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Lim J, Vujkovic M, Levin MG, Lorenz K, Voight BF, Zhang DY, Dudek MF, Pahl MC, Pippin JA, Su C, Manduchi E, Wells AD, Grant SFA, Abramowitz S, Damrauer SM, Mukherjee S, Yang G, Kaplan DE, Rader DJ. Trans-ancestry genome-wide association meta-analysis of gallstone disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.16.25324077. [PMID: 40166541 PMCID: PMC11957090 DOI: 10.1101/2025.03.16.25324077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Gallstone disease is a highly prevalent and costly gastrointestinal disease. Yet, genetic variation in susceptibility to gallstone disease and its implication in metabolic regulatory pathways remain to be explored. We report a trans-ancestry genome-wide association meta-analysis of gallstone disease including 88,063 cases and 1,490,087 controls in the UK Biobank, FinnGen, Biobank Japan, and Million Veteran Program. We identified 91 (37 novel) risk loci across the meta-analysis and found replication in statistically compelling signals in the All of Us Research Program. A polygenic risk score constructed from trans-ancestry lead variants was positively associated with liver chemistry and alpha-1-antitrypsin deficiency and negatively associated with total cholesterol and low-density lipoprotein levels among trans-ancestry and European ancestry groups in the Penn Medicine BioBank. Cross-trait colocalization analysis between risk loci and 44 liver, metabolic, renal, and inflammatory traits yielded 350 significant colocalizations as well as 97 significant colocalizations and 65 prioritized genes from expression quantitative trait loci from eight tissues. These findings broaden our understanding of the genetic architecture of gallstone disease.
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Aziz B, Beverley Kok, Cheah M, Lytvyak E, Moctezuma-Velazquez C, Wasilenko S, Tsochatzis E, Ravikumar R, Jose S, Allison M, Gunson B, Manas D, Monaco A, Mirza D, Fusai G, Owen N, Thorburn D, Roberts K, Srinivasan P, Wigmore S, Athale A, Creamer F, Fernando B, Iyer V, Madanur M, Sen G, Montano-Loza AJ, Hansen B, Mason AL. Severe Cholestasis Predicts Recurrent Primary Sclerosing Cholangitis Following Liver Transplantation. Am J Gastroenterol 2025; 120:459-468. [PMID: 39888688 PMCID: PMC11774198 DOI: 10.14309/ajg.0000000000002977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) may reoccur following liver transplantation (LT), and the diagnosis established once imaging studies demonstrate the diagnostic cholangiographic appearance. To evaluate whether the development of recurrent PSC (rPSC) is associated with cholestasis soon after LT, we studied whether changes in hepatic biochemistry within the first 12 months were linked with the development of rPSC and graft loss. METHODS We conducted a retrospective cohort analysis of 158 transplant recipients with PSC in Canada and 549 PSC transplant recipients from the United Kingdom. We evaluated serum liver tests within 12 months after LT and the subsequent development of a cholangiographic diagnosis of rPSC as a time-dependent covariate using Cox regression. Severe cholestasis was defined as either alkaline phosphatase > 3× upper limit of normal or total bilirubin > 100 μmol/L. RESULTS Patients who developed rPSC were more likely to have severe cholestasis vs those without at 3 months (20.5% vs 8.2%, P = 0.011), at 6 months (17.9% vs 10.0%, P = 0.026), and 12 months (15.4% vs 7.8%, P = 0.051) in the Canadian cohort and at 12 months in the UK cohort (27.9% vs 12.6%, P < 0.0001). By multivariable analysis, development of severe cholestasis in the Canadian cohort at 3 months (hazard ratio [HR] = 2.41, P = 0.046) and in the UK cohort at 12 months (HR = 3.141, P < 0.0001) was both associated with rPSC. Severe cholestasis at 3 months in the Canadian cohort was predictive of graft loss (HR = 3.88, P = 0.0001). DISCUSSION The development of cholestasis within 3-12 months following LT was predictive of rPSC and graft loss.
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Affiliation(s)
- Bishoi Aziz
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| | - Beverley Kok
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Matthew Cheah
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| | - Ellina Lytvyak
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | | | - Shawn Wasilenko
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Reena Ravikumar
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Sophie Jose
- Research Department of Infection and Population Health, University College London, UK
| | - Michael Allison
- Cambridge Transplant Unit, Cambridge University Hospitals, Cambridge, UK
| | - Bridget Gunson
- The Liver Unit, University Hospital Birmingham, Birmingham, UK
| | - Derek Manas
- Institute of Transplantation, Freeman Hospital, Newcastle, UK
| | - Andrea Monaco
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Darius Mirza
- The Liver Unit, University Hospital Birmingham, Birmingham, UK
| | - Giuseppe Fusai
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Nicola Owen
- Cambridge Transplant Unit, Cambridge University Hospitals, Cambridge, UK
| | - Douglas Thorburn
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Keith Roberts
- The Liver Unit, University Hospital Birmingham, Birmingham, UK
| | | | - Stephen Wigmore
- Department of HPB and Liver Transplant Surgery, Royal Infirmary of Edinburgh, Edinburgh, Scotland
| | - Anuja Athale
- Institute of Liver Studies, Kings College Hospital, London, UK
| | - Felicity Creamer
- Department of HPB and Liver Transplant Surgery, Royal Infirmary of Edinburgh, Edinburgh, Scotland
| | - Bimbi Fernando
- Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Vikram Iyer
- Royal Melbourne Hospital, Parkville, Australia
| | - Mansoor Madanur
- Institute of Liver Studies, Kings College Hospital, London, UK
| | - Gourab Sen
- Institute of Transplantation, Freeman Hospital, Newcastle, UK
| | - Aldo J. Montano-Loza
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| | - Bettina Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Andrew L. Mason
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
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Wu Z, Shi J, Zhang Y, Shi R, Guo Q, Zhang J, Lu B, Huang Z, Ji L. Uncovering the pharmacological mechanism and the main herbal medicine contributing to the efficacy of Xiaoyanlidan Tablet (XYLDT) in treating cholestatic liver injury. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119163. [PMID: 39613007 DOI: 10.1016/j.jep.2024.119163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 12/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xiaoyanlidan Tablet (XYLDT) is a Chinese patent medicine consisted of three traditional Chinese medicines (TCMs) including Andrographis Herba (AH), Linearstripe Rabdosia Herba (LRH) and Picrasmae Ramulus et Folium (PRF). In Chinese traditional medicine theory, XYLDT has the "heat-clearing, dampness-dispelling and gallbladder function promoting" properties, and was widely used in the clinic for decades to treat pain in the subcostal region or bitter taste in the mouth, which were induced by liver-gallbladder dampness-heat. Meanwhile, it was also used for the therapy of acute cholecystitis and cholangitis. AIM OF THE STUDY To explore the mechanism of XYLDT in alleviating the alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury (CLI), and to find out which TCM consisted in XYLDT contributed the most to the therapeutic efficacy of XYLDT. METHODS ANIT was orally given to mice to induce CLI in vivo. Each TCM in XYLDT alone, XYLDT-without one TCM or XYLDT was orally given to mice before or after ANIT administration. Serum biochemical indicators were measured by using commercial kits. Liver histopathology was observed. Clinical data analysis was used to predict molecules and signal pathways involved in the XYLDT-provided improvement on CLI, which was further verified by using RT-PCR and Western-blot assay. RESULTS The alleviation of XYLDT on ANIT-induced CLI was proved by the data of serum biochemical indicators and liver histological observation. Results from clinical data analysis indicated that XYLDT improved CLI via improving mitochondrial function, oxidative phosphorylation, oxidative stress. XYLDT reduced the ROS level, MDA content, and increased GSH content. Meanwhile XYLDT improved the level of Nrf2 into the nucleus and mRNA expression of Nqo1, Gclc, Gclm. Andrographis Herba was proved to be the most crucial for the XYLDT-provided therapeutic efficacy on CLI. Moreover, andrographolide and neoandrographolide, two main active compounds in Andrographis Herba, had the apparent anti-inflammatory ability in LPS-stimulated RAW264.7 cells. Andrographolide also promoted nuclear translocation activation of Nrf2 in antioxidant response elements (ARE)-luciferin transfected L-02 cells. CONCLUSION XYLDT alleviated the ANIT-induced CLI via improving oxidative stress and activated Nrf2-related signaling pathways. Andrographis Herba was important for the XYLDT-provided alleviation on CLI.
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Affiliation(s)
- Zeqi Wu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jionghua Shi
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ruijia Shi
- School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qian Guo
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jingnan Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Wang S, Liu Q, Sun X, Wei W, Ding L, Zhao X. Identification of novel ABCB4 variants and genotype-phenotype correlation in progressive familial intrahepatic cholestasis type 3. Sci Rep 2024; 14:27381. [PMID: 39521930 PMCID: PMC11550383 DOI: 10.1038/s41598-024-79123-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe hepatic disorder characterized by cholestasis. Elucidating the genotype-phenotype correlations and expanding the mutational spectrum of the ABCB4 gene are crucial for enhancing diagnostic accuracy and therapeutic strategies.Clinical and genetic data from 2 original PFIC3 patients from our institution, along with 118 additional cases identified through a comprehensive literature review, were integrated for a comprehensive analysis. The study included statistical analysis of clinical information, genetic analysis, multi-species sequence alignment, protein structure modeling, and pathogenicity assessment. Machine learning techniques were applied to identify genotype-phenotype relationships. We identified three novel ABCB4 mutations: two missense mutations (c.904G > T and c.2493G > C) and one splicing mutation (c.1230 + 1G > A). Homozygous mutations were associated with significantly earlier disease onset compared to compound heterozygous mutations (p < 0.0001). Missense mutations were predominant (76.9%), with Exon 7 being the most frequently affected region. A random forest model indicated that Exon 10 had the highest feature importance score (9.9%). Liver transplantation remains the most effective treatment modality for PFIC3. This investigation broadens the known mutation spectrum of the ABCB4 gene and identifies key variant sites associated with clinical manifestations. These insights lay a foundation for early diagnosis, optimal treatment selection, and further research into PFIC3.
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Affiliation(s)
- Senyan Wang
- Translational Medicine Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qi Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Sun
- Department of Oncology, Henan Cancer Hospital, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, China
| | - Wenjuan Wei
- Translational Medicine Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, China
| | - Leilei Ding
- Department of Obstetrics and Gynecology, Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Xiaofang Zhao
- Translational Medicine Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, China.
