Oral Biology and Biomedical Sciences Faculty of DentistryMAHSA UniversitySelangor 42610Malaysia Department of Biomedical Science and Therapeutics Faculty of Medicine and Health ScienceUniversiti Malaysia SabahKota Kinabalu 88400Malaysia Department of Pharmaceutical Life Sciences Faculty of PharmacyUniversity of MalayaKuala Lumpur 50603Malaysia Department of Biochemistry Faculty of Medicine Bioscience and NursingMAHSA UniversitySelangor 42610Malaysia

Activated pancreatic stellate cells(PSCs)have been widely accepted as a key precursor of excessive pancreatic fibrosis,which is a crucial hallmark of chronic pancreatitis(CP)and its formidable associated disease,pancreatic cancer(PC).Hence,anti-fibrotic therapy has been identified as a novel therapeutic strategy for treating CP and PC by targeting *** of the anti-fibrotic agents have been limited to phaseⅠ/Ⅱclinical trials involving vitamin analogs,which are abundant in medicinal plants and have proved to be promising for clinical *** use of phytomedicines,as new anti-fibrotic agents,has been applied to a variety of complementary and alternative *** aim of this review was to present a focused update on the selective new potential anti-fibrotic agents,including curcumin,resveratrol,rhein,emodin,green tea catechin derivatives,metformin,eruberin A,and ellagic acid,in combating PSC in CP and PC *** aimed to describe the mechanism(s)of the phytochemicals used,either alone or in combination,and the associated molecular *** of them were tested in PC models with similar mechanism of actions,and curcumin was tested *** research may explore the issues of bioavailability,drug design,and nano-formulation,in order to achieve successful clinical outcomes with promising activity and tolerability.

关键词： Pancreatic stellate cells anti-fibrotic Chronic pancreatitis Pancreatic cancer Phytochemicals Curcumin Resverastrol Rhein Emodin Green tea catechin

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Determination of mefunidone, a novel anti-fibrotic agent analogue of pirfenidone, in plasma by HPLC-UV and its pharmacokinetic application in rats

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Journal of Chinese Pharmaceutical Sciences 2017年第1期26卷 45-52页

作者： Zhou Wen Shan Ji Feifan Xie Gaoyun Hu Zeneng Cheng School of Pharmaceutical Sciences Central South University Changsha 410013 China Laboratory of Medical Biochemistry and Clinical Analysis Faculty of Pharmaceutical Science Ghent University Ghent B-9000 Belgium

Mefunidone （MFD）, a pirfenidone analogue, has been suggested as a novel anti-fibrotic agent in preclinical research stage. In this work, we developed a sensitive and specified HPLC-UV method and validated it for the determination of MFD in rat plasma. A cost-effective protein precipitation method using methanol was used to process the plasma samples, and pirfenidone was employed as the internal standard （IS）. Chromatographic separation was performed on an Agilent ZORBAX SB-Aq column （4.6 mm 250 mm, 5 μm） with a mobile phase consisting of 10 mM ammonium formate solution （pH 3.0, adjusted by 1.5%o formic acid）-acetonitrile-methanol （60：23：17, v/v/v） at a flow rate of 1.0 mL/min, and the samples were monitored at an ultraviolet wavelength of 245 nm. The retention times of MFD and IS were 5.5 and 7.8 min, respectively. The calibration curve was linear （r2 = 0.9997） between 0.1 and 20 pg/mL. The intra- and inter-day precisions were within 8.6%, and the bias of intra- and inter-accuracies of the method was between -4.2% and 6.5%. The method was successfully applied to pharmacokinetic study of MFD after i.g. and i.v. administration in rats. The elimination half-life was （3.41±0.81） h for i.g. administration and （2.26±0.87） h for i.v. administration. The absolute bioavailability of MFD in rat was 79.1%.

