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He R, Zhong H, He C, Li H, Wang Z, Zheng J, Li G, An T. Individual and mixture effects of BTEX occupational exposure with hematologic and hepatic profiles in petrochemical workers and the metabolic mechanism. J Environ Sci (China) 2025; 154:163-173. [PMID: 40049865 DOI: 10.1016/j.jes.2024.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/07/2024] [Accepted: 06/15/2024] [Indexed: 05/13/2025]
Abstract
Evidence on the association of occupational exposure to benzene, toluene, ethylbenzene, and xylene (BTEX) with hematologic and hepatic profiles were equivocal, and few studies have investigated overall effect of BTEX mixtures. Herein, significant higher concentrations (p < 0.05) of hippuric acid, 1,2-dihydroxybenzene, mandelic acid, trans, trans-muconic acid and phenylglyoxylic acid were found in petrochemical workers than the controls, in accordance with higher levels of hematologic and hepatic profiles found in petrochemical workers (p < 0.05). Occupational exposure to individual BTEX was associated with elevated levels of white blood cell (WBC), lymphocyte (LYMPH), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT). Further, the Weighted Quantile Sum Regression model and Bayesian Kernel Machine Regression model consistently identified a positive association between BTEX mixture exposure and WBC, LYMPH, and GGT. Xylene was the primary contributor to increased WBC, LYMPH, and GGT levels. Furthermore, BTEX exposure resulting in the increased inflammation indices were mainly related to perturbations of sphingolipid metabolism, biosynthesis of unsaturated fatty acids, and primary bile acid biosynthesis. Whereas metabolites mediated the correlation between BTEX exposure and liver function indices were related to the perturbations of biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, sphingolipid metabolism, primary bile acid biosynthesis, etc. Our findings revealed potential health risk of occupational exposure to BTEX and might help one to understand the link between BTEX exposure and hematologic and hepatic profiles.
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Affiliation(s)
- Rujian He
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Hongjie Zhong
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Chang He
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Hailing Li
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Zhanxiang Wang
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Jing Zheng
- State Environmental Protection Key Laboratory of Environmental Pollution Health Risk Assessment, South China Institute of Environmental Sciences, Ministry of Ecology and Environment, Guangzhou 510530, China
| | - Guiying Li
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China
| | - Taicheng An
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory for City Cluster Environmental Safety and Green Development of the Ministry of Education, School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China.
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Wu X, Yu Q, Hou Y, Zhang X, Ocholi SS, Wang L, Yan Z, Li J, Han L. Emodin-8-O-β-D-glucopyranoside alleviates cholestasis by maintaining intestinal homeostasis and regulating lipids and bile acids metabolism in mice. J Pharm Biomed Anal 2025; 258:116734. [PMID: 39933397 DOI: 10.1016/j.jpba.2025.116734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/12/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Cholestatic liver disease(CLD) is caused by impaired bile flow due to obstruction of the biliary tract, and long-term exposure to bile acids in the liver triggers inflammation, eventually leading to liver toxicity and liver fibrosis. Emodin-8-O-β-D-glucopyranoside(EG) is anthraquinone compound that is widely found in traditional Chinese medicine. It possessed antioxidative and anti-inflammatory activities. However, the effect of EG on cholestatic liver injury(CLI) has not been explored. In this study, Alpha-naphthyl isothiocyanate(ANIT)-induced CLI mice were used to investigate the anti-cholestasis and hepatoprotective effects of EG through serum biochemical index detection, non-targeted metabolomics, lipidomics, and intestinal flora 16S rRNA sequencing. The results suggested that EG restores homeostasis of the gut microbiome while regulating bile acids metabolism and lipid-related metabolic pathways to reduce liver damage in ANIT-induced cholestasis. This study provides a new perspective on the mechanism of EG, and help offer a more natural approach to managing liver damage.
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Affiliation(s)
- Xiaolin Wu
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Qiao Yu
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Yuzhao Hou
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Xuemei Zhang
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Simon Sani Ocholi
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Liming Wang
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China
| | - Ziping Yan
- Tianjin Armed Police Corps Hospital, Tianjin 300162, China
| | - Jie Li
- Tianjin Key Laboratory of Clinical Multi-omics, Airport Economy Zone, Tianjin, China.
| | - Lifeng Han
- State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Instrumental analysis & Research Center, Tianjin University of Traditional Chinese Medicine, No.10 Poyanghu Road, Jinghai District, Tianjin 301617, China.
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Zhou Z, Yong K, Luo Z, Du Z, Zhou T, Li X, Yao X, Shen L, Yu S, Huang Y, Cao S. The Positive Regulatory Effect of DBT on Lipid Metabolism in Postpartum Dairy Cows. Metabolites 2025; 15:58. [PMID: 39852401 PMCID: PMC11767874 DOI: 10.3390/metabo15010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/08/2025] [Accepted: 01/13/2025] [Indexed: 01/26/2025] Open
Abstract
BACKGROUND/OBJECTIVES The transition from a non-lactating to a lactating state is a critical period for lipid metabolism in dairy cows. Danggui Buxue Tang (DBT), stimulating energy metabolism, ameliorates diseases related to lipid metabolism disorders and is expected to be an effective supplement for alleviating excessive lipid mobilisation in periparturient dairy cows. This study aimed to investigate the effects of supplemental DBT on serum biochemical indices, faecal microbial communities, and plasma metabolites in dairy cows. METHODS Thirty cows were randomly divided into three groups: H-DBT group, L-DBT group, and control group. DBT administration was started on the day of calving and continued once daily for seven days. Faecal and blood samples were collected on calving day, 7 days after calving, and 14 days after calving. The levels of serum biochemical indices were measured at three time points in the three groups using commercial kits. Cows in the H-DBT group and control group were selected for metabolome and 16S rRNA amplicon sequencing. RESULTS Our research shows that, in dairy cows 7 days postpartum, DBT significantly reduced serum 3-hydroxybutyric acid (BHB) concentrations and the number of cows with BHB concentrations ≥ 1 mmol/L. Additionally, DBT increased serum total cholesterol contents at both 7 and 14 days postpartum. Analysis of the microbiota community showed that DBT modulated the composition and structure of the hindgut microbiota. Metabolomic analysis revealed decreased plasma acetylcarnitine, 2-hydroxybutyric acid, and BHB levels 7 days postpartum, whereas the TCA cycle was enhanced. At 14 days postpartum, DBT altered the plasma bile acid profile, especially glycine-conjugated bile acids, including GCDCA, GUDCA, and GDCA. Correlation analyses showed that the relative abundances of Bacillus, Solibacillus, Dorea, and Romboutsia were strongly correlated with the differential metabolites, which is crucial for the beneficial effects of DBT. CONCLUSIONS DBT improves energy status and lipid metabolism in postpartum dairy cows by modulating hindgut microbiota and serum lipid metabolites.
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Affiliation(s)
- Zheng Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Department of Animal Husbandry and Veterinary Medicine, College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing 404105, China;
| | - Kang Yong
- Department of Animal Husbandry and Veterinary Medicine, College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing 404105, China;
| | - Zhengzhong Luo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Department of Animal Husbandry and Veterinary Medicine, College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing 404105, China;
| | - Zhenlong Du
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Tao Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiaoping Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
| | - Xueping Yao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Liuhong Shen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Shumin Yu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yixin Huang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Suizhong Cao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Z.Z.); (Z.D.); (T.Z.); (X.Y.); (L.S.); (S.Y.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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Li X, Ruan T, Wang S, Sun X, Liu C, Peng Y, Tao Y. Mitochondria at the Crossroads of Cholestatic Liver Injury: Targeting Novel Therapeutic Avenues. J Clin Transl Hepatol 2024; 12:792-801. [PMID: 39280065 PMCID: PMC11393838 DOI: 10.14218/jcth.2024.00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/13/2024] [Accepted: 06/19/2024] [Indexed: 09/18/2024] Open
Abstract
Bile acids are byproducts of cholesterol metabolism in the liver and constitute the primary components of bile. Disruption of bile flow leads to cholestasis, characterized by the accumulation of hydrophobic bile acids in the liver and bloodstream. Such accumulation can exacerbate liver impairment. This review discussed recent developments in understanding how bile acids contribute to liver damage, including disturbances in mitochondrial function, endoplasmic reticulum stress, inflammation, and autophagy dysfunction. Mitochondria play a pivotal role in cholestatic liver injury by influencing hepatocyte apoptosis and inflammation. Recent findings linking bile acids to liver damage highlight new potential treatment targets for cholestatic liver injury.
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Affiliation(s)
- Xutao Li
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tianyin Ruan
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Siyuan Wang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, China
| | - Yuan Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanyan Tao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, China
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İpek G, Tanaçan A, Peker A, Ağaoğlu Z, Kara Ö, Şahin D. Systemic Inflammation Response Index as a diagnostic and prognostic predictor of intrahepatic cholestasis of pregnancy: A case-control study from a tertiary center. Int J Gynaecol Obstet 2024; 165:717-722. [PMID: 37922220 DOI: 10.1002/ijgo.15216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/15/2023] [Accepted: 10/12/2023] [Indexed: 11/05/2023]
Abstract
OBJECTIVE To investigate the diagnostic and prognostic value of the Systemic Inflammation Response Index (SIRI) in intrahepatic cholestasis of pregnancy (ICP). METHODS The present case-control study comprised 386 participants, including 192 women with ICP and 194 gestational age-matched pregnant women. Increased fasting biliary acid (FBA) levels (≥10 μmol/L) were accepted as ICP criteria. SIRI values were calculated for the first trimester (SIRI 1), time of diagnosis (SIRI 2), and time of delivery (SIRI 3). The ICP and control groups were compared based on SIRI values, and on obstetrical and neonatal outcomes. The ICP subgroups based on FBA levels (severe ICP [FBA ≥40 μmol/L] and mild ICP [FBA <40 μmol/L]) were also compared for SIRI and pregnancy outcomes. RESULTS Adverse outcomes were significantly higher in the ICP group (P < 0.001). SIRI 2 and SIRI 3 showed negative significant differences between the ICP and control groups, with P values of 0.001 and 0.009, respectively. A significant difference in ICP severity subgroups (P = 0.046) was observed for SIRI 3. In receiver operating characteristics curve analyses, optimal cut-off values for the prediction of ICP were found to be 2.01 and 2.08 for SIRI 2 and SIRI 3, respectively. A cut-off value 1.74 was determined to predict the disease severity for SIRI 3. CONCLUSION SIRI has clinical significance in accordance with the inflammatory etiology of ICP. SIRI might be used with other clinical and laboratory findings for ICP diagnosis and prediction.
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Affiliation(s)
- Göksun İpek
- Division of Perinatology, Department of Obstetrics and Gynecology, Turkish Ministry of Health Ankara City Hospital, Ankara, Turkey
| | - Atakan Tanaçan
- Division of Perinatology, Department of Obstetrics and Gynecology, Turkish Ministry of Health Ankara City Hospital, Ankara, Turkey
| | - Ayça Peker
- Division of Perinatology, Department of Obstetrics and Gynecology, Turkish Ministry of Health Ankara City Hospital, Ankara, Turkey
| | - Zahid Ağaoğlu
- Division of Perinatology, Department of Obstetrics and Gynecology, Turkish Ministry of Health Ankara City Hospital, Ankara, Turkey
| | - Özgür Kara
- Division of Perinatology, Department of Obstetrics and Gynecology, Turkish Ministry of Health Ankara City Hospital, Ankara, Turkey
| | - Dilek Şahin
- Division of Perinatology, Department of Obstetrics and Gynecology, Turkish Ministry of Health Ankara City Hospital, Ankara, Turkey
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Gadour E, Kaballo MA, Shrwani K, Hassan Z, Kotb A, Aljuraysan A, Miuţescu B, Sherwani N, Mahallawi W. Safety and efficacy of Single-Pass Albumin Dialysis (SPAD), Prometheus, and Molecular Adsorbent Recycling System (MARS) liver haemodialysis vs. Standard Medical Therapy (SMT): meta-analysis and systematic review. PRZEGLAD GASTROENTEROLOGICZNY 2024; 19:101-111. [PMID: 38939063 PMCID: PMC11200067 DOI: 10.5114/pg.2024.139297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 11/27/2023] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Because not all liver dysfunction patients are suitable for transplantations and there is a shortage of grafts, liver support therapies have gained interest. In this regard, extracorporeal albumin dialysis devices such as single-pass albumin dialysis (SPAD), Prometheus, and molecular adsorbent recycling system (MARS) have been valuable in supplementing standard medical therapy (SMT). However, the efficacy and safety of these devices is often questioned.Aim: We performed a systematic review to summarize the efficacy and safety of MARS, SPAD, and Prometheus as supportive treatments for liver dysfunction. MATERIAL AND METHODS PubMed, Medline, Cochrane Library, Web of Science, and Google Scholar electronic databases were extensively searched for all randomized trials published in English. In addition, meta-analytic analyses were performed with Review Manager software, and Cochrane's risk of bias tool embedded in this software was used for bias assessment. RESULTS Twelve trials including a total of 653 patients were eligible for inclusion. Subgroup analyses of data from these trials revealed that MARS and Prometheus were associated with significant removal of bilirubin (MD = -5.14 mg/dl; 95% CI: -7.26 - -3.02; p < 0.00001 and MD = -8.11 mg/dl; 95% CI: -12.40 - -3.82; p = 0.0002, respectively) but not bile acids and ammonia when compared to SMT. Furthermore, MARS was as effective as Prometheus and SPAD in the reduction of bilirubin (MD = 2.98 mg/dl; 95% CI: -4.26 - 10.22; p = 0.42 and MD = 0.67 mg/dl; 95% CI: -2.22 - 3.56; p = 0.65), bile acids (MD = -17.06 µmol/l; 95% CI: -64.33 - 30.20; p = 0.48 and MD = 16.21 µmol/l; 95% CI: -17.26 - 49.68; p = 0.34), and ammonia (MD = 26 µmol/l; 95% CI: -12.44 - 64.44; p = 0.18). In addition, MARS had a considerable effect in improving hepatic encephalopathy (HE) (RR = 1.54; 95% CI: 1.15-2.05; p = 0.004). However, neither MARS nor Prometheus had a mortality benefit compared to SMTRR (0.86; 95% CI: 0.71-1.03; p = 0.11 and RR = 0.87; 95% CI: 0.66-1.14; p = 0.31, respectively). CONCLUSIONS MARS, SPAD, and Prometheus, as liver support therapies, are equally effective in reducing albumin-bound and water-soluble substances. Moreover, MARS is associated with HE improvement. However, none of the therapies was associated with a significant reduction in mortality or adverse events.
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Affiliation(s)
- Eyad Gadour
- Department of Gastroenterology and Hepatology, King Abdulaziz National Guard Hospital, Al-Ahsa, Saudi Arabia
| | | | - Khalid Shrwani
- Saudi Centre for Disease Prevention and Control, Public Health Authority, Jazan, Saudi Arabia
| | - Zeinab Hassan
- Department of Internal Medicine, Stockport Hospital NHS Foundation Trust, Manchester, United Kingdom
| | - Ahmed Kotb
- Department of Vascular Surgery, Glan Clwyd Hospital, Rhyl, United Kingdom
| | - Ahmed Aljuraysan
- Department of Gastroenterology and Hepatology, King Abdulaziz National Guard Hospital, Al-Ahsa, Saudi Arabia
| | - Bogdan Miuţescu
- Department of Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Nouf Sherwani
- Department of Surgery, Mohammed bin Nasser Hospital, Jazan, Saudi Arabia
| | - Waleed Mahallawi
- College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
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Li T, Hasan MN, Gu L. Bile acids regulation of cellular stress responses in liver physiology and diseases. EGASTROENTEROLOGY 2024; 2:e100074. [PMID: 39027418 PMCID: PMC11257078 DOI: 10.1136/egastro-2024-100074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Bile acids are physiological detergents and signalling molecules that are critically implicated in liver health and diseases. Dysregulation of bile acid homeostasis alters cell function and causes cell injury in chronic liver diseases. Therapeutic agents targeting bile acid synthesis, transport and signalling hold great potential for treatment of chronic liver diseases. The broad cellular and physiological impacts of pharmacological manipulations of bile acid metabolism are still incompletely understood. Recent research has discovered new links of bile acid signalling to the regulation of autophagy and lysosome biology, redox homeostasis and endoplasmic reticulum stress. These are well-conserved mechanisms that allow cells to adapt to nutrient and organelle stresses and play critical roles in maintaining cellular integrity and promoting survival. However, dysregulation of these cellular pathways is often observed in chronic liver diseases, which exacerbates cellular dysfunction to contribute to disease pathogenesis. Therefore, identification of these novel links has significantly advanced our knowledge of bile acid biology and physiology, which is needed to understand the contributions of bile acid dysregulation in disease pathogenesis, establish bile acids as diagnostic markers and develop bile acid-based pharmacological interventions. In this review, we will first discuss the roles of bile acid dysregulation in the pathogenesis of chronic liver diseases, and then discuss the recent findings on the crosstalk of bile acid signalling and cellular stress responses. Future investigations are needed to better define the roles of these crosstalks in regulating cellular function and disease processes.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Mohammad Nazmul Hasan
- Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Lijie Gu
- Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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Hollenback D, Hambruch E, Fink G, Birkel M, Schulz A, Hornberger M, Liu K, Staiger KM, Krol HD, Deuschle U, Steeneck C, Kinzel O, Liles JT, Budas G, Watkins WJ, Kremoser C. Development of Cilofexor, an Intestinally-Biased Farnesoid X Receptor Agonist, for the Treatment of Fatty Liver Disease. J Pharmacol Exp Ther 2024; 389:61-75. [PMID: 38409114 DOI: 10.1124/jpet.123.001900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/17/2024] [Accepted: 02/06/2024] [Indexed: 02/28/2024] Open
Abstract
The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid (Px-102), to develop cilofexor, a potent, non-steroidal FXR agonist with a more manageable safety profile. Px-102 demonstrated the anticipated pharmacodynamic (PD) effects in healthy volunteers but caused a 2-fold increase in alanine aminotransferase (ALT) activity and changes in cholesterol levels. These data guided development of a high fat diet mouse model to screen FXR agonists based on ALT and cholesterol changes. Cilofexor was identified to elicit only minor changes in these parameters. The differing effects of cilofexor and Px-102 on ALT/cholesterol in the model could not be explained by potency or specificity, and we hypothesized that the relative contribution of intestinal and liver FXR activation may be responsible. Gene expression analysis from rodent studies revealed that cilofexor, but not Px-102, had a bias for FXR transcriptional activity in the intestine compared with the liver. Fluorescent imaging in hepatoma cells demonstrated similar subcellular localization for cilofexor and Px-102, but cilofexor was more rapidly washed out, consistent with a lower membrane residence time contributing to reduced hepatic transcriptional effects. Cilofexor demonstrated antisteatotic and antifibrotic efficacy in rodent models and antisteatotic efficacy in a monkey model, with the anticipated PD and a manageable safety profile in human phase I studies. SIGNIFICANCE STATEMENT: Farnesoid X receptor (FXR) agonists have shown promise in treating non-alcoholic steatohepatitis and other liver diseases in the clinic, but balancing efficacy with undesired side effects has been difficult. Here, we examined the preclinical and clinical effects of the first-generation FXR agonist, 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid, to enable the selection of an analog, cilofexor, with unique properties that reduced side effects yet maintained efficacy. Cilofexor is one of the few remaining FXR agonists in clinical development.
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Affiliation(s)
- David Hollenback
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Eva Hambruch
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Gero Fink
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Manfred Birkel
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Andreas Schulz
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Martin Hornberger
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Kathy Liu
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Kelly MacLennan Staiger
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Helen Desiree Krol
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Ulrich Deuschle
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Christoph Steeneck
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Olaf Kinzel
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - John T Liles
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Grant Budas
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - William J Watkins
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
| | - Claus Kremoser
- Gilead Sciences, Inc., Foster City, California (D.H., K.L., K.M.S., J.T.L., G.B., W.J.W.) and Phenex Pharmaceuticals, Heidelberg, Germany (E.H., G.F., M.B., A.S., M.H., H.D.K., U.D., C.S., O.K., C.K.)
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9
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Melis M, Marino R, Tian J, Johnson C, Sethi R, Oertel M, Fox IJ, Locker J. Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver Failure. Cell Mol Gastroenterol Hepatol 2023; 17:453-479. [PMID: 37993018 PMCID: PMC10837635 DOI: 10.1016/j.jcmgh.2023.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 11/14/2023] [Accepted: 11/14/2023] [Indexed: 11/24/2023]
Abstract
BACKGROUND & AIMS HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. METHODS Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. RESULTS HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. CONCLUSIONS Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.
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Affiliation(s)
- Marta Melis
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Rebecca Marino
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jianmin Tian
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Carla Johnson
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Rahil Sethi
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Oertel
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ira J Fox
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Joseph Locker
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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11
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Kister B, Viehof A, Rolle-Kampczyk U, Schwentker A, Treichel NS, Jennings SA, Wirtz TH, Blank LM, Hornef MW, von Bergen M, Clavel T, Kuepfer L. A physiologically based model of bile acid metabolism in mice. iScience 2023; 26:107922. [PMID: 37817939 PMCID: PMC10561051 DOI: 10.1016/j.isci.2023.107922] [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: 02/16/2023] [Revised: 07/04/2023] [Accepted: 09/12/2023] [Indexed: 10/12/2023] Open
Abstract
Bile acid (BA) metabolism is a complex system that includes a wide variety of primary and secondary, as well as conjugated and unconjugated BAs that undergo continuous enterohepatic circulation (EHC). Alterations in both composition and dynamics of BAs have been associated with various diseases. However, a mechanistic understanding of the relationship between altered BA metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of BAs along the gut-liver axis. In this study, we developed a physiologically based model of murine BA metabolism describing synthesis, hepatic and microbial transformations, systemic distribution, excretion, and EHC of BAs at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) mice was characterized in vivo by measuring BA levels and composition in various organs, expression of transporters along the gut, and cecal microbiota composition. We found significantly different BA levels between male and female mice that could only be explained by adjusted expression of the hepatic enzymes and transporters in the model. Of note, this finding was in agreement with experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching off microbial activity in the intestine. The here presented model can therefore facilitate and guide functional analyses of BA metabolism in mice, e.g., the effect of pathophysiological alterations on BA metabolism and translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.
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Affiliation(s)
- Bastian Kister
- Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Alina Viehof
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany
| | - Annika Schwentker
- Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Nicole Simone Treichel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Susan A.V. Jennings
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Theresa H. Wirtz
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars M. Blank
- Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
| | - Mathias W. Hornef
- Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany
- German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
- Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Leipzig, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Lars Kuepfer
- Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany
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12
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Shen EYL, U MRA, Cox IJ, Taylor-Robinson SD. The Role of Mass Spectrometry in Hepatocellular Carcinoma Biomarker Discovery. Metabolites 2023; 13:1059. [PMID: 37887384 PMCID: PMC10609223 DOI: 10.3390/metabo13101059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the main liver malignancy and has a high mortality rate. The discovery of novel biomarkers for early diagnosis, prognosis, and stratification purposes has the potential to alleviate its disease burden. Mass spectrometry (MS) is one of the principal technologies used in metabolomics, with different experimental methods and machine types for different phases of the biomarker discovery process. Here, we review why MS applications are useful for liver cancer, explain the MS technique, and briefly summarise recent findings from metabolomic MS studies on HCC. We also discuss the current challenges and the direction for future research.
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Affiliation(s)
- Eric Yi-Liang Shen
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City 333, Taiwan
- Clinical Metabolomics Core Laboratory, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City 333, Taiwan
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W2 1NY, UK
| | - Mei Ran Abellona U
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W2 1NY, UK
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK
| | - I. Jane Cox
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences & Medicine, King’s College London, London SE5 8AF, UK
| | - Simon D. Taylor-Robinson
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W2 1NY, UK
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13
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Xu F, Yu Z, Liu Y, Du T, Yu L, Tian F, Chen W, Zhai Q. A High-Fat, High-Cholesterol Diet Promotes Intestinal Inflammation by Exacerbating Gut Microbiome Dysbiosis and Bile Acid Disorders in Cholecystectomy. Nutrients 2023; 15:3829. [PMID: 37686860 PMCID: PMC10489946 DOI: 10.3390/nu15173829] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/21/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Patients with post-cholecystectomy (PC) often experience adverse gastrointestinal conditions, such as PC syndrome, colorectal cancer (CRC), and non-alcoholic fatty liver disease (NAFLD), that accumulate over time. An epidemiological survey further revealed that the risk of cholecystectomy is associated with high-fat and high-cholesterol (HFHC) dietary intake. Mounting evidence suggests that cholecystectomy is associated with disrupted gut microbial homeostasis and dysregulated bile acids (BAs) metabolism. However, the effect of an HFHC diet on gastrointestinal complications after cholecystectomy has not been elucidated. Here, we aimed to investigate the effect of an HFHC diet after cholecystectomy on the gut microbiota-BA metabolic axis and elucidate the association between this alteration and the development of intestinal inflammation. In this study, a mice cholecystectomy model was established, and the levels of IL-Iβ, TNF-α, and IL-6 in the colon were increased in mice fed an HFHC diet for 6 weeks. Analysis of fecal BA metabolism showed that an HFHC diet after cholecystectomy altered the rhythm of the BA metabolism by upregulating liver CPY7A1, CYP8B1, and BSEP and ileal ASBT mRNA expression levels, resulting in increased fecal BA levels. In addition, feeding an HFHC diet after cholecystectomy caused a significant dysbiosis of the gut microbiota, which was characterized by the enrichment of the metabolic microbiota involved in BAs; the abundance of pro-inflammatory gut microbiota and related pro-inflammatory metabolite levels was also significantly higher. In contrast, the abundance of major short-chain fatty acid (SCFA)-producing bacteria significantly decreased. Overall, our study suggests that an HFHC diet after cholecystectomy promotes intestinal inflammation by exacerbating the gut microbiome and BA metabolism dysbiosis in cholecystectomy. Our study also provides useful insights into the maintenance of intestinal health after cholecystectomy through dietary or probiotic intervention strategies.
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Affiliation(s)
- Fusheng Xu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Zhiming Yu
- Wuxi People’s Hospital Afliated to Nanjing Medical University, Wuxi 214023, China;
| | - Yaru Liu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Ting Du
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Leilei Yu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Fengwei Tian
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
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14
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Tveter KM, Mezhibovsky E, Wu Y, Roopchand DE. Bile acid metabolism and signaling: Emerging pharmacological targets of dietary polyphenols. Pharmacol Ther 2023; 248:108457. [PMID: 37268113 PMCID: PMC10528343 DOI: 10.1016/j.pharmthera.2023.108457] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/03/2023] [Accepted: 05/22/2023] [Indexed: 06/04/2023]
Abstract
Beyond their role as emulsifiers of lipophilic compounds, bile acids (BAs) are signaling endocrine molecules that show differential affinity and specificity for a variety of canonical and non-canonical BA receptors. Primary BAs (PBAs) are synthesized in the liver while secondary BAs (SBAs) are gut microbial metabolites of PBA species. PBAs and SBAs signal to BA receptors that regulate downstream pathways of inflammation and energy metabolism. Dysregulation of BA metabolism or signaling has emerged as a feature of chronic disease. Dietary polyphenols are non-nutritive plant-derived compounds associated with decreased risk of metabolic syndrome, type-2 diabetes, hepatobiliary and cardiovascular disease. Evidence suggests that the health promoting effects of dietary polyphenols are linked to their ability to alter the gut microbial community, the BA pool, and BA signaling. In this review we provide an overview of BA metabolism and summarize studies that link the cardiometabolic improvements of dietary polyphenols to their modulation of BA metabolism and signaling pathways, and the gut microbiota. Finally, we discuss approaches and challenges in deciphering cause-effect relationships between dietary polyphenols, BAs, and gut microbes.
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Affiliation(s)
- Kevin M Tveter
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Esther Mezhibovsky
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA.
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15
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Lin X, Zhu X, Xin Y, Zhang P, Xiao Y, He T, Guo H. Intermittent Fasting Alleviates Non-Alcoholic Steatohepatitis by Regulating Bile Acid Metabolism and Promoting Fecal Bile Acid Excretion in High-Fat and High-Cholesterol Diet Fed Mice. Mol Nutr Food Res 2023; 67:e2200595. [PMID: 37148502 DOI: 10.1002/mnfr.202200595] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 02/15/2023] [Indexed: 05/08/2023]
Abstract
SCOPE Intermittent fasting (IF) has a protective role across a wide range of chronic disorders, including obesity, diabetes, and cardiovascular disease, but its protection against non-alcoholic steatohepatitis (NASH) is still lacking. This study seeks to investigate how IF alleviates NASH by regulating gut microbiota and bile acids (BAs) composition. METHODS AND RESULTS Male C57BL/6 mice are fed a high-fat and high-cholesterol (HFHC) diet for 16 weeks to establish a NASH model. Mice then continued HFHC feeding and are treated with or without every other day fasting for 10 weeks. Hepatic pathology is assessed using hematoxylin-eosin staining. Gut microbiota of the cecum are profiled using 16S rDNA gene sequencing and the levels of BAs in serum, colon contents, and feces are measured using ultra-performance liquid chromatography-tandem mass spectrometry. Results indicate that IF significantly decreases murine body weight, insulin resistance, hepatic steatosis, ballooning, and lobular inflammation. IF reshapes the gut microbiota, reduces the accumulation of serum BAs, and increases total colonic and fecal BAs. Moreover, IF increases the expression of cholesterol 7α-hydroxylase 1 in liver, but decreases the expressions of both farnesoid-X-receptor and fibroblast growth factor 15 in the ileum. CONCLUSION IF alleviates NASH by regulating bile acid metabolism and promoting fecal bile acid excretion.
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Affiliation(s)
- Xiaozhuan Lin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Zhanjiang, 524023, China
| | - Xuan Zhu
- Department of Nutrition, School of Public Health, Guangdong Medical University, Zhanjiang, 524023, China
| | - Yan Xin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Zhanjiang, 524023, China
| | - Peiwen Zhang
- Department of Nutrition, School of Public Health, Guangdong Medical University, Zhanjiang, 524023, China
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Yunjun Xiao
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Taiping He
- Department of Nutrition, School of Public Health, Guangdong Medical University, Zhanjiang, 524023, China
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Zhanjiang, 524023, China
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
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Gao X, Lin X, Xin Y, Zhu X, Li X, Chen M, Huang Z, Guo H. Dietary cholesterol drives the development of non-alcoholic steatohepatitis by altering gut microbiota mediated bile acid metabolism in high-fat diet fed mice. J Nutr Biochem 2023; 117:109347. [PMID: 37031879 DOI: 10.1016/j.jnutbio.2023.109347] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 04/11/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most widespread chronic liver disorder globally. Unraveling the pathogenesis of simple fatty liver to non-alcoholic steatohepatitis (NASH) has important clinical significance for improving the prognosis of NAFLD. Here, we explored the role of a high-fat diet alone or combined with high cholesterol in causing NASH progression. Our results demonstrated that high dietary cholesterol intakes accelerate the progression of spontaneous NAFLD and induces liver inflammation in mice. An elevation of hydrophobic unconjugated bile acids cholic acid (CA), deoxycholic acid (DCA), muricholic acid and chenodeoxycholic acid, was observed in high-fat and high-cholesterol diet fed mice. Full-length sequencing of the 16S rRNA gene of gut microbiota revealed a significant increase in the abundance of Bacteroides, Clostridium and Lactobacillus that possess bile salt hydrolase activity. Furthermore, the relative abundance of these bacterial species was positively correlated with content of unconjugated bile acids in liver. Moreover, the expression of genes related to bile acid reabsorption (organic anion-transporting polypeptides, Na+-taurocholic acid cotransporting polypeptide, apical sodium dependent bile acid transporter and organic solute transporter β) was found to be increased in mice with a high-cholesterol diet. Lastly, we observed that hydrophobic bile acids CA and DCA induce an inflammatory response in free fatty acids-induced steatotic HepG2 cells. In conclusion, high dietary cholesterol promotes the development of NASH by altering gut microbiota composition and abundance and thereby influencing with bile acid metabolism.
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Affiliation(s)
- Xuebin Gao
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Department of Science and Education, Yuebei People's Hospital, Shaoguan 512026, China
| | - Xiaozhuan Lin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Yan Xin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Xuan Zhu
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Xiang Li
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Ming Chen
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Zhigang Huang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.
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Zhao J, Yang Q, Liu Z, Xu P, Tian L, Yan J, Li K, Lin B, Bian L, Xi Z, Liu X. The impact of subchronic ozone exposure on serum metabolome and the mechanisms of abnormal bile acid and arachidonic acid metabolisms in the liver. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 252:114573. [PMID: 36701875 DOI: 10.1016/j.ecoenv.2023.114573] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 12/28/2022] [Accepted: 01/22/2023] [Indexed: 06/17/2023]
Abstract
Ambient ozone (O3) pollution can induce respiratory and cardiovascular toxicity. However, its impact on the metabolome and the underlying mechanisms remain unclear. This study first investigated the serum metabolite changes in rats exposed to 0.5 ppm O3 for 3 months using untargeted metabolomic approach. Results showed chronic ozone exposure significantly altered the serum levels of 34 metabolites with potential increased risk of digestive, respiratory and cardiovascular disease. Moreover, bile acid synthesis and secretion, and arachidonic acid (AA) metabolism became the most prominent affected metabolic pathways after O3 exposure. Further studies on the mechanisms found that the elevated serum toxic bile acid was not due to the increased biosynthesis in the liver, but the reduced reuptake from the portal vein to hepatocytes owing to repressed Ntcp and Oatp1a1, and the decreased bile acid efflux in hepatocytes as a results of inhibited Bsep, Ostalpha and Ostbeta. Meanwhile, decreased expressions of detoxification enzyme of SULT2A1 and the important regulators of FXR, PXR and HNF4α also contributed to the abnormal bile acids. In addition, O3 promoted the conversion of AA into thromboxane A2 (TXA2) and 20-hydroxyarachidonic acid (20-HETE) in the liver by up-regulation of Fads2, Cyp4a and Tbxas1 which resulting in decreased AA and linoleic acid (LA), and increased thromboxane B2 (TXB2) and 20-HETE in the serum. Furthermore, apparent hepatic chronic inflammation, fibrosis and abnormal function were found in ozone-exposed rats. These results indicated chronic ozone exposure could alter serum metabolites by interfering their metabolism in the liver, and inducing liver injury to aggravate metabolic disorders.
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Affiliation(s)
- Jiao Zhao
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Qingcheng Yang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Zhiyuan Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Pengfei Xu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Lei Tian
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Jun Yan
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Kang Li
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Bencheng Lin
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Liping Bian
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Zhuge Xi
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Xiaohua Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
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18
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Guo Q, Wang M, Zhong K, Li J, Jiang T, Ran B, Shalayiadang P, Zhang R, Tuergan T, Aji T, Shao Y. Application of hepatic lobe hyperplasia techniques in the treatment of advanced hepatic alveolar echinococcosis: a single-centre experience. BMC Surg 2022; 22:415. [PMID: 36474286 PMCID: PMC9724394 DOI: 10.1186/s12893-022-01864-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND This study was designed to investigate clinical efficiency and application indications of hepatic lobe hyperplasia techniques for advanced hepatic alveolar echinococcosis (AE) patients. METHODS A retrospective case series covering 19 advanced hepatic AE patients admitted to the First Affiliated Hospital of Xinjiang Medical University from September 2014 to December 2021 and undergoing hepatic lobe hyperplasia techniques due to insufficient remnant liver volume were analyzed. Changes of liver function, lesions volume, remnant liver volume, total liver volume before and after operation have been observed. RESULTS Among the patients, 15 underwent portal vein embolization (PVE). There was no statistical difference in total liver volume and lesions volume before and after PVE (P > 0.05). However, the remnant liver volume was significantly increased after PVE (P < 0.05). The median monthly increase rate in future liver remnant volume (FLRV) after PVE stood at 4.49% (IQR 3.55-7.06). Among the four patients undergoing two-stage hepatectomy (TSH), FLRV was larger than that before the first stage surgery, and the median monthly increase rate in FLRV after it stood at 3.34% (IQR 2.17-4.61). Despite no statistical difference in total bilirubin (TBil), albumin (Alb), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) in all patients with PVE, four patients who underwent TSH showed a decrease in ALT, AST and GGT. During the waiting process before the second stage operation, no serious complications occurred in all patients. CONCLUSIONS For patients suffering from advanced hepatic AE with insufficient FLRV, PVE and TSH are safe and feasible in promoting hepatic lobe hyperplasia.
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Affiliation(s)
- Qiang Guo
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Maolin Wang
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Kai Zhong
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Jialong Li
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Tiemin Jiang
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Bo Ran
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Paizula Shalayiadang
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Ruiqing Zhang
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Talaiti Tuergan
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Tuerganaili Aji
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
| | - Yingmei Shao
- grid.412631.3Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang China ,Clinical Medical Research Center of Echinococcosis and Hepatobiliary Disease of Xinjiang Uygur Autonomous Region, Urumqi, 830054 Xinjiang China
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19
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Diagnostic and prognostic value of blood inflammation and biochemical indicators for intrahepatic cholestasis of pregnancy in Chinese pregnant women. Sci Rep 2022; 12:20833. [PMID: 36460663 PMCID: PMC9718819 DOI: 10.1038/s41598-022-22199-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 10/11/2022] [Indexed: 12/04/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a common liver disease during pregnancy, that has serious complications. This study aimed to compare the blood inflammation and biochemical markers of pregnant women with ICP in Southwest China and analyse their diagnostic value for ICP. A controlled cross-sectional study was conducted, and routine blood and biochemical indicators of 304 diagnosed ICP patients and 363 healthy pregnant women undergoing routine prenatal examination were assessed. The blood inflammatory indicators and biochemical indicators were compared between the ICP groups and normal groups. In this study, the levels of the ALT, AST, GGT, TBIL and DBIL biochemical indicators and the levels of WBC, neutrophils, NLR and PLR inflammatory indicators in the ICP group were significantly higher than those in healthy pregnant women (p < 0.001). The PA and lymphocytes of the ICP group were significantly lower than those of the normal group (p < 0.001). ROC curves showed that ALT and the NLR had higher predictive value for ICP. The GGT, TBA and NLR of pregnant women with ICP in the preterm group were significantly higher than those in the term group, and the combined NLR and TBA had a certain predictive value for preterm birth.
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20
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Protective Effect of Rhus chinensis Mill. Fruits on 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine-Induced Cholestasis in Mice via Ameliorating Oxidative Stress and Inflammation. Nutrients 2022; 14:nu14194090. [PMID: 36235742 PMCID: PMC9573408 DOI: 10.3390/nu14194090] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022] Open
Abstract
This study focused on the preventive effects of the extracts of Rhus chinensis Mill. (RCM) fruits on cholestasis induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in mice. The results showed that RCM extracts could significantly ameliorate DDC-induced cholestasis via multiple mechanisms, including (1) alleviating liver damage via enhancing antioxidant capacity, such as increasing the contents of glutathione, superoxide dismutase, and catalase and inhibiting the levels of malondialdehyde; (2) preventing liver inflammation by suppressing NF-κB pathway and reducing proinflammatory cytokines secretion (e.g., tumor necrosis factor-α, interleukin-1β, and interleukin-6); (3) inhibiting liver fibrosis and collagen deposition by regulating the expression of transforming growth factor-β and α-smooth muscle actin; (4) modulating abnormal bile acid metabolism through increasing the expression of bile salt export pump and multidrug resistance-associated protein 2. This study was the first to elucidate the potential preventive effect of RCM extracts on DDC-induced cholestasis in mice from multiple pathways, which suggested that RCM fruits could be considered as a potential dietary supplement to prevent cholestasis.
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21
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Truong JK, Bennett AL, Klindt C, Donepudi AC, Malla SR, Pachura KJ, Zaufel A, Moustafa T, Dawson PA, Karpen SJ. Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury. J Lipid Res 2022; 63:100261. [PMID: 35934110 PMCID: PMC9460185 DOI: 10.1016/j.jlr.2022.100261] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 07/29/2022] [Accepted: 07/30/2022] [Indexed: 02/07/2023] Open
Abstract
Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models. Here, we aimed to determine if IBAT inhibition with SC-435 is protective in Cyp2c70 KO mice. As compared to WT mice, we found male and female Cyp2c70 KO mice exhibited increased levels of serum liver injury markers, and our evaluation of liver histology revealed increased hepatic inflammation, macrophage infiltration, and biliary cell proliferation. We demonstrate serum and histologic markers of liver damage were markedly reduced with SC-435 treatment. Additionally, we show hepatic gene expression in pathways related to immune cell activation and inflammation were significantly upregulated in Cyp2c70 KO mice and reduced to levels indistinguishable from WT with IBAT inhibition. In Cyp2c70 KO mice, the liver BA content was significantly increased, enriched in chenodeoxycholic acid, and more hydrophobic, exhibiting a hydrophobicity index value and red blood cell lysis properties similar to human liver BAs. Furthermore, we determined IBAT inhibition reduced the total hepatic BA levels but did not affect overall hydrophobicity of the liver BAs. These findings suggest that there may be a threshold in the liver for pathological accretion of hydrophobic BAs and reducing hepatic BA accumulation can be sufficient to alleviate liver injury, independent of BA pool hydrophobicity.
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Affiliation(s)
- Jennifer K Truong
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Ashley L Bennett
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Caroline Klindt
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Ajay C Donepudi
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Sudarshan R Malla
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Kimberly J Pachura
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Alex Zaufel
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Tarek Moustafa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Paul A Dawson
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
| | - Saul J Karpen
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
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22
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Abstract
ABSTRACT Gastric intestinal metaplasia (GIM) is a precancerous lesion of gastric cancer (GC) and is considered an irreversible point of progression for GC. Helicobacter pylori infection can cause GIM, but its eradication still does not reverse the process. Bile reflux is also a pathogenic factor in GIM and can continuously irritate the gastric mucosa, and bile acids in refluxed fluid have been widely reported to be associated with GIM. This paper reviews in detail the relationship between bile reflux and GIM and the mechanisms by which bile acids induce GIM.
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23
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Ye X, Zhang T, Han H. PPARα: A potential therapeutic target of cholestasis. Front Pharmacol 2022; 13:916866. [PMID: 35924060 PMCID: PMC9342652 DOI: 10.3389/fphar.2022.916866] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 06/29/2022] [Indexed: 12/12/2022] Open
Abstract
The accumulation of bile acids in the liver leads to the development of cholestasis and hepatocyte injury. Nuclear receptors control the synthesis and transport of bile acids in the liver. Among them, the farnesoid X receptor (FXR) is the most common receptor studied in treating cholestasis. The activation of this receptor can reduce the amount of bile acid synthesis and decrease the bile acid content in the liver, alleviating cholestasis. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have a FXR excitatory effect, but the unresponsiveness of some patients and the side effect of pruritus seriously affect the results of UDCA or OCA treatment. The activator of peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a new target for controlling the synthesis and transport of bile acids during cholestasis. Moreover, the anti-inflammatory effect of PPARα can effectively reduce cholestatic liver injury, thereby improving patients’ physiological status. Here, we will focus on the function of PPARα and its involvement in the regulation of bile acid transport and metabolism. In addition, the anti-inflammatory effects of PPARα will be discussed in some detail. Finally, we will discuss the application of PPARα agonists for cholestatic liver disorders.
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Affiliation(s)
- Xiaoyin Ye
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Zhang
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Tong Zhang, ; Han Han,
| | - Han Han
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Tong Zhang, ; Han Han,
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24
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Wang Q, Song GC, Weng FY, Zou B, Jin JY, Yan DM, Tan B, Zhao J, Li Y, Qiu FR. Hepatoprotective Effects of Glycyrrhetinic Acid on Lithocholic Acid-Induced Cholestatic Liver Injury Through Choleretic and Anti-Inflammatory Mechanisms. Front Pharmacol 2022; 13:881231. [PMID: 35712714 PMCID: PMC9194553 DOI: 10.3389/fphar.2022.881231] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/26/2022] [Indexed: 11/17/2022] Open
Abstract
Cholestasis is a clinical syndrome triggered by the accumulation and aggregation of bile acids by subsequent inflammatory responses. The present study investigated the protective effect of glycyrrhetinic acid (GA) on the cholestatic liver injury induced by lithocholic acid (LCA) from both anti-inflammatory and choleretic mechanistic standpoints. Male C57BL/6 mice were treated with LCA twice daily for 4 days to induce intrahepatic cholestasis. GA (50 mg/kg) and pregnenolone 16α-carbonitrile (PCN, 45 mg/kg) were intraperitoneally injected 3 days before and throughout the administration of LCA, respectively. Plasma biochemical indexes were determined by assay kits, and hepatic bile acids were quantified by LC-MS/MS. Hematoxylin and eosin staining of liver sections was performed for pathological examination. Protein expression of the TLRs/NF-κB pathway and the mRNA levels of inflammatory cytokines and chemokines were examined by Western blotting and PCR, respectively. Finally, the hepatic expression of pregnane X receptor (PXR) and farnesoid X receptor (FXR) and their target genes encoding metabolic enzymes and transporters was evaluated. GA significantly reversed liver necrosis and decreased plasma ALT and ALP activity. Plasma total bile acids, total bilirubin, and hepatic bile acids were also remarkably preserved. More importantly, the recruitment of inflammatory cells to hepatic sinusoids was alleviated. Additionally, the protein expression of TLR2, TLR4, and p-NF-κBp65 and the mRNA expression of CCL2, CXCL2, IL-1β, IL-6, and TNF-α were significantly decreased. Moreover, GA significantly increased the expression of hepatic FXR and its target genes, including BSEP, MRP3, and MRP4. In conclusion, GA protects against LCA-induced cholestatic liver injury by inhibiting the TLR2/NF-κB pathway and upregulating hepatic FXR expression.
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Affiliation(s)
- Qian Wang
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guo-Chao Song
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feng-Yi Weng
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bin Zou
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing-Yi Jin
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dong-Ming Yan
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bo Tan
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Zhao
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Li
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fu-Rong Qiu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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25
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Shulpekova Y, Zharkova M, Tkachenko P, Tikhonov I, Stepanov A, Synitsyna A, Izotov A, Butkova T, Shulpekova N, Lapina N, Nechaev V, Kardasheva S, Okhlobystin A, Ivashkin V. The Role of Bile Acids in the Human Body and in the Development of Diseases. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113401. [PMID: 35684337 PMCID: PMC9182388 DOI: 10.3390/molecules27113401] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/13/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022]
Abstract
Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. In spite, this is a very perspective direction for pharmacology.
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Affiliation(s)
- Yulia Shulpekova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Maria Zharkova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Pyotr Tkachenko
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Igor Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexander Stepanov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Alexandra Synitsyna
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
- Correspondence: ; Tel.: +7-499-764-98-78
| | - Alexander Izotov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Tatyana Butkova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | | | - Natalia Lapina
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Nechaev
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Svetlana Kardasheva
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexey Okhlobystin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
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Celik S, Golbasi H, Gulucu S, Guclu M, Caliskan CS, Celik S, Akpak YK, Golbasi C. Role of Vitamin B12 and Vitamin D levels in intrahepatic cholestasis of pregnancy and correlation with total bile acid. J OBSTET GYNAECOL 2022; 42:1847-1852. [PMID: 35482784 DOI: 10.1080/01443615.2022.2042797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
This study aimed to evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and Vitamin D and B12 levels. The study was a retrospective, cross-sectional, case-control study that evaluated 92 ICP cases and 102 pregnant women without any additional disease. ICP cases were grouped as mild and severe according to their total bile acid (TBA) levels, and their relationship with Vitamin D and B12 levels and perinatal outcomes was evaluated. Vitamin D and B12 levels of the ICP group were significantly lower than those of the control group. There was a moderate negative correlation between TBA and Vitamin D levels and a low negative correlation between TBA and Vitamin B12 levels. Adverse neonatal outcomes were significantly higher in the severe ICP group than in the mild ICP group. IMPACT STATEMENTWhat is already known on this subject? The pathophysiology of ICP, which can lead to adverse perinatal outcomes, is not yet fully understood, and there is no preventive treatment.What do the results of this study add? This study showed that Vitamins B12 and D levels were low in women with ICP and that TBA levels were negatively correlated with Vitamin D and B12 levels.What are the implications of these findings for clinical practice and/or further research? This study may guide future studies in terms of explaining the etiopathogenesis of ICP and developing treatment options.
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Affiliation(s)
- Sebahattin Celik
- Department of Obstetrics and Gynecology, Balikesir State Hospital, Balikesir, Turkey
| | - Hakan Golbasi
- Department of Obstetrics and Gynecology, Division of Perinatology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Selim Gulucu
- Department of Obstetrics and Gynecology, Gaziosmanpasa University, Tokat, Turkey
| | - Mehmet Guclu
- Department of Obstetrics and Gynecology, Marmara University, Pendik Training and Research Hospital, Istanbul, Turkey
| | - Canan Soyer Caliskan
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Samettin Celik
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Yasam Kemal Akpak
- Department of Obstetrics and Gynecology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Ceren Golbasi
- Department of Obstetrics and Gynecology, Tinaztepe University, Izmir, Turkey
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Mihajlovic M, Vinken M. Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods. Int J Mol Sci 2022; 23:ijms23063315. [PMID: 35328737 PMCID: PMC8951158 DOI: 10.3390/ijms23063315] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
One of the major mechanisms of drug-induced liver injury includes mitochondrial perturbation and dysfunction. This is not a surprise, given that mitochondria are essential organelles in most cells, which are responsible for energy homeostasis and the regulation of cellular metabolism. Drug-induced mitochondrial dysfunction can be influenced by various factors and conditions, such as genetic predisposition, the presence of metabolic disorders and obesity, viral infections, as well as drugs. Despite the fact that many methods have been developed for studying mitochondrial function, there is still a need for advanced and integrative models and approaches more closely resembling liver physiology, which would take into account predisposing factors. This could reduce the costs of drug development by the early prediction of potential mitochondrial toxicity during pre-clinical tests and, especially, prevent serious complications observed in clinical settings.
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Shen R, Ke L, Li Q, Dang X, Shen S, Shen J, Li S, Liang L, Peng B, Kuang M, Ma Y, Yang Z, Hua Y. Abnormal bile acid-microbiota crosstalk promotes the development of hepatocellular carcinoma. Hepatol Int 2022; 16:396-411. [PMID: 35211843 PMCID: PMC9013324 DOI: 10.1007/s12072-022-10299-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
Abstract
Background Gut microbiota and microbe-derived metabolites are involved in the development of HCC. Bile acids (BAs) are the most important gut microbiota-modulated endogenous signaling molecules. Methods We tested serum bile acid levels and gut microbiome compositions in patients with HCC, chemical-induced HCC mouse models (DEN-HCC mice) and mouse orthotopic implanted liver tumor models with vancomycin treatment (vancomycin-treated mice). Then, we screened an important kind of HCC-related BAs, and verified its effect on the growth of HCC in vivo and in vitro. Results We found that the remarkably decreasing percentages of serum secondary BAs in the total bile acids of patients and DEN-HCC mice, especially, conjugated deoxycholic acids (DCA). The relative abundance of the bile salt hydrolase (BSH)-rich bacteria (Bifidobacteriales, Lactobacillales, Bacteroidales, and Clostridiales) was decreased in the feces of patients and DEN-HCC mice. Then, in vancomycin-treated mice, vancomycin treatment induced a reduction in the BSH-rich bacteria and promoted the growth of liver tumors. Similarly, the percentage of conjugated DCA after vancomycin treatment was significantly declined. We used a kind of conjugated DCA, Glyco-deoxycholic acid (GDCA), and found that GDCA remarkably inhibited the growth of HCC in vivo and in vitro. Conclusions We conclude that the remarkably decreasing percentages of serum conjugated DCA may be closely associated with HCC, which may be induced by the reducing gut BSH-rich bacteria. The mechanisms may be correlated with conjugated DCA directly inhibiting the growth and migration of HCC cells. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-022-10299-7.
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Affiliation(s)
- Rui Shen
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Lixin Ke
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Qiao Li
- Department of Liver Surgery, Guangdong Provincial People's Hospital, Guangzhou, People's Republic of China
| | - Xi Dang
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Shunli Shen
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Jianming Shen
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Shaoqiang Li
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Lijian Liang
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China
| | - Baogang Peng
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China.
| | - Ming Kuang
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China.
| | - Yi Ma
- Department of Organ Transplantation, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
| | - Zhonghan Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
| | - Yunpeng Hua
- Hepatobiliary and Pancreatic Surgery Center, First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China.
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Juanola O, Hassan M, Kumar P, Yilmaz B, Keller I, Simillion C, Engelmann C, Tacke F, Dufour JF, De Gottardi A, Moghadamrad S. Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns. Gut Microbes 2022; 13:1-20. [PMID: 33847205 PMCID: PMC8049203 DOI: 10.1080/19490976.2021.1911534] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Intestinal microbiota regulates multiple host metabolic and immunological processes. Consequently, any difference in its qualitative and quantitative composition is susceptible to exert significant effects, in particular along the gut-liver axis. Indeed, recent findings suggest that such changes modulate the severity and the evolution of a wide spectrum of hepatobiliary disorders. However, the mechanisms linking intestinal microbiota and the pathogenesis of liver disease remain largely unknown. In this work, we investigated how a distinct composition of the intestinal microbiota, in comparison with germ-free conditions, may lead to different outcomes in an experimental model of acute cholestasis. Acute cholestasis was induced in germ-free (GF) and altered Schaedler's flora (ASF) colonized mice by common bile duct ligation (BDL). Studies were performed 5 days after BDL and hepatic histology, gene expression, inflammation, lipids metabolism, and mitochondrial functioning were evaluated in normal and cholestatic mice. Differences in plasma concentration of bile acids (BA) were evaluated by UHPLC-HRMS. The absence of intestinal microbiota was associated with significant aggravation of hepatic bile infarcts after BDL. At baseline, we found the absence of gut microbiota induced altered expression of genes involved in the metabolism of fatty and amino acids. In contrast, acute cholestasis induced altered expression of genes associated with extracellular matrix, cell cycle, autophagy, activation of MAPK, inflammation, metabolism of lipids, and mitochondrial functioning pathways. Ductular reactions, cell proliferation, deposition of collagen 1 and autophagy were increased in the presence of microbiota after BDL whereas GF mice were more susceptible to hepatic inflammation as evidenced by increased gene expression levels of osteopontin, interleukin (IL)-1β and activation of the ERK/MAPK pathway as compared to ASF colonized mice. Additonally, we found that the presence of microbiota provided partial protection to the mitochondrial functioning and impairment in the fatty acid metabolism after BDL. The concentration of the majority of BA markedly increased after BDL in both groups without remarkable differences according to the hygiene status of the mice. In conclusion, acute cholestasis induced more severe liver injury in GF mice compared to mice with limited intestinal bacterial colonization. This protective effect was associated with different hepatic gene expression profiles mostly related to tissue repair, metabolic and immune functions. Our findings suggest that microbial-induced differences may impact the course of cholestasis and modulate liver injury, offering a background for novel therapies based on the modulation of the intestinal microbiota.
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Affiliation(s)
- Oriol Juanola
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università Della Svizzera Italiana, Lugano, Switzerland
| | - Mohsin Hassan
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Pavitra Kumar
- Hepatology, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Bahtiyar Yilmaz
- Gastroenterology, Department for Biomedical Research, University of Bern, Bern, Switzerland,University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Irene Keller
- Department for Biomedical Research and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Cédric Simillion
- Department for Biomedical Research and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Cornelius Engelmann
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany,Institute for Liver and Digestive Health, University College London, London, UK,Berlin Institute of Health (BIH), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jean-François Dufour
- Hepatology, Department for Biomedical Research, University of Bern, Bern, Switzerland,University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Andrea De Gottardi
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università Della Svizzera Italiana, Lugano, Switzerland,Hepatology, Department for Biomedical Research, University of Bern, Bern, Switzerland,University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Sheida Moghadamrad
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università Della Svizzera Italiana, Lugano, Switzerland,Hepatology, Department for Biomedical Research, University of Bern, Bern, Switzerland,University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland,CONTACT Sheida Moghadamrad Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Università Della Svizzera Italiana, Lugano, Switzerland
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Xie AJ, Mai CT, Zhu YZ, Liu XC, Xie Y. Bile acids as regulatory molecules and potential targets in metabolic diseases. Life Sci 2021; 287:120152. [PMID: 34793769 DOI: 10.1016/j.lfs.2021.120152] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/06/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Bile acids are important hydroxylated steroids that are synthesized in the liver from cholesterol for intestinal absorption of lipids and other fatty-nutrient. They also display remarkable and immense functions such as regulating immune responses, managing the apoptosis of cells, participating in glucose metabolism, and so on. Some bile acids were used for the treatment or prevention of diseases such as gallstones, primary biliary cirrhosis, and colorectal cancer. Meanwhile, the accumulation of toxic bile acids leads to apoptosis, necrosis, and inflammation. Alteration of bile acids metabolism, as well as the gut microbiota that interacted with bile acids, contributes to the pathogenesis of metabolic diseases. Therefore, the purpose of this review is to summarize the current functions and pre-clinical or clinical applications of bile acids, and to further discuss the alteration of bile acids in metabolic disorders as well as the manipulation of bile acids metabolism as potential therapeutic targets.
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Affiliation(s)
- Ai-Jin Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Chu-Tian Mai
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Yi-Zhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Xian-Cheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
| | - Ying Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau.
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Tarantino G, Citro V, Capone D, Gaudiano G, Sinatti G, Santini SJ, Balsano C. Copper concentrations are prevalently associated with antithrombin III, but also with prothrombin time and fibrinogen in patients with liver cirrhosis: A cross-sectional retrospective study. J Trace Elem Med Biol 2021; 68:126802. [PMID: 34091123 DOI: 10.1016/j.jtemb.2021.126802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/21/2021] [Accepted: 05/27/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Concerning the link between copper excess and the pathogenesis of chronic liver diseases, its retention is reckoned to develop as a complication of cholestasis. Recently, it has been found that cholestatic liver injury involves largely inflammatory cell-mediated liver cell necrosis, with consequent reduced hepatic mass, more than occurring through direct bile acid-induced apoptosis. On the other hand, interference with protein synthesis could be expected to result, ending in an altered ability of the liver to retain copper. Little is known about the association between serum copper and clotting factors in cirrhotics. We aimed at studying a possible relationship between increased levels of copper and an aspect of the haemostatic process in liver cirrhosis patients, assessing an index of protein synthesis (albumin) and parameters of protein synthesis/coagulation/fibrinolysis, such as prothrombin time (PT), antithrombin (AT) III and fibrinogen. METHODS Records from 85 patients suffering from liver cirrhosis of various aetiology and different severity were retrospectively examined. Serum concentrations of copper were determined by atomic absorption spectrophotometer. An index of protein synthesis, such as albumin and parameters of both synthesis and coagulation/hypercoagulation such as PT %, AT III%, levels of fibrinogen were taken into account to study possible correlations to serum copper. The severity of cirrhosis was evaluated by the Child-Pugh (C-P) classification. The relationship among variables were studied by linear regression. RESULTS Copper levels of patients suffering from liver cirrhosis were increased respect to those of controls, 102.7+/-28.7 versus 80.4+/-19.5 mcg/dL, (P = .0009), independently from disease severity, and were positively predicted by PT% (P = 0. 017), fibrinogen (P = 0.007) and AT III% (P = 0.000), at linear regression. Among the previous parameters, to which serum albumin was added, the unique predictor of copper levels was AT III%, at multiple regression (P = 0. 010); AT III% was negatively predicted by the C-P classification (P = 0.000); copper levels, adjusted for C-P classification, were predicted by AT III% (P = 0.020) and fibrinogen concentrations, but not by PT% (P = 0.09). CONCLUSION The copper concentration is reckoned as responsible for production of the hydroxyl radicals. On the basis that oxidants may enhance the activity of the extrinsic coagulation cascade, ultimately leading to thrombin formation, via their combined effects on stimulation of tissue factor activity and inhibition of fibrinolytic pathways, the positive relationship of copper to coagulation/hypercoagulation parameters (mainly AT III) in our research could find a plausible interpretation.
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Affiliation(s)
- Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, 80131, Naples, Italy.
| | - Vincenzo Citro
- Department of General Medicine, "Umberto I" Hospital, 84014, Nocera Inferiore (SA), Italy
| | | | - Giuseppe Gaudiano
- Clinical Pathology Unit,"Umberto I" Hospital, 84014, Nocera Inferiore (SA), Italy
| | - Gaia Sinatti
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila, 67100 L, Aquila, Italy
| | - Silvano Junior Santini
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila, 67100 L, Aquila, Italy
| | - Clara Balsano
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila, 67100 L, Aquila, Italy
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Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner. Cells 2021; 10:cells10102618. [PMID: 34685598 PMCID: PMC8534222 DOI: 10.3390/cells10102618] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/10/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.
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Shan D, Dong R, Hu Y. Current understanding of autophagy in intrahepatic cholestasis of pregnancy. Placenta 2021; 115:53-59. [PMID: 34560328 DOI: 10.1016/j.placenta.2021.09.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy. Manifested with pruritus and elevation in bile acids, the etiology of ICP is still poorly understood. Although ICP is considered relatively benign for the mother, increased rates of adverse fetal outcomes including sudden fetal demise are possible devastating outcomes associated with ICP. Limited understanding of the underlying mechanisms restricted treatment options and managements of ICP. In recent decades, evolving evidence indicated the significance of autophagy in pregnancy and pregnancy complications. Autophagy is an ancient self-defense mechanism which is essential for cell survival, differentiation and development. Autophagy has pivotal roles in embryogenesis, implantation, and maintenance of pregnancy, and is involved in the orchestration of diverse physiological and pathological cellular responses in patients with pregnancy complications. Recent advances in these research fields provide tantalizing targets on autophagy to improve the care of pregnant women. This review summarizes recent advances in understanding autophagy in ICP and its possible roles in the causation and prevention of ICP.
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Affiliation(s)
- Dan Shan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Ruihong Dong
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China
| | - Yayi Hu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China.
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Meng F, Zong W, Wei X, Tao Y, Wang G, Liao Z, Chen M. Dolomiaea souliei ethyl acetate extract protected against α-naphthylisothiocyanate-induced acute intrahepatic cholestasis through regulation of farnesoid x receptor-mediated bile acid metabolism. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 87:153588. [PMID: 34091148 DOI: 10.1016/j.phymed.2021.153588] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/25/2021] [Accepted: 04/29/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Cholestasis is characterized by accumulation of bile components in liver and systemic circulation. Restoration of bile acid homeostasis via activating farnesoid x receptor (FXR) is a promising strategy for the treatment of cholestasis. FXR-SHP (small heterodimer partner) axis plays an important role in maintaining bile acid homeostasis. PURPOSE To investigate the anti-cholestasis effect of Dolomiaea souliei (Franch.) C.Shih (D. souliei) and clarify its underlying mechanism against α-naphthylisothiocyanate (ANIT) induced acute intrahepatic cholestasis. METHODS ANIT-induced Sprague-Dawley rats were employed to investigate the anti-cholestasis effect of D. souliei ethyl acetate extract (DSE). Ursodeoxycholic acid (UDCA) was used as positive control. Bile flow and blood biochemical parameters were measured. Liver histopathological examination was conducted via hematoxylin-eosin staining. Western blot analysis was carried out to evaluate the protein levels related to bile acids metabolism and inflammation. The interactions between FXR and costunolide or dehydrocostus lactone, were conducted by molecular docking experiments. The effect of costunolide and dehydrocostus lactone on aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and FXR expression were also evaluated using guggulsterone-induced L02 cells. RESULTS DSE could promote bile excretions and protect against ANIT-induced liver damage in cholestasis rats. Protein levels of FXR, SHP, Na+/taurocholate cotransporter (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2) were increased and the expressions of cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) were decreased by DSE. Meanwhile, the anti-inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) were also significantly increased, and the pro-inflammatory factor, interleukin-10 (IL-10), was significantly decreased in rats of DSE groups. Molecular docking revealed that costunolide and dehydrocostus lactone could be well docked into the FXR protein molecule, and hydrophobic interactions played the main function. Costunolide could reverse the increased AST and ALT levels and increase the FXR expression in guggulsterone-induced L02 cells. CONCLUSION DSE had an anti-cholestasis effect by activating FXR-SHP axis, inhibiting synthesis of bile acid, and increasing bile secretion, together with inflammatory response and improving liver injury. Costunolide may be the main active component. This study provided a potential therapeutic mechanism for D. souliei as an anti-cholestasis medicine in the treatment of cholestasis liver diseases.
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Affiliation(s)
- FanCheng Meng
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - Wei Zong
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - XiaoDong Wei
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - YunYi Tao
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - GuoWei Wang
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - ZhiHua Liao
- School of Life Sciences, Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - Min Chen
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China.
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Xiong F, Zheng Z, Xiao L, Su C, Chen J, Gu X, Tang J, Zhao Y, Luo H, Zha L. Soyasaponin A 2 Alleviates Steatohepatitis Possibly through Regulating Bile Acids and Gut Microbiota in the Methionine and Choline-Deficient (MCD) Diet-induced Nonalcoholic Steatohepatitis (NASH) Mice. Mol Nutr Food Res 2021; 65:e2100067. [PMID: 34047448 DOI: 10.1002/mnfr.202100067] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/21/2021] [Indexed: 12/21/2022]
Abstract
SCOPE Nonalcoholic steatohepatitis (NASH) is a chronic progressive disease with complex pathogenesis of which the bile acids (BAs) and gut microbiota are involved. Soyasaponins (SS) exhibits many health-promoting effects including hepatoprotection, but its prevention against NASH is unclear. This study aims to investigate the preventive bioactivities of SS monomer (SS-A2 ) against NASH and further clarify its mechanism by targeting the BAs and gut microbiota. METHODS AND RESULTS The methionine and choline deficient (MCD) diet-fed male C57BL/6 mice were intervened with obeticholic acid or SS-A2 for 16 weeks. Hepatic pathology is assessed by hematoxylin-eosin and Masson's trichrome staining. BAs in serum, liver, and colon are measured by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS). Gut microbiota in caecum are determined by 16S rDNA amplicon sequencing. In the MCD diet-induced NASH mice, SS-A2 significantly reduces hepatic steatosis, lobular inflammation, ballooning, nonalcoholic fatty liver disease activity score (NAS) scores, and fibrosis, decreases Erysipelotrichaceae (Faecalibaculum) and Lactobacillaceae (Lactobacillus) and increases Desulfovibrionaceae (Desulfovibrio). Moreover, SS-A2 reduces serum BAs accumulation and promotes fecal BAs excretion. SS-A2 changes the BAs profiles in both liver and serum and specifically increases the taurohyodeoxycholic acid (THDCA) level. Faecalibaculum is negatively correlated with serum THDCA. CONCLUSION SS-A2 alleviates steatohepatitis possibly through regulating BAs and gut microbiota in the MCD diet-induced NASH mice.
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Affiliation(s)
- Fei Xiong
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Zhongdaixi Zheng
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Lingyu Xiao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Chuhong Su
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Junbin Chen
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Xiangfu Gu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Jiaqi Tang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Yue Zhao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Huiyu Luo
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China
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Zhang J, Li H, Dong J, Zhang N, Liu Y, Luo X, Chen J, Wang J, Wang A. Omics-Based Identification of Shared and Gender Disparity Routes in Hras12V-Induced Hepatocarcinogenesis: An Important Role for Dlk1-Dio3 Genomic Imprinting Region. Front Genet 2021; 12:620594. [PMID: 34135934 PMCID: PMC8202007 DOI: 10.3389/fgene.2021.620594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/02/2021] [Indexed: 12/13/2022] Open
Abstract
The phenomenon of gender disparity is very profound in hepatocellular carcinoma (HCC). Although previous research has revealed important roles of microRNA (miRNA) in HCC, there are no studies investigating the role of miRNAs in gender disparity observed hepatocarcinogenesis. In the present study, we investigated the global miRNAomics changes related to Ras-induced male-prevalent hepatocarcinogenesis in a Hras12V-transgenic mouse model (Ras-Tg) by next-generation sequencing (NGS). We identified shared by also unique changes in miRNA expression profiles in gender-dependent hepatocarcinogenesis. Two hundred sixty-four differentially expressed miRNAs (DEMIRs) with q value ≤0.05 and fold change ≥2 were identified. A vertical comparison revealed that the lower numbers of DEMIRs in the hepatic tumor (T) compared with the peri-tumor precancerous tissue (P) of Ras-Tg and normal liver tissue of wild-type C57BL/6J mice (W) in males indicated that males are more susceptible to develop HCC. The expression pattern analysis revealed 43 common HCC-related miRNAs and 4 Ras-positive-related miRNAs between males and females. By integrating the mRNA transcriptomic data and using 3-node FFL analysis, a group of significant components commonly contributing to HCC between sexes were filtered out. A horizontal comparison showed that the majority of DEMIRs are located in the Dlk1-Dio3 genomic imprinting region (GIR) and that they are closely related to not only hepatic tumorigenesis but also to gender disparity in hepatocarcinogenesis. This is achieved by regulating multiple metabolic pathways, including retinol, bile acid, and steroid hormones. In conclusion, the identification of shared and gender-dependent DEMIRs in hepatocarcinogenesis provides valuable insights into the mechanisms that contribute to male-biased Ras-induced hepatic carcinogenesis.
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Affiliation(s)
- Jing Zhang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Huiling Li
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Jianyi Dong
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Nan Zhang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Yang Liu
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Xiaoqin Luo
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Jun Chen
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Jingyu Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Aiguo Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
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Xue H, Fang S, Zheng M, Wu J, Li H, Zhang M, Li Y, Wang T, Shi R, Ma Y. Da-Huang-Xiao-Shi decoction protects against3, 5-diethoxycarbonyl-1,4-dihydroxychollidine-induced chronic cholestasis by upregulating bile acid metabolic enzymes and efflux transporters. JOURNAL OF ETHNOPHARMACOLOGY 2021; 269:113706. [PMID: 33346024 DOI: 10.1016/j.jep.2020.113706] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/09/2020] [Accepted: 12/15/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chronic cholestasis is a usual clinical pathological process in hepatopathy and has few treatment options; it is classified under the category of jaundice in Chinese medicine. Da-Huang-Xiao-Shi decoction (DHXSD) is a classic Chinese prescription which is used to treat jaundice. AIM OF THE STUDY We aimed to examine the protective effect of DHXSD on liver and its potential mechanism of action against chronic cholestasis. MATERIALS AND METHODS Chronic cholestasis was induced using 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) in mice. Mice were then administered DHXSD intragastrically at doses of 3.68, 7.35, and 14.70 g/kg for four weeks followed by further analyses. Serum biochemical indices and liver pathology were explored. Eighteen individual bile acids (BAs) in mice serum and liver were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The expression of BA related metabolic enzymes, transporters, along with nuclear receptor farnesoid X receptor (FXR) was detected by real-time qPCR and Western blot. RESULTS DHXSD treatment reduced the serum biochemical indices, ameliorated pathological injury, and improved the disordered BA homeostasis. Mice treated with DHXSD showed significantly upregulated expression of the metabolic enzymes, cytochrome P450 2b10 (Cyp2b10), Cyp3a11, and UDP-glucuronosyltransferase 1a1 (Ugt1a1); and the bile acid transporters, multidrug resistance protein 2 (Mdr2), bile salt export pump (Bsep), and multidrug resistance-associated protein 3 (Mrp3). DHXSD treatment also significantly upregulated FXR expression in mice with DDC-induced chronic cholestasis. CONCLUSIONS DHXSD exerted protective effects on chronic cholestasis in DDC-treated mice by alleviating the disordered homeostasis of BAs through increased expression of BA related metabolic enzymes and efflux transporters.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- Angiogenic Proteins/genetics
- Angiogenic Proteins/metabolism
- Animals
- Bile Acids and Salts/analysis
- Bile Acids and Salts/chemistry
- Bile Acids and Salts/metabolism
- Chemical and Drug Induced Liver Injury/drug therapy
- Chemical and Drug Induced Liver Injury/pathology
- Cholestasis/chemically induced
- Cholestasis/drug therapy
- Chromatography, Liquid
- Chronic Disease/drug therapy
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Enzymes/genetics
- Enzymes/metabolism
- Ethnopharmacology
- Homeostasis/drug effects
- Liver/drug effects
- Male
- Mice, Inbred C57BL
- Protective Agents/pharmacology
- Protective Agents/therapeutic use
- Pyridines/toxicity
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Tandem Mass Spectrometry
- Up-Regulation/drug effects
- ATP-Binding Cassette Sub-Family B Member 4
- Mice
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Affiliation(s)
- Haoyu Xue
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Su Fang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Min Zheng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Jiasheng Wu
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hongyu Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Mengdie Zhang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yuanyuan Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Tianming Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Rong Shi
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yueming Ma
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Gijbels E, Devisscher L, Vinken M. Testing in vitro tools for the prediction of cholestatic liver injury induced by non-pharmaceutical chemicals. Food Chem Toxicol 2021; 152:112165. [PMID: 33819548 DOI: 10.1016/j.fct.2021.112165] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/15/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
Bile acid accumulation and subsequent liver damage is a frequent adverse effect induced by drugs. Considerable efforts have therefore been focused on the introduction and characterization of tools that allow reliable prediction of this type of drug-induced liver injury. Among those are the cholestatic index and transcriptomic profiling, which are typically assessed in in vitro settings. The present study was set up to test the applicability of both tools to non-pharmaceutical compounds with cholestatic potential, including the industrial compound bis(2-ethylhexyl)phthalate, the cosmetic ingredients triclosan and octynoic acid, the herbicides paraquat and quizalofop-para-ethyl, and the food additives sunset yellow and tartrazine, in a human hepatoma cell culture model of cholestatic liver injury. The cholestatic index method showed cholestatic liability of sunset yellow, tartrazine and triclosan. Of those, tartrazine induced transcriptional changes reminiscent of the transcriptional profile of cholestatic drugs. Furthermore, a number of genes were found to be uniquely modulated by tartrazine, in accordance with the cholestatic drugs atazanavir, cyclosporin A and nefazodone, which may have potential as novel transcriptomic biomarkers of chemical-induced cholestatic liver injury. In conclusion, unambiguous identification of the non-pharmaceutical compounds tested in this study as inducers of cholestasis could not be achieved.
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Affiliation(s)
- Eva Gijbels
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium; Gut-Liver Immunopharmacology Unit, Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Basic and Applied Medical Sciences, Liver Research Center Ghent, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
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Abstract
Clinical disorders that impair bile flow result in retention of bile acids and cholestatic liver injury, characterized by parenchymal cell death, bile duct proliferation, liver inflammation and fibrosis. However, the pathogenic role of bile acids in the development of cholestatic liver injury remains incompletely understood. In this review, we summarize the current understanding of this process focusing on the experimental and clinical evidence for direct effects of bile acids on each major cellular component of the liver: hepatocytes, cholangiocytes, stellate cells and immune cells. During cholestasis bile acids accumulated in the liver, causing oxidative stress and mitochondrial injury in hepatocytes. The stressed hepatocytes respond by releasing inflammatory cytokines through activation of specific signaling pathways and transcription factors. The recruited neutrophils and other immune cells then cause parenchymal cell death. In addition, bile acids also stimulate the proliferation of cholangiocytes and stellate cells that are responsible for bile duct proliferation and liver fibrosis. This review explores the evidence for bile acid involvement in these phenomena. The role of bile acid receptors, TGR5, FXR and the sphingosine-1-phosphate receptor 2 and the inflammasome are also examined. We hope that better understanding of these pathologic effects will facilitate new strategies for treating cholestatic liver injury.
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Affiliation(s)
- Shi-Ying Cai
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
| | - James L Boyer
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
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40
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Xiang D, Yang J, Xu Y, Lan L, Li G, Zhang C, Liu D. Estrogen cholestasis induces gut and liver injury in rats involving in activating PI3K/Akt and MAPK signaling pathways. Life Sci 2021; 276:119367. [PMID: 33775691 DOI: 10.1016/j.lfs.2021.119367] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/28/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUNDS Estrogen and its metabolites often lead to intrahepatic cholestasis in susceptible women with pregnancy, administration of oral contraceptives and postmenopausal hormone replacement therapy. Recently, dysfunction of the gut-liver axis has been suggested to play a pivotal role in the progression of cholestasis, but details about estrogen cholestasis (EC)-induced gut and liver injury are still largely unknown. This study aims to gain insight into EC-induced gut and liver injury and cell signaling implicated. METHODS Male rats were exposed to 5 and 10 mg/kg of 17α-ethinylestradiol via subcutaneous injection for 5 successive days to simulate human EC. RESULTS By detection of these estrogen cholestatic rats, we found that EC induced inflammation in the liver but not in the intestine through activating NF-κB signaling pathway. EC strongly induced oxidative stress in both the liver and intestine, and activated the hepatic Nrf2/Gclm/Gclc pathway and the intestinal Nrf2/Ho-1 pathway, respectively, for adaptively regulating oxidative stress. EC increased cell apoptosis in both the liver and intestine. Additionally, EC elevated phosphorylation of Akt, ERK1/2, and p38 in the liver and increased phosphorylation of p38 in the intestine. CONCLUSIONS EC induces liver inflammation, both gut and liver oxidative stress and apoptosis, involving in activating PI3K/Akt and MAPK signaling pathways. Investigation of EC-induced gut and liver injury contributes to the development of new potential therapeutic strategies.
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Affiliation(s)
- Dong Xiang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jinyu Yang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yanjiao Xu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lulu Lan
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guodong Li
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chengliang Zhang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Ommati MM, Amjadinia A, Mousavi K, Azarpira N, Jamshidzadeh A, Heidari R. N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats. Stress 2021; 24:213-228. [PMID: 32510264 DOI: 10.1080/10253890.2020.1777970] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, Peoples' Republic of China
| | - Ali Amjadinia
- Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khadijeh Mousavi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Cai SY, Yu D, Soroka CJ, Wang J, Boyer JL. Hepatic NFAT signaling regulates the expression of inflammatory cytokines in cholestasis. J Hepatol 2021; 74:550-559. [PMID: 33039404 PMCID: PMC7897288 DOI: 10.1016/j.jhep.2020.09.035] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 09/18/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS The nuclear factor of activated T-cells (NFAT) plays an important role in immune responses by regulating the expression of inflammatory genes. However, it is not known whether NFAT plays any role in the bile acid (BA)-induced hepatic inflammatory response. Thus, we aimed to examine the functional role of NFATc3 in cholestatic liver injury in mice and humans. METHODS Gene and protein expression and cellular localization were assessed in primary hepatocyte cultures (mouse and human) and cholestatic liver tissues (murine models and patients with primary biliary cholangitis [PBC] or primary sclerosing cholangitis [PSC]) by quantitative PCR, western blot and immunohistochemistry. Specific NFAT inhibitors were used in vivo and in vitro. Gene reporter assays and ChIP-PCR were used to determine promoter activity. RESULTS NFAT isoforms c1 and c3 were expressed in human and mouse hepatocytes. When treated with cholestatic levels of BAs, nuclear translocation of NFATc3 was increased in both human and mouse hepatocytes and was associated with elevated mRNA levels of IL-8, CXCL2, and CXCL10 in these cells. Blocking NFAT activation with pathway-specific inhibitors or knocking down Nfatc3 expression significantly decreased BA-driven induction of these cytokines in mouse hepatocytes. Nuclear expression of NFATc3/Nfatc3 protein was increased in cholestatic livers, both in mouse models (bile duct ligation or Abcb4-/- mice) and in patients with PBC and PSC in association with elevated tissue levels of Cxcl2 (mice) or IL-8 (humans). Gene reporter assays and ChIP-PCR demonstrated that the NFAT response element in the IL-8 promoter played a key role in BA-induced human IL-8 expression. Finally, blocking NFAT activation in vivo in Abcb4-/- mice reduced cholestatic liver injury. CONCLUSIONS NFAT plays an important role in BA-stimulated hepatic cytokine expression in cholestasis. Blocking hepatic NFAT activation may reduce cholestatic liver injury in humans. LAY SUMMARY Bile acid induces liver injury by stimulating the expression of inflammatory genes in hepatocytes through activation of the transcription factor NFAT. Blocking this activation in vitro (in hepatocyte cultures) and in vivo (in cholestatic mice) decreased the expression of inflammatory genes and reduced liver injury.
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Affiliation(s)
- Shi-Ying Cai
- Department of Internal Medicine, Liver Center, Yale University School of Medicine, New Haven, CT 06520.
| | - Dongke Yu
- Department of Internal Medicine, Liver Center, Yale University School of Medicine, New Haven, CT 06520
| | - Carol J Soroka
- Department of Internal Medicine, Liver Center, Yale University School of Medicine, New Haven, CT 06520
| | - Jing Wang
- Department of Internal Medicine, Liver Center, Yale University School of Medicine, New Haven, CT 06520
| | - James L Boyer
- Department of Internal Medicine, Liver Center, Yale University School of Medicine, New Haven, CT 06520.
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Moheimani HR, Amiriani T, Alizadeh AM, Jand Y, Shakiba D, Ensan PS, Jafarzadeh F, Rajaei M, Enayati A, Pourabouk M, Aliazadeh S, Pourkhani AH, Mazaheri Z, Zeyghami MA, Dehpour A, Khori V. Preconditioning and anti-apoptotic effects of Metformin and Cyclosporine-A in an isolated bile duct-ligated rat heart. Eur J Pharmacol 2021; 893:173807. [PMID: 33359222 DOI: 10.1016/j.ejphar.2020.173807] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 11/18/2020] [Accepted: 12/08/2020] [Indexed: 12/18/2022]
Abstract
Despite all previous studies relating to the mechanism of cirrhotic cardiomyopathy (CCM), the role of cirrhosis on Ischemic Preconditioning (IPC) has not yet been explored. The present study strives to assess the cardioprotective role of IPC in bile duct ligated (BDL) rats as well as the cardioprotective role of Cyclosporin-A (CsA) and Metformin (Met) in CCM. Cirrhosis was induced by bile duct ligation (BDL). Rats' hearts were isolated and attached to a Langendorff Apparatus. The pharmacological preconditioning with Met and CsA was done before the main ischemia. Myocardial infarct size, hemodynamic and electrophysiological parameters, biochemical markers, and apoptotic indices were determined at the end of the experiment. Infarct size, apoptotic indices, arrhythmia score, and incidence of VF decreased significantly in the IPC group in comparison with the I/R group. These significant decreases were abolished in the IPC (BDL) group. Met significantly decreased the infarct size and apoptotic indices compared with I/R (BDL) and normal groups, while CsA led to similar decreases except in the level of caspase-3 and -8. Met and CsA decreased and increased the arrhythmia score and incidence of VF in the BDL groups, respectively. Functional recovery indices decreased in the I/R (BDL) and IPC (BDL) groups. Met improved these parameters. Therefore, the current study depicted that the cardioprotective effect of Met and CsA on BDL rats is mediated through the balance between pAMPK and apoptosis in the mitochondria.
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Key Words
- Bile duct ligation
- Caspase
- Cyclosporin-A
- Cyclosporin-A (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-Ethyl-33-[(E,1R,2R)-1-Hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, PubChemCID: 5284373
- Ischemic preconditioning
- Metformin
- Metformin 3-(diaminomethylidene)-1,1-dimethylguanidine, PubChem CID:4091
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Affiliation(s)
- Hamid Reza Moheimani
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Taghi Amiriani
- Golestan Research Center of Gastroenterology and Hepatology, Gorgan, Iran
| | - Ali Mohammad Alizadeh
- Cancer Research Center of Institute Cancer, Tehran University of Medical Science, Tehran, Iran
| | - Yahya Jand
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Delaram Shakiba
- Department of Mechanical Engineering and Material Science, Washington University in St. Louis, St. Louis, MO, USA
| | - Parham Sayyah Ensan
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Fatemeh Jafarzadeh
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Maryam Rajaei
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ayesheh Enayati
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mona Pourabouk
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shahriar Aliazadeh
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amir Hoshang Pourkhani
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Zohreh Mazaheri
- Basic Medical Science Research Center, Histogenotech Company, Tehran, Iran
| | - Mohammad Ali Zeyghami
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ahmadreza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Vahid Khori
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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44
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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45
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Betaine alleviates cholestasis-associated renal injury by mitigating oxidative stress and enhancing mitochondrial function. Biologia (Bratisl) 2021. [DOI: 10.2478/s11756-020-00576-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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46
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Silva J, Magenta M, Sisti G, Serventi L, Gaither K. Association Between Complete Blood Count Components and Intrahepatic Cholestasis of Pregnancy. Cureus 2020; 12:e12381. [PMID: 33532148 PMCID: PMC7846282 DOI: 10.7759/cureus.12381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Objective Some components of the routine complete blood count (CBC) and their ratios, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been found to be sensitive biomarkers of preeclampsia and other inflammatory obstetric conditions. We wanted to evaluate whether they can be associated with intrahepatic cholestasis of pregnancy (ICP). Materials and Methods We conducted a retrospective case-control study between May 1, 2015 and July 1, 2018. Cases were considered pregnancies with ICP and control healthy pregnancies. Cases and controls were matched for age, parity, and race. We compared the levels of white blood cells (WBC), hemoglobin, neutrophils, lymphocytes, NLR, PLR, platelets, red cell distribution width (RDW), and mean platelet volume (MPV) in the first and third trimesters between cases and controls. In addition, we compared the same components in the third trimester between patients with mild (serum total bile acid (TBA) of 10 - 40 µmols/L) and severe (TBA > 40 µmols/L) ICP. Results There were 33 patients with ICP and 33 controls. There were no significant differences between the two groups in the first trimester. WBC, neutrophil count, and NLR were decreased in women with ICP in the third trimester compared to controls. MPV was significantly higher in the third trimester of patients with ICP compared to controls. RDW was lower in mild ICP compared to severe ICP in the third trimester. Conclusion Decreased WBC, neutrophil, NLR, and MPV values are associated with ICP and may be useful additions to the diagnostic algorithm for ICP. Larger studies are needed to assess the responsible underlying molecular pathogenic mechanisms.
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Affiliation(s)
- Jessica Silva
- Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, USA
| | - Melissa Magenta
- Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, USA
| | - Giovanni Sisti
- Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, USA
| | - Lisa Serventi
- Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, USA
| | - Kecia Gaither
- Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, USA
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47
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Arsenic-induced autophagy regulates apoptosis in AML-12 cells. Toxicol In Vitro 2020; 72:105074. [PMID: 33352257 DOI: 10.1016/j.tiv.2020.105074] [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: 07/30/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/23/2022]
Abstract
Arsenic (As), a potent toxicant, is known to be a hepatotoxicant. Although As induced liver apoptosis and autophagy, the relationship between apoptosis and autophagy of hepatocytes caused by As remains largely unknown. 3-methyladenine (3-MA) and rapamycin can inhibit and promote autophagy of AML-12 cells, respectively. Hence, in this study, AML-12 cells were treated with different concentrations (0, 2, 4, 6, 8, 10 and 12 μmol/L) of As2O3, and 5 mmol/L 3-MA or 100 nmol/L rapamycin were applied to distinguish the effect of autophagy on apoptosis in AML-12. Results showed that exposure to As induced cell apoptosis and autophagy, which were mediated by the significantly altered expression levels of autophagy markers (mTOR, LC3, PI3K and P62), and apoptosis markers (Bcl-2 and caspase-3). Further analysis indicated that a certain dosage of 3-MA and rapamycin decreased apoptosis and the caspase-3 expression, which suggested that As-induced autophagy regulated AML-12 cells apoptosis through the expressions of PI3K, mTOR, P62 and Bcl-2.
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48
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Park JH, Kwak BJ, Choi HJ, Kim OH, Hong HE, Lee SC, Kim KH, You YK, Lee TY, Ahn J, Kim SJ. PGC-1α is downregulated in a mouse model of obstructive cholestasis but not in a model of liver fibrosis. FEBS Open Bio 2020; 11:61-74. [PMID: 32860664 PMCID: PMC7780111 DOI: 10.1002/2211-5463.12961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 08/03/2020] [Accepted: 08/21/2020] [Indexed: 11/13/2022] Open
Abstract
Several studies have indicated that cholestatic liver damage involves mitochondria dysfunction. However, the precise mechanism by which hydrophobic bile salts cause mitochondrial dysfunction is not clear. In this study, we intended to determine the pathogenesis of cholestatic liver injury associated with peroxisome proliferator‐activated receptor‐γ co‐activator 1α (PGC‐1α). A mouse model of cholestatic liver disease was generated by surgical ligation of the bile duct (BDL), and a mouse model of fibrosis was developed through serial administration of thioacetamide. After obtaining liver specimens on scheduled days, we compared the expression of the antioxidant enzymes (superoxide dismutase 2 [SOD2], catalase, and glutathione peroxidase‐1[GPx‐1]) and PGC‐1α in livers from mice with fibrosis and cholestasis using western blotting, immunohistochemistry, and immunofluorescence. We found that cholestatic livers exhibit lower expression of antioxidant enzymes, such as SOD2, catalase, and PGC‐1α. In contrast, fibrotic livers exhibit higher expression of antioxidant enzymes and PGC‐1α. In addition, cholestatic livers exhibited significantly lower expression of pro‐apoptotic markers (Bax) as compared to fibrotic livers. It is well known that overexpression of PGC‐1α increases mitochondrial antioxidant enzyme expression, and vice versa. Thus, we concluded that obstructive cholestasis decreases expression of PGC‐1α, which may lead to decreased expression of mitochondrial antioxidant enzymes, thereby rendering mice with cholestatic livers vulnerable to ROS‐induced cell death.
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Affiliation(s)
- Jung Hyun Park
- Department of Surgery, College of Medicine, Eunpyeong St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Bong Jun Kwak
- Department of Surgery, College of Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Korea
| | - Ho Joong Choi
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Ok-Hee Kim
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ha-Eun Hong
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Sang Chul Lee
- Department of Surgery, College of Medicine, Daejeon St. Mary's Hospital, the Catholic University of Korea, Daejeon, Korea
| | - Kee-Hwan Kim
- Department of Surgery, College of Medicine, Uijeongbu St. Mary's Hospital, the Catholic University of Korea, Gyeonggi-do, Korea
| | - Young Kyoung You
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Tae Yun Lee
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Joseph Ahn
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Say-June Kim
- Department of Surgery, College of Medicine, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea.,Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
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49
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Panzitt K, Fickert P, Wagner M. Regulation of autophagy by bile acids and in cholestasis - CholestoPHAGY or CholeSTOPagy. Biochim Biophys Acta Mol Basis Dis 2020; 1867:166017. [PMID: 33242590 DOI: 10.1016/j.bbadis.2020.166017] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/13/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022]
Abstract
Autophagy is a lysosomal degradation pathway in which the cell self-digests its own components to provide nutrients in harsh environmental conditions. It also represents an opportunity to rid the cell of superfluous and damaged organelles, misfolded proteins or invaded microorganisms. Liver autophagy contributes to basic hepatic functions such as lipid, glycogen and protein turnover. Deregulated hepatic autophagy has been linked to many liver diseases including alpha-1-antitrypsin deficiency, alcoholic and non-alcoholic fatty liver diseases, hepatitis B and C infections, liver fibrosis as well as liver cancer. Recently, bile acids and the bile acid receptor FXR have been implicated in the regulation of hepatic autophagy, which implies a role of autophagy also for cholestatic liver diseases. This review summarizes the current evidence of bile acid mediated effects on autophagy and how this affects cholestatic liver diseases. Although detailed studies are lacking, we suggest a concept that the activity of autophagy in cholestasis depends on the disease stage, where autophagy may be induced at early stages ("cholestophagy") but may be impaired in prolonged cholestatic states ("cholestopagy").
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Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria.
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50
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Effects of Rhein on Bile Acid Homeostasis in Rats. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8827955. [PMID: 33274227 PMCID: PMC7679202 DOI: 10.1155/2020/8827955] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/04/2020] [Accepted: 10/20/2020] [Indexed: 01/11/2023]
Abstract
Rhein, the active ingredient of rhubarb, a medicinal and edible plant, is widely used in clinical practice. However, the effects of repeated intake of rhein on liver function and bile acid metabolism are rarely reported. In this work, we investigated the alterations of 14 bile acids and hepatic transporters after rats were administered with rhein for 5 weeks. There was no obvious injury to the liver and kidney, and there were no significant changes in biochemical indicators. However, 1,000 mg/kg rhein increased the liver total bile acid (TBA) levels, especially taurine-conjugated bile acids (t-CBAs), inhibited the expression of farnesoid X receptor (FXR), small heterodimer partner (SHP), and bile salt export pump (BSEP) mRNA, and upregulated the expression of (cholesterol 7α-hydroxylase) CYP7A1 mRNA. Rhein close to the clinical dose (10 mg/kg and 30 mg/kg) reduced the amounts of TBAs, especially unconjugated bile acids (UCBAs), and elevated the expression of FXR and multidrug resistance-associated protein 3 (Mrp3) mRNA. These results denote that rhein is relatively safe to use at a reasonable dose and timing. 30 mg/kg rhein may promote bile acid transport and reduce bile acid accumulation by upregulating the expression of FXR mRNA and Mrp3 mRNA, potentially resulting in the decrease in serum UBCAs.
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