Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in m...Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.展开更多
Cholestatic liver disease,caused by the accumulation of hazardous bile acids in the liver,may result in cirrhosis,fibrosis,or liver failure.Activation of sirtuin 6(SIRT6)prevents cholestasis-associated pathological ev...Cholestatic liver disease,caused by the accumulation of hazardous bile acids in the liver,may result in cirrhosis,fibrosis,or liver failure.Activation of sirtuin 6(SIRT6)prevents cholestasis-associated pathological events,such as oxidative stress and mitochondrial biogenesis dysfunction,and inhibits bile acid synthesis to alleviate cholestatic liver injury.However,it remains uncertain which pathway mediates the therapeutic effect of SIRT6 in reducing cholestasis.Therefore,we treated liver-specific Sirt6 knockout mice with N-acetylcysteine,KEAP1-NRF2-IN-1,or acadesine to alleviate oxidative stress and/or promote mitochondrial biogenesis after modeling cholestatic liver disease,but these measures did not significantly improve cholestatic symptoms.However,MDL801,a SIRT6 agonist that downregulates cholesterol 7α-hydroxylase(CYP7A1,the key enzyme in bile acid synthesis)levels,exhibited favorable therapeutic effects.Additionally,the hepatic knockdown of Cyp7a1 further demonstrated that inhibiting hepatic bile acid synthesis might be the main pathway through which SIRT6 alleviates cholestatic liver disease.These findings provide a solid basis for the potential application of SIRT6 agonists in treating cholestatic liver disease.展开更多
Xiaohuang Qudan decoction(XHQDD)is a classical traditional Chinese medicine(TCM)formula widely used in the treatment of cholestatic liver injury.Despite its widespread use,the protective mechanism of XHQDD against cho...Xiaohuang Qudan decoction(XHQDD)is a classical traditional Chinese medicine(TCM)formula widely used in the treatment of cholestatic liver injury.Despite its widespread use,the protective mechanism of XHQDD against cholestatic liver injury remains incompletely understood.The aim of this study was to investigate whether XHQDD mediates its beneficial effects by inhibiting the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)pathway and regulating TH17/Treg balance.To this end,the researchers used Sprague-Dawley(SD)rats and established a cholestatic liver injury model by oral administration of alpha-naphthylisothiocyanate(ANIT).The experimental group was divided into six groups:Control(CON),ANIT,ursodeoxycholic acid(UDCA),XHQDD-low dose(XHQDD-L)group,XHQDD-medium dose(XHQDD-M)group,and XHQDD-high dose(XHQDD-H)groups.Then,after 7 d of treatment,various tests were performed to verify the results.Firstly,XHQDD and its drug-containing serum were analyzed by ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry(UPLC-MS/MS),and 14 blood-entry components were identified.Then,bile flow was monitored and found to be significantly reduced in the model group,which was significantly reversed in the UDCA and XHQDD groups.To further assess ANIT-induced liver injury,hematoxylin and eosin(H&E)and Sirius red staining,alongside transmission electron microscopy(TEM),were employed to observe liver tissues,revealing hepatocellular injury,cholestasis,and hepatic fibrotic changes.Serum inflammatory factors and liver injury indicators were assessed using enzyme-linked immunosorbent assay(ELISA),indicating an inflammatory state in ANIT-induced liver injury rats.The expression levels of JAK2/STAT3-related genes and proteins in liver and intestinal tissues were measured via quantitative reverse transcription polymerase chain reaction(qRT-PCR),immunohistochemistry,immunofluorescence(IF)staining,and Western blotting(WB)assays.These studies revealed that the inflammatory state of liver-injured rats was inextricably linked to the inflammatory cascade associated with the JAK2/STAT3 pathway and that XHQDD may exert anti-inflammatory efficacy by inhibiting the JAK2/STAT3 pathway.Flow cytometry was used to determine the percentage of T helper 17(Th17)/regulatory T(Treg)cells in serum and hepatocytes,and it was further found that XHQDD was able to regulate Th17/Treg immune homeostasis in liver-injured rats.The findings suggest that XHQDD markedly alleviates inflammation in ANIT rats,potentially treating cholestasis and liver injury through JAK2/STAT3 inhibition and Th17/Treg balance regulation.展开更多
Objective To compare the therapeutic efficacy of portal and tail vein transplantation of bone marrowderived mesenchymal stem cells(BMSCs) against cholestatic liver fibrosis in mice.Methods BMSCs were isolated and co-c...Objective To compare the therapeutic efficacy of portal and tail vein transplantation of bone marrowderived mesenchymal stem cells(BMSCs) against cholestatic liver fibrosis in mice.Methods BMSCs were isolated and co-cultured with starvation-activated hepatic stellate cells(HSCs).HSC activation markers were identified using immunofluorescence and qRT-PCR. BMSCs were injected into the liver tissues of bile duct ligation(BDL) mice via the tail and portal veins. Histomorphology, liver function, inflammatory cytokines, and the expression of key proteins were all determined in the liver tissues.Results BMSCs inhibited HSC activation by reducing α-SMA and collagen I expression. Compared to tail vein injection, DIL-labeled BMSCs injected through the portal vein maintained a high homing rate in the liver. Moreover, BMSCs transplanted through the portal vein resulted in greater improvement in liver color, hardness, and gallbladder size than did those transplanted through the tail vein. Furthermore,BMSCs injected by portal vein, but not tail vein, markedly ameliorated liver function, reduced the secretion of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and decreased α-SMA + hepatic stellate cell(HSC) activation and collagen fiber formation.Conclusion The therapeutic effect of BMSCs on cholestatic liver fibrosis in mice via portal vein transplantation was superior to that of tail vein transplantation. This comparative study provides reference information for further BMSC studies focused on clinical cholestatic liver diseases.展开更多
Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of th...Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.展开更多
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating Syst...Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.展开更多
Primary biliary cholangitis and primary sclerosing cholangitis(PSC)are the most common cholestatic liver diseases(CLD)in adults and are both characterized by an immune pathogenesis.While primary biliary cholangitis is...Primary biliary cholangitis and primary sclerosing cholangitis(PSC)are the most common cholestatic liver diseases(CLD)in adults and are both characterized by an immune pathogenesis.While primary biliary cholangitis is a model autoimmune disease,with over 90%of patients presenting very specific autoantibodies against mitochondrial antigens,PSC is considered an immune mediated disease.Osteoporosis is the most common bone disease in CLD,resulting in frequent fractures and leading to significant morbidity.Further,sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients.The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected.Although timely diagnosis,prevention,and management of osteosarcopenia are crucial to limit the consequences,there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD.International guidelines recommend screening for bone disease at the time of diagnosis of CLD.However,the optimal monitoring strategies and treatments have not been defined yet and vary among centers.We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD,and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.展开更多
Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease.Novel anti-chole...Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease.Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid(UDCA),the current standard treatment for cholestatic liver disease.Important novel treatment targets now also include nuclear receptors involved in bile acid(BA)homoeostasis like farnesoid X receptor and G proteincoupled receptors e.g.,the G-protein-coupled BA receptor“transmembrane G coupled receptor 5”.Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA.In this review,we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.展开更多
Selective cyclooxygenase-2 （COX-2） inhibitors are widely used due to their efficacy and good safety profile. However, recent case reports have described varying degrees of liver injudes associated with the use of CO...Selective cyclooxygenase-2 （COX-2） inhibitors are widely used due to their efficacy and good safety profile. However, recent case reports have described varying degrees of liver injudes associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.展开更多
Fibrosing cholestatic hepatitis(FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver,renal or bone transplantation recipients and in leukemia and lymphoma patients aft...Fibrosing cholestatic hepatitis(FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver,renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy.FCH constitutes a well-described form of fulminant hepatitis having extensive fibrosis and severe cholestasis as its most characteristic pathological findings.Here,we report a case of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression.This is the first reported case in the literature of FCH after conventional chemotherapy for a solid tumor.In addition to a detailed report of the case,a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.展开更多
OBJECTIVE:To investigate the targets and mechanisms of action of Qingkailing injection(清开灵注射液,QKL)in the treatment of cholestatic hepatitis.METHODS:A network pharmacology method was implemented using drug and di...OBJECTIVE:To investigate the targets and mechanisms of action of Qingkailing injection(清开灵注射液,QKL)in the treatment of cholestatic hepatitis.METHODS:A network pharmacology method was implemented using drug and disease databases to target QKL and cholestasis hepatitis,respectively.The functional protein association network STRING database was used to construct a protein-protein interaction network using R language and the Bioconductor toolkit.The org.Hs.eg.db and cluster Profiler packages were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis,which explored biological functions and pathways of potential targets.Targets were then visualized using Cytoscape 3.6.0 software.RESULTS:We screened 121 compounds in QKL and identified 112 targets for the treatment of cholestatic hepatitis.QKL played a role in the treatment of cholestatic hepatitis through 305 biology process terms,15 cellular component and 29 molecular function terms.The mechanism of QKL action was mainly related to tumor necrosis factor,mitogen-activated protein kinase,and PI3 K-Akt signaling pathways.CONCLUSION:The treatment of cholestatic hepatitis by QKL involved multiple targets,biological functions,and signaling pathways that are closely associated with the disease.展开更多
OBJECTIVE: To observe the therapeutic effect of Chishaodanpi decoction(CSDPD) on chronic viral cholestatic hepatitis.METHODS: A total of 107 subjects with chronic viral cholestatic hepatitis were enrolled in our hospi...OBJECTIVE: To observe the therapeutic effect of Chishaodanpi decoction(CSDPD) on chronic viral cholestatic hepatitis.METHODS: A total of 107 subjects with chronic viral cholestatic hepatitis were enrolled in our hospital from March 2007 to November 2012. Patients were randomly divided into treatment(54 cases)and control groups(53 cases). The control group was treated with potassium magnesium aspartate,diammonium glycyrrhizinate, glucurolactone, vitamin C, and lamivudine, once a day. The treatment group was treated with modified CSDPD, 100 m L a time, twice a day, in addition to the treatment given to the control group. The patients in both groups were treated for 8 weeks. The main symptoms and signs were recorded every day throughout the clinical trial. Before and after the trial,changes in liver function including total bilirubin(TBil), direct bilirubin(DBil), total bile acid(TBA),and the activities of alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), and γ-glutamyl transferase(γ-GT),were all detected. Adverse reactions were also recorded.RESULTS: There were no differences in gender, age,disease duration, symptoms, signs, or laboratory findings between the two groups(P>0.05). After an8-week treatment, improvements in jaundice, weakness, poor appetite, abdominal distention, and skin itching were significantly better in the treatment group than in the control group(P<0.05). In the treatment group, 43 patients had a significant response to the treatment, seven patients had a response, and four patients had no response, with 21,12, and 20 patients in the control group, respectively. The total effective rate was 92.6% in the treatment group and 62.3% in the control group, which was a significant difference(P<0.05). The levels of TBil, DBil, TBA, ALP, ALT, AST, and γ-GT in both groups were significantly lower after treatment,and were significantly different between the two groups(P<0.05). A few patients in the treatment group had mild adverse effects such as increased bowel movement frequency and mild stomachache. No other adverse reactions were observed in either group.CONCLUSION: CSDPD has a satisfactory therapeutic effect on chronic viral cholestatic hepatitis.展开更多
Severe acute hepatitis of unknown etiology is difficult to treat and often progresses to subacute fulminant hepatitis or late-onset hepatic failure. A 45-year-old wellnourished, healthy man had progressive fatigue and...Severe acute hepatitis of unknown etiology is difficult to treat and often progresses to subacute fulminant hepatitis or late-onset hepatic failure. A 45-year-old wellnourished, healthy man had progressive fatigue and his liver function tests showed severe liver dysfunction. The etiology of sever acute cholestatic hepatitis was unknown. The liver function tests normalized gradually, which excluded high persistent total bilirubin after starting on predonine. A liver biopsy showed chronic active hepatitis with mild f ibrosis (A2, F1). Oral Inchinko-to, a Chinese herbal medicine, at 7.5 g daily was prescribed. The treatment was effective with no adverse effects. We present a successfully treated case and discuss hepatoprotective and choleretic effects of Inchinko-to.展开更多
Chuanxiong Rhizoma(CX,the dried rhizome of Ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic ...Chuanxiong Rhizoma(CX,the dried rhizome of Ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies.Currently,little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells(HSCs).The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous,alkaloid,phenolic acid and phthalide extracts of CX(CX_(AE),CX_(AL),CX_(PA)and CX_(PHL))and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury.The active compounds of different CX extracts were identified by UPLC-MS/MS.A cholestatic liver injury mouse model induced by bile duct ligation(BDL),and transforming growth factor-β(TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes(HIBECs)and HSC cell line(LX-2 cells)were used for in vivo and in vitro studies.Histological and other biological techniques were also applied.The results indicated that CX_(AE),CX_(AL)and CX_(PHL)significantly reduced ductular reaction(DR)and improved liver fibrosis in the BDL mice.Meanwhile,both CX_(AE)and CX_(PHL)suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β.CX_(PHL)suppressed the transcription and transfer of plasminogen activator inhibitor-1(PAI-1)and fibronectin(FN)from the‘DR-like’cholangiocytes to activated HSCs.Mechanistically,the inhibition of PAI-1 and FN by CX_(PHL)was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3,followdd by the suppression of histone 3 lysine 9 acetylation(H3K9ac)-mediated transcription in cholangiocytes.In conclusion,CX_(PHL)exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts,and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.展开更多
The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differenti...The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differential gene expression patterns were analyzed in the lower thoracic spinal cord involved in cholestatic pruritus after BDL operation using high-throughput RNA sequencing. At 21st day after BDL, the expression levels of ENSRNOG00000060523, ENSRNOG00000058405 and ENSRNOG00000055193 mRNA were significantly up-regulated, and those of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289, Gemin8, Serpina3n and Trim63 mRNA were significantly down-regulated in BDL group. The RNAseq data of selected mRNAs were validated by RT-qPCR. The expression levels of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289 and Serpina3n mRNA were significantly down-regulated in BDL group. This study suggested that cholestatic pruritus in experimental obstructive jaundice mouse model is related with in the changes of gene expression profiles in spinal cord.展开更多
Liver diseases pose a significant threat to human health.Although effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment ...Liver diseases pose a significant threat to human health.Although effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes.This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease(ALD),as reported by Koizumi et al in the World Journal of Gastroenterology.We summarize the impact and mechanisms of Elafibranor on ALD,metabolic-associated fatty liver disease,and cholestatic liver disease based on current research.We also explore its potential as a dual agonist of PPARα/δ,which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis.Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.展开更多
To explore the pathological features and thedifferential diagnosis of recurrent HBV after livertransplantation.Methods: One case of liver transplantation for HBVcirrhosis was subjected to liver biopsises on time post-...To explore the pathological features and thedifferential diagnosis of recurrent HBV after livertransplantation.Methods: One case of liver transplantation for HBVcirrhosis was subjected to liver biopsises on time post-operatively.Results: 25 days after liver transplantation, serologicHBsAg, HBeAg and HBV-DNA of the patient becamenegative, but HBsAg was positive again on day 58 af-ter liver transplantation. Histopathological examina-tion showed balloon-like changes of hepatocytes withfragmental necrosis, fibrosis in the portal areas andaround the portal veins, cholestasis in some hepato-cytes and canaliculi, and positive HBsAg and HBcAgwith immunohistochemical staining. Clinically hepaticenzyme levels progressively increased, maintained forsome time, and decreased rapidly at last. Stubborn hy-poproteinemia was associated with the aggregation ofgeneral condition of the patient.Conclusions: Fibrosing cholestatic hepatitis (FCH) is aspecial type in recurrent infection of HBV after livertransplantation. It has a serious clinical process andspecific pathological changes different from those ofthe usual HBV.展开更多
Cholestatic liver disease (CLD) is a common problem in clinical practice with the main manifestation being cholestasis.Recently,there has been a steady increase in knowledge associated with the diagnosis and treatment...Cholestatic liver disease (CLD) is a common problem in clinical practice with the main manifestation being cholestasis.Recently,there has been a steady increase in knowledge associated with the diagnosis and treatment of CLD.Therefore,the experts in China were organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases (Electronic Edition),Chinese Journal of Liver Diseases (Electronic Edition) and Infection International (Electronic Edition) to collect and analyze relevant research,ultimately resulting in the development of this work (Chinese Expert consensus for the diagnosis and treatment of CLDs,also abbreviated as consensus).展开更多
Febrile cholestatic liver disease is an extremely unusual presentation of Hodgkin lymphoma(HL).The liver biopsy of a 40-year-old man with febrile episodes and cholestatic laboratory pattern disclosed an uncommon subty...Febrile cholestatic liver disease is an extremely unusual presentation of Hodgkin lymphoma(HL).The liver biopsy of a 40-year-old man with febrile episodes and cholestatic laboratory pattern disclosed an uncommon subtype of HL,a nodular lymphocyte-predominant HL(NLPHL).Liver involvement in the early stage of the usually indolent NLPHL's clinical course suggests an aggressiveness and unfavorable outcome.Emphasizing a liver biopsy early in the diagnostic algorithm enables accurate diagnosis and appropriate treatment.Although rare,HL should be considered in the differential diagnosis of cholestasis.展开更多
基金supported by the National Science Foundation of China(No.82405004,82474253)the Natural Science Foundation postdoctoral project of Chongqing(CSTB2022NSCQ-BHX0709)+2 种基金Chongqing Wanzhou District doctoral“through train”scientific research project(wzstc-20220124)Natural Science Foundation of Chongqing,China(No.Cstc2021jcyj-msxmX0996)Chongqing Wanzhou District Science and Health Joint Medical Research Project(wzstc-kw2023032)。
文摘Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.
基金supported by the National Natural Science Foundation of China(Grant No.82170877).
文摘Cholestatic liver disease,caused by the accumulation of hazardous bile acids in the liver,may result in cirrhosis,fibrosis,or liver failure.Activation of sirtuin 6(SIRT6)prevents cholestasis-associated pathological events,such as oxidative stress and mitochondrial biogenesis dysfunction,and inhibits bile acid synthesis to alleviate cholestatic liver injury.However,it remains uncertain which pathway mediates the therapeutic effect of SIRT6 in reducing cholestasis.Therefore,we treated liver-specific Sirt6 knockout mice with N-acetylcysteine,KEAP1-NRF2-IN-1,or acadesine to alleviate oxidative stress and/or promote mitochondrial biogenesis after modeling cholestatic liver disease,but these measures did not significantly improve cholestatic symptoms.However,MDL801,a SIRT6 agonist that downregulates cholesterol 7α-hydroxylase(CYP7A1,the key enzyme in bile acid synthesis)levels,exhibited favorable therapeutic effects.Additionally,the hepatic knockdown of Cyp7a1 further demonstrated that inhibiting hepatic bile acid synthesis might be the main pathway through which SIRT6 alleviates cholestatic liver disease.These findings provide a solid basis for the potential application of SIRT6 agonists in treating cholestatic liver disease.
基金supported by the Natural Science Foundation of Hubei Province(No.2022CFD020)the Postdoctoral Research Initiation Fund(No.20211015KY19)the Hubei Provincial Medical Young Top Talents[No.2019(48)]。
文摘Xiaohuang Qudan decoction(XHQDD)is a classical traditional Chinese medicine(TCM)formula widely used in the treatment of cholestatic liver injury.Despite its widespread use,the protective mechanism of XHQDD against cholestatic liver injury remains incompletely understood.The aim of this study was to investigate whether XHQDD mediates its beneficial effects by inhibiting the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)pathway and regulating TH17/Treg balance.To this end,the researchers used Sprague-Dawley(SD)rats and established a cholestatic liver injury model by oral administration of alpha-naphthylisothiocyanate(ANIT).The experimental group was divided into six groups:Control(CON),ANIT,ursodeoxycholic acid(UDCA),XHQDD-low dose(XHQDD-L)group,XHQDD-medium dose(XHQDD-M)group,and XHQDD-high dose(XHQDD-H)groups.Then,after 7 d of treatment,various tests were performed to verify the results.Firstly,XHQDD and its drug-containing serum were analyzed by ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry(UPLC-MS/MS),and 14 blood-entry components were identified.Then,bile flow was monitored and found to be significantly reduced in the model group,which was significantly reversed in the UDCA and XHQDD groups.To further assess ANIT-induced liver injury,hematoxylin and eosin(H&E)and Sirius red staining,alongside transmission electron microscopy(TEM),were employed to observe liver tissues,revealing hepatocellular injury,cholestasis,and hepatic fibrotic changes.Serum inflammatory factors and liver injury indicators were assessed using enzyme-linked immunosorbent assay(ELISA),indicating an inflammatory state in ANIT-induced liver injury rats.The expression levels of JAK2/STAT3-related genes and proteins in liver and intestinal tissues were measured via quantitative reverse transcription polymerase chain reaction(qRT-PCR),immunohistochemistry,immunofluorescence(IF)staining,and Western blotting(WB)assays.These studies revealed that the inflammatory state of liver-injured rats was inextricably linked to the inflammatory cascade associated with the JAK2/STAT3 pathway and that XHQDD may exert anti-inflammatory efficacy by inhibiting the JAK2/STAT3 pathway.Flow cytometry was used to determine the percentage of T helper 17(Th17)/regulatory T(Treg)cells in serum and hepatocytes,and it was further found that XHQDD was able to regulate Th17/Treg immune homeostasis in liver-injured rats.The findings suggest that XHQDD markedly alleviates inflammation in ANIT rats,potentially treating cholestasis and liver injury through JAK2/STAT3 inhibition and Th17/Treg balance regulation.
基金supported by grants from the Natural Science Research Project of Shanxi Basic Research Program [20210302123246]the Scientific Research Project of Shanxi Provincial Health Commission [2020079]+1 种基金the Natural Science Foundation Youth Fund of Hebei Province[C2022402032]the Shanxi Province Higher Education “Billion Project” Science and Technology Guidance Project [BYJL036]。
文摘Objective To compare the therapeutic efficacy of portal and tail vein transplantation of bone marrowderived mesenchymal stem cells(BMSCs) against cholestatic liver fibrosis in mice.Methods BMSCs were isolated and co-cultured with starvation-activated hepatic stellate cells(HSCs).HSC activation markers were identified using immunofluorescence and qRT-PCR. BMSCs were injected into the liver tissues of bile duct ligation(BDL) mice via the tail and portal veins. Histomorphology, liver function, inflammatory cytokines, and the expression of key proteins were all determined in the liver tissues.Results BMSCs inhibited HSC activation by reducing α-SMA and collagen I expression. Compared to tail vein injection, DIL-labeled BMSCs injected through the portal vein maintained a high homing rate in the liver. Moreover, BMSCs transplanted through the portal vein resulted in greater improvement in liver color, hardness, and gallbladder size than did those transplanted through the tail vein. Furthermore,BMSCs injected by portal vein, but not tail vein, markedly ameliorated liver function, reduced the secretion of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and decreased α-SMA + hepatic stellate cell(HSC) activation and collagen fiber formation.Conclusion The therapeutic effect of BMSCs on cholestatic liver fibrosis in mice via portal vein transplantation was superior to that of tail vein transplantation. This comparative study provides reference information for further BMSC studies focused on clinical cholestatic liver diseases.
文摘Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.
文摘Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.
文摘Primary biliary cholangitis and primary sclerosing cholangitis(PSC)are the most common cholestatic liver diseases(CLD)in adults and are both characterized by an immune pathogenesis.While primary biliary cholangitis is a model autoimmune disease,with over 90%of patients presenting very specific autoantibodies against mitochondrial antigens,PSC is considered an immune mediated disease.Osteoporosis is the most common bone disease in CLD,resulting in frequent fractures and leading to significant morbidity.Further,sarcopenia is emerging as a frequent complication of chronic liver diseases with a significant prognostic impact and severe implications on the quality of life of patients.The mechanisms underlying osteoporosis and sarcopenia in CLD are still largely unknown and the association between these clinical conditions remains to be dissected.Although timely diagnosis,prevention,and management of osteosarcopenia are crucial to limit the consequences,there are no specific guidelines for management of osteoporosis and sarcopenia in patients with CLD.International guidelines recommend screening for bone disease at the time of diagnosis of CLD.However,the optimal monitoring strategies and treatments have not been defined yet and vary among centers.We herein aim to comprehensively outline the pathogenic mechanisms and clinical implications of osteosarcopenia in CLD,and to summarize expert recommendations for appropriate diagnostic and therapeutic approaches.
文摘Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease.Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid(UDCA),the current standard treatment for cholestatic liver disease.Important novel treatment targets now also include nuclear receptors involved in bile acid(BA)homoeostasis like farnesoid X receptor and G proteincoupled receptors e.g.,the G-protein-coupled BA receptor“transmembrane G coupled receptor 5”.Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA.In this review,we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.
文摘Selective cyclooxygenase-2 （COX-2） inhibitors are widely used due to their efficacy and good safety profile. However, recent case reports have described varying degrees of liver injudes associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.
文摘Fibrosing cholestatic hepatitis(FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver,renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy.FCH constitutes a well-described form of fulminant hepatitis having extensive fibrosis and severe cholestasis as its most characteristic pathological findings.Here,we report a case of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression.This is the first reported case in the literature of FCH after conventional chemotherapy for a solid tumor.In addition to a detailed report of the case,a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.
基金Supported by a grant from the National Natural Science Foundation of China(Study on Qingkailing’s Intervention Mechanism on"No Reflow"Phenomenon after Cerebral Infarction and Pericyte"Rho A/ROCK"Pathway,No.81973789)。
文摘OBJECTIVE:To investigate the targets and mechanisms of action of Qingkailing injection(清开灵注射液,QKL)in the treatment of cholestatic hepatitis.METHODS:A network pharmacology method was implemented using drug and disease databases to target QKL and cholestasis hepatitis,respectively.The functional protein association network STRING database was used to construct a protein-protein interaction network using R language and the Bioconductor toolkit.The org.Hs.eg.db and cluster Profiler packages were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis,which explored biological functions and pathways of potential targets.Targets were then visualized using Cytoscape 3.6.0 software.RESULTS:We screened 121 compounds in QKL and identified 112 targets for the treatment of cholestatic hepatitis.QKL played a role in the treatment of cholestatic hepatitis through 305 biology process terms,15 cellular component and 29 molecular function terms.The mechanism of QKL action was mainly related to tumor necrosis factor,mitogen-activated protein kinase,and PI3 K-Akt signaling pathways.CONCLUSION:The treatment of cholestatic hepatitis by QKL involved multiple targets,biological functions,and signaling pathways that are closely associated with the disease.
文摘OBJECTIVE: To observe the therapeutic effect of Chishaodanpi decoction(CSDPD) on chronic viral cholestatic hepatitis.METHODS: A total of 107 subjects with chronic viral cholestatic hepatitis were enrolled in our hospital from March 2007 to November 2012. Patients were randomly divided into treatment(54 cases)and control groups(53 cases). The control group was treated with potassium magnesium aspartate,diammonium glycyrrhizinate, glucurolactone, vitamin C, and lamivudine, once a day. The treatment group was treated with modified CSDPD, 100 m L a time, twice a day, in addition to the treatment given to the control group. The patients in both groups were treated for 8 weeks. The main symptoms and signs were recorded every day throughout the clinical trial. Before and after the trial,changes in liver function including total bilirubin(TBil), direct bilirubin(DBil), total bile acid(TBA),and the activities of alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), and γ-glutamyl transferase(γ-GT),were all detected. Adverse reactions were also recorded.RESULTS: There were no differences in gender, age,disease duration, symptoms, signs, or laboratory findings between the two groups(P>0.05). After an8-week treatment, improvements in jaundice, weakness, poor appetite, abdominal distention, and skin itching were significantly better in the treatment group than in the control group(P<0.05). In the treatment group, 43 patients had a significant response to the treatment, seven patients had a response, and four patients had no response, with 21,12, and 20 patients in the control group, respectively. The total effective rate was 92.6% in the treatment group and 62.3% in the control group, which was a significant difference(P<0.05). The levels of TBil, DBil, TBA, ALP, ALT, AST, and γ-GT in both groups were significantly lower after treatment,and were significantly different between the two groups(P<0.05). A few patients in the treatment group had mild adverse effects such as increased bowel movement frequency and mild stomachache. No other adverse reactions were observed in either group.CONCLUSION: CSDPD has a satisfactory therapeutic effect on chronic viral cholestatic hepatitis.
文摘Severe acute hepatitis of unknown etiology is difficult to treat and often progresses to subacute fulminant hepatitis or late-onset hepatic failure. A 45-year-old wellnourished, healthy man had progressive fatigue and his liver function tests showed severe liver dysfunction. The etiology of sever acute cholestatic hepatitis was unknown. The liver function tests normalized gradually, which excluded high persistent total bilirubin after starting on predonine. A liver biopsy showed chronic active hepatitis with mild f ibrosis (A2, F1). Oral Inchinko-to, a Chinese herbal medicine, at 7.5 g daily was prescribed. The treatment was effective with no adverse effects. We present a successfully treated case and discuss hepatoprotective and choleretic effects of Inchinko-to.
基金the Beijing Municipal Science&Technology Commission(No.7212174)the National High-Level Talents Special Support Program to XL,the National Natural Science Foundation of China(Nos.82274186 and 82004045)+1 种基金National Key Research and Development Program on Modernization of Traditional Chinese Medicine(No.2022YFC-3502100)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202006).
文摘Chuanxiong Rhizoma(CX,the dried rhizome of Ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies.Currently,little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells(HSCs).The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous,alkaloid,phenolic acid and phthalide extracts of CX(CX_(AE),CX_(AL),CX_(PA)and CX_(PHL))and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury.The active compounds of different CX extracts were identified by UPLC-MS/MS.A cholestatic liver injury mouse model induced by bile duct ligation(BDL),and transforming growth factor-β(TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes(HIBECs)and HSC cell line(LX-2 cells)were used for in vivo and in vitro studies.Histological and other biological techniques were also applied.The results indicated that CX_(AE),CX_(AL)and CX_(PHL)significantly reduced ductular reaction(DR)and improved liver fibrosis in the BDL mice.Meanwhile,both CX_(AE)and CX_(PHL)suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β.CX_(PHL)suppressed the transcription and transfer of plasminogen activator inhibitor-1(PAI-1)and fibronectin(FN)from the‘DR-like’cholangiocytes to activated HSCs.Mechanistically,the inhibition of PAI-1 and FN by CX_(PHL)was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3,followdd by the suppression of histone 3 lysine 9 acetylation(H3K9ac)-mediated transcription in cholangiocytes.In conclusion,CX_(PHL)exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts,and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.
文摘The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differential gene expression patterns were analyzed in the lower thoracic spinal cord involved in cholestatic pruritus after BDL operation using high-throughput RNA sequencing. At 21st day after BDL, the expression levels of ENSRNOG00000060523, ENSRNOG00000058405 and ENSRNOG00000055193 mRNA were significantly up-regulated, and those of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289, Gemin8, Serpina3n and Trim63 mRNA were significantly down-regulated in BDL group. The RNAseq data of selected mRNAs were validated by RT-qPCR. The expression levels of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289 and Serpina3n mRNA were significantly down-regulated in BDL group. This study suggested that cholestatic pruritus in experimental obstructive jaundice mouse model is related with in the changes of gene expression profiles in spinal cord.
文摘Liver diseases pose a significant threat to human health.Although effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes.This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease(ALD),as reported by Koizumi et al in the World Journal of Gastroenterology.We summarize the impact and mechanisms of Elafibranor on ALD,metabolic-associated fatty liver disease,and cholestatic liver disease based on current research.We also explore its potential as a dual agonist of PPARα/δ,which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis.Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.
文摘To explore the pathological features and thedifferential diagnosis of recurrent HBV after livertransplantation.Methods: One case of liver transplantation for HBVcirrhosis was subjected to liver biopsises on time post-operatively.Results: 25 days after liver transplantation, serologicHBsAg, HBeAg and HBV-DNA of the patient becamenegative, but HBsAg was positive again on day 58 af-ter liver transplantation. Histopathological examina-tion showed balloon-like changes of hepatocytes withfragmental necrosis, fibrosis in the portal areas andaround the portal veins, cholestasis in some hepato-cytes and canaliculi, and positive HBsAg and HBcAgwith immunohistochemical staining. Clinically hepaticenzyme levels progressively increased, maintained forsome time, and decreased rapidly at last. Stubborn hy-poproteinemia was associated with the aggregation ofgeneral condition of the patient.Conclusions: Fibrosing cholestatic hepatitis (FCH) is aspecial type in recurrent infection of HBV after livertransplantation. It has a serious clinical process andspecific pathological changes different from those ofthe usual HBV.
文摘Cholestatic liver disease (CLD) is a common problem in clinical practice with the main manifestation being cholestasis.Recently,there has been a steady increase in knowledge associated with the diagnosis and treatment of CLD.Therefore,the experts in China were organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases (Electronic Edition),Chinese Journal of Liver Diseases (Electronic Edition) and Infection International (Electronic Edition) to collect and analyze relevant research,ultimately resulting in the development of this work (Chinese Expert consensus for the diagnosis and treatment of CLDs,also abbreviated as consensus).
文摘Febrile cholestatic liver disease is an extremely unusual presentation of Hodgkin lymphoma(HL).The liver biopsy of a 40-year-old man with febrile episodes and cholestatic laboratory pattern disclosed an uncommon subtype of HL,a nodular lymphocyte-predominant HL(NLPHL).Liver involvement in the early stage of the usually indolent NLPHL's clinical course suggests an aggressiveness and unfavorable outcome.Emphasizing a liver biopsy early in the diagnostic algorithm enables accurate diagnosis and appropriate treatment.Although rare,HL should be considered in the differential diagnosis of cholestasis.