关键词： Mefunidone anti-fibrotic HPLC-UV Pharmacokinetics Bioavailability

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Plant-derived phosphocholine facilitates cellular uptake of anti-pulmonary fibrotic HJT-sRNA-m7

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Science China(Life Sciences) 2019年第3期62卷 309-320页

作者： Jianchao Du Zhu Liang Jiantao Xu Yan Zhao Xiaoyun Li Yanli Zhang DANDan Zhao Ruxuan Chen Yang Liu Trupti Joshi Jiahui Chang Zhiqing Wang Yanxu Zhang Jindong Zhu Qiang Liu Dong Xu Chengyu Jiang State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical SciencesDepartment of Biochemistry Peking Union Medical College Department of Internal Medicine Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Department of Computer Science Informatics Institute and Christopher S.Bond Life Science Center University of Missouri Department of Health Management and Informatics and Office of Medical Research School of Medicine University of Missouri State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy West China Hospital Sichuan University

Pulmonary fibrosis, a progressive chronic disease with a high mortality rate, has limited treatment options. Currently, lung transplantation remains the only effective treatment. Here we report that a small RNA, HJT-sRNA-m7, from a Chinese herbal medicine Hong Jing Tian(HJT, RHODIOHAE CRENULATAE RADIX ET RHIZOMA, Rhodiola crenulata) can effectively reduce the expressions of fibrotic hallmark genes and proteins both in alveolar in vitro and in mouse lung tissues in vivo. We also discovered over one hundred oil-soluble chemicals from HJT decoctions, most of which are found in lipid extracts from other Chinese herbals decoctions, including Pu Gong Ying(PGY, TARAXACI HERBA, Taraxacum mongolicum), Chuan Xin Lian(CXL, changed to "ANDROGRAPHIS HERBA, Andrographis paniculata"), and Jin Yin Hua(JYH, lonicera japonica or Honeysuckle). We identified the active component in these decoctions as two forms of phosphocholines, PC(18:0/18:2) and PC(16:0/18:2). These PCs potentially could form liposomes with small RNAs to enter human alveolar and gastric cells. Our experimental results suggest an unprecendent lipid complex route through which botanic small RNA can enter human *** results provide an innovative treatment strategy for oral delivery of siRNAs as therapeutic medication.

关键词： PC cellular uptake anti-fibrotic HJT sRNA

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Inflammation and fibrosis in chronic liver diseases including nonalcoholic fatty liver disease and hepatitis C

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World Journal of Gastroenterology 2020年第2期26卷 109-133页

作者： Sudeep Tanwar Freya Rhodes Ankur Srivastava Paul M Trembling William M Rosenberg UCL Institute for Liver and Digestive Health Division of MedicineUniversity College LondonRoyal Free CampusHampsteadLondon NW32PF United Kingdom Department of Gastroenterology Whipps Cross University HospitalBarts Health NHS TrustLeytonstoneLondon E111NRUnited Kingdom

At present chronic liver disease(CLD),the third commonest cause of premature death in the United Kingdom is detected late,when interventions are ineffective,resulting in considerable morbidity and *** to the liver,the largest solid organ in the body,leads to a cascade of inflammatory *** inflammation leads to the activation of hepatic stellate cells that undergo transdifferentiation to become myofibroblasts,the main extra-cellular matrix producing cells in the liver;over time increased extra-cellular matrix production results in the formation of liver *** fibrogenesis may be viewed as having evolved as a“wound healing”process that preserves tissue integrity,sustained chronic fibrosis can become pathogenic culminating in CLD,cirrhosis and its associated *** the reference standard for detecting liver fibrosis,liver biopsy,is invasive and has an associated morbidity,the diagnostic assessment of CLD by non-invasive testing is ***,in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical *** to differing disease prevalence and treatment efficacy,disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C *** facilitate this,a review of the pathogenesis of both conditions is also ***,the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed,including the current use of antifibrotic therapy.

关键词： Liver inflammation Fibrosis Cirrhosis Non-alcoholic fatty liver disease Chronic hepatitis C Chronic liver disease anti-fibrotic Biomarker

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Codonopsis tangshen *** Effect on Diabetic Kidney Disease Rats Induced by High Fat Diet Feeding Combined with Streptozotocin

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Natural Products and Bioprospecting 2018年第6期8卷 441-451页

作者： Xian-Yuan Lu Feng-Hua Zhou Ya-Qian Dong Lin-Na Gong Qing-Yun Li Lan Tang Zheng Cai Jing-Yu He Meng-Hua Liu Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China School of Traditional Chinese Medicine Southern Medical UniversityGuangzhou 510515China Bioengineering Research Centre Guangzhou Institute of Advanced TechnologyChinese Academy of SciencesGuangzhou 511458China

Diabetic kidney disease(DKD)is the most serious microvascular complication during the development of diabetes with the characterizations of glomerular basement membrane thickening,mesangial expansion,and glomerular sclerosis,eventually leading to end-stage renal *** study aimed to investigate the melioration effect of Codonopisis tangshen Oliv.(COD)on the DKD model,which was established by unilateral nephrectomy(UN)-high fat diet feeding(HFD)combined with streptozotocin(STZ).After the DKD rats were oral treated with COD at a dose of 2.7 mg/kg for 4 consecutive weeks,the blood glucose,lipid metabolism,renal function,inflammatory mediators,and fibrosis-associated proteins were *** vivo,the COD administration obviously relieved the weight loss,water intake,and blood glucose;decreased the total cholesterol,triglyceride,and low-density lipoprotein cholesterol levels;and improved the renal function by reducing the expression of serum creatinine,uric acid,and urinary protein compared with the model *** levels of pro-inflammatory cytokines of tumor necrosis factor-a,interleukin-1β,and IL-6 were significantly inhibited by ***,the deposition of collagen fiber was markedly increased,and the protein and mRNA expressions of transforming growth factor-b1 and a-smooth muscle actin were markedly elevated in DKD rats,but they were decreased to some extent after the COD *** conclusion,COD exhibited a protective effect on the UN-HFD feeding combined with STZ-induced DKD model by improving the blood glucose and lipid metabolism,relieving the inflammatory response,and mitigating the renal fibrosis,which provided scientific evidence for its applications in clinic.

关键词： Diabetic kidney disease Codonopisis tangshen Oliv. Lipid metabolism anti-inflammatory anti-fibrotic

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Role of ferroptosis in fibrosis:From mechanism to potential therapy

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Chinese Medical Journal 2024年第7期137卷 806-817页

作者： Xuemeng Qiu Qing Bi Jiyue Wu Zejia Sun Wei Wang Department of Urology Beijing Chao-Yang HospitalCapital Medical UniversityBeijing 100020China Department of Surgery Third Clinical Medical CollegeCapital Medical UniversityBeijing 100020China Urinary and Nephropathy Center Beijing Chao-Yang HospitalCapital Medical UniversityBeijing 100020China Institute of Urology Capital Medical UniversityBeijing 100020China

Fibrosis,which is a manifestation of the physiological response to injury characterized by excessive accumulation of extracellular matrix components,is a ubiquitous outcome of the repair ***,in cases of repetitive or severe injury,fibrosis may become dysregulated,leading to a pathological state and organ *** recent years,a novel form of regulated cell death,referred to as ferroptosis,has been identified as a possible contributor to fibrosis;it is characterized by iron-mediated lipid *** has garnered attention due to the growing body of evidence linking ferroptosis and fibrogenesis,which is believed to be driven by underlying inflammation and immune *** the increasing interest in the relationship between ferroptosis and fibrosis,a comprehensive understanding of the precise role that ferroptosis plays in the formation of fibrotic tissue remains *** review seeks to synthesize previous research related to the *** categorized the different direct and indirect mechanisms by which ferroptosis may contribute to fibrosis into three categories:(1)iron overload toxicity;(2)ferroptosis-evoked necroinflammation,with a focus on ferroptosis and macrophage interplay;and(3)ferroptosis-associated pro-fibrotic factors and ***,the review considers the potential implications of these findings and highlights the utilization of ferroptosis-targeted therapies as a promising strategy for mitigating the progression of *** conclusion,novel anti-fibrotic treatments targeting ferroptosis could be an effective treatment for fibrosis.

关键词： Ferroptosis Fibrosis anti-fibrotic Iron metabolism Necroinflammation Epithelial-mesenchymal transition

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Decorin prevents the development of CCl4-induced liver fibrosis in mice

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Chinese Medical Journal 2014年第6期127卷 1100-1104页

作者： Ma Rui He Shilin Liang Xiao Yu Hong Liang Yuelong Cai Xiujun Department of General Surgery Institute of Minimally Invasive Surgery Sir Run Run Shaw Hospital College of Medicine Zhejiang University Hangzhou Zhejiang 310016 China

Background Liver fibrosis normally progresses to cirrhosis and destroys the normal architecture of the liver, resulting inliver dysfunction and irreversible cirrhosis. The aim of this study was to investigate the anti... 详细信息

关键词： decorin liver fibrosis carbon tetrachloride anti-fibrotic effect hepatic stellate cells

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