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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 PSCs.Most 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 application.The use of phytomedicines,as new anti-fibrotic agents,has been applied to a variety of complementary and alternative approaches.The 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 models.It aimed to describe the mechanism(s)of the phytochemicals used,either alone or in combination,and the associated molecular targets.Most of them were tested in PC models with similar mechanism of actions,and curcumin was tested intensively.Future 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

Inhibitory effects of prostaglandin E₁ on activation of hepatic stellate cells in rabbits with schistosomiasis

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Hepatobiliary & Pancreatic Diseases International 2007年第2期6卷 176-181页

作者： WeiLong Zou Zhen Yang YunJin Zang DongJian Li ZhiPeng Liang ZhongYang Shen Institute of Transplantation General Hospital of the Chinese People's Armed Police Forces Beijing China. wlzouah@***

BACKGROUND: Liver fibrosis is the result of an imbalance between synthesis and degradation of extracellular matrix proteins of the liver. At the cellular and molecular levels, this progressive process is mainly characterized by activation of hepatic stellate cells (HSCs). Schistosoma japonica is one of the most prevalent causes of liver fibrosis in China. It is characterized by hepatocyte damage, inflammation, and chronic parasite egg-induced granuloma formation leading to fibrosis. This study aimed to investigate the inhibitory effects of prostaglandin E1 (PGE1) on activation of HSCs and the alteration of type Ⅰ and Ⅲ collagen in rabbits with schistosomiasis. The study may promote the clinical application of praziquantel and PGE1 as a combined therapy to reverse hepatic fibrosis caused by schistosomiasis. METHODS: Rabbits were percutaneously infected with cercaria of S. japonicum. Seven rabbits were subjected to intravenous injections of PGE1 (2.5 μg/kg daily) from days 60 to 120 after infection. The ultrastructural changes in activated HSCs were observed under transmission electron microscopy. The expression of α-smooth muscle actin (α-SMA) was detected by immunohistochemistry. Fibril-forming collagens were detected by picrosirius staining. RESULTS: Activation of HSCs was a characteristic alteration in schistosome-induced hepatic fibrosis. The expression of contraction-related α-SMA and thecontent of collagens were increased. Exogenous PGE1 markedly inhibited the activation of HSCs and reduced the expression of α-SMA around the hepatic sinusoids (P<0.01). The contents of type Ⅰ and Ⅲ collagens were significantly attenuated. The ratio of staining area to the whole field (10×3.3) under a polarized light microscope in the untreated and treated groups was 37.25±9.71 vs. 13.38±4.24 (P<0.01) and 9.66±3.52 vs. 6.23±1.81 (P<0.05), respectively. CONCLUSIONS: Activation of HSCs may play a key role in the progress of schistosome-induced hepatic fibrosis. PGE1 effectively protects rabbit liver from fibrosis, at le

关键词： hepatic fibrosis schistosome hepatic stellate cells prostaglandin E1 fibril-forming collagen

Effects of retinoic acid on proliferation,phenotype and expression of cyclin-dependent kinase inhibitors in TGF-β1-stimulated rat hepatic stellate cells

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World Journal of Gastroenterology 2000年第6期6卷 819-823页

作者： Guang Cun Huang Jin Sheng Zhang Yue E Zhang Department of Pathology School of Basic Medical Sciences,Fudan University.Shanghai 200032,China 复旦大学上海

AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransforming growth factor beta 1(TGF-β1).METHODS HSC were isolated from healthy ratlivers and cultured.After stimulated with1 mg/L TGF-β1,subcultured HSC were treatedwith or without 1 nmol/L RA.MTT assay,immunocytochemistry(ICC)for p16,p21,p27and α-smooth muscle actin(α-SMA)protein,insitu hybridization(ISH)for retinoic acidreceptor beta 2(RAR-β2)and p16,p21 and p27mRNA and quantitative image analysis(partially)were performed.RESULTS RA inhibited HSC proliferation(41.50%,P<0.05),decreased the protein levelof α-SMA(55.09%,P<0.05),and induced HSCto express RAR-β2 mRNA.In addition,RAincreased the protein level of p16(218.75%,P<0.05)and induced p21 protein expression;meanwhile,p27 was undetectable by ICC in bothcontrol and RA-treated HSC.However,RA hadno influence on the mRNA levels of p16,p21 orp27 as determined by ISH.CONCLISION Up-regulation of p16 and p21 on post-transcriptional level may contribule, in part to RA inhibition of TGF-β1-initiated rat HSC activation in vitro.