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Guan G, Cao H, Tang Z, Zhang K, Zhong M, Lv R, Wan W, Guo F, Wang Y, Gao Y. Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118108. [PMID: 38574780 DOI: 10.1016/j.jep.2024.118108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/09/2024] [Accepted: 03/23/2024] [Indexed: 04/06/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1β, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.
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Affiliation(s)
- Guoqiang Guan
- Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, China; Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Houkang Cao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Zixuan Tang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Kefeng Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Mingli Zhong
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Rui Lv
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Weimin Wan
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Fengyue Guo
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Yongwang Wang
- Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, China.
| | - Ya Gao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China.
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Zhao H, Yu X, Cheng J, Chen D, Xu Q, Sheng J, Shi Y. Citrullinemia type II accompanied by mental derangement combined with multidrug resistance 3 decrease, case report. Heliyon 2023; 9:e21760. [PMID: 38027652 PMCID: PMC10663841 DOI: 10.1016/j.heliyon.2023.e21760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 06/02/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Background Here we report a rare case of citrullinemia type II (CTLN2) accompanied by mental derangement with a deficiency of multidrug resistance 3 (MDR3) in the liver. Case presentation The clinical data of a 17-year-old girl were collected. Liver puncture was performed, and hepatic expression of MDR3 was determined by immunohistochemistry. Serum amino acids of the patient and her parents wwere determined by a chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Genetic mutations of ABCB4 and SLC25A13 were screened by whole-exome sequencing. Immunohistochemical analysis showed a remarkably lower expression of MDR3. Mutation in ABCB4 gene was not found and whole-exome sequencing revealed the SLC25A13 mutation 852-855 del. Elevated serum levels of citrulline, homocitrulline, and homoarginine in the patient and her mother were found. Conclusions We reported a rare case of CTLN2 combined with MDR3 deficiency, without mutation of ABCB4. The link between MDR3 down-expression and CTLN2 warrants further investigation. Meanwhile, clinicians need to further rule out the possibility of CTLN2 if MDR3 decreases in adolescent patients with mental disorders and abnormal liver function.
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Affiliation(s)
| | | | - Jinlin Cheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Deying Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qiaomai Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jifang Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yu Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
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Song G, Zou B, Zhao J, Weng Y, Li Y, Xu X, Zhang S, Yan D, Jin J, Sun X, Liu C, Qiu F. Yinchen decoction protects against cholic acid diet-induced cholestatic liver injury in mice through liver and ileal FXR signaling. JOURNAL OF ETHNOPHARMACOLOGY 2023; 313:116560. [PMID: 37149065 DOI: 10.1016/j.jep.2023.116560] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/18/2023] [Accepted: 04/26/2023] [Indexed: 05/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cholestasis is a pathophysiological syndrome characterized by the accumulation of bile acids (BAs) that leads to severe liver disease. Artemisia capillaris is documented in Chinese Pharmacopoeia as the authentic resources for Yinchen. Although Yinchen (Artemisia capillaris Thunb.) decoction (YCD) has been used in China for thousands of years to treat jaundice, the underlying mechanisms to ameliorate cholestatic liver injury have not been elucidated. AIM OF THE STUDY To investigate the molecular mechanism of how YCD protects against 1% cholic acid (CA) diet-induced intrahepatic cholestasis through FXR signaling. MATERIALS AND METHODS Wild-type and Fxr-deficient mice were fed a diet containing 1% CA to establish the intrahepatic cholestasis model. The mice received low-, medium-, or high-dose YCD for 10 days. Plasma biochemical markers were analyzed, liver injury was identified by histopathology, and hepatic and plasma BA content was analyzed. Western blot was used to determine the expression levels of transporters and enzymes involved in BA homeostasis in the liver and intestine. RESULTS In wild-type mice, YCD significantly improved plasma transaminase levels, multifocal hepatocellular necrosis, and hepatic and plasma BA contents, upregulated the expression of hepatic FXR and downstream target enzymes and transporters. Meanwhile, YCD significantly induced the expressions of intestinal FXR and FGF15 and hepatic FGFR4. In contrast, the hepatic protective effect of YCD on cholestasis was abolished in Fxr-deficient mice. CONCLUSION YCD protects against cholestatic liver injury induced by a CA diet by restoring the homeostasis of BAs via activation of the liver FXR/SHP and ileal FXR/FGF15 signaling pathways. Furthermore, chlorogenic acid and caffeic acid may be the pharmacological agents in YCD responsible for protecting against cholestatic liver injury.
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Affiliation(s)
- Guochao Song
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Bin Zou
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Zhao
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yifeng Weng
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yue Li
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaoqing Xu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shuang Zhang
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dongming Yan
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jingyi Jin
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xin Sun
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chenghai Liu
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Furong Qiu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Zheng Z, Xiong H, Zhao Z, Zhou K, Fu M, Liu X, Mei Z. Tibetan medicine Si-Wei-Qiang-Wei Powder ameliorates cholecystitis via inhibiting the production of pro-inflammatory cytokines and regulating the MAPK signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:116026. [PMID: 36503031 DOI: 10.1016/j.jep.2022.116026] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/14/2022] [Accepted: 12/03/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Si-Wei-Qiang-Wei Powder (SWQ) is a formulated traditional Tibetan medicine preparation that has been used clinically to treat liver and gallbladder diseases for centuries. Previous work has confirmed its clinical effectiveness, however, the specific mechanism of SWQ is still unknown. AIM OF THE STUDY This study aims to explore the anti-inflammatory effect of SWQ on cholecystitis and its possible mechanism. MATERIALS AND METHODS The main chemical components of SWQ were analyzed by HPLC. The network pharmacology database was used to screen and construct the network of the main components and molecular targets of SWQ, and to predict the molecular pathways of its core targets. Cholecystitis guinea pig model and LPS stimulated cultured human gallbladder epithelial cells (HGBEC) were used, as in vivo and in vitro methods respectively, to study the anti-cholecystitis activity of SWQ. Specifically, gallbladder wall thickness, hematoxylin-eosin (H&E) staining, and liver function indexes were used to evaluate the anti-inflammatory activities of SWQ in cholecystitis; qRT-PCR and ELISA were used to detect the changes of the production of inflammatory cytokines; Western blot analysis was used to analyze the effects of SWQ on phosphorylation of P38, ERK1/2, JNK and AKT. RESULTS SWQ decreased the indexes of ALT, AST, TBA, CHOL, DBIL in serum and TBIL, TC and Ca2+ in bile, and alleviated the wall thickness of gallbladder and hepatobiliary fibrosis in LCA-induced guinea pigs. In addition, SWQ attenuated the expression and production of TNF-α, IL-6, IL-1β, COX-2 both in liver and gallbladder. Moreover, SWQ reversed the up-regulation of p-P38, p-ERK1/2, and p-JNK in animals with cholecystitis and LPS-induced HGBEC. Furthermore, mechanistic studies indicated that SWQ inhibited the activation of ERK1/2, thereby decreasing the expression of TNF-α, IL-6, IL-1β and phosphorylation P38 and JNK. CONCLUSION In summary, our research showed that SWQ relieves gallbladder inflammation by inhibiting the MAPK pathway.
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Affiliation(s)
- Zhe Zheng
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, China
| | - Hui Xiong
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, China
| | - Zhongqiu Zhao
- Barnes-Jewish Hospital, St Louis, MO, 63110, USA; Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, 63110, USA
| | - Keli Zhou
- Hospital of Central South University for Nationalities, China
| | - Miao Fu
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, China
| | - Xinqiao Liu
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, China.
| | - Zhinan Mei
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, China; College of Plant Science and Technology, Huazhong Agricultural University, China.
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9
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Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1589388. [PMID: 36506808 PMCID: PMC9729052 DOI: 10.1155/2022/1589388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 10/18/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022]
Abstract
Background Qingre Lidan tablets (QLTs) are a compound preparation of Chinese medicine that have long been used clinically to treat poor bile circulation caused by the inflammation and obstruction of the gallbladder and bile duct and to relieve jaundice and other symptoms. However, its material basis and mechanism are still unclear. The purpose of this study was to investigate the mechanism and active components of QLTs for treating intrahepatic cholestasis (IHC) in rat models. Methods In vivo experiments verified the effect of QLTs on alpha-naphthyl isothiocyanate (ANIT)-induced IHC models in rats. The mRNA and protein expression levels of farnesoid X receptor (FXR), bile salt export pump (BSEP), and multidrug-associated protein 2 (MRP2) in the rat liver were detected. UPLC/Q-TOF-MS was used to separate and identify the monomers in QLTs, and a dual-luciferase reporter assay was used to select effective the monomers that stimulate FXR. Among the selected monomers, baicalein was used as a representative to verify the effect on rat IHC models. Results QLTs and baicalein significantly reduced the serum biochemical indicators reflecting the changes in liver function among IHC rats and remitted the ANIT-induced liver histopathological changes. The expression levels of FXR, BSEP, and MRP2 in the liver were significantly increased after QLT treatment in a dose-dependent manner. Moreover, six types of active components that activate FXR were selected in QLTs, namely baicalein, wogonin, baicalein II, emodin, dibutyl phthalate, and diisooctyl phthalate. Conclusions QLTs and the active component, baicalein, can alleviate IHC in model rats.
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10
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Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis. Viruses 2022; 14:v14091941. [PMID: 36146750 PMCID: PMC9502388 DOI: 10.3390/v14091941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the viral infection with the disease is not a straight-forward process because PBC is a complex multifactorial disease influenced by genetic, hormonal, autoimmune, environmental, and other factors. Currently, PBC is assumed to have an autoimmune etiology, but the evidence is lacking to support this conjecture. In this review, we describe different approaches connecting HBRV with PBC. Initially, we used co-cultivation of HBRV with biliary epithelial cells to trigger the PBC-specific phenotype with cell surface expression of cryptic mitochondrial autoantigens linked with antimitochondrial antibody expression. Subsequently, we have derived layers of proof to support the role of betaretrovirus infection in mouse models of autoimmune biliary disease with spontaneous AMA production and in patients with PBC. Using Hill’s criteria, we provide an overview of how betaretrovirus infection may trigger autoimmunity and propagate biliary disease. Ultimately, the demonstration that disease can be cured with antiviral therapy may sway the argument toward an infectious disease etiology in an analogous fashion that was used to link H. pylori with peptic ulcer disease.
