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Schauermann M, Wang R, Pons-Kuehnemann J, Hartmann MF, Remer T, Hua Y, Bereket A, Wasniewska M, Shmoish M, Hochberg Z, Gawlik A, Wudy SA. Targeted quantitative analysis of urinary bile acids by liquid chromatography-tandem mass spectrometry: Method development and application to healthy and obese children. J Steroid Biochem Mol Biol 2025; 249:106712. [PMID: 39988143 DOI: 10.1016/j.jsbmb.2025.106712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/14/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Bile acids (BA) are C24 steroids synthesized from cholesterol in liver. Hardly any data exist on BA in the most accessible human biofluid urine. As bile acids bear great potential as future biomarkers in diagnosis and monitoring of metabolic diseases, we aimed at developing and implementing a new method for the quantification of urinary bile acids using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). A second goal consisted in creating first reference values of urinary bile acids during childhood and to investigate their excretion patterns in obese children and adolescents. Our method required 2 mL of urine and sample preparation consisting of protein precipitation and solid phase extraction. Stable isotopes of BA were included as internal standards (IS). Our method is capable of simultaneously determining 18 BA: the primary BA cholic acid (CA) and chenodeoxycholic acid (CDCA), and the secondary BA deoxycholic acid (DCA) and lithocholic acid (LCA) as well as glycine and taurine conjugates of these four BA. Furthermore, ursodeoxycholic acid (UDCA) and five BA in their sulfated forms (LCA-S, GLCA-S, TLCA-S, GCDCA-S, GDCA-S) were analyzed. After successful validation (intra-day precision 1.02 % - 11.07 %; inter-day precision 0.42-11.47 %.; intra-day accuracy 85.75 % - 108.90 %; inter-day accuracy 86.76 % - 110.99 %; no significant matrix effect; recovery 90.49 % - 113.99 %)., the method was applied to samples of 80 healthy children as well as 237 obese children of various age groups. Sulfated BA showed the highest concentrations, with GCDCA-S (nmol/L, medians, controls vs. obese 588.4 vs. 360.2) being the most abundant among all BA, followed by GLCA-S (353.9 vs. 344.8) and GDCA-S (319,3 vs. 323.9). CA (135.1 vs. 174.6) and GCA (100.2 vs. 92.4) were the two dominant non-sulfated BA. In conclusion, we developed a LC-MS/MS method for the simultaneous determination of 18 urinary bile acids in children and adolescents. We created reference values and investigated obese children. Sulfated bile acids dominated in both study groups. Lower bile acid sulfation and amidation in obese children point to limitations in their hepatic metabolic capacity.
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Affiliation(s)
- M Schauermann
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - R Wang
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - J Pons-Kuehnemann
- Institute of Medical Informatics, Department of Medical Statistics, Justus Liebig University, Giessen, Germany
| | - M F Hartmann
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - T Remer
- DONALD Study Center, Department of Nutritional Epidemiology, Institute of Nutrition and Food Science, University of Bonn, Dortmund, Germany
| | - Y Hua
- DONALD Study Center, Department of Nutritional Epidemiology, Institute of Nutrition and Food Science, University of Bonn, Dortmund, Germany
| | - A Bereket
- Department of Pediatric Endocrinology, Marmara University Faculty of Medicine, Istanbul, Turkey
| | - M Wasniewska
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Italy
| | - M Shmoish
- Bioinformatics Knowledge Unit, Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Z Hochberg
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - A Gawlik
- Department of Pediatrics and Pediatric Endocrinology, School of Medicine in Katowice, Medical University of Silesia, Upper Silesia Children's Care Health Center, Katowice, Poland
| | - S A Wudy
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany.
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Liu JJ, Mei HW, Jing YY, Li ZL, Wu SG, Yuan HX, Zhang XB. Yinchenhao decoction alleviates obstructive jaundice liver injury by modulating epidermal growth factor receptor and constitutive androstane receptor signaling. World J Hepatol 2025; 17:101724. [DOI: 10.4254/wjh.v17.i3.101724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/18/2025] [Accepted: 03/04/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Yinchenhao decoction (YCHD) is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice (OJ). Although YCHD has demonstrated protective effects against liver damage, reduced apoptosis, and mitigated oxidative stress in OJ, the precise molecular mechanisms involved remain poorly understood.
AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.
METHODS The active constituents of YCHD were identified using liquid chromatography-tandem mass spectrometry, and their potential targets for OJ treatment were predicted through network pharmacology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. An OJ rat model was established by common bile duct ligation. Rats were divided into three groups: Sham surgery (S Group), model (O Group), and YCHD (Y Group). YCHD was administered to Group Y for one week. Bilirubin levels, liver function parameters, and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay. The bile acid renal clearance rate (Clr) was calculated. Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining. Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues. The expression of the constitutive androstane receptor (CAR) and its nuclear localization were evaluated by immunohistochemistry. Molecular docking studies identified the epidermal growth factor receptor (EGFR) as a potential target of YCHD's active components. An OJ cell model was created using human liver (L02) and renal tubular epithelial (HK-2) cells, which were treated with YCHD-containing serum. Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.
RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ. In vivo experiments showed that YCHD improved liver function, reduced OJ-induced pathology in liver and kidney tissues, and decreased serum bile acid content by enhancing bile acid Clr and urine output. YCHD also increased CAR expression and nuclear heterotopy, upregulating proteins involved in bile acid metabolism and transport, including CYP3A4, UGT1A1, MRP3, and MRP4 in the liver, and MRP2 and MRP4 in the kidneys. In vitro, YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells, an effect that was reversed by EGFR agonists.
CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys, ameliorating liver damage caused by OJ. These effects are likely mediated by the upregulation of CAR and its nuclear translocation.
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Affiliation(s)
- Jun-Jian Liu
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
- Tianjin Key Laboratory, Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300102, China
| | - Han-Wei Mei
- Department of Gastrointestinal Surgery 3, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 301617, China
| | - Yan-Yan Jing
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhong-Lian Li
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
| | - Su-Guo Wu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hong-Xia Yuan
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xi-Bo Zhang
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
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Guo R, Chang Y, Wang D, Sun H, Gu T, Zong Y, Zhou S, Huang Z, Chen L, Tian Y, Xu W, Lu L, Zeng T. Interaction between cecal microbiota and liver genes of laying ducks with different residual feed intake. Anim Microbiome 2025; 7:30. [PMID: 40119394 PMCID: PMC11929276 DOI: 10.1186/s42523-025-00394-z] [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: 11/05/2024] [Accepted: 03/08/2025] [Indexed: 03/24/2025] Open
Abstract
BACKGROUND The gut microbiota exerts a critical influence on energy metabolism homeostasis and productive performance in avian species. Given the diminishing availability of arable land and intensifying competition for finite resources between livestock production and human populations, the agricultural sector faces dual imperatives to enhance productive efficiency while mitigating ecological footprints. Within this paradigm, optimizing nutrient assimilation efficiency in commercial waterfowl operations emerges as a strategic priority. This investigation employs an integrated multi-omics approach framework (metagenomic, metabolomic, and transcriptomic analyses) to elucidate the mechanistic relationships between cecal microbial consortia and feed conversion ratios in Shan Partridge ducks. RESULTS Based on the analysis of metagenome data, a total of 34 phyla, 1033 genera and 3262 species of bacteria were identified by metagenomic sequencing analysis. At the phylum level, 31 phylums had higher mean abundance in the low residual feed intake ( LRFI) group than in the high residual feed intake (HRFI) group. Among them, the expression of microbiome Elusimicrobiota was significantly higher in the LRFI group than in the HRFI group (P < 0.05). And we also found a significant differences in secondary metabolites biosynthesis, transport, and catabolism pathways between the two groups in microbial function (P < 0.05). Based on metabolomic analysis, 17 different metabolites were found. Among them, Lipids and lipid molecules accounted for the highest proportion. Whereas the liver is very closely related to lipid metabolism, we are close to understanding whether an individual's energy utilization efficiency is related to gene expression in the liver. We selected six ducks from each group of six ducks each for liver transcriptome analysis. A total of 322 differential genes were identified in the transcriptome analysis results, and 319 genes were significantly down-regulated. Among them, we found that prostaglandin endoperoxide synthase 2 (PTGS2) might be a key hub gene regulating RFI by co-occurrence network analysis. Interestingly, the differential gene PTGS2 was enriched in the arachidonic acid pathway at the same time as the differential metabolite 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2). In addition, the results of the association analysis of differential metabolites with microorganisms also revealed a significant negative correlation between 15d-PGJ2 and Elusimicrobiota. CONCLUSION Based on comprehensive analysis of the research results, we speculate that the Elusimicrobiota may affect the feed utilization efficiency in ducks by regulating the expression of the PTGS2 gene.
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Affiliation(s)
- Rongbing Guo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Yuguang Chang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Dandan Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Hanxue Sun
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Tiantian Gu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Yibo Zong
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Shiheng Zhou
- Cherry Valley Agricultural Technology Co. Ltd, Zhoukou, 461300, China
| | - Zhizhou Huang
- Cherry Valley Agricultural Technology Co. Ltd, Zhoukou, 461300, China
| | - Li Chen
- Xianghu Laboratory, Hangzhou, 311231, China
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Yong Tian
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Wenwu Xu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Lizhi Lu
- Xianghu Laboratory, Hangzhou, 311231, China.
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China.
| | - Tao Zeng
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Key Laboratory of Livestock and Poultry Resources (Poultry) Evaluation and Utilization, Zhejiang Provincial Engineering Research Center for Poultry Breeding Industry and Green Farming Technology, Institute of Animal Science & Veterinary, Ministry of Agriculture and Rural Affairs of China, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China.
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Fang Q, Hou X, Fan L, Deng Y, Li X, Zhang H, Wang H, Fu Z, Sun B, Shu X, Du H, Liu Y. Gut microbiota derived DCA enhances FOLFOX efficacy via Ugt1a6b mediated enterohepatic circulation in colon cancer. Pharmacol Res 2025; 213:107636. [PMID: 39894186 DOI: 10.1016/j.phrs.2025.107636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/04/2025]
Abstract
FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX in vitro, however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX's therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX's anti-colon cancer effects in vivo. Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment.