关键词： retinoic acid cyclindependent kinase inhibitor hepatic stellate cell cell culture transforming growth factor beta 1 liver fibrosis

Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation

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World Journal of Gastroenterology 2015年第27期21卷 8326-8339页

作者： Yu-Gang Wang Ling Xu Ting Wang Jue Wei Wen-Ying Meng Na Wang Min Shi Department of Gastroenterology Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation.METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclin D1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy.RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediatedthrough p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase(acetyl K68) and nuclear factor-κB p65(acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models.CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis.

关键词： Givinostat Hepatic stellate cells Histonedeacetylase inhibitor Nuclear factor-κB Superoxidedismutase

Integrated network analysis of transcriptomic and protein-protein interaction data in taurine-treated hepatic stellate cells

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World Journal of Gastroenterology 2019年第9期25卷 1067-1079页

作者： Xing-Qiu Liang Jian Liang Xiao-Fang Zhao Xin-Yuan Wang Xin Deng Department of Science and Technology Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine College of Medical Guangxi University School of Basic Sciences Guangxi University of Chinese Medicine

BACKGROUND Studies show that the antifibrotic mechanism of taurine may involve its inhibition of the activation and proliferation of hepatic stellate cells(HSCs). Since the molecular mechanism of taurine-mediated antifibrotic activity has not been fully unveiled and is little studied, it is imperative to use "omics" methods to systematically investigate the molecular mechanism by which taurine inhibits liver fibrosis.AIM To establish a network including transcriptomic and protein-protein interaction data to elucidate the molecular mechanism of taurine-induced HSC apoptosis.METHODS We used microarrays, bioinformatics, protein-protein interaction(PPI) network,and sub-modules to investigate taurine-induced changes in gene expression in human HSCs(LX-2). Subsequently, all of the differentially expressed genes(DEGs) were subjected to gene ontology function and Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Furthermore, the interactions of DEGs were explored in a human PPI network, and sub-modules of the DEGs interaction network were analyzed using Cytoscape software.RESULTS A total of 635 DEGs were identified in taurine-treated HSCs when compared with the controls. Of these, 304 genes were statistically significantly up-regulated, and 331 down-regulated. Most of these DEGs were mainly located on the membrane and extracellular region, and are involved in the biological processes of signal transduction, cell proliferation, positive regulation of extracellular regulated protein kinases 1(ERK1) and ERK2 cascade, extrinsic apoptotic signaling pathway and so on. Fifteen significantly enriched pathways with DEGs were identified, including mitogen-activated protein kinase(MAPK) signaling pathway, peroxisome proliferators-activated receptor signaling pathway,estrogen signaling pathway, Th1 and Th2 cell differentiation, cyclic adenosine monophosphate signaling pathway and so on. By integrating the transcriptomics and human PPI data, nine critical genes, including MMP2, MMP9, MMP21,TIMP3, KLF10, CX3CR1, TGF

关键词： Taurine Hepatic stellate cells Differentially expressed genes Liver fibrogenesis Transcriptomic Protein-protein interaction network

Effect of NLRC5 on activation and reversion of hepatic stellate cells by regulating the nuclear factor-κB signaling pathway

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World Journal of Gastroenterology 2019年第24期25卷 3044-3055页

作者： Yan-Zhen Zhang Jian-Ning Yao Lian-Feng Zhang Chun-Feng Wang Xue-Xiu Zhang Bing Gao Department of Second Gastroenterology the First Affiliated Hospital of Zhengzhou University

BACKGROUND The formation of liver fibrosis is mainly caused by the activation of hepatic stellate cells(HSCs)and the imbalance of extracellular matrix(ECM)production and degradation.The treatment of liver fibrosis mainly includes removing the cause,inhibiting the activation of HSCs,and inhibiting inflammation.NOD-like receptor(NLR)family,caspase activation and recruitment domain(CARD)domain containing 5/NOD27/CLR16.1(NLRC5)is a highly conserved member of the NLR family and is involved in inflammation and immune responses by regulating various signaling pathways such as nuclear factor-κB(NF-κB)signaling.It has been found that NLRC5 plays an important role in liver fibrosis,but its specific effect and possible mechanism remain to be fully elucidated.AIM To investigate the role of NLRC5 in the activation and reversion of HSCs induced with transforming growth factor-β(TGF-β)and MDI,and to explore its relationship with liver fibrosis.METHODS A total of 24 male C57BL/6 mice were randomly divided into three groups,including normal,fibrosis,and recovery groups.Twenty-four hours after a liver fibrosis and spontaneous reversion model was established,the mice were sacrificed and pathological examination of liver tissue was performed to observe the degree of liver fibrosis in each group.LX-2 cells were cultured in vitro and treated with TGF-β1 and MDI.Real-time quantitative PCR(qPCR)and Western blot were used to analyze the expression levels of NLRC5,α-smooth muscle actin(α-SMA),and collagen type I alpha1(Col1a1)in each group.The activity of NF-κB in each group of cells transfected with NLRC5-siRNA was detected.RESULTS Compared with the normal mice,the expression level of NLRC5 increased significantly(P<0.01)in the fibrosis group,but decreased significantly in the recovery group(P<0.01).In in vitro experiments,the content of NLRC5 was enhanced after TGF-β1 stimulation and decreased to a lower level when treated with MDI(P<0.01).The expression ofα-SMA and Col1a1 proteins and mRNAs in TGF-β1-mediated cells was suppressed by tr

关键词： NLRC5 Hepatic stellate cells Liver fibrosis Recovery

Efficacy and safety of stellate ganglion block in chronic ulcerative colitis

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World Journal of Gastroenterology 2017年第3期23卷 533-539页

作者： Hong-Ying Zhao Guo-Tao Yang Ning-Ning Sun Yu Kong Yun-Feng Liu Department of Elderly Internal Medicine Cangzhou Central HospitalCangzhou Clinical Medical School of Hebei Medical UniversityCangzhou 061001Hebei ProvinceChina Department of Third Neurology Cangzhou Central HospitalCangzhou Clinical Medical School of Hebei Medical UniversityCangzhou 061001Hebei ProvinceChina Department of First Digestion Cangzhou Central HospitalCangzhou Clinical Medical School of Hebei Medical UniversityCangzhou 061001Hebei ProvinceChina Department of Second Digestion Cangzhou Central HospitalCangzhou Clinical Medical School of Hebei Medical UniversityCangzhou 061001Hebei ProvinceChina

AIM To investigate the efficacy and safety of stellate ganglion block for the treatment of patients with chronic ulcerative colitis.METHODS A total of 120 randomly selected patients with chronic ulcerative colitis treated in Cangzhou Central Hospital from January 2014 to January 2016 were included in this study. These patients were divided into two groups: control group(n = 30), patients received oral sulfasalazine treatment; experimental group(n = 90), patients received stellate ganglion block treatment. Clinical symptoms and disease activity in these two groups were compared before and after treatment using endoscopy. Blood was collected from patients on day 0, 10, 20 and 30 after treatment. Enzyme-linked immunosorbent assay was performed to determine interleukin-8(IL-8) level. The changes in IL-8 level post-treatment in the two groups were compared using repeated measures analysis of variance.RESULTS After treatment, clinical symptoms and disease activity were shown to be alleviated by endoscopy in both the control and experimental groups. However, patients in the control group did not have obvious abdominal pain relief. In addition, the degree of pain relief in the experimental group was statistically better than that in the control group(P stellate ganglion block effectively improves treatment efficacy in chronic ulcerative colitis, relieves clinical symptoms in patients, and reduces the level of inflammatory factors. Furthermore, this approach also had a positive impact on the disease to a certain extent.

关键词： stellate ganglion block Chronic ulcerative colitis

Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury

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World Journal of Gastroenterology 2015年第14期21卷 4184-4194页

作者： Wen-Ju Chang Lu-Jun Song Tuo Yi Kun-Tang Shen Hong-Shan Wang Xiao-Dong Gao Min Li Jian-Min Xu Wei-Xin Niu Xin-Yu Qin Department of General Surgery Zhongshan HospitalInstitute of General SurgeryFudan University

AIM: To test whether hepatic stellate cells(HSCs) at different activation stages play different roles in acetaminophen(APAP)-induced acute liver injury(ALI).METHODS: HSCs were isolated from mouse liver and cultured in vitro.Morphological changes of initiation HSCs [HSCs(5d)] and perpetuation HSCs [HSCs(p3)] were observed by immunofluorescence and transmission electron microscopy.The protective effects of HSCderived molecules, cell lysates and HSC-conditioned medium(HSC-CM) were tested in vivo by survival and histopathological analyses.Liver injury was determined by measuring aminotransferase levels in the serum and by histologic examination of tissue sections under a light microscope.Additionally, to determine the molecular mediators of the observed protective effects of initiation HSCs, we examined HSC-CM using a highdensity protein array.RESULTS: HSCs(5d) and HSCs(p3) had different morphological and phenotypic traits.HSCs(5d) presented a star-shaped appearance with expressing α-SMA at non-uniform levels between cells.However, HSCs(p3) evolved into myofibroblast-like cells without lipid droplets and expressed a uniform and higher level of α-SMA.HSC-CM(5d), but not HSC-CM(p3), provided a significant survival benefit and showed a dramatic reduction of hepatocellular necrosis and panlobular leukocyte infiltrates in mice exposed to APAP.However, this protective effect was abrogated at higher cell masses, indicating a therapeutic window of effectiveness.Furthermore, the protein array screenrevealed that HSC-CM(5d) was composed of many chemokines and growth factors that correlated with inflammatory inhibition and therapeutic activity.When compared with HSC-CM(p3), higher levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1γ, hepatocyte growth factor, interleukin-10, and matrix metalloproteinase-2, but lower levels of stem cell factor and Fas-Ligand were observed in HSCCM(5d).CONCLUSION: These data indicated that initiation HSCs and perpetuation HSCs were different in morphology and protein e

关键词： Hepatic stellate cells Acute liver injury Initiati

Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway

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World Journal of Gastroenterology 2019年第30期25卷 4222-4234页

作者： Gao-Liang Zou Shi Zuo Shuang Lu Rui-Han Hu Yin-Ying Lu Jing Yang Kai-Sheng Deng Ye-Ting Wu Mao Mu Juan-Juan Zhu Jing-Zhang Zeng Bao-Fang Zhang Xian Wu Xue-Ke Zhao Hai-Yang Li Department of Infectious Diseases Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina Department of Hepatobiliary Surgery Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina Comprehensive Liver Cancer Center 302 HospitalBeijing 100039China

BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor-beta(TGF-β)superfamily,bone morphogenetic protein 7(BMP7)has anti-liver fibrosis functions.However,little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-βduring liver fibrosis.In addition,the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.AIM To investigate changes in the dynamic expression of BMP7 during liver fibrosis,interactions between BMP7 and TGF-β1,and possible mechanisms underlying the anti-liver fibrosis function of BMP7.METHODS Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed.Exogenous BMP7 was used to treat mouse primary hepatic stellate cells(HSCs)to observe its effect on activation,migration,and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7.Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin(α-SMA)and the collagen formation associated protein type I collagen(Col I).Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.RESULTS In the process of liver fibrosis induced by carbon tetrachloride(CCl4)in mice,BMP7 protein expression first increased,followed by a decrease;there was a similar trend in the human body.This process was accompanied by a sustained increase in TGF-β1 protein expression.In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time-and dose-dependent manner.In contrast,high doses of exogenous BMP7 inhibited TGF-β1-induced activation,migration,and proliferation of HSCs;this inhibi

关键词： Liver fibrosis Bone morphogenetic protein Transforming growth factor Hepatic stellate cells