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11
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Mapping of de novo mutations in primary biliary cholangitis to a disease-specific co-expression network underlying homeostasis and metabolism. J Genet Genomics 2021; 49:145-154. [PMID: 34433101 DOI: 10.1016/j.jgg.2021.07.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/22/2021] [Accepted: 07/26/2021] [Indexed: 02/08/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease involving dysregulation of a broad array of homeostatic and metabolic processes. Although considerable single-nucleotide polymorphisms have been unveiled, a large fraction of risk factors remains enigmatic. Candidate genes with rare mutations that tend to confer more deleterious effects need to be identified. To help pinpoint cellular and developmental mechanisms beyond common noncoding variants, we integrated whole exome sequencing with integrative network analysis to investigate genes harboring de novo mutations. Prominent convergence has been revealed on a network of disease-specific co-expression comprised of 55 genes associated with homeostasis and metabolism. The transcription factor MEF2D and the DNA repair gene PARP2 were highlighted as hub genes and identified to be up- and down-regulated, respectively, in peripheral blood data set. Enrichment analysis demonstrated altered expression of MEF2D and PARP2 may trigger a series of molecular and cellular processes with pivotal roles in PBC pathophysiology. Our study identified genes with de novo mutations in PBC and suggested a subset of genes in homeostasis and metabolism tend to act in synergy through converging on co-expression network, providing novel insights into the etiology of PBC and expanding the pool of molecular candidates for discovering clinically actionable biomarkers.
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12
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Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults. J Pediatr Gastroenterol Nutr 2021; 72:654-660. [PMID: 33720099 DOI: 10.1097/mpg.0000000000003094] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVES Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis. METHODS A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA). RESULTS A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57% <1 year old) included 583 P variants, 79 LP variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel. The panel's overall diagnostic yield was 12% (n = 265/2171) representing 32 genes. The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG. CONCLUSIONS These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis.
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13
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Wang M, Liu F, Yao Y, Zhang Q, Lu Z, Zhang R, Liu C, Lin C, Zhu C. Network pharmacology-based mechanism prediction and pharmacological validation of Xiaoyan Lidan formula on attenuating alpha-naphthylisothiocyanate induced cholestatic hepatic injury in rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113816. [PMID: 33444723 DOI: 10.1016/j.jep.2021.113816] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The well-known Chinese prescription, Xiaoyan Lidan Formula (XYLDF), possesses efficiency of heat-clearing, dampness-eliminating and jaundice-removing. It has long been used clinically for the treatment of hepatobiliary diseases due to intrahepatic cholestasis (IHC). However, the mechanism of XYLDF for its therapeutic effects remains elusive. AIM OF THE STUDY The study aimed to explore the potential targets for liver protective mechanism of XYLDF based on network pharmacology and experimental assays in ANIT-induced cholestatic hepatic injury (CHI) in rats. MATERIALS AND METHODS On the basis of the 29 serum migrant compounds of XYLDF elucidated by UPLC-TOF-MS/MS, a network pharmacology approach was applied for the mechanism prediction. Systematic networks were constructed to identify potential molecular targets, biological processes, and signaling pathways. And the interactions between significantly potential targets and active compounds were simulated by molecular docking. For the mechanism validation, an ANIT-induced rat model was used to evaluate the effects of XYLDF on CHI according to serum biochemistry, bile flow rates, histopathological examination, and the gene and protein expression including enzymes related to synthesis, export, and import of bile acid in liver and ileum, and those of inflammatory cytokines, analyzed by RT-qPCR and WB. RESULTS The results of network pharmacology research indicated TNF (TNF-α), RELA (NF-κB), NR1H4 (FXR), and ICAM1 (ICAM-1) to be the important potential targets of XYLDF for cholestatic liver injury, which are related to bile metabolism and NF-κB-mediated inflammatory signaling. And the molecular docking had pre-validated the prediction of network pharmacology, as the core active compounds of XYLDF had shown strong simulation binding affinity with FXR, followed by NF-κB, TNF-α, and ICAM-1. Meanwhile, the effects of XYLDF after oral administration on ANIT-induced CHI in rats exhibited the decreased levels of transaminases (ALT and AST), TBA, and TBIL in serum, raised bile flow rates, and markedly improved hepatic histopathology. Furthermore, consistent to the above targets prediction and molecular docking, XYLDF significantly up-regulated the expression of FXR, SHP, BSEP, and MRP2, and down-regulated CYP7A1 and NTCP in liver, and promoted expression of IBABP and OSTα/β in ileum, suggesting the activation of FXR-mediated pathway referring to bile acid synthesis, transportation, and reabsorption. Moreover, the lower levels of TNF-α in plasma and liver, as well as the reduced hepatic gene and protein expression of NF-κB, TNF-α, and ICAM-1 after XYLDF treatment revealed the suppression of NF-κB-mediated inflammatory signaling pathway, as evidenced by the inhibition of nuclear translocation of NF-κB. CONCLUSIONS XYLDF exhibited an ameliorative liver protective effect on ANIT-induced cholestatic hepatic injury. The present study has confirmed its mechanism as activating the FXR-regulated bile acid pathway and inhibiting inflammation via the NF-κB signaling pathway.
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MESH Headings
- 1-Naphthylisothiocyanate/toxicity
- Animals
- Bile Acids and Salts/metabolism
- Chemical and Drug Induced Liver Injury/blood
- Chemical and Drug Induced Liver Injury/drug therapy
- Chemical and Drug Induced Liver Injury/pathology
- Cholestasis, Intrahepatic/blood
- Cholestasis, Intrahepatic/chemically induced
- Cholestasis, Intrahepatic/drug therapy
- Cholestasis, Intrahepatic/pathology
- Disease Models, Animal
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Inflammation/drug therapy
- Inflammation/metabolism
- Male
- Metabolic Networks and Pathways/drug effects
- Molecular Docking Simulation
- NF-kappa B/metabolism
- Protective Agents/pharmacology
- Protective Agents/therapeutic use
- Protein Interaction Maps/drug effects
- Rats, Sprague-Dawley
- Receptors, Cytoplasmic and Nuclear/chemistry
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction/drug effects
- Rats
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Affiliation(s)
- Meiqi Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Fangle Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yufeng Yao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Qiuyu Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Zenghui Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Runjing Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Chaozhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
| | - Chenchen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
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14
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Su H, Wang Q, Li Y, Jin J, Tan B, Yan D, Zou B, Song G, Weng F, Qiu F. Effect of Different Ratios of Yinchen and Gancao Decoction on ANIT-Treated Cholestatic Liver Injury in Mice and Its Potential Underlying Mechanism. Front Pharmacol 2021; 12:611610. [PMID: 33935705 PMCID: PMC8082238 DOI: 10.3389/fphar.2021.611610] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 03/04/2021] [Indexed: 11/28/2022] Open
Abstract
Cholestasis is a pathological state that leads to serious liver disease; however, therapeutic options remain limited. Yinchen and Gancao are often used in combination at different ratios in traditional Chinese formulae for the treatment of jaundice and cholestasis. In the present study, we investigated the effect of decoctions containing different ratios of Yinchen and Gancao (YGD) on alpha-naphthyl isothiocyanate (ANIT)-treated intrahepatic cholestasis (IC) in mice, and further explored the underlying mechanism. Treatment with 0:4 and 1:4 YGD significantly reduced plasma total bile acid (TBA), total bilirubin (TBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities; decreased unconjugated and conjugated bile acid levels; and improved hepatocyte necrosis and inflammatory cells recruitment to hepatic sinusoids. Moreover, the expression levels of Toll-like receptor 4 (TLR4), interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), C-C ligand 2 (CCL2), and C-X-C ligand 2 (CXCL2) in the liver were significantly reduced. However, treatment with 4:1 and 4:0 YGD increased plasma TBA, TBIL, AST, ALT, and ALP activities and aggravated liver cell injury and inflammation. Moreover, the mRNA expression of the bile salt export pump (BSEP) in the liver was significantly increased in mice treated with 4:0 YGD. The present study demonstrates that YGD containing a high proportion of Gancao, which inhibits the TLR4/NF-κB pathway and reduces the inflammatory response, had protective effects against ANIT-treated IC in mice. However, YGD containing a high proportion of Yinchen aggravated the ANIT-treated IC in mice, which may be related to upregulation of BSEP and boosting bile acid regurgitation from damage cholangiocytes to liver in ANIT-treated IC mice.
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Affiliation(s)
- Huizong Su
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qian Wang
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Li
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingyi Jin
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bo Tan
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dongming Yan
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bin Zou
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guochao Song
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fengyi Weng
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Furong Qiu
- Clinical Pharmacokinetic Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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15
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Pieters A, Gijbels E, Cogliati B, Annaert P, Devisscher L, Vinken M. Biomarkers of cholestasis. Biomark Med 2021; 15:437-454. [PMID: 33709780 DOI: 10.2217/bmm-2020-0691] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestasis is a major pathological manifestation, often resulting in detrimental liver conditions, which occurs in a variety of indications collectively termed cholestatic liver diseases. The frequent asymptomatic character and complexity of cholestasis, together with the lack of a straightforward biomarker, hampers early detection and treatment of the condition. The 'omics' era, however, has resulted in a plethora of cholestatic indicators, yet a single clinically applicable biomarker for a given cholestatic disease remains missing. The criteria to fulfil as an ideal biomarker as well as the challenging molecular pathways in cholestatic liver diseases advocate for a scenario in which multiple biomarkers, originating from different domains, will be assessed concomitantly. This review gives an overview of classical clinical and novel molecular biomarkers in cholestasis, focusing on their benefits and drawbacks.
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Affiliation(s)
- Alanah Pieters
- Department of In Vitro Toxicology & Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium
| | - Eva Gijbels
- Department of In Vitro Toxicology & Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine & Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, Cidade Universitária, SP, 05508-270, Brazil
| | - Pieter Annaert
- Drug Delivery & Disposition, Department of Pharmaceutical & Pharmacological Sciences, Katholieke Universiteit Leuven, ON II Herestraat 49, Box 921, Leuven, 3000, Belgium
| | - Lindsey Devisscher
- Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Faculty of Medicine & Health Sciences, Ghent University, C Heymanslaan 10, Ghent, 9000, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology & Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium
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16
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Hua W, Zhang S, Lu Q, Sun Y, Tan S, Chen F, Tang L. Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice. JOURNAL OF ETHNOPHARMACOLOGY 2021; 266:113432. [PMID: 33011367 DOI: 10.1016/j.jep.2020.113432] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/15/2020] [Accepted: 09/27/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Veronica ciliata Fisch. is a traditional medical herb that present in more than 100 types of Tibetan medicine prescriptions, most of which are used for liver disease therapy. Iridoid glycosides have been identified as the major active components of V.ciliata with a variety of biological activities. AIMS OF THE STUDY The aim of this study is to explore the protective effect and potential mechanism of n-Butanol extract (BE) and iridoid glycosides (IG) from V.ciliata against ɑ-naphthyl isothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in mice. MATERIALS AND METHODS Mice were intragastrically (i.g.) given BE and IG at different dose or positive control ursodeoxycholic acid (UCDA) once a day for 14 consecutive days, and were treated with ANIT to cause liver injury on day 12th. Serum levels of hepatic injury markers and cholestasis indicators, liver index and liver histopathology were measured to evaluate the effect of BE and IG on liver injury caused by ANIT. The protein levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B(NF-κB), interleukin-6 (IL-6), Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and the levels of oxidative stress indicators in liver tissue were investigated to reveal the underlying protective mechanisms of BE and IG against ANIT-induced hepatotoxicity and cholestasis. RESULTS The n-Butanol extract (BE) and iridoid glycosides (IG) isolated from V.ciliata significantly decreased serum level of cholestatic liver injury markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) in ANIT-treated mice. Histopathology of the liver tissue showed that pathological damages were relieved upon BE and IG treatment. Meanwhile, the results indicated BE and IG notably restored relative liver weights, inhibited oxidative stress induced by ANIT through increasing hepatic level of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and decreasing hepatic content of malondialdehyde (MDA). Western blot revealed that BE and IG inhibited the expression of pro-inflammatory factors TGF-α, IL-6 and NF-κB. Furthermore, the decreased protein expression of bile acid transporters NTCP, BSEP, MRP2 were upregulated by BE and IG in a dose-dependent manner. CONCLUSION The results have demonstrated that BE and IG exhibited a dose-dependently protective effect against ANIT-induced liver injury with acute intrahepatic cholestasis in mice, which might be related to the regulation of oxidative stress, inflammatory response and bile acid transport. In addition, these findings pointed out that iridoid glycosides as main active components of V.ciliata play a critical role in hepatoprotective effect of V.ciliata.
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Affiliation(s)
- Wan Hua
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Shiyan Zhang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Qiuxia Lu
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Yiran Sun
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Shancai Tan
- College of Pharmacy, Tongren Polytechnic College, Guizhou, China
| | - Fang Chen
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China
| | - Lin Tang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; National and Local Joint Engineering Laboratory for Energy Plant Bio-Oil Production and Application, Chengdu, China.
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17
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Mawardi M, Alalwan A, Fallatah H, Abaalkhail F, Hasosah M, Shagrani M, Alghamdi M, Alghamdi A. Cholestatic liver disease: Practice guidelines from the Saudi Association for the Study of Liver diseases and Transplantation. Saudi J Gastroenterol 2021. [PMCID: PMC8411950 DOI: 10.4103/sjg.sjg_112_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Cholestatic liver diseases (CLDs) are a group of diseases characterized by jaundice and cholestasis as the main presentation with different complications, which have considerable impact on the liver and can lead to end-stage liver disease, cirrhosis, and liver-related complications. In the last few years, tremendous progress has been made in understanding the pathophysiology, diagnosis, and treatment of patients with these conditions. However, several aspects related to the management of CLDs remain deficient and unclear. Due to the lack of recommendations that can help in the management, treatment of those conditions, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) has created a task force group to develop guidelines related to CLDs management in order to provide a standard of care for patients in need. These guidelines provide general guidance for health care professionals to optimize medical care for patients with CLDs for both adult and pediatric populations, in association with clinical judgments to be considered on a case-by-case basis. These guidelines describe common CLDs in Saudi Arabia, with recommendations on the best approach for diagnosis and management of different diseases based on the Grading of Recommendation Assessment (GRADE), combined with a level of evidence available in the literature.
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18
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Oliveira AG, Fiorotto R. Novel approaches to liver disease diagnosis and modeling. Transl Gastroenterol Hepatol 2021; 6:19. [PMID: 33824923 PMCID: PMC7829068 DOI: 10.21037/tgh-20-109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/08/2020] [Indexed: 12/12/2022] Open
Abstract
Lack of a prompt and accurate diagnosis remains on top of the list of challenges faced by patients with rare liver diseases. Although rare liver diseases affect a significant percentage of the population as a group, when taken singularly they represent unique diseases and the approaches used for diagnosis of common liver diseases are insufficient. However, the development of new methods for the acquisition of molecular and clinical data (i.e., genomic, proteomics, metabolomics) and computational tools for their analysis and integration, together with advances in modeling diseases using stem cell-based technology [i.e., induced pluripotent stem cells (iPSCs) and tissue organoids] represent a promising and powerful tool to improve the clinical management of these patients. This is the goal of precision medicine, a novel approach of modern medicine that aims at delivering a specific treatment based on disease-specific biological insights and individual profile. This review will discuss the application and advances of these technologies and how they represent a new opportunity in hepatology.
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Affiliation(s)
- André G. Oliveira
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Romina Fiorotto
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, USA
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19
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Goubran M, Aderibigbe A, Jacquemin E, Guettier C, Girgis S, Bain V, Mason AL. Case report: progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15 years after liver transplantation. BMC MEDICAL GENETICS 2020; 21:238. [PMID: 33256620 PMCID: PMC7708126 DOI: 10.1186/s12881-020-01173-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/12/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) type 3 is an autosomal recessive disorder arising from mutations in the ATP-binding cassette subfamily B member 4 (ABCB4) gene. This gene encodes multidrug resistance protein-3 (MDR3) that acts as a hepatocanalicular floppase that transports phosphatidylcholine from the inner to the outer canalicular membrane. In the absence of phosphatidylcholine, the detergent activity of bile salts is amplified and this leads to cholangiopathy, bile duct loss and biliary cirrhosis. Patients usually present in infancy or childhood and often progress to end-stage liver disease before adulthood. CASE PRESENTATION We report a 32-year-old female who required cadaveric liver transplantation at the age of 17 for cryptogenic cirrhosis. When the patient developed chronic ductopenia in the allograft 15 years later, we hypothesized that the patient's original disease was due to a deficiency of a biliary transport protein and the ductopenia could be explained by an autoimmune response to neoantigen that was not previously encountered by the immune system. We therefore performed genetic analyses and immunohistochemistry of the native liver, which led to a diagnosis of PFIC3. However, there was no evidence of humoral immune response to the MDR3 and therefore, we assumed that the ductopenia observed in the allograft was likely due to chronic rejection rather than autoimmune disease in the allograft. CONCLUSIONS Teenage patients referred for liver transplantation with cryptogenic liver disease should undergo work up for PFIC3. An accurate diagnosis of PFIC 3 is key for optimal management, therapeutic intervention, and avoidance of complications before the onset of end-stage liver disease.
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Affiliation(s)
- Mariam Goubran
- Department of Medicine, University of Alberta Hospital, Edmonton, Canada
| | - Ayodeji Aderibigbe
- Department of Medicine, University of Alberta Hospital, Edmonton, Canada
| | - Emmanuel Jacquemin
- Paediatric Hepatology & Paediatric Liver Transplant Department, Reference Center for Rare Paediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medicine and University Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Catherine Guettier
- Pathology Department, Assistance Publique-Hôpitaux de Paris, Faculty of Medicine and University Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Safwat Girgis
- Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Canada
| | - Vincent Bain
- Department of Medicine, University of Alberta Hospital, Edmonton, Canada
| | - Andrew L Mason
- Department of Medicine, University of Alberta Hospital, Edmonton, Canada.
- Division of Gastroenterology, 7-142 KGR, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada.
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Yokoda RT, Rodriguez EA. Review: Pathogenesis of cholestatic liver diseases. World J Hepatol 2020; 12:423-435. [PMID: 32952871 PMCID: PMC7475774 DOI: 10.4254/wjh.v12.i8.423] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/07/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver diseases (CLD) begin to develop after an impairment of bile flow start to affect the biliary tree. Cholangiocytes actively participate in the liver response to injury and repair and the intensity of this reaction is a determinant factor for the development of CLD. Progressive cholangiopathies may ultimately lead to end-stage liver disease requiring at the end orthotopic liver transplantation. This narrative review will discuss cholangiocyte biology and pathogenesis mechanisms involved in four intrahepatic CLD: Primary biliary cholangitis, primary sclerosing cholangitis, cystic fibrosis involving the liver, and polycystic liver disease.
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Affiliation(s)
- Raquel T Yokoda
- Department of Anatomic and Clinical Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, United States
| | - Eduardo A Rodriguez
- Department of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, UT 84132, United States
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21
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Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging. Physiol Rev 2020; 101:683-731. [PMID: 32790577 DOI: 10.1152/physrev.00049.2019] [Citation(s) in RCA: 235] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Hadrien Demagny
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Laura Velazquez-Villegas
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
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22
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Kunst RF, Niemeijer M, van der Laan LJW, Spee B, van de Graaf SFJ. From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease. Biochem Pharmacol 2020; 180:114173. [PMID: 32717228 DOI: 10.1016/j.bcp.2020.114173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 02/08/2023]
Abstract
A large variety of model systems are used in hepatobiliary research. In this review, we aim to provide an overview of established and emerging models for specific research questions. We specifically discuss the value and limitations of these models for research on metabolic associated fatty liver disease (MAFLD), (previously named non-alcoholic fatty liver diseases/non-alcoholic steatohepatitis (NAFLD/NASH)) and cholestasis-related diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). The entire range of models is discussed varying from immortalized cell lines, mature or pluripotent stem cell-based models including organoids/spheroids, to animal models and human ex vivo models such as normothermic machine perfusion of livers and living liver slices. Finally, the pros and cons of each model are discussed as well as the need in the scientific community for continuous innovation in model development to better mimic the human (patho)physiology.
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Affiliation(s)
- Roni F Kunst
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Marije Niemeijer
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
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23
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Li T, Xu L, Zheng R, Wang X, Li L, Ji H, Hu Q. Picroside II protects against cholestatic liver injury possibly through activation of farnesoid X receptor. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 68:153153. [PMID: 32018210 DOI: 10.1016/j.phymed.2019.153153] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/13/2019] [Accepted: 12/15/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUD Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear. PURPOSE This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro. METHODS The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro. RESULTS Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II. CONCLUSION Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.
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Affiliation(s)
- Tingting Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lijie Xu
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Rongyao Zheng
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xinjie Wang
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Liwen Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Hui Ji
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Qinghua Hu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Zhang G, Bashiri K, Kneteman M, Cave K, Hong Y, Mackey JR, Alter HJ, Mason AL. Seroprevalence of Human Betaretrovirus Surface Protein Antibodies in Patients with Breast Cancer and Liver Disease. JOURNAL OF ONCOLOGY 2020; 2020:8958192. [PMID: 32411244 PMCID: PMC7204138 DOI: 10.1155/2020/8958192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 12/07/2019] [Accepted: 01/02/2020] [Indexed: 12/18/2022]
Abstract
Mouse mammary tumor virus (MMTV) is a betaretrovirus that plays a causal role in the development of breast cancer and lymphoma in mice. Closely related sequences that share 91-99% nucleotide identity with MMTV have been repeatedly found in humans with neoplastic and inflammatory diseases. Evidence for infection with a betaretrovirus has been found in patients with breast cancer and primary biliary cholangitis and referred to as the human mammary tumor virus and the human betaretrovirus (HBRV), respectively. Using the gold standard technique of demonstrating retroviral infection, HBRV proviral integrations have been detected in cholangiocytes, lymph nodes, and liver of patients with primary biliary cholangitis. However, the scientific biomedical community has not embraced the hypothesis that MMTV like betaretroviruses may infect humans because reports of viral detection have been inconsistent and robust diagnostic assays are lacking. Specifically, prior serological assays using MMTV proteins have produced divergent results in human disease. Accordingly, a partial HBRV surface (Su) construct was transfected into HEK293 to create an ELISA. The secreted HBRV gp52 Su protein was then used to screen for serological responses in patients with breast cancer and liver disease. A greater proportion of breast cancer patients (n = 98) were found to have serological reactivity to HBRV Su as compared to age- and sex-matched control subjects (10.2% versus 2.0%, P=0.017, OR = 5.6 [1.25-26.3]). Similarly, the frequency of HBRV Su reactivity was higher in patients with primary biliary cholangitis (n = 156) as compared to blood donors (11.5% vs. 3.1%, P=0.0024, OR = 4.09 [1.66-10.1]). While the sensitivity of the HBRV Su ELISA was limited, the assay was highly specific for serologic detection in patients with breast cancer or primary biliary cholangitis, respectively (98.0% [93.1%-99.7%] and 97.0% [93.4%-98.6%]). Additional assays will be required to link immune response to betaretrovirus infection and either breast cancer or primary biliary cholangitis.
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Affiliation(s)
- Guangzhi Zhang
- Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- National Microbiology Laboratory, Winnipeg, MB R3E 3M4, Canada
| | - Kiandokht Bashiri
- Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Mark Kneteman
- Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Kevan Cave
- Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Youngkee Hong
- Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - John R. Mackey
- Department of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Harvey J. Alter
- Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD 20892, USA
| | - Andrew L. Mason
- Center of Excellence for Gastrointestinal Inflammation and Immunity Research, Division of Gastroenterology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
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Molecular findings in children with inherited intrahepatic cholestasis. Pediatr Res 2020; 87:112-117. [PMID: 31450232 DOI: 10.1038/s41390-019-0548-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 08/01/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Genetic defects account for a substantial proportion of pediatric cholestasis. This study explored the molecular findings in a large cohort of Chinese patients with inherited cholestasis. METHODS Between January 2012 and June 2016, 809 Chinese pediatric patients with suspected inherited intrahepatic cholestasis were evaluated by Sanger sequencing and/or panel sequencing. RESULTS Of the 809 patients, 273 (33.7%) obtained a genetic diagnosis. The rate of positive genetic diagnosis in patients with disease onset at 0-3 month of age was higher than that in patients with disease onset at 4 month of age or later. There were 17 distinct genetic defects diagnosed. The top 4 resulted from mutations in SLC25A13 (44.3%), JAG1 (24.5%), ABCB11 (11.0%), and ATP8B1 (5.9%). All 17 genetic disorders were diagnosed in patients with disease onset at 0-3 months of age; but only 5 were diagnosed in patients with disease onset beyond 4 months of age. A total of 217 distinct pathogenic variants, including 41 novel variants, were identified. Ten recurrent mutations were detected in SLC25A13, ATP8B1, and CYP27A1. They accounted for 48.2% of the total 477 mutant alleles. CONCLUSIONS There were 17 distinct genetic disorders diagnosed in Chinese pediatric patients with inherited cholestasis.
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Salvianolic acid B protects against ANIT-induced cholestatic liver injury through regulating bile acid transporters and enzymes, and NF-κB/IκB and MAPK pathways. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1169-1180. [PMID: 31098695 DOI: 10.1007/s00210-019-01657-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
Abstract
The purpose of this study was to investigate the pharmacological effects of salvianolic acid B (SA-B) on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury with the focus on bile acid homeostasis and anti-inflammatory pathways. Rats were randomly assigned into four groups. The control group was given normal saline (i.p.) for 7 consecutive days and on the 5th day was given the vehicle (i.g.). Model group was treated with normal saline (i.p.) for 7 days and administrated with ANIT (75 mg/kg, i.g.) on the 5th day. The SA-B groups were treated with SA-B (15 mg/kg and 30 mg/kg, i.p.) for 7 consecutive days as well as ANIT (75 mg/kg, i.g.) on the 5th day. We found that the serum levels of ALT, γ-GT, TBA, and other liver function indexes were found to be lower in the SA-B treatment groups than in the model group. SA-B also upregulated the transporters and enzymes involved in bile acid homeostasis such as Bsep, Oatp2, and Cyp3a2 in rats and BSEP, CYP3A4, and OATP2 in human cell lines. Moreover, SA-B suppressed NF-κB translocation into the nucleus, inhibited phosphorylation of p38 and JNK, and inhibited inflammation markers including IL-1β, IL-6, TGF-β, TNF-α, and COX-2 to extenuate cholestatic liver injury both in vivo and vitro. Taken together, our findings suggest that anti-cholestatic effects of SA-B may be associated with its ability to regulate NF-κB/IκB and MAPK inflammatory signaling pathways to inhibit inflammation and regulate transporters and enzymes to maintain bile acid homeostasis.
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Lytvyak E, Hosamani I, Montano-Loza AJ, Saxinger L, Mason AL. Randomized clinical trial: Combination antiretroviral therapy with tenofovir-emtricitabine and lopinavir-ritonavir in patients with primary biliary cholangitis. CANADIAN LIVER JOURNAL 2019; 2:31-44. [PMID: 33981960 DOI: 10.3138/canlivj.2018-0020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Prior studies using reverse transcriptase inhibitors to treat a human betaretrovirus (HBRV) in patients with primary biliary cholangitis (PBC) resulted in a 21% reduction in alkaline phosphatase (ALP). Herein, we studied the safety and efficacy of combination tenofovir-emtricitabine (TDF/FTC) and lopinavir-ritonavir (LPRr) in PBC patients unresponsive to ursodeoxycholic acid (UDCA). METHODS A double-blind randomized controlled trial was performed in patients on UDCA for 6 months or more with ALP levels greater than two-fold the upper limit of normal or bilirubin greater than the upper limit of normal. Patients were randomized to daily TDF/FTC 300/200 mg and LPRr 800/200 mg versus identical placebo for 6 months. The primary endpoint was reduction of ALP below 1.67 × ULN or normalization of bilirubin. HBRV DNA levels were assessed in peripheral blood mononuclear cells (PBMC) using digital droplet polymerase chain reaction. RESULTS The enrolment was limited to 13 patients because most patients were unable to tolerate LPRr due to the development of gastrointestinal symptoms. No difference in the primary endpoint was achieved. A significant reduction was observed in ALP by 25% (P < 0.05) and in HBRV proviral load (P < 0.05) after 6 months of combination antiretroviral therapy. The majority of patients had diminished levels of LPRr after 6 months' therapy suggesting inadequate intake of protease inhibitor toward the end of the study. CONCLUSIONS Combination anti-retroviral therapy resulted in improvement in hepatic biochemistry with reduction in proviral load. The frequency of side effects from LPRr in patients with PBC exceeds the frequency reported for HIV, warranting the search for better tolerated combinations in future studies.
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Affiliation(s)
- Ellina Lytvyak
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada
| | - Ishwar Hosamani
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada
| | - Aldo J Montano-Loza
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada
| | - Lynora Saxinger
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Andrew L Mason
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, Alberta, Canada
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Tanaka H, Imasato M, Yamazaki Y, Matsumoto K, Kunimoto K, Delpierre J, Meyer K, Zerial M, Kitamura N, Watanabe M, Tamura A, Tsukita S. Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice. J Hepatol 2018; 69:1308-1316. [PMID: 30213590 DOI: 10.1016/j.jhep.2018.08.025] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 08/24/2018] [Accepted: 08/28/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstones, with particular interest in the role of phosphate ion, a common food additive and preservative. METHODS We focused on claudin-3 (Cldn3), a paracellular barrier-forming tight junction protein whose expression in mouse liver decreases with age. Since Cldn3-knockout mice exhibited gallstone diseases, we used them to assess the causal relationship between paracellular phosphate ion permeability and the core formation of cholesterol gallstones. RESULTS In the liver of Cldn3-knockout mice, the paracellular phosphate ion permeability through hepatic tight junctions was significantly increased, resulting in calcium phosphate core formation. Cholesterol overdose caused cholesterol gallstone disease in these mice. CONCLUSION We revealed that in the hepatobiliary system, Cldn3 functions as a paracellular barrier for phosphate ions, to help maintain biliary ion homeostasis. We provide in vivo evidence that elevated phosphate ion concentrations play a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease under cholesterol overdose. LAY SUMMARY Herein, we reveal a new mechanism for cholesterol gallstone formation, in which increased paracellular phosphate ion permeability across hepatobiliary epithelia causes calcium phosphate core formation and cholesterol gallstones. Thus, altered phosphate ion metabolism under cholesterol overdose plays a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease.
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Affiliation(s)
- Hiroo Tanaka
- Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Mitsunobu Imasato
- Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuji Yamazaki
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
| | - Kengo Matsumoto
- Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Koshi Kunimoto
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Julien Delpierre
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Kirstin Meyer
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Marino Zerial
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Center for Advancing Electronics Dresden, Technische Universitat Dresden, Dresden, Germany
| | - Naho Kitamura
- Graduate School of Media and Governance, Faculty of Environment Information Studies, Keio University, Kanagawa, Japan
| | - Mitsuhiro Watanabe
- Graduate School of Media and Governance, Faculty of Environment Information Studies, Keio University, Kanagawa, Japan; Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Atsushi Tamura
- Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Sachiko Tsukita
- Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
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Min J, Chen H, Gong Z, Liu X, Wu T, Li W, Fang J, Huang T, Zhang Y, Zhao W, Zhu C, Wang Q, Mi S, Wang N. Pharmacokinetic and Pharmacodynamic Properties of Rosmarinic Acid in Rat Cholestatic Liver Injury. Molecules 2018; 23:E2287. [PMID: 30205454 PMCID: PMC6225135 DOI: 10.3390/molecules23092287] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/18/2018] [Accepted: 08/29/2018] [Indexed: 12/11/2022] Open
Abstract
The objective of this study was to evaluate the hepatoprotective and metabolic effects of rosmarinic acid (RA) in rats. RA [100 mg/kg body weight (BW)] was intragastrically (i.g.) administered to Sprague-Dawley (SD) rats once a day for seven consecutive days. The rats were then i.g. administered α-naphthylisothiocyanate (ANIT) (80 mg/kg once on the 5th day) to induce acute intrahepatic cholestasis after the last administration of RA. Blood samples were collected at different time points (0.083 h, 0.17 h, 0.33 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 20 h) after administration, and the levels of RA were estimated by HPLC. Plasma and bile biochemical analysis, bile flow rate, and liver histopathology were measured to evaluate the hepatoprotective effect of RA. The PK-PD curves showed obviously clockwise (AST and ALT) or anticlockwise (TBA, TBIL). Pretreatment with RA at different doses significantly restrained ANIT-induced pathological changes in bile rate, TBA, TBIL, ALT, AST (p < 0.05 or p < 0.01). The relationship between RA concentration and its hepatoprotective effects on acute cholestasis responses was assessed by PK-PD modeling.
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Affiliation(s)
- Jianbin Min
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Hao Chen
- College of Food and Drug, Anhui Science and Technology of University, Fengyang 233100, Anhui, China.
| | - Zipeng Gong
- Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Beijing Road, Guiyang 550004, China.
| | - Xian Liu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Tian Wu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Weirong Li
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Jiansong Fang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Tianlai Huang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Yingfeng Zhang
- College of Chinese Medicine, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Wei Zhao
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Chenchen Zhu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Qi Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Suiqing Mi
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
| | - Ningsheng Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, China.
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Single-nucleotide rs738409 polymorphisms in the PNPLA3 gene are strongly associated with alcoholic liver disease in Han Chinese males. Hepatol Int 2018; 12:429-437. [PMID: 30132178 DOI: 10.1007/s12072-018-9889-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/21/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Alcoholic liver disease (ALD) is a chronic liver disorder caused by the consumption of large amounts of alcohol. Genome-wide association studies have recently confirmed that polymorphisms in PNPLA3 predispose individuals to ALD and have identified risk loci of MBOAT7 and TM6SF2 in persons of European descent. However, the association with alcoholic liver damage has not been evaluated thus far in a Han Chinese population. METHODS We performed a large case-control multicenter study of 507 ALD patients and 645 ethnically matched healthy controls. Five SNPs were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry, and association analysis was performed using PLINK 1.07 software. RESULTS The rs738409 in the PNPLA3 gene was found to be significantly associated with ALD in allele and genotype frequencies (p = 6.25 × 10-14 and p = 9.05 × 10-13). The frequencies of the risk allele G in rs738409 were notably higher in ALD compared to controls (odds ratio = 1.93, 95% confidence interval = 1.63-2.28). The current study showed that the genotype frequencies of three genetic models were also statistically significant (p = 1.07 × 10-13, p = 9.3 × 10-8, and p = 1.57 × 10-12). Additionally, the G-allele of rs738409 was associated with a variety of clinical manifestations such as elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), and mean corpuscular volume (MCV) in the patients with ALD. CONCLUSION In a Han Chinese population, the present study confirmed that PNPLA3 polymorphism rs738409 was more likely to influence the susceptibility to ALD. However, no statistically significant differences for the allele and genotype frequencies of rs626283, rs641738 in MBOAT7, rs10401969 in SUGP1 and rs58542926 in TM6SF2 were found between ALD patients and healthy controls.
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Rebholz C, Krawczyk M, Lammert F. Genetics of gallstone disease. Eur J Clin Invest 2018; 48:e12935. [PMID: 29635711 DOI: 10.1111/eci.12935] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 03/31/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Gallstone disease (GD) belongs to the most frequent disorders in gastroenterology and causes high costs in our health-care systems. Gallstones are uncommon in children but frequent in adults, in particular in women, and are triggered by exogenous risk factors. Here, we summarize the current knowledge concerning the contribution of inherited predisposition to gallstone risk. DESIGN In this review, we present the current data and recent research on the genetics of gallstone disease. RESULTS Several GD-predisposing gene variants have been reported, with most prominent effects being conferred by a common variant (p.D19H) of the hepatic and intestinal cholesterol transporter ABCG5/G8. A smaller group of patients might develop gallstones primarily due low phosphatidylcholine concentrations in bile as a result of loss-of-function mutations of the ABCB4 transporter (low phospholipid-associated cholelithiasis syndrome). Regardless of the origin, the risk factors for gallstones lead to the supersaturation of bile with insoluble compounds, in particular cholesterol. As result, cholesterol stones develop and present the most frequent type of gallstones. Laparoscopic cholecystectomy with low morbidity and mortality is currently the most common and effective method for the therapy of symptomatic gallbladder stones. CONCLUSIONS Gallstone disease represents a multifactorial condition and previous studies have identified the major genetic contributors to gallstone formation. The increasing knowledge about the pathomechanisms of hepatobiliary metabolism and GD as well as the identification of additional risk factors might help to overcome the current invasive therapy by specific lifestyle intervention and precise molecular treatment.
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Affiliation(s)
- Charlotte Rebholz
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
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32
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Abstract
The human betaretrovirus and the closely related mouse mammary tumor virus have been linked with the development of cholangitis and mitochondrial antibody production in patients with primary biliary cholangitis (PBC) and mouse models of autoimmune biliary disease, respectively. In vitro, betaretroviruses have been found to stimulate the expression of mitochondrial autoantigens on the cell surface of biliary epithelial cells. In vivo, both mitochondrial autoantigens and viral proteins have been shown to be co-expressed in biliary epithelium and lymphoid tissue. Notably, both mice and humans make poor antibody responses to betaretrovirus infection, whereas proinflammatory responses to viral proteins have been observed in T lymphocyte studies. Furthermore, proviral integration studies have confirmed the presence of human betaretrovirus in biliary epithelium of patients with PBC. Preliminary proof of principal studies using combination antiretroviral therapy have shown that suppression of viral expression is associated with sustained biochemical response. As the previous regimen used was poorly tolerated, further randomized controlled trials are planned to determine whether betaretrovirus infection plays an important role in the development of PBC.
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Affiliation(s)
- Andrew L Mason
- Department of Medicine, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
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Asuri S, McIntosh S, Taylor V, Rokeby A, Kelly J, Shumansky K, Field LL, Yoshida EM, Arbour L. Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci. Liver Int 2018; 38:940-948. [PMID: 29297981 DOI: 10.1111/liv.13686] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 12/21/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations. METHODS In all, 44 individuals with Primary Biliary Cholangitis and 61 unaffected relatives from 32 First Nations families participated. Family history and co-morbidities were documented. Medical records were reviewed and available biopsies were re-reviewed by our team pathologist. Genotyping was performed on DNA from 36 affected persons and 27 unaffected relatives using the Affymetrix Human Mapping 500K Array Set. MERLIN software was used to carry out multipoint parametric and nonparametric linkage analysis. Candidate genes were identified and entered into InnateDB and KEGG software to identify potential pathways affecting pathogenesis. RESULTS In all, 34% of families were multiplex. Fifty per cent of cases and 33% of unaffected relatives reported other autoimmune disease. Three genomic regions (9q21, 17p13 and 19p13) produced LOD scores of 2.3 or greater suggestive of linkage, but no single linkage peak reached statistical significance. Candidate genes identified in the three regions suggested involvement of IL17, NFκB, IL6, JAK-STAT, IFNγ and TGFβ immune signalling pathways. Specifically, four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in these pathways that may influence Primary Biliary Cholangitis pathogenesis. CONCLUSIONS Our whole genome linkage study results reflect the multifactorial nature of Primary Biliary Cholangitis, support previous studies suggesting signalling pathway involvement and identify new candidate genes for consideration.
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Affiliation(s)
- Sirisha Asuri
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Sarah McIntosh
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Valerie Taylor
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Andrew Rokeby
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - James Kelly
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Karey Shumansky
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Lanora Leigh Field
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
| | - Laura Arbour
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.,Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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Mason AL, Siminovitch KA. New perspectives on the complexity of genetic predisposition to autoimmune liver disease in indigenous Canadians. Liver Int 2018; 38:789-791. [PMID: 29702744 DOI: 10.1111/liv.13722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Affiliation(s)
- Andrew L Mason
- Center of Excellence in Gastrointestinal Inflammation and Immunity Research, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Katherine A Siminovitch
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
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35
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Vasconcellos M, Cozer K, Diniz VS, Baetas-da-Cruz W, Ferreira ML, Silva PC, Schanaider A. Cholecystectomy during ceftriaxone therapy. A translational study with a new rabbit model. Acta Cir Bras 2018; 32:995-1005. [PMID: 29319728 DOI: 10.1590/s0102-865020170120000001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/29/2017] [Indexed: 11/21/2022] Open
Abstract
PURPOSE To evaluate the actual incidence of both microlithiasis and acute cholecystitis during treatment with intravenous ceftriaxone in a new rabbit model. METHODS New Zealand rabbits were treated with intravenous ceftriaxone or saline for 21 days. Ultrasound monitoring of the gallbladder was performed every seven days until the 21st day when histopathology, immunohistochemistry for proliferating cell nuclear antigen (PCNA), pro-caspase-3 and CD68, liver enzyme biochemistry, and chromatography analysis of the bile and sediments were also performed. RESULTS All animals treated with ceftriaxone developed acute cholecystitis, confirmed by histopathology (P<0.05) and biliary microlithiasis, except one that exhibited sediment precipitation. In the group treated with ceftriaxone there was an increase in pro-caspase-3, gamma-glutamyl transpeptidase concentration, PCNA expression and in the number of cells positive for anti-CD68 (P<0.05). In the ceftriaxone group, the cholesterol and lecithin concentrations increased in the bile and a high concentration of ceftriaxone was found in the microlithiasis. CONCLUSION Ceftriaxone administered intravenously at therapeutic doses causes a high predisposition for lithogenic bile formation and the development of acute lithiasic cholecystitis.
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Affiliation(s)
- Marcel Vasconcellos
- Fellow Master degree, Postgraduate Program in Surgical Science, Department of Surgery, School of Medicine, Universidade Federal do Rio de Janeiro (UFRJ), Brazil. Conception of the study, acquisition and interpretation of data
| | - Keren Cozer
- Graduate student, Department of Surgery, School of Medicine, UFRJ, Rio de Janeiro-RJ, Brazil. Acquisition of data
| | - Victor Senna Diniz
- Graduate student, Department of Surgery, School of Medicine, UFRJ, Rio de Janeiro-RJ, Brazil. Acquisition of data
| | - Wagner Baetas-da-Cruz
- PhD, Associate Professor, Department of Surgery, School of Medicine, UFRJ, Rio de Janeiro-RJ, Brazil. Analysis and interpretation of data
| | - Manoel Luiz Ferreira
- PhD, Associate Professor, Department of Surgery, School of Medicine, UFRJ, Rio de Janeiro-RJ, Brazil. Analysis and interpretation of data
| | - Paulo Cesar Silva
- PhD, Associate Professor, Department of Surgery, School of Medicine, UFRJ, Rio de Janeiro-RJ, Brazil. Analysis and interpretation of data
| | - Alberto Schanaider
- PhD, Full Professor, Head, Center of Experimental Surgical, Coordinator of Postgraduate Program in Surgical Science, Department of Surgery, School of Medicine, UFRJ, Rio de Janeiro-RJ, Brazil. Conception and design of the study, critical revision
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36
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van Golen RF, Olthof PB, de Haan LR, Coelen RJ, Pechlivanis A, de Keijzer MJ, Weijer R, de Waart DR, van Kuilenburg ABP, Roelofsen J, Gilijamse PW, Maas MA, Lewis MR, Nicholson JK, Verheij J, Heger M. The pathophysiology of human obstructive cholestasis is mimicked in cholestatic Gold Syrian hamsters. Biochim Biophys Acta Mol Basis Dis 2017; 1864:942-951. [PMID: 29196240 DOI: 10.1016/j.bbadis.2017.11.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 11/25/2017] [Accepted: 11/27/2017] [Indexed: 12/12/2022]
Abstract
Obstructive cholestasis causes liver injury via accumulation of toxic bile acids (BAs). Therapeutic options for cholestatic liver disease are limited, partially because the available murine disease models lack translational value. Profiling of time-related changes following bile duct ligation (BDL) in Gold Syrian hamsters revealed a biochemical response similar to cholestatic patients in terms of BA pool composition, alterations in hepatocyte BA transport and signaling, suppression of BA production, and adapted BA metabolism. Hamsters tolerated cholestasis well for up to 28days and progressed relatively slowly to fibrotic liver injury. Hepatocellular necrosis was absent, which coincided with preserved intrahepatic energy levels and only mild oxidative stress. The histological response to cholestasis in hamsters was similar to the changes seen in 17 patients with prolonged obstructive cholestasis caused by cholangiocarcinoma. Hamsters moreover upregulated hepatic fibroblast growth factor 15 (Fgf15) expression in response to BDL, which is a cytoprotective adaptation to cholestasis that hitherto had only been documented in cholestatic human livers. Hamster models should therefore be added to the repertoire of animal models used to study the pathophysiology of cholestatic liver disease.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Pim B Olthof
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Lianne R de Haan
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Robert J Coelen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Alexandros Pechlivanis
- Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK
| | - Mark J de Keijzer
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ruud Weijer
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk R de Waart
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - André B P van Kuilenburg
- Laboratory Genetic Metabolic Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jeroen Roelofsen
- Laboratory Genetic Metabolic Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Pim W Gilijamse
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Martinus A Maas
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Matthew R Lewis
- Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK; MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK
| | - Jeremy K Nicholson
- Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK; MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands.
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Tordai H, Jakab K, Gyimesi G, András K, Brózik A, Sarkadi B, Hegedus T. ABCMdb reloaded: updates on mutations in ATP binding cassette proteins. DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION 2017; 2017:3074791. [PMID: 28365738 PMCID: PMC5467578 DOI: 10.1093/database/bax023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 02/23/2017] [Indexed: 12/26/2022]
Abstract
ABC (ATP-Binding Cassette) proteins with altered function are responsible for numerous human diseases. To aid the selection of positions and amino acids for ABC structure/function studies we have generated a database, ABCMdb (Gyimesi et al., ABCMdb: a database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application. Hum Mutat 2012; 33:1547–1556.), with interactive tools. The database has been populated with mentions of mutations extracted from full text papers, alignments and structural models. In the new version of the database we aimed to collect the effect of mutations from databases including ClinVar. Because of the low number of available data, even in the case of the widely studied disease-causing ABC proteins, we also included the possible effects of mutations based on SNAP2 and PROVEAN predictions. To aid the interpretation of variations in non-coding regions, the database was supplemented with related DNA level information. Our results emphasize the importance of in silico predictions because of the sparse information available on variants and suggest that mutations at analogous positions in homologous ABC proteins have a strong predictive power for the effects of mutations. Our improved ABCMdb advances the design of both experimental studies and meta-analyses in order to understand drug interactions of ABC proteins and the effects of mutations on functional expression. Database URL:http://abcm2.hegelab.org
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Affiliation(s)
- Hedvig Tordai
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary
| | - Kristóf Jakab
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary
| | - Gergely Gyimesi
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland and
| | - Kinga András
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary
| | - Anna Brózik
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary
| | - Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary
| | - Tamás Hegedus
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest 1094, Hungary
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Abstract
The association of inflammatory arthritis with intestinal pathology extends back more than 100 years. This association is now supported by epidemiologic studies demonstrating an elevated prevalence of inflammatory bowel disease in spondyloarthritis and vice versa, compared with the general population. Genetic and intestinal microbiome studies have further linked these diseases. Although diabetes and nonalcoholic fatty liver disease disproportionately affect individuals with psoriatic arthritis, diseases of the esophagus, stomach, pancreas, and liver are not particularly common in spondyloarthritis. Clinicians should be aware of the differential diagnosis and the appropriate diagnostic tools available when evaluating digestive and hepatic disorders in spondyloarthritis.
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Ding L, Zhang B, Li J, Yang L, Wang Z. Beneficial effect of resveratrol on α‑naphthyl isothiocyanate‑induced cholestasis via regulation of the FXR pathway. Mol Med Rep 2017; 17:1863-1872. [PMID: 29138819 DOI: 10.3892/mmr.2017.8051] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 09/25/2017] [Indexed: 11/06/2022] Open
Abstract
Cholestasis is defined as a functional impairment of bile secretion which results in the accumulation of bile acids (BAs) and other toxic molecules in the blood and liver, however, there are very few effective therapies for cholestasis. The farnesoid X receptor (FXR), as a nuclear receptor for BAs, is important in the regulation of BA levels in enterohepatic circulation. It has previously been demonstrated that activation of the FXR pathway may be a useful strategy with which to treat cholestasis. Resveratrol, one of the important ingredients from grape skins and Chinese medicine Polygonum cuspidatum, resulted in FXR‑activated effects in vitro and exhibited a protective effect against α‑naphthylisothiocyanate (ANIT)‑induced cholestasis through FXR regulation in vivo. The underlying mechanisms of resveratrol against ANIT‑induced cholestasis may be due to the regulation of BA homeostasis, improvement of liver injury and attenuation of the inflammatory response, which were regulated in a FXR‑dependent manner and in turn contributed to overall cholestasis alleviation. Overall, resveratrol as a FXR agonist may act as a potential compound for the treatment of drug‑induced cholestasis.
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Affiliation(s)
- Lili Ding
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Binfeng Zhang
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Jinmei Li
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Li Yang
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Voiosu A, Wiese S, Voiosu T, Bendtsen F, Møller S. Bile acids and cardiovascular function in cirrhosis. Liver Int 2017; 37:1420-1430. [PMID: 28222247 DOI: 10.1111/liv.13394] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/12/2017] [Indexed: 02/13/2023]
Abstract
Cirrhotic cardiomyopathy and the hyperdynamic syndrome are clinically important complications of cirrhosis, but their exact pathogenesis is still partly unknown. Experimental models have proven the cardiotoxic effects of bile acids and recent studies of their varied receptor-mediated functions offer new insight into their involvement in cardiovascular dysfunction in cirrhosis. Bile acid receptors such as farnesoid X-activated receptor and TGR5 are currently under investigation as potential therapeutic targets in a variety of pathological conditions. These receptors have also recently been identified in cardiomyocytes, vascular endothelial cells and smooth muscle cells where they seem to play an important role in cellular metabolism. Chronic cholestasis leading to abnormal levels of circulating bile acids alters the normal signalling pathways and contributes to the development of profound cardiovascular disturbances. This review summarizes the evidence regarding the role of bile acids and their receptors in the generation of cardiovascular dysfunction in cirrhosis.
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Affiliation(s)
- Andrei Voiosu
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.,Gastroenterology and Hepatology Department, Colentina Clinical Hospital, Bucharest, Romania.,"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Signe Wiese
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Theodor Voiosu
- Gastroenterology and Hepatology Department, Colentina Clinical Hospital, Bucharest, Romania.,"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Flemming Bendtsen
- Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.,Gastro Unit, Medical Division, Hvidovre Hospital, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Reichert MC, Hall RA, Krawczyk M, Lammert F. Genetic determinants of cholangiopathies: Molecular and systems genetics. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1484-1490. [PMID: 28757171 DOI: 10.1016/j.bbadis.2017.07.029] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/24/2017] [Accepted: 07/25/2017] [Indexed: 12/16/2022]
Abstract
Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts ("ascending pathophysiology") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage "descending" down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1-6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present "system genetics" as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Rabea A Hall
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Chair of Internal Medicine II, Saarland University, Saarbrücken, Germany.
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Montano‐Loza AJ, Mason AL. Recurrence of primary biliary cholangitis after liver transplantation: A Japanese perspective. Hepatol Commun 2017; 1:391-393. [PMID: 29404467 PMCID: PMC5721417 DOI: 10.1002/hep4.1058] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 05/19/2017] [Indexed: 01/23/2023] Open
Affiliation(s)
- Aldo J. Montano‐Loza
- Division of Gastroenterology and Liver UnitUniversity of Alberta HospitalEdmontonCanada
| | - Andrew L. Mason
- Division of Gastroenterology and Liver UnitUniversity of Alberta HospitalEdmontonCanada
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43
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Yu L, Liu X, Yuan Z, Li X, Yang H, Yuan Z, Sun L, Zhang L, Jiang Z. SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model. Front Pharmacol 2017; 8:256. [PMID: 28553227 PMCID: PMC5425580 DOI: 10.3389/fphar.2017.00256] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 04/25/2017] [Indexed: 12/18/2022] Open
Abstract
Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in mice. The findings revealed that SRT1720 treatment increased FXR and Nrf2 gene expressions to shield against hepatotoxicity and cholestasis induced by ANIT. The mRNA levels of hepatic bile acid transporters were also altered by SRT1720. Furthermore, SRT1720 enhanced the antioxidative system by increasing Nrf2, SOD, GCLc, GCLm, Nqo1, and HO-1 gene expressions. In conclusion, a protective influence could be provided by SRT1720 to cure ANIT-induced hepatotoxicity and cholestasis, which was partly through FXR and Nrf2 activations. These results indicated that SIRT1 could be regarded as a therapeutic target to cure the cholestasis.
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Affiliation(s)
- Linxi Yu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Xiaoxin Liu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Zihang Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Xiaojiaoyang Li
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Hang Yang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Ziqiao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Lixin Sun
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China.,Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical UniversityNanjing, China.,State Key Laboratory of Natural Medicines, China Pharmaceutical UniversityNanjing, China
| | - Zhengzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University - Ministry of EducationNanjing, China
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44
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Chapman RW. Update on primary sclerosing cholangitis. Clin Liver Dis (Hoboken) 2017; 9:107-110. [PMID: 30992971 PMCID: PMC6467155 DOI: 10.1002/cld.633] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 03/06/2017] [Accepted: 03/16/2017] [Indexed: 02/04/2023] Open
Affiliation(s)
- Roger W. Chapman
- Nuffield Department of MedicineOxford UniversityOxfordUnited Kingdom
- Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
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45
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Cheung AC, LaRusso NF, Gores GJ, Lazaridis KN. Epigenetics in the Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. Semin Liver Dis 2017; 37:159-174. [PMID: 28564724 PMCID: PMC5553635 DOI: 10.1055/s-0037-1603324] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epigenomics, the study of modifications to genetic material that do not alter the underlying DNA sequence, is generating increasing interest as a means to help clarify disease pathogenesis and outcomes. Although genome-wide association studies have identified several potential candidate genes that may be implicated in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it is estimated that these genes explain less than 20% of the heritability of these diseases. Thus, to date, the origins of “missing heritability” for PBC and PSC remain elusive. The epigenome may provide a potentially elegant solution to this phenomenon, as it can be modified by both internal and external exposures (coined the “exposome”). This may explain differences in disease presentation, treatment response, and rates of progression between individuals. Epigenetic changes may also provide a framework for discovering potential biomarkers for diagnosis and screening of PBC and PSC. Importantly, because the epigenome is modifiable, it may also highlight novel pathways for therapeutic discovery and interventions of these diseases.
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Affiliation(s)
- Angela C. Cheung
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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46
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Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease. J Pharm Sci 2017; 106:2295-2301. [PMID: 28385542 DOI: 10.1016/j.xphs.2017.03.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/11/2017] [Accepted: 03/27/2017] [Indexed: 12/12/2022]
Abstract
Bile formation is a key function of the liver. Disturbance of bile flow may lead to liver disease and is called cholestasis. Cholestasis may be inherited, for example, in progressive familial intrahepatic cholestasis or acquired, for example, by drug-mediated inhibition of bile salt export from hepatocytes into the canaliculi. The key transport system for exporting bile salts into the canaliculi is the bile salt export pump. Inhibition of the bile salt export pump by drugs is a well-established cause of drug-induced cholestasis. Investigation of the role of the multidrug resistance protein 3, essential for biliary phospholipid secretion, is emerging now. This overview summarizes current concepts and methods with an emphasis on in vitro model systems for the investigation of drug-induced cholestasis in the general context of drug-induced liver injury.
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47
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Shagrani M, Burkholder J, Broering D, Abouelhoda M, Faquih T, El-Kalioby M, Subhani SN, Goljan E, Albar R, Monies D, Mazhar N, AlAbdulaziz BS, Abdelrahman KA, Altassan N, Alkuraya FS. Genetic profiling of children with advanced cholestatic liver disease. Clin Genet 2017; 92:52-61. [PMID: 28039895 DOI: 10.1111/cge.12959] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 12/27/2016] [Indexed: 12/12/2022]
Abstract
Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next-generation sequencing-based multi-gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono-allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high-carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.
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Affiliation(s)
- M Shagrani
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - J Burkholder
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - D Broering
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - M Abouelhoda
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - T Faquih
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - M El-Kalioby
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - S N Subhani
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - E Goljan
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - R Albar
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - D Monies
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - N Mazhar
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - B S AlAbdulaziz
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - K A Abdelrahman
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - N Altassan
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - F S Alkuraya
- Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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48
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Zhang FM, Chen LH, Chen HT, Shan GD, Hu FL, Yang M, Chen WG, Xu GQ. Hepatitis C Virus Infection Is Positively Associated with Gallstones in Liver Cirrhosis. Digestion 2017; 93:221-8. [PMID: 27093174 DOI: 10.1159/000444252] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 01/26/2016] [Indexed: 02/04/2023]
Abstract
AIM To elucidate the prevalence and risk factors of gallstone disease (GD) among patients with liver disease and explore their association with the aetiology and severity of hepatic injury. METHODS We analysed 4,832 subjects of hepatic injury induced by one of the following aetiologies: hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, excessive alcohol consumption. The risk factors significantly associated with GD were analysed using stepwise logistic regression analysis, the influence of aetiology and severity of liver disease on the prevalence of GD were assessed by multiple logistic regression analysis adjusting for confounding factors. RESULTS Three thousand forty eight patients were of positive HBV surface antigen alone with a prevalence of GD of 18.6%, 526 were tested as positive Anti-HCV alone with a prevalence of GD of 22.4%, and 1,258 were identified with excessive alcohol consumption patterns with a prevalence of GD of 13.5%. In each aetiological category, the prevalence of GD increased by age. Stepwise logistic regression analysis showed that age, female, low-density lipoprotein-cholesterol (LDL-Cho), family history of GD, HBV infection, HCV infection, chronic hepatitis and cirrhosis were independent factors associated with GD. After adjusting for age, LDL-Cho and family history of GD, the prevalence of gallstone disease was significantly associated with HCV-related cirrhosis in both genders, HBV-related cirrhosis in males and alcohol-related cirrhosis in females compared with patients with less severe liver disease [corrected]. After adjusting for gender, age, LDL-Cho and family history of GD, patients with HCV-related cirrhosis (OR 2.66, 95% CI 1.49-3.84) but not HBV-related cirrhosis (OR 1.52, 95% CI 0.73-1.82) were more likely to have GD compared with alcohol-related cirrhosis. CONCLUSION HCV infection is positively associated with gallstone formation especially in those with cirrhosis patients.
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Affiliation(s)
- Fen-Ming Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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49
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Montano-Loza AJ, Bhanji RA, Wasilenko S, Mason AL. Systematic review: recurrent autoimmune liver diseases after liver transplantation. Aliment Pharmacol Ther 2017; 45:485-500. [PMID: 27957759 DOI: 10.1111/apt.13894] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 10/21/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Autoimmune liver diseases (AILD) constitute the third most common indication for liver transplantation (LT) worldwide. Outcomes post LT are generally good but recurrent disease is frequently observed. AIMS To describe the frequency and risk factors associated with recurrent AILD post-LT and provide recommendations to reduce the incidence of recurrence based on levels of evidence. METHODS A systematic review was performed for full-text papers published in English-language journals, using the keywords 'autoimmune hepatitis (AIH)', 'primary biliary cholangitis and/or cirrhosis (PBC)', 'primary sclerosing cholangitis (PSC)', 'liver transplantation' and 'recurrent disease'. Management strategies to reduce recurrence after LT were classified according to grade and level of evidence. RESULTS Survival rates post-LT are approximately 90% and 70% at 1 and 5 years and recurrent disease occurs in a range of 10-50% of patients with AILD. Recurrent AIH is associated with elevated liver enzymes and IgG before LT, lymphoplasmacytic infiltrates in the explants and lack of steroids after LT (Grade B). Tacrolimus use is associated with increased risk; use of ciclosporin and preventive ursodeoxycholic acid with reduced risk of PBC recurrence (all Grade B). Intact colon, active ulcerative colitis and early cholestasis are associated with recurrent PSC (Grade B). CONCLUSIONS Recommendations based on grade A level of evidence are lacking. The need for further study and management includes active immunosuppression before liver transplantation and steroid use after liver transplantation in autoimmune hepatitis; selective immunosuppression with ciclosporin and preventive ursodeoxycholic acid treatment for primary biliary cholangitis; and improved control of inflammatory bowel disease or even colectomy in primary sclerosing cholangitis.
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Affiliation(s)
- A J Montano-Loza
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - R A Bhanji
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - S Wasilenko
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - A L Mason
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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50
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Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol 2017; 66:195-211. [PMID: 27575312 DOI: 10.1016/j.jhep.2016.08.011] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/15/2016] [Accepted: 08/16/2016] [Indexed: 12/19/2022]
Abstract
The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3, TM6SF2 and MBOAT7, have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.
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Affiliation(s)
- Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Switzerland.
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, UK
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