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Affiliation(s)
- Qian Fang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiaoying Hou
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Limei Fan
- Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Yufei Deng
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiaoxuan Li
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Hongyun Zhang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Haiping Wang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Zhengqi Fu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Binlian Sun
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiji Shu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Hongzhi Du
- Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China; Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan 430065, China.
| | - Yuchen Liu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China; Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China.
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Eden J, Thorne AM, Bodewes SB, Patrono D, Roggio D, Breuer E, Lonati C, Dondossola D, Panayotova G, Boteon APCS, Walsh D, Carvalho MF, Schurink IJ, Ansari F, Kollmann D, Germinario G, Rivas Garrido EA, Benitez J, Rebolledo R, Cescon M, Ravaioli M, Berlakovich GA, De Jonge J, Uluk D, Lurje I, Lurje G, Boteon YL, Guarrera JV, Romagnoli R, Galkin A, Meierhofer D, Porte RJ, Clavien PA, Schlegel A, de Meijer VE, Dutkowski P. Assessment of liver graft quality during hypothermic oxygenated perfusion: The first international validation study. J Hepatol 2025; 82:523-534. [PMID: 39251091 PMCID: PMC11830552 DOI: 10.1016/j.jhep.2024.08.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND & AIMS While it is currently assumed that liver assessment is only possible during normothermic machine perfusion, there is uncertainty regarding a reliable and quick prediction of graft injury during ex situ hypothermic oxygenated perfusion (HOPE). We therefore intended to test, in an international liver transplant cohort, recently described mitochondrial injury biomarkers measured during HOPE before liver transplantation. METHODS Perfusate samples of human livers from ten centers in seven countries with HOPE experience were analyzed for released mitochondrial compounds, i.e. flavin mononucleotide (FMN), NADH, purine derivatives and inflammatory markers. Livers deemed unsuitable for transplantation served as negative controls. RESULTS We collected 473 perfusate samples of human donation after cardiac death (n = 315) and donation after brain death (n = 158) livers. Fluorometric assessment of FMN in perfusate was validated by mass spectrometry (R = 0.7011, p <0.0001). Graft loss due to primary non-function or cholangiopathy was predicted by perfusate FMN values (c-statistic mass spectrometry 0.8418, 95% CI 0.7466-0.9370, p <0.0001; c-statistic fluorometry 0.7733, 95% CI 0.7006-0.8461, p <0.0001). Perfusate FMN values were also significantly correlated with symptomatic non-anastomotic strictures and kidney failure, and superior for the prediction of graft loss than conventional scores derived from donor and recipient parameters, such as the donor risk index and the balance of risk score. Mitochondrial FMN values in liver tissues of non-utilized livers were low, and inversely correlated to high perfusate FMN values and purine metabolite release. CONCLUSIONS This first international study validates the predictive value of the mitochondrial cofactor FMN, released from complex I during HOPE, and may therefore contribute to a better risk stratification of injured livers before implantation. IMPACT AND IMPLICATIONS Analysis of 473 perfusates, collected from ten international centers during HOPE (hypothermic oxygenated perfusion), revealed that mitochondria-derived flavin mononucleotide values in perfusate are predictive of graft loss, cholangiopathy, and kidney failure after liver transplantation. This result is of high clinical relevance, as recognition of graft quality is urgently needed to improve the safe utilization of marginal livers. Ex situ machine perfusion approaches, such as HOPE, are therefore likely to increase the number of useable liver grafts.
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Affiliation(s)
- Jahnina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Adam M Thorne
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Silke B Bodewes
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Dorotea Roggio
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Eva Breuer
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - Caterina Lonati
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, Milan, Italy, Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, Milan, Italy, Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy
| | - Guergana Panayotova
- Department of Surgery, Division of Transplant and HPB Surgery, Rutgers NJMS/University Hospital, Newark, NJ, USA
| | | | | | | | - Ivo J Schurink
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC Transplant Insititute, University Medical Center, Rotterdam, the Netherlands
| | - Fariha Ansari
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Dagmar Kollmann
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Wien, Austria
| | - Giuliana Germinario
- Hepatobiliary and Transplant Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Elisabeth Alexis Rivas Garrido
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río and Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Julio Benitez
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río and Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rolando Rebolledo
- Hepato-Pancreato-Biliary Surgery Unit, Surgery Service, Complejo Asistencial Dr. Sótero Del Río and Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Matteo Cescon
- Hepatobiliary and Transplant Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Matteo Ravaioli
- Hepatobiliary and Transplant Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Gabriela A Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Wien, Austria
| | - Jeroen De Jonge
- Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC Transplant Insititute, University Medical Center, Rotterdam, the Netherlands
| | - Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum-Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Isabella Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum-Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany; Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum-Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Yuri L Boteon
- Liver Unit, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - James V Guarrera
- Department of Surgery, Division of Transplant and HPB Surgery, Rutgers NJMS/University Hospital, Newark, NJ, USA
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Alexander Galkin
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, Berlin, Germany
| | - Robert J Porte
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Pierre Alain Clavien
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - Andrea Schlegel
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, Milan, Italy, Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100, Milan, Italy; Transplantation Center, Digestive Disease and Surgery Institute and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; Division of Visceral Surgery, University Digestive Health Care Centre Clarunis, University Hospital Basel, Switzerland.
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6
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De Vos K, Mols R, Chatterjee S, Huang MC, Augustijns P, Wolters JC, Annaert P. In Vitro-In Silico Models to Elucidate Mechanisms of Bile Acid Disposition and Cellular Aerobics in Human Hepatocytes. AAPS J 2025; 27:51. [PMID: 40016501 DOI: 10.1208/s12248-024-01010-9] [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: 09/16/2024] [Accepted: 12/08/2024] [Indexed: 03/01/2025] Open
Abstract
Understanding the kinetics of hepatic processes, such as bile acid (BA) handling and cellular aerobic metabolism, is crucial for advancing our knowledge of liver toxicity, particularly drug-induced cholestasis (DiCho). This article aimed to construct interpretable models with parameter estimations serving as reference values when investigating these cell metrics. Longitudinal datasets on BA disposition and oxygen consumption rates were collected using sandwich-cultured human hepatocytes. Chenodeoxycholic acid (CDCA), lithocholic acid (LCA), as well as their amidated and sulfate-conjugated metabolites were quantified with liquid chromatography-mass spectrometry. The bile salt export pump (BSEP) abundance was monitored with targeted proteomics and modelled for activity assessment. Oxygen consumption was measured using Seahorse XFp analyser. Ordinary differential equation-based models were solved in R. The basolateral uptake and efflux clearance of glycine-conjugated CDCA (GCDCA) were estimated at 1.22 µL/min/106 cells (RSE 14%) and 0.11 µL/min/106 cells (RSE 10%), respectively. The GCDCA clearance from canaliculi back to the medium was 2.22 nL/min/106 cells (RSE 17%), and the dissociation constant between (G)CDCA and FXR for regulating BSEP abundance was 25.73 nM (RSE 11%). Sulfation clearance for LCA was 0.19 µL/min/106 cells (RSE 11%). Model performance was further demonstrated by a maximum two-fold deviation of the 95% confidence boundaries from parameter estimates. These in vitro-in silico models provide a quantitative framework for exploring xenobiotic impacts on BA disposition, BSEP activity, and cellular aerobic metabolism in hepatocytes. Model simulations were consistent with reported in vivo data in progressive familial intrahepatic cholestasis type II patients.
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Affiliation(s)
- Kristof De Vos
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Raf Mols
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Sagnik Chatterjee
- DMPK Department, AstraZeneca, Västra Götaland County, Gothenburg, Sweden
| | - Miao-Chan Huang
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Patrick Augustijns
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Justina Clarinda Wolters
- Section Systems Medicine of Metabolism and Signaling, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands
| | - Pieter Annaert
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium.
- BioNotus GCV, 2845, Niel, Belgium.
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7
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Fouad OA, Zaghlol DF, Sweed DM, Saber MA, Sira MM. Hepatic Expression of Fibroblast Growth Factor 19 Significantly Correlates With Serum Bile Acids in Neonatal Cholestasis. Pediatr Dev Pathol 2025:10935266251322941. [PMID: 40012171 DOI: 10.1177/10935266251322941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
BACKGROUND Bile acids in the ileum act as a feedback regulator of their own synthesis by inducing the release of ileal fibroblast growth factor 19 (FGF19), which inhibits the cholesterol-7-alpha hydroxylase enzyme. In cholestasis, this feedback mechanism is dysregulated. FGF19 is not expressed in the healthy liver. We aimed to assess the hepatic expression of FGF19 in neonatal cholestasis (NC) and its relation to serum bile acids. METHODS The study included 41 patients with NC. FGF19 immunohistochemical staining in liver tissue (hepatocytes, endothelial cells, bile ducts, and bile canaliculi) was evaluated as negative, weak, moderate, and strong staining. FGF19 staining in 6 liver samples from explants of children with Crigler-Najjar syndrome type-1 served as controls. RESULTS Hepatocyte, endothelial, and canalicular FGF19 expression was significantly higher in cholestasis group compared to controls (P = .039, .006, and .028 respectively). Serum bile acids had significant correlation with hepatocyte FGF19, endothelial, and bile duct FGF19 expressions (P = .002, .003, and .01, respectively) but not with canalicular FGF19 expression. Hepatocyte FGF19 expression significantly associated with cholestasis severity in terms of serum total bilirubin, direct bilirubin, and aspartate transaminase levels (P = .01, .02, and .02, respectively). CONCLUSION Hepatic FGF19 expression significantly upregulated in NC and correlated with cholestasis severity.
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Affiliation(s)
- Ola A Fouad
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Doaa F Zaghlol
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Dina M Sweed
- Department of Pathology, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Magdy A Saber
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Mostafa M Sira
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, Menoufia, Egypt
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8
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Ahmed Taher H, Zalzala MH. Ellagic acid mitigates alpha-naphthyl isothiocyanate-induced cholestasis in rats via FXR activation and inflammatory pathway modulation. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2025:jcim-2024-0425. [PMID: 39924693 DOI: 10.1515/jcim-2024-0425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/07/2025] [Indexed: 02/11/2025]
Abstract
OBJECTIVES The liver is vital for metabolism, detoxification, storage, and secretion. Cholestasis, in which bile flow is hindered, can cause serious harm to the liver. This study examines the potential of ellagic acid to prevent cholestasis in male rats that has been caused by alpha-naphthyl isothiocyanate (ANIT). METHOD Male rats were divided into four groups for an 8-day study. The control group received 5 % dimethyl sulfoxide (DMSO) orally for eight days and maize oil (1 mL/kg, orally) 48 h before sacrifice. The ANIT Group received 5 % DMSO orally for 8 days, the ANIT (100 mg/kg, orally) administered on the 6th day, 48 h before sacrifice. The low-Dose Ellagic Acid + ANIT Group was given ellagic acid (5 mg/kg, orally) for eight days, with ANIT (100 mg/kg, orally) on the 6th day, 48 h prior to sacrifice. The high-Dose Ellagic Acid + ANIT Group received ellagic acid (10 mg/kg, orally) for eight days, the ANIT (100 mg/kg, orally) on the 6th day, 48 h before sacrifice. Different biochemical and histopathological analyses were conducted to assess the protective effects of ellagic acid on ANIT-induced liver injury. RESULTS ANIT significantly elevated serum of liver enzymes. It caused severe bile duct inflammation and reduced bile salt export pump (BSEP) and Na+-taurocholate cotransporting polypeptide (NTCP) expression, indicating liver injury. Ellagic acid treatment mitigated these changes, improving biochemical parameters and reducing liver damage. ANIT-induced cholestasis results in bile acid accumulation due to decreased BSEP and NTCP expression linked to impaired farnesoid X receptor (FXR) signaling. Ellagic acid restored BSEP and NTCP levels via FXR activation, reducing bile acids and inflammatory markers IL-1β and TNF-α. Ellagic acid also enhanced SIRT1 activity, further improving FXR function and bile acid homeostasis. CONCLUSIONS Ellagic acid exhibits protective effects against cholestasis by enhancing the FXR signaling and ntcp and bsep expression with mitigating liver damage and inflammation.
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Affiliation(s)
| | - Munaf Hashim Zalzala
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
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9
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Ohtsuki Y, Fujiki J, Maeda N, Iwano H. Enhanced expression of Cyp17a1 and production of DHEA-S in the liver of late-pregnant rats. Gen Comp Endocrinol 2025; 362:114661. [PMID: 39761705 DOI: 10.1016/j.ygcen.2025.114661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/29/2024] [Accepted: 01/03/2025] [Indexed: 01/12/2025]
Abstract
Cytochrome P450 17A1 (CYP17A1) catalyzes two enzymatic reactions in the biosynthesis of dehydroepiandrosterone (DHEA) from pregnenolone. In pregnant humans, the adrenal gland is responsible for DHEA biosynthesis, which is then sulfated by SULT2A1 and released into the bloodstream. This sulfated DHEA is subsequently taken up by the placenta and deconjugated to serve as a precursor for estrogen biosynthesis. The expression of Cyp17a1 is regulated by methylation, typically showing marked interspecies differences, including repression of Cyp17a1 expression in the adrenal gland of rodents. This study focused on the liver, an extragonadal steroidogenic organ showing active sulfate conjugation, as a site for DHEA-sulfate (DHEA-S) biosynthesis during pregnancy in rodents, rather than the adrenal glands. Cyp17a1 expression in rat liver was significantly lower than in the testis, with no differences between sexes. However, Cyp17a1 expression increased significantly before parturition (gestational days [GD] 19-21) compared to late pregnancy (GD 15-18). The Sult2a family were expressed in the livers of both pregnant and non-pregnant rats. We also observed increased DHEA and DHEA-S levels in the liver of pregnant rats before parturition compared to non-pregnant rats, with DHEA-S concentrations being significantly higher at GD 19-21 than at days 15-18. These findings suggest that increased expression of Cyp17a1 in the last trimester enhances DHEA synthesis in the liver, and that DHEA is quickly conjugated by Sult2a. In rodents, the liver may be involved in DHEA-S biosynthesis before parturition, compensating for the repression of Cyp17a1 in the adrenal glands.
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Affiliation(s)
- Yuya Ohtsuki
- Laboratory of Veterinary Biochemistry, Department of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
| | - Jumpei Fujiki
- Laboratory of Veterinary Biochemistry, Department of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan.
| | - Naoyuki Maeda
- Laboratory of Meat Science, Department of Food Science and Human Wellness, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
| | - Hidetomo Iwano
- Laboratory of Veterinary Biochemistry, Department of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
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10
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Tiley JB, Beaudoin JJ, Derebail VK, Murphy WA, Park CC, Veeder JA, Tran L, Beers JL, Jia W, Stewart PW, Brouwer KLR. Altered bile acid and coproporphyrin-I disposition in patients with autosomal dominant polycystic kidney disease. Br J Clin Pharmacol 2025; 91:353-364. [PMID: 39317666 DOI: 10.1111/bcp.16221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 06/22/2024] [Accepted: 07/30/2024] [Indexed: 09/26/2024] Open
Abstract
AIMS Serum, liver and urinary bile acids are increased, and hepatic transport protein levels are decreased in a non-clinical model of polycystic kidney disease. Similar changes in patients with autosomal dominant polycystic kidney disease (ADPKD) may predispose them to drug-induced liver injury (DILI) and hepatic drug-drug interactions (DDIs). Systemic coproporphyrin-I (CP-I), an endogenous biomarker for hepatic OATP1B function and MRP2 substrate, is used to evaluate OATP1B-mediated DDI risk in humans. In this clinical observational cohort-comparison study, bile acid profiles and CP-I concentrations in healthy volunteers and patients with ADPKD were compared. METHODS Serum and urine samples from healthy volunteers (n = 16) and patients with ADPKD (n = 8) were collected. Serum bile acids, and serum and urine CP-I concentrations, were quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS Patients with ADPKD exhibited increased serum concentrations of total (1.3-fold) and taurine-conjugated (2.8-fold) bile acids compared to healthy volunteers. Specifically, serum concentrations of six bile acids known to be more hydrophobic/hepatotoxic (glycochenodeoxycholate, taurochenodeoxycholate, taurodeoxycholate, lithocholate, glycolithocholate and taurolithocholate) were increased (1.5-, 2.9-, 2.8-, 1.6-, 1.7- and 2.7-fold, respectively) in patients with ADPKD. Furthermore, serum CP-I concentrations were elevated and the renal clearance of CP-I was reduced in patients with ADPKD compared to healthy volunteers. CONCLUSIONS Increased exposure to bile acids may increase susceptibility to DILI in some patients with ADPKD. Furthermore, the observed increase in serum CP-I concentrations could be attributed, in part, to impaired OATP1B function in patients with ADPKD, which could increase the risk of DDIs involving OATP1B substrates compared to healthy volunteers.
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Affiliation(s)
- Jacqueline B Tiley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - James J Beaudoin
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Vimal K Derebail
- UNC Kidney Center, Division of Nephrology and Hypertension, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - William A Murphy
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Christine C Park
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Justin A Veeder
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Lana Tran
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jessica L Beers
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Wei Jia
- University of Hawaii Cancer Center, Honolulu, Hawaii, USA
| | - Paul W Stewart
- Department of Biostatistics, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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11
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Zhang G, Jia W, Liu L, Wang L, Xu J, Tao J, Xu M, Yue M, Luo H, Hai P, Yue H, Zhang D, Zhao X. Caffeoylquinic acids from Silphium perfoliatum L. show hepatoprotective effects on cholestatic mice by regulating enterohepatic circulation of bile acids. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118870. [PMID: 39357582 DOI: 10.1016/j.jep.2024.118870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/04/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The incidence of cholestatic liver disease (CLD), which is primarily marked by abnormal bile acids (BAs) metabolism and can result in significant hepatic injury, is rising. Nevertheless, there remains a lack of effective treatments and drugs in clinical practice. Silphium perfoliatum L. (SP) is rich in various structural types of caffeoylquinic acid (CQA) compounds, and it is a traditional herb of North American Indians with hepatobiliary therapy effects. However, its therapeutic effect and mechanism of action on CLD have never been studied. AIM OF THE STUDY To determine if SP-8, an extract rich in CQAs from SP, protects against cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) and to clarify its mechanism based on the farnesoid x receptor (FXR) signaling pathway and enterohepatic circulation of BAs. MATERIALS AND METHODS The therapeutic efficacy of SP-8 was evaluated by assessing the serum biochemical indices, inflammatory factors, and liver histopathology. Targeted metabolomics of the BAs was studied in the feces, liver, serum, and bile using UPLC-MS/MS. Additionally, a Western blot analysis was used to examine the expression levels of the peroxisome proliferator-activated receptor γ (PPARγ), the FXR, and proteins related to the synthesis and transport of BAs. 16S rRNA gene sequencing was performed to evaluate the gut microbiota (GM). Finally, molecular docking simulations were conducted to assess the interaction between seven types of CQAs from SP-8 with FXR and PPARγ. RESULTS SP-8 significantly enhanced the health status of cholestatic mice induced by ANIT as evidenced by a notable reduction in the liver function indices and pro-inflammatory factors, restoration of liver pathological damage, and acceleration of BAs excretion through the feces. In addition, the levels of harmful secondary BAs in the liver and blood were significantly reduced by SP-8. Furthermore, the results of the study on the mechanism of action confirmed that SP-8 not only regulated FXR and PPARγ but also significantly ameliorated the GM structure, thereby promoting the enterohepatic circulation of BAs and achieving the homeostasis of the BAs in the blood and liver. In addition, SP-8 successfully reduced the inflammatory response by strongly suppressing the nuclear translocation of NF-κBp65. According to the molecular docking results, the extract's primary active ingredients could be the seven CQAs in SP-8, as they exhibited a strong affinity for both FXR and PPARγ. Finally, the Mantel test analysis revealed a significant correlation among cholestatic-associated parameters, the GM, and BAs. CONCLUSION It was confirmed for the first time that the SP-8 extract of Silphium perfoliatum L. that is rich in seven CQAs had a strong therapeutic effect on ANIT-induced CLD. Its mechanism may involve the regulation of the FXR signaling pathway and the amelioration of the GM structure to promote the homeostasis of BAs enterohepatic circulation. This study provides a potential candidate medicinal herb and its components for the development of CLD therapeutic drugs.
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Affiliation(s)
- Guoying Zhang
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China.
| | - Wenjing Jia
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China; University of Chinese Academy of Sciences, China.
| | - Liying Liu
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China; University of Chinese Academy of Sciences, China.
| | - Luya Wang
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China; University of Chinese Academy of Sciences, China.
| | - Jiyu Xu
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China.
| | - Jihong Tao
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China.
| | - Mingting Xu
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China; University of Chinese Academy of Sciences, China.
| | - Min Yue
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China.
| | - Huiqin Luo
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China.
| | - Ping Hai
- Qinghai Institute for Drug Control, China.
| | - Huilan Yue
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China.
| | - Dejun Zhang
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China.
| | - Xiaohui Zhao
- Qinghai Key Laboratory of Qinghai-Tibetan Plateau Biological Resources, Northwest Institute of Plateau Biology, CAS, Qinghai, 810008, China.
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12
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Bintee B, Banerjee R, Hegde M, Vishwa R, Alqahtani MS, Abbas M, Alqahtani A, Rangan L, Sethi G, Kunnumakkara AB. Exploring bile acid transporters as key players in cancer development and treatment: Evidence from preclinical and clinical studies. Cancer Lett 2025; 609:217324. [PMID: 39571783 DOI: 10.1016/j.canlet.2024.217324] [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: 07/11/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 12/01/2024]
Abstract
Bile acid transporters (BATs) are integral membrane proteins belonging to various families, such as solute carriers, organic anion transporters, and ATP-binding cassette families. These transporters play a crucial role in bile acid transportation within the portal and systemic circulations, with expression observed in tissues, including the liver, kidney, and small intestine. Bile acids serve as signaling molecules facilitating the absorption and reabsorption of fats and lipids. Dysregulation of bile acid concentration has been implicated in tumorigenesis, yet the role of BATs in this process remains underexplored. Emerging evidence suggests that BATs may modulate various stages of cancer progression, including initiation, development, proliferation, metastasis, and tumor microenvironment regulation. Targeting BATs using siRNAs, miRNAs, and small compound inhibitors in preclinical models and their polymorphisms are well-studied for transporters like BSEP, MDR1, MRP2, OATP1A2, etc., and have shed light on their involvement in tumorigenesis, particularly in cancers such as those affecting the liver and gastrointestinal tract. While BATs' role in diseases like Alagille syndrome, biliary atresia, and cirrhosis have been extensively studied, their implications in cancer warrant further investigation. This review highlights the expression and function of BATs in cancer development and emphasizes the potential of targeting these transporters as a novel therapeutic strategy for various malignancies.
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Affiliation(s)
- Bintee Bintee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ruchira Banerjee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India; Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Athba Alqahtani
- Research Centre, King Fahad Medical City, P.O. Box: 59046, Riyadh, 11525, Saudi Arabia
| | - Latha Rangan
- Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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13
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Kastrinou-Lampou V, Rodríguez-Pérez R, Poller B, Huth F, Schadt HS, Kullak-Ublick GA, Arand M, Camenisch G. Drug-induced cholestasis (DIC) predictions based on in vitro inhibition of major bile acid clearance mechanisms. Arch Toxicol 2025; 99:377-391. [PMID: 39542928 DOI: 10.1007/s00204-024-03895-z] [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: 09/28/2023] [Accepted: 10/17/2024] [Indexed: 11/17/2024]
Abstract
Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (p-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision-recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.
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Affiliation(s)
- Vlasia Kastrinou-Lampou
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Birk Poller
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Felix Huth
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Heiko S Schadt
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, CMO and Patient Safety, Global Drug Development, Novartis, Basel, Switzerland
| | - Michael Arand
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Gian Camenisch
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland.
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14
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Fuchs CD, Simbrunner B, Baumgartner M, Campbell C, Reiberger T, Trauner M. Bile acid metabolism and signalling in liver disease. J Hepatol 2025; 82:134-153. [PMID: 39349254 DOI: 10.1016/j.jhep.2024.09.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.
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Affiliation(s)
- Claudia D Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximillian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Clarissa Campbell
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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15
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Zheng W, Xu L, Jin M, Wang J, Rietjens IMCM. Effects of lambda-cyhalothrin on gut microbiota and related bile acid metabolism in mice. JOURNAL OF HAZARDOUS MATERIALS 2024; 480:136417. [PMID: 39536348 DOI: 10.1016/j.jhazmat.2024.136417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Since the gut microbiota plays a crucial role in host metabolism and homeostasis, its alterations induced by xenobiotics such as pesticides, could pose a risk to host health. The pyrethroid insecticides were frequently detected in surface water (up to 13 mg/L worldwide), sediments, and agricultural products; additionally, some previous studies indicated that pyrethroid insecticides could cause disruption of gut homeostasis. Hence herein, the normally used pyrethroid lambda-cyhalothrin (LCT) was selected and studied for its effects on the intestinal microbial community and its related bile acid metabolism using mice as the model species. Results showed that the total amount of bile acids in plasma and fecal samples from LCT treated mice markedly increased compared to controls, which could be mainly ascribed to the significantly raised proportions of taurine conjugated bile acids in plasma, and the increase in fecal secondary bile acids. In gut microbial profiles, a significantly increased richness of Prevotellacea and a depletion of Lachnospiraceae were found at the family level upon the treatment with lambda-cyhalothrin. In conclusion, results obtained on bacterial and bile acid profiles corroborate that the treatment of mice with LCT could affect gut microbial community with accompanying changes in bile acid homeostasis.
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Affiliation(s)
- Weijia Zheng
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands; Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Lingyuan Xu
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Maojun Jin
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
| | - Jing Wang
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Sanya National Nanfan Research Institute of the Chinese Academy of Agricultural Sciences, Sanya 572024, China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China.
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE Wageningen, the Netherlands
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16
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Shijing T, Yinping P, Qiong Y, Deshuai L, Liancai Z, Jun T, Shaoyong L, Bochu W. Synthesis of TUDCA from chicken bile: immobilized dual-enzymatic system for producing artificial bear bile substitute. Microb Cell Fact 2024; 23:326. [PMID: 39623449 PMCID: PMC11613824 DOI: 10.1186/s12934-024-02592-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/12/2024] [Indexed: 12/06/2024] Open
Abstract
Bear bile, a valuable animal-derived medicinal substance primarily composed of tauroursodeoxycholic acid (TUDCA), is widely distributed in the medicinal market across various countries due to its significant therapeutic potential. Given the extreme cruelty involved in bear bile extraction, researchers are focusing on developing synthetic bear bile powder as a more humane alternative. This review presents an industrially practical and environmentally friendly process for producing an artificial substitute for bear bile powder using inexpensive and readily available chicken bile powder through an immobilized 7α-,7β-HSDH dual-enzymatic syste. Current technology has facilitated the industrial production of TUDCA from Tauodeoxycholic acid (TCDCA) using chicken bile powder. The review begins by examining the chemical composition, structure, and properties of bear bile, followed by an outline of the pharmacological mechanisms and manufacturing methods of TUDCA, covering chemical synthesis and biotransformation methods, and a discussion on their respective advantages and disadvantages. Finally, the process of converting chicken bile powder into bear bile powder using an immobilized 7α-Hydroxysteroid Dehydrogenases(7α-HSDH) with 7β- Hydroxysteroid Dehydrogenases (7β-HSDH) dual-enzyme system is thoroughly explained. The main objective of this review is to propose a comprehensive strategy for the complete synthesis of artificial bear bile from chicken bile within a controlled laboratory setting.
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Affiliation(s)
- Tang Shijing
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Pan Yinping
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Yang Qiong
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Lou Deshuai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Zhu Liancai
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
| | - Tan Jun
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Liu Shaoyong
- Shanghai Kaibao Pharmaceutical Co., LTD., Shanghai, 200030, People's Republic of China
| | - Wang Bochu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
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17
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Liu Y, Li X, Guo Z, Li G, He L, Liu H, Cai S, Huo T. Diammonium glycyrrhizinate alleviates iron overload-induced liver injury in mice via regulating the gut-liver axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156216. [PMID: 39547094 DOI: 10.1016/j.phymed.2024.156216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/19/2024] [Accepted: 11/03/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Evidence indicates a close association between iron overload (IO) and the pathogenesis of chronic liver diseases, highlighting the potential for interventions targeted at IO to impede or decelerate the progression of chronic liver diseases. Diammonium glycyrrhizinate (DG), the medicinal form of glycyrrhizic acid, a principal constituent of licorice, has been clinically employed as a hepatoprotective agent; however, its protective effect against IO-induced liver injury and underlying molecular mechanisms remain elusive. PURPOSE The aim of the present study is to investigate the hepatoprotective effect of DG against IO-induced liver injury with a focus on the gut-liver axis. STUDY DESIGN AND METHODS Animal models of IO-induced liver injury and DG treatment have been established in vivo. Iron deposition, liver injury, intestinal barrier damage, and liver inflammation were assessed in mice treated with iron dextran or DG. The microbiome composition in feces was analyzed using 16S rRNA full-length sequencing. Bile acids (BAs) profiles in feces were detected by UPLC-Q-TOF-MS technique, and the expression levels of receptors, enzymes or transporters involved in BAs metabolism were also determined. RESULTS DG partially reduced the iron deposition and the levels of ferrous ion in the livers of mice with IO, thereby mitigating oxidative damage. DG also improved gut microbiota dysbiosis, repaired intestinal barrier damage, inhibited endotoxin translocation to the liver, and subsequently suppressed TLR4/NF-κB/NLRP3 pathway-mediated liver inflammation caused by IO. Moreover, DG modulated BAs metabolism disorder in IO mice, reducing the accumulation of BAs in the liver. CONCLUSION DG alleviates IO-induced liver injury in mice by regulating the gut-liver axis. This study provides novel insights into the underlying mechanisms through which DG ameliorates liver injury caused by IO.
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Affiliation(s)
- Yu Liu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122
| | - Xiaohong Li
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China
| | - Ziwei Guo
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122
| | - Guangyan Li
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122
| | - Lu He
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122
| | - Huan Liu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122
| | - Shuang Cai
- The First Affiliated Hospital of China Medical University, Shenyang, 110001, PR China.
| | - Taoguang Huo
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, China, 110122; Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122.
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18
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Zhao L, Jiang Q, Lei J, Cui J, Pan X, Yue Y, Zhang B. Bile acid disorders and intestinal barrier dysfunction are involved in the development of fatty liver in laying hens. Poult Sci 2024; 103:104422. [PMID: 39418789 PMCID: PMC11532484 DOI: 10.1016/j.psj.2024.104422] [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: 07/19/2024] [Revised: 09/16/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024] Open
Abstract
The pathogenesis of fatty liver is highly intricate. The role of the gut-liver axis in the development of fatty liver has gained increasing recognition in recent years. This study was conducted to explore the role of bile acid signaling and gut barrier in the pathogenesis of fatty liver. A total of 100 "Jing Tint 6" laying hens, 56-week-old, were used and fed basal diets until 60 weeks of age. At the end of the experiment, thirty individuals were selected based on the degree of hepatic steatosis. The hens with minimal hepatic steatosis (< 5 %) were chosen as healthy controls, while those with severe steatosis (> 33 %) in the liver were classified as the fatty liver group. Laying hens with fatty liver and healthy controls showed significant differences in body weight, liver index, abdominal fat ratio, feed conversion ratio (FCR), albumin height, Haugh unit, and biochemical indexes. The results of bile acid metabolomics revealed a clear separation in hepatic bile acid profiles between the fatty liver group and healthy controls, and multiple secondary bile acids were decreased in the fatty liver group, indicating disordered bile acid metabolism. Additionally, the mRNA levels of farnesoid X receptor (FXR) and genes related to bile acid transport were significantly decreased in both the liver and terminal ileum of hens with fatty liver. Moreover, the laying hens with fatty liver exhibited significant decreases in ileal crypt depth, the number of goblet cells, and the mRNA expression of tight junction-related proteins, alongside a significant increase in ileal permeability. Collectively, these findings suggest that disordered bile acids, suppressed FXR-mediated signaling, and impaired intestinal barrier function are potential factors promoting the development of fatty liver. These insights indicate that regulating bile acids and enhancing intestinal barrier function may become new preventive and therapeutic strategies for fatty liver in the near future.
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Affiliation(s)
- Lihua Zhao
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Qiuyu Jiang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Jiaqi Lei
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Jian Cui
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Xianjie Pan
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yuan Yue
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Bingkun Zhang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
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Ikeda H, Watanabe S, Sato S, Fee EL, Carter SWD, Kumagai Y, Takahashi T, Kawamura S, Hanita T, Illanes SE, Choolani MA, Saito M, Kikuchi A, Kemp MW, Usuda H. Upregulation of hepatic nuclear receptors in extremely preterm ovine fetuses undergoing artificial placenta therapy. J Matern Fetal Neonatal Med 2024; 37:2301651. [PMID: 38195120 DOI: 10.1080/14767058.2023.2301651] [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: 09/28/2023] [Accepted: 12/30/2023] [Indexed: 01/11/2024]
Abstract
OBJECTIVE Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses. This fetal model, resembling a "knockout placenta," lacks placental and maternal support, while maintaining a healthy extrauterine survival. METHODS Six ovine fetuses at 95 ± 1 d gestational age (GA; term = ∼150 d)/∼600 g delivery weight were maintained on an APT platform for a period of 120 h (APT Group). Six age-matched, in utero control fetuses were delivered at 99-100 d GA (Control Group). Fetal liver tissue samples and blood samples were collected at delivery from both groups and assessed mRNA expression of NRs and target transporters involved in the hepatobiliary transport system using quantitative PCR. Data were tested for group differences with ANOVA (p < .05 deemed significant). RESULTS mRNA expression of NRs was identified in both the placenta and the extremely preterm ovine fetal liver. The expression of HNF4α, LRH1, LXR, ESR1, PXR, CAR, and PPARα/γ were significantly elevated in the liver of the APT Group compared to the Control Group. Moreover, target transporters NTCP, OATP1B3, BSEP, and MRP4 were upregulated, whereas MRP2 and MRP3 were unchanged. Although there was no evidence of liver necrosis or apoptotic changes histologically, there was an impact in the fetal liver of the ATP group at the tissue level with a significant increase in TNFα mRNA, a cytokine involved in liver inflammation, and blood elevation of transaminases. CONCLUSION A number of NRs in the fetal liver were significantly upregulated after loss of placental-maternal support. However, the expression of target transporter genes appeared to be insufficient to compensate role of the placenta and maternal liver and avoid fetal liver damage, potentially due to insufficient excretion of organic anions.
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Affiliation(s)
- Hideyuki Ikeda
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Shimpei Watanabe
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Shinichi Sato
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Erin L Fee
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia
| | - Sean W D Carter
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yusaku Kumagai
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tsukasa Takahashi
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | | | - Takushi Hanita
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Sebastian E Illanes
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Mahesh A Choolani
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Masatoshi Saito
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Atsuo Kikuchi
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Matthew W Kemp
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
- Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- School of Veterinary and Life Sciences, Murdoch University, Murdoch, Australia
- Women and Infants Research Foundation, King Edward Memorial Hospital, Subiaco, Australia
| | - Haruo Usuda
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia
- Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
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Elbahnsi A, Dudas B, Callebaut I, Hinzpeter A, Miteva MA. ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches. Pharmaceuticals (Basel) 2024; 17:1602. [PMID: 39770445 PMCID: PMC11676857 DOI: 10.3390/ph17121602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
The ATP-binding cassette (ABC) and solute carrier (SLC) transporters play pivotal roles in cellular transport mechanisms, influencing a wide range of physiological processes and impacting various medical conditions. Recent advancements in structural biology and computational modeling have provided significant insights into their function and regulation. This review provides an overview of the current knowledge of human ABC and SLC transporters, emphasizing their structural and functional relationships, transport mechanisms, and the contribution of computational approaches to their understanding. Current challenges and promising future research and methodological directions are also discussed.
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Affiliation(s)
- Ahmad Elbahnsi
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
| | - Balint Dudas
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
| | - Isabelle Callebaut
- Muséum National d’Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie—IMPMC, Sorbonne Université, 75005 Paris, France
| | - Alexandre Hinzpeter
- CNRS, INSERM, Institut Necker Enfants Malades—INEM, Université Paris Cité, 75015 Paris, France
| | - Maria A. Miteva
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
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21
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Habermaass V, Bartoli F, Gori E, Dini R, Cogozzo A, Puccinelli C, Pierini A, Marchetti V. Fecal Bile Acids in Canine Chronic Liver Disease: Results from 46 Dogs. Animals (Basel) 2024; 14:3051. [PMID: 39518774 PMCID: PMC11545594 DOI: 10.3390/ani14213051] [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: 09/09/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
The concentrations of fecal and serum bile acids (BAs) are known to be altered in human patients with chronic liver diseases (CLDs), especially those with biliary tract involvement (BTD). Scarce literature is available regarding fecal BA modifications during canine CLDs. This study aimed to evaluate fecal BAs in canine CLDs according to different clinical and clinicopathological variables. Forty-six dogs were enrolled. Canine feces were analyzed by HPLC. Cholic Acid (CA), Chenodeoxycholic Acid (CDCA), Ursodeoxycholic Acid (UDCA), Deoxycholic Acid (DCA), and Lithocholic Acid (LCA) were measured, and primary BAs (CA + CDCA), secondary BAs (UDCA + DCA + LCA), and the primary/secondary (P/S) ratio were calculated. Primary BAs (p < 0.0001), CA (p = 0.0003), CDCA (p = 0.003), the P/S ratio (p = 0.002), and total BAs (p = 0.005) were significatively higher in BTD dogs (n = 18) compared to in non-BTD dogs (n = 28). Fecal secondary BAs did not statistically differ between BTD and non-BTD dogs. Gastrointestinal clinical signs (p = 0.028) and diarrhea (p = 0.03) were significantly more prevalent in BTD dogs compared to in non-BTD dogs, supporting the hypothesis of some pathological mechanisms assimilable to bile acid diarrhea (BAD). Our results could reflect imbalances of the fecal BA metabolism in dogs with CLDs. Further studies involving gut microbiome and metabolomic assessment are needed to better understand the possible clinical implications of BA metabolism disruption and their potential role in canine CLDs.
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Affiliation(s)
- Verena Habermaass
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
| | - Francesco Bartoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Savi 10, 56126 Pisa, Italy
| | - Eleonora Gori
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
| | - Rebecca Dini
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
| | - Aurora Cogozzo
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
| | - Caterina Puccinelli
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
| | - Alessio Pierini
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
| | - Veronica Marchetti
- Department of Veterinary Sciences, Veterinary Teaching Hospital “Mario Modenato”, University of Pisa, Via Livornese Lato Monte, San Piero a Grado, 56122 Pisa, Italy; (V.H.); (V.M.)
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22
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Schneeweiss-Gleixner M, Krenn K, Petter M, Haselwanter P, Kraft F, Adam L, Semmler G, Hartl L, Halilbasic E, Buchtele N, Krall C, Staudinger T, Zauner C, Trauner M, Stättermayer AF. Presence of cholestasis and its impact on survival in SARS-CoV-2 associated acute respiratory distress syndrome. Sci Rep 2024; 14:23377. [PMID: 39379494 PMCID: PMC11461911 DOI: 10.1038/s41598-024-73948-x] [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: 04/16/2024] [Accepted: 09/23/2024] [Indexed: 10/10/2024] Open
Abstract
Data on cholestasis and biliary injury in patients with COVID-19 are scarce. The primary aim of this study was to evaluate the prevalence of cholestasis and factors associated with its development and outcome in critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS). In this retrospective exploratory study, COVID-19 patients with ARDS admitted to an intensive care unit (ICU) at the Medical University of Vienna were evaluated for the development of cholestasis defined as an alkaline phosphatase level of 1.67x upper limit of normal for at least three consecutive days. Simple and multiple logistic regression analysis was used to evaluate parameters associated with development of cholestasis and survival. Of 225 included patients 119 (53%) developed cholestasis during ICU stay. Patients with cholestasis had higher peak levels of alkaline phosphatase, gamma-glutamyl transferase, bilirubin and inflammation parameters. Factors independently associated with cholestasis were extracorporeal membrane oxygenation support, ketamine use, high levels of inflammation parameters and disease severity. Presence of cholestasis and peak ALP levels were independently associated with worse ICU and 6-month survival. Development of cholestasis is a common complication in critically ill COVID-19 patients and represents a negative prognostic marker for survival. It is associated with disease severity and specific treatment modalities of intensive care.
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Affiliation(s)
- Mathias Schneeweiss-Gleixner
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Katharina Krenn
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Mathias Petter
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Patrick Haselwanter
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Felix Kraft
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Lukas Adam
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Nina Buchtele
- Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, Vienna, Austria
| | - Christoph Krall
- Department of Medical Statistics, Medical University of Vienna, Vienna, Austria
| | - Thomas Staudinger
- Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, Vienna, Austria
| | - Christian Zauner
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria.
| | - Albert Friedrich Stättermayer
- Department of Medicine III, Division of Gastroenterology and Hepatology with Intensive Care Unit 13h1, Medical University of Vienna, Vienna, Austria.
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24
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Fiorucci S, Urbani G, Di Giorgio C, Biagioli M, Distrutti E. Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments. Cells 2024; 13:1650. [PMID: 39404413 PMCID: PMC11475195 DOI: 10.3390/cells13191650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/19/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein-coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Cristina Di Giorgio
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy;
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25
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Kastrinou-Lampou V, Rodríguez-Pérez R, Poller B, Huth F, Gáborik Z, Mártonné-Tóth B, Temesszentandrási-Ambrus C, Schadt HS, Kullak-Ublick GA, Arand M, Camenisch G. Identification of reversible OATP1B1 and time-dependent CYP3A4 inhibition as the major risk factors for drug-induced cholestasis (DIC). Arch Toxicol 2024; 98:3409-3424. [PMID: 39023798 DOI: 10.1007/s00204-024-03794-3] [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: 09/28/2023] [Accepted: 05/22/2024] [Indexed: 07/20/2024]
Abstract
Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.
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Affiliation(s)
- Vlasia Kastrinou-Lampou
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Birk Poller
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Felix Huth
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Zsuzsanna Gáborik
- SOLVO Biotechnology, Charles River Laboratories Hungary, 1117, Budapest, Hungary
| | - Beáta Mártonné-Tóth
- SOLVO Biotechnology, Charles River Laboratories Hungary, 1117, Budapest, Hungary
| | | | - Heiko S Schadt
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis, Basel, Switzerland
| | - Michael Arand
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Gian Camenisch
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland.
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26
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Dicks L, Schuh-von Graevenitz K, Prehn C, Sadri H, Murani E, Hosseini Ghaffari M, Häussler S. Bile acid profiles and mRNA abundance of bile acid-related genes in adipose tissue of dairy cows with high versus normal body condition. J Dairy Sci 2024; 107:6288-6307. [PMID: 38490538 DOI: 10.3168/jds.2024-24346] [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: 10/25/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024]
Abstract
Besides their lipid-digestive role, bile acids (BA) influence overall energy homeostasis, such as glucose and lipid metabolism. We hypothesized that BA along with their receptors, regulatory enzymes, and transporters are present in subcutaneous adipose tissue (scAT). In addition, we hypothesized that their mRNA abundance varies with the body condition of dairy cows around calving. Therefore, we analyzed BA in serum and scAT as well as the mRNA abundance of BA-related enzymes, transporters, and receptors in scAT during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into either a high (HBCS; n = 19) or normal BCS (NBCS; n = 19) group based on their BCS and back-fat thickness (BFT). Cows were fed different diets to achieve the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off at 7 wk antepartum. During the dry period and subsequent lactation, both groups were fed the same diets according to their energy demands. Using a targeted metabolomics approach via liquid chromatography-electrospray ionization-MS /MS, BA were analyzed in serum and scAT at wk -7, 1, 3, and 12 relative to parturition. In serum, 15 BA were observed: cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid, deoxycholic acid (DCA), lithocholic acid, glycodeoxycholic acid (GDCA), glycolithocholic acid, taurodeoxycholic acid, taurolithocholic acid, β-muricholic acid, tauromuricholic acid (sum of α and β), and glycoursodeoxycholic acid, whereas in scAT 7 BA were detected: CA, GCA, TCA, GCDCA, taurochenodeoxycholic acid, GDCA, and taurodeoxycholic acid. In serum and scAT samples, the primary BA CA and its conjugate GCA were predominantly detected. Increasing serum concentrations of CA, CDCA, TCA, GCA, GCDCA, DCA, and β-muricholic acid with the onset of lactation might be related to the increasing DMI after parturition. Furthermore, serum concentrations of CA, CDCA, GCA, DCA, GCDCA, TCA, lithocholic acid, and GDCA were lower in HBCS cows compared with NBCS cows, concomitant with increased lipolysis in HBCS cows. The correlation between CA in serum and scAT may point to the transport of CA across cell membranes. Overall, the findings of the present study suggest a potential role of BA in lipid metabolism depending on the body condition of periparturient dairy cows.
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Affiliation(s)
- Lena Dicks
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Katharina Schuh-von Graevenitz
- Department of Life Sciences and Engineering, Animal Nutrition and Hygiene Unit, University of Applied Sciences Bingen, 55411 Bingen am Rhein, Germany
| | - Cornelia Prehn
- Helmholtz Zentrum München, German Research Center for Environmental Health, Metabolomics and Proteomics Core, 85764 Neuherberg, Germany
| | - Hassan Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 516616471 Tabriz, Iran
| | - Eduard Murani
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | | | - Susanne Häussler
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
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27
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Shang T, Zhang C, Liu D. Drug disposition in cholestasis: An important concern. Pharmacol Res Perspect 2024; 12:e1220. [PMID: 38899589 PMCID: PMC11187734 DOI: 10.1002/prp2.1220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/08/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Cholestasis, a chronic liver condition, disrupts bile acid homeostasis and complicates drug disposition, posing significant challenges in medicating cholestatic patients. Drug metabolism enzymes and transporters (DMETs) are pivotal in drug clearance. Research indicates that cholestasis leads to alterations in both hepatic and extrahepatic DMETs, with changes in expression and function documented in rodents and humans. This review synthesizes the modifications in key drug disposition components within cholestasis, focusing on cytochrome P450 (CYP450), drug transporters, and their substrates. Additionally, we briefly discuss certain drugs that have demonstrated efficacy in restoring DMET expression in cholestatic conditions. Ultimately, these insights necessitate a reevaluation of drug selection and dosing guidelines for patients with cholestasis.
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Affiliation(s)
- Tianze Shang
- Department of Pharmacy, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Chengliang Zhang
- Department of Pharmacy, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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28
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Zhou Y, Li M, Cao Y, Chang W, Jia H, Wang L, Xu H, Wang Y, Liu P, Chen WD. Farnesoid X Receptor: Effective alleviation of rifampicin -induced liver injury. Int Immunopharmacol 2024; 139:112799. [PMID: 39068755 DOI: 10.1016/j.intimp.2024.112799] [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: 04/07/2024] [Revised: 06/25/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
Antituberculosis drugs induce pharmacologic cholestatic liver injury with long-term administration. Liver injury resulting from rifampicin is potentially related to the bile acid nuclear receptor Farnesoid X Receptor (FXR). To investigate this, cholestasis was induced in both wild-type (C57BL/6N) mice and FXR knockout (FXR-null) mice through administration of rifampicin (200 mg/kg) via gavage for 7 consecutive days. Compared with C57BL/6N mice, FXR-null mice exhibited more severe liver injury after rifampicin administration, characterized by enlarged liver size, elevated transaminases, and increased inflammation. Moreover, under rifampicin treatment, FXR knockout impairs lipid secretion and exacerbates hepatic steatosis. Significantly, the expression of metabolism molecules BSEP increased, while NTCP and CYP7A1 decreased following rifampicin administration in C57BL/6N mice, whereas these changes were absent in FXR knockout mice. Furthermore, rifampicin treatment in both C57BL/6N and FXR-null mice was associated with elevated c-Jun N-terminal kinase phosphorylation (p-JNK) levels, with a more pronounced elevation in FXR-null mice. Our study suggests that rifampicin-induced liver injury, steatosis, and cholestasis are associated with FXR dysfunction and altered bile acid metabolism, and that the JNK signaling pathway is partially implicated in this injury. Based on these results, we propose that FXR might be a novel therapeutic target for addressing drug-induced liver injury.
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Affiliation(s)
- Yun Zhou
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China; Hebi Key Laboratory of Liver Disease, Hebi Key Laboratory of Cardiovascular Diseases, Hebi Key Laboratory of Energy Metabolism, People's Hospital of Hebi, Henan University, Henan, PR China
| | - Meijie Li
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China
| | - Yutong Cao
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China
| | - Weihua Chang
- Hebi Key Laboratory of Liver Disease, Hebi Key Laboratory of Cardiovascular Diseases, Hebi Key Laboratory of Energy Metabolism, People's Hospital of Hebi, Henan University, Henan, PR China
| | - Hao Jia
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China
| | - Longmei Wang
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China
| | - Huimin Xu
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China
| | - Yandong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, PR China
| | - Peng Liu
- Hebi Key Laboratory of Liver Disease, Hebi Key Laboratory of Cardiovascular Diseases, Hebi Key Laboratory of Energy Metabolism, People's Hospital of Hebi, Henan University, Henan, PR China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Henan, PR China; Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, PR China.
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29
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Huang Y, Xu W, Dong W, Chen G, Sun Y, Zeng X. Anti-diabetic effect of dicaffeoylquinic acids is associated with the modulation of gut microbiota and bile acid metabolism. J Adv Res 2024:S2090-1232(24)00264-9. [PMID: 38969095 DOI: 10.1016/j.jare.2024.06.027] [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: 03/30/2024] [Revised: 06/06/2024] [Accepted: 06/30/2024] [Indexed: 07/07/2024] Open
Abstract
INTRODUCTION The human gut microbiome plays a pivotal role in health and disease, notably through its interaction with bile acids (BAs). BAs, synthesized in the liver, undergo transformation by the gut microbiota upon excretion into the intestine, thus influencing host metabolism. However, the potential mechanisms of dicaffeoylquinic acids (DiCQAs) from Ilex kudingcha how to modulate lipid metabolism and inflammation via gut microbiota remain unclear. OBJECTIVES AND METHODS The objectives of the present study were to investigate the regulating effects of DiCQAs on diabetes and the potential mechanisms of action. Two mice models were utilized to investigate the anti-diabetic effects of DiCQAs. Additionally, analysis of gut microbiota structure and functions was conducted concurrently with the examination of DiCQAs' impact on gut microbiota carrying the bile salt hydrolase (BSH) gene, as well as on the enterohepatic circulation of BAs and related signaling pathways. RESULTS Our findings demonstrated that DiCQAs alleviated diabetic symptoms by modulating gut microbiota carrying the BSH gene. This modulation enhanced intestinal barrier integrity, increased enterohepatic circulation of conjugated BAs, and inhibited the farnesoid X receptor-fibroblast growth factor 15 (FGF15) signaling axis in the ileum. Consequently, the protein expression of hepatic FGFR4 fibroblast growth factor receptor 4 (FGFR4) decreased, accompanied by heightened BA synthesis, reduced hepatic BA stasis, and lowered levels of hepatic and plasma cholesterol. Furthermore, DiCQAs upregulated glucolipid metabolism-related proteins in the liver and muscle, including v-akt murine thymoma viral oncogene homolog (AKT)/glycogen synthase kinase 3-beta (GSK3β) and AMP-activated protein kinase (AMPK), thereby ameliorating hyperglycemia and mitigating inflammation through the down-regulation of the MAPK signaling pathway in the diabetic group. CONCLUSION Our study elucidated the anti-diabetic effects and mechanism of DiCQAs from I. kudingcha, highlighting the potential of targeting gut microbiota, particularly Acetatifactor sp011959105 and Acetatifactor muris carrying the BSH gene, as a therapeutic strategy to attenuate FXR-FGF15 signaling and ameliorate diabetes.
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Affiliation(s)
- Yujie Huang
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China; School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, China
| | - Weiqi Xu
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Wei Dong
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Guijie Chen
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Yi Sun
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Xiaoxiong Zeng
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.
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30
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Karakus E, Proksch AL, Moritz A, Geyer J. Quantitative bile acid profiling in healthy adult dogs and pups from serum, plasma, urine, and feces using LC-MS/MS. Front Vet Sci 2024; 11:1380920. [PMID: 38948668 PMCID: PMC11211631 DOI: 10.3389/fvets.2024.1380920] [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: 02/02/2024] [Accepted: 04/29/2024] [Indexed: 07/02/2024] Open
Abstract
Synthesis and secretion of bile acids (BA) is a key physiological function of the liver. In pathological conditions like portosystemic shunt, hepatic insufficiency, hepatitis, or cirrhosis BA metabolism and secretion are disturbed. Quantification of total serum BA is an established diagnostic method to assess the general liver function and allows early detection of abnormalities, liver disease progression and guidance of treatment decisions. To date, data on comparative BA profiles in dogs are limited. However, BA profiles might be even better diagnostic parameters than total BA concentrations. On this background, the present study analyzed and compared individual BA profiles in serum, plasma, urine, and feces of 10 healthy pups and 40 adult healthy dogs using ultra-high performance liquid chromatography coupled to electrospray ionization mass spectrometry. Sample preparation was performed by solid-phase extraction for serum, plasma, and urine samples or by protein precipitation with methanol for the feces samples. For each dog, 22 different BA, including unconjugated BA and their glycine and taurine conjugates, were analyzed. In general, there was a great interindividual variation for the concentrations of single BA, mostly exemplified by the fact that cholic acid (CA) was by far the most prominent BA in blood and urine samples of some of the dogs (adults and pups), while in others, CA was under the detection limit. There were no significant age-related differences in the BA profiles, but pups showed generally lower absolute BA concentrations in serum, plasma, and urine. Taurine-conjugated BA were predominant in the serum and plasma of both pups (68%) and adults (74-75%), while unconjugated BA were predominant in the urine and feces of pups (64 and 95%, respectively) and adults (68 and 99%, respectively). The primary BA chenodeoxycholic acid and taurocholic acid and the secondary BA deoxycholic acid and lithocholic acid were the most robust analytes for potential diagnostic purpose. In conclusion, this study reports simultaneous BA profiling in dog serum, plasma, urine, and feces and provides valuable diagnostic data for subsequent clinical studies in dogs with different kinds of liver diseases.
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Affiliation(s)
- Emre Karakus
- Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany
| | - Anna-Lena Proksch
- Clinic of Small Animals—Internal Medicine, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany
| | - Andreas Moritz
- Clinic of Small Animals—Internal Medicine, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany
| | - Joachim Geyer
- Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany
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31
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Dicks L, Schuh-von Graevenitz K, Prehn C, Sadri H, Ghaffari MH, Häussler S. Bile acid profiles and mRNA expression of bile acid-related genes in the liver of dairy cows with high versus normal body condition. J Dairy Sci 2024:S0022-0302(24)00922-6. [PMID: 38876220 DOI: 10.3168/jds.2024-24844] [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: 02/28/2024] [Accepted: 05/12/2024] [Indexed: 06/16/2024]
Abstract
Bile acids (BA) play a crucial role not only in lipid digestion but also in the regulation of overall energy homeostasis, including glucose and lipid metabolism. The aim of this study was to investigate BA profiles and mRNA expression of BA-related genes in the liver of high versus normal body condition in dairy cows. We hypothesized that body condition and the transition from gestation to lactation affect hepatic BA concentrations as well as the mRNA abundance of BA-related receptors, regulatory enzymes, and transporters. Therefore, we analyzed BA in the liver as well as the mRNA abundance of BA-related synthesizing enzymes, transporters, and receptors in the liver during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into groups with high body condition score (BCS) (HBCS; n = 19) or normal BCS (NBCS; n = 19) based on BCS and backfat thickness (BFT). Cows were fed diets aimed at achieving the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until they were dried off at wk 7 before parturition. Both groups were fed identical diets during the dry period and subsequent lactation. Liver biopsies were taken at wk -7, 1, 3, and 12 relative to parturition. For BA measurement, a targeted metabolomics approach with LC-ESI-MS/MS was used to analyze BA in the liver. The mRNA abundance of targeted genes related to BA-synthesizing enzymes, transporters, and receptors in the liver was analyzed using microfluidic quantitative PCR. In total, we could detect 14 BA in the liver: 6 primary and 8 secondary BA, with glycocholic acid (GCA) being the most abundant one. The increase of glycine-conjugated BA after parturition, in parallel to increasing serum glycine concentrations may originate from an enhanced mobilization of muscle protein to meet the high nutritional requirements in early lactating cows. Higher DMI in NBCS cows compared with HBCS cows was associated with higher liver BA concentrations such as GCA, deoxycholic acid (DCA), and cholic acid (CA). The mRNA abundance of BA-related enzymes measured herein suggests the dominance of the alternative signaling pathway in the liver of HBCS cows. Overall, BA profiles and BA metabolism in the liver depend on both, the body condition and lactation-induced effects in periparturient dairy cows.
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Affiliation(s)
- Lena Dicks
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Katharina Schuh-von Graevenitz
- Department of Life Sciences and Engineering, Animal Nutrition and Hygiene Unit, University of Applied Sciences Bingen, 55411 Bingen am Rhein, Germany
| | - Cornelia Prehn
- Helmholtz Zentrum München, German Research Center for Environmental Health, Metabolomics and Proteomics Core, 85764 Neuherberg, Germany
| | - Hassan Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 516616471 Tabriz, Iran
| | - Morteza H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Susanne Häussler
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
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Xie Y, Shao X, Zhang P, Zhang H, Yu J, Yao X, Fu Y, Wei J, Wu C. High Starch Induces Hematological Variations, Metabolic Changes, Oxidative Stress, Inflammatory Responses, and Histopathological Lesions in Largemouth Bass ( Micropterus salmoides). Metabolites 2024; 14:236. [PMID: 38668364 PMCID: PMC11051861 DOI: 10.3390/metabo14040236] [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: 03/25/2024] [Revised: 04/09/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
This study evaluated effects of high starch (20%) on hematological variations, glucose and lipid metabolism, antioxidant ability, inflammatory responses, and histopathological lesions in largemouth bass. Results showed hepatic crude lipid and triacylglycerol (TAG) contents were notably increased in fish fed high starch. High starch could increase counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils and serum contents of TAG, TBA, BUN, and LEP (p < 0.05). There were increasing trends in levels of GLUT2, glycolysis, gluconeogenesis, and LDH in fish fed high starch through the AKT/PI3K signal pathway. Meanwhile, high starch not only triggered TAG and cholesterol synthesis, but mediated cholesterol accumulation by reducing ABCG5, ABCG8, and NPC1L1. Significant increases in lipid droplets and vacuolization were also shown in hepatocytes of D3-D7 groups fed high starch. In addition, high starch could decrease levels of mitochondrial Trx2, TrxR2, and Prx3, while increasing ROS contents. Moreover, high starch could notably increase amounts of inflammatory factors (IL-1β, TNF-α, etc.) by activating NLRP3 inflammasome key molecules (GSDME, caspase 1, etc.). In conclusion, high starch could not only induce metabolic disorders via gluconeogenesis and accumulation of glycogen, TAG, and cholesterol, but could disturb redox homeostasis and cause inflammatory responses by activating the NLRP3 inflammasome in largemouth bass.
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Affiliation(s)
| | - Xianping Shao
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Department of Fisheries, School of Life Science, Huzhou University, 759 East 2nd Road, Huzhou 313000, China; (Y.X.); (P.Z.); (H.Z.); (J.Y.); (X.Y.); (Y.F.); (J.W.)
| | | | | | | | | | | | | | - Chenglong Wu
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Department of Fisheries, School of Life Science, Huzhou University, 759 East 2nd Road, Huzhou 313000, China; (Y.X.); (P.Z.); (H.Z.); (J.Y.); (X.Y.); (Y.F.); (J.W.)
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Yuan P, Ma R, Hu L, Li R, Wang P, Lin S, Huang J, Wen H, Huang L, Li H, Feng B, Chen H, Liu Y, Zhang X, Lin Y, Xu S, Li J, Zhuo Y, Hua L, Che L, Wu D, Fang Z. Zearalenone Decreases Food Intake by Disrupting the Gut-Liver-Hypothalamus Axis Signaling via Bile Acids. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:8200-8213. [PMID: 38560889 DOI: 10.1021/acs.jafc.4c00421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Zearalenone (ZEN) is a mycotoxin that is harmful to humans and animals. In this study, female and male rats were exposed to ZEN, and the results showed that ZEN reduced the farnesoid X receptor (FXR) expression levels in the liver and disrupted the enterohepatic circulation of bile acids (BAs). A decrease in food intake induced by ZEN was negatively correlated with an increase in the level of total BAs. BA-targeted metabolomics revealed that ZEN increased glycochenodeoxycholic acid levels and decreased the ratio of conjugated BAs to unconjugated BAs, which further increased the hypothalamic FXR expression levels. Preventing the increase in total BA levels induced by ZEN via Lactobacillus rhamnosus GG intervention restored the appetite. In conclusion, ZEN disrupted the enterohepatic circulation of BAs to decrease the level of food intake. This study reveals a possible mechanism by which ZEN affects food intake and provides a new approach to decrease the toxic effects of ZEN.
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Affiliation(s)
- Peiqiang Yuan
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
| | - Rongman Ma
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Liang Hu
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
| | - Ran Li
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
| | - Peng Wang
- College of Biology Engineering, Henan University of Technology, Zhengzhou 450001, People's Republic of China
| | - Sen Lin
- Key Laboratory of Urban Agriculture in South China, Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, People's Republic of China
| | - Jiancai Huang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Hongmei Wen
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Lingjie Huang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
| | - Hua Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Bin Feng
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Hong Chen
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
| | - Yuntao Liu
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
| | - Xiaoling Zhang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Yan Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Shengyu Xu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Jian Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Yong Zhuo
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Lun Hua
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Lianqiang Che
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
| | - Zhengfeng Fang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Huimin Road 211, Wenjiang District, Chengdu 611130, People's Republic of China
- Key Laboratory of Agricultural Product processing and Nutrition Health (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, College of Food Science, Sichuan Agricultural University, Ya'an 625014, People's Republic of China
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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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Liu H, Zakrzewicz D, Nosol K, Irobalieva RN, Mukherjee S, Bang-Sørensen R, Goldmann N, Kunz S, Rossi L, Kossiakoff AA, Urban S, Glebe D, Geyer J, Locher KP. Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP. Nat Commun 2024; 15:2476. [PMID: 38509088 PMCID: PMC10954734 DOI: 10.1038/s41467-024-46706-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/06/2024] [Indexed: 03/22/2024] Open
Abstract
Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor's extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.
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Affiliation(s)
- Hongtao Liu
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Dariusz Zakrzewicz
- Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany
| | - Kamil Nosol
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | | | - Somnath Mukherjee
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA
| | - Rose Bang-Sørensen
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Nora Goldmann
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF) - Giessen-Marburg-Langen Partner Site, Giessen, Germany
| | - Sebastian Kunz
- Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany
| | - Lorenzo Rossi
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Anthony A Kossiakoff
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
- German Center for Infection Research (DZIF) - partner site Heidelberg, Heidelberg, Germany.
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, Germany.
- German Center for Infection Research (DZIF) - Giessen-Marburg-Langen Partner Site, Giessen, Germany.
| | - Joachim Geyer
- Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany.
| | - Kaspar P Locher
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland.
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Zhang Y, Tang N, Zhou H, Zhu Y. The role of microbial metabolites in endocrine tumorigenesis: From the mechanistic insights to potential therapeutic biomarkers. Biomed Pharmacother 2024; 172:116218. [PMID: 38308969 DOI: 10.1016/j.biopha.2024.116218] [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: 09/26/2023] [Revised: 12/28/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
Microbial metabolites have been indicated to communicate with the host's endocrine system, regulating hormone production, immune-endocrine communications, and interactions along the gut-brain axis, eventually affecting the occurrence of endocrine cancer. Furthermore, microbiota metabolites such as short-chain fatty acids (SCFAs) have been found to affect the tumor microenvironment and boost immunity against tumors. SCFAs, including butyrate and acetate, have been demonstrated to exert anti-proliferative and anti-protective activity on pancreatic cancer cells. The employing of microbial metabolic products in conjunction with radiation and chemotherapy has shown promising outcomes in terms of reducing treatment side effects and boosting effectiveness. Certain metabolites, such as valerate and butyrate, have been made known to improve the efficiency of CAR T-cell treatment, whilst others, such as indole-derived tryptophan metabolites, have been shown to inhibit tumor immunity. This review explores the intricate interplay between microbial metabolites and endocrine tumorigenesis, spanning mechanistic insights to the discovery of potential therapeutic biomarkers.
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Affiliation(s)
- Yiyi Zhang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Nie Tang
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
| | - Hui Zhou
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
| | - Ying Zhu
- Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China.
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Liu W, Li Z, Ze X, Deng C, Xu S, Ye F. Multispecies probiotics complex improves bile acids and gut microbiota metabolism status in an in vitro fermentation model. Front Microbiol 2024; 15:1314528. [PMID: 38444809 PMCID: PMC10913090 DOI: 10.3389/fmicb.2024.1314528] [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: 10/10/2023] [Accepted: 01/31/2024] [Indexed: 03/07/2024] Open
Abstract
The consumption of probiotics has been extensively employed for the management or prevention of gastrointestinal disorders by modifying the gut microbiota and changing metabolites. Nevertheless, the probiotic-mediated regulation of host metabolism through the metabolism of bile acids (BAs) remains inadequately comprehended. The gut-liver axis has received more attention in recent years due to its association with BA metabolism. The objective of this research was to examine the changes in BAs and gut microbiota using an in vitro fermentation model. The metabolism and regulation of gut microbiota by commercial probiotics complex containing various species such as Lactobacillus, Bifidobacterium, and Streptococcus were investigated. The findings indicated that the probiotic strains had produced diverse metabolic profiles of BAs. The probiotics mixture demonstrated the greatest capacity for Bile salt hydrolase (BSH) deconjugation and 7α-dehydroxylation, leading to a significant elevation in the concentrations of Chenodeoxycholic acid, Deoxycholic acidcholic acid, and hyocholic acid in humans. In addition, the probiotic mixtures have the potential to regulate the microbiome of the human intestines, resulting in a reduction of isobutyric acid, isovaleric acid, hydrogen sulfide, and ammonia. The probiotics complex intervention group showed a significant increase in the quantities of Lactobacillus and Bifidobacterium strains, in comparison to the control group. Hence, the use of probiotics complex to alter gut bacteria and enhance the conversion of BAs could be a promising approach to mitigate metabolic disorders in individuals.
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Affiliation(s)
- Wei Liu
- Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Zhongxia Li
- BYHEALTH Institute of Nutrition and Health, Guangzhou, China
| | - Xiaolei Ze
- BYHEALTH Institute of Nutrition and Health, Guangzhou, China
| | - Chaoming Deng
- BYHEALTH Institute of Nutrition and Health, Guangzhou, China
| | - Shunfu Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Xu L, Kong X, Li X, Zhang B, Deng Y, Wang J, Duan C, Zhang D, Liu W. Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties. Molecules 2024; 29:746. [PMID: 38398498 PMCID: PMC10892972 DOI: 10.3390/molecules29040746] [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: 01/02/2024] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.
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Affiliation(s)
- Lingwen Xu
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Xiangyu Kong
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Xinzhi Li
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Bin Zhang
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Yuxiao Deng
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Jinhu Wang
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Chonggang Duan
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Daizhou Zhang
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
| | - Wentao Liu
- Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China; (L.X.); (X.K.); (X.L.); (B.Z.); (Y.D.); (J.W.); (C.D.)
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China
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Huang W, Cao Z, Wang W, Yang Z, Jiao S, Chen Y, Chen S, Zhang L, Li Z. Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease. Bioorg Chem 2024; 143:107071. [PMID: 38199141 DOI: 10.1016/j.bioorg.2023.107071] [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: 11/03/2023] [Revised: 12/14/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024]
Abstract
Farnesoid X receptor (FXR) was considered as a promising drug target in the treatment of cholestasis, drug-induced liver injury, and non-alcoholic steatohepatitis (NASH). However, the existing FXR agonists have shown different degrees of side effects in clinical trials without clear interpretation. MET-409 in clinical phase Ⅲ, has been proven significantly fewer side effects than that of other FXR agonists. This may be due to the completely different structure of FEX and other non-steroidal FXR agonists. Herein, the structure-based drug design was carried out based on FEX, and the more active FXR agonist LH10 (FEX EC50 = 0,3 μM; LH10 EC50 = 0.14 μM)) was screened out by the comprehensive SAR studies. Furthermore, LH10 exhibited robust hepatoprotective activity on the ANIT-induced cholestatic model and APAP-induced acute liver injury model, which was even better than positive control OCA. In the nonalcoholic steatohepatitis (NASH) model, LH10 significantly improved the pathological characteristics of NASH by regulating several major pathways including lipid metabolism, inflammation, oxidative stress, and fibrosis. With the above attractive results, LH10 is worthy of further evaluation as a novel agent for the treatment of liver disorders.
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Affiliation(s)
- Wanqiu Huang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Zhijun Cao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Wenxin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Zhongcheng Yang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Shixuan Jiao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Ya Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Siliang Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Luyong Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, PR China.
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Ortiz K, Cetin Z, Sun Y, Hu Z, Kurihara T, Tafaleng EN, Florentino RM, Ostrowska A, Soto-Gutierrez A, Faccioli LA. Human Hepatocellular response in Cholestatic Liver Diseases. Organogenesis 2023; 19:2247576. [PMID: 37598346 PMCID: PMC10444014 DOI: 10.1080/15476278.2023.2247576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/26/2023] [Accepted: 08/09/2023] [Indexed: 08/22/2023] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the most common types of cholestatic liver disease (CLD), result in enterohepatic obstruction, bile acid accumulation, and hepatotoxicity. The mechanisms by which hepatocytes respond to and cope with CLD remain largely unexplored. This study includes the characterization of hepatocytes isolated from explanted livers of patients with PBC and PSC. We examined the expression of hepatocyte-specific genes, intracellular bile acid (BA) levels, and oxidative stress in primary-human-hepatocytes (PHHs) isolated from explanted livers of patients with PBC and PSC and compared them with control normal human hepatocytes. Our findings provide valuable initial insights into the hepatocellular response to cholestasis in CLD and help support the use of PHHs as an experimental tool for these diseases.
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Affiliation(s)
- Kimberly Ortiz
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Zeliha Cetin
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yiyue Sun
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Zhiping Hu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Takeshi Kurihara
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Edgar N. Tafaleng
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Rodrigo M. Florentino
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alina Ostrowska
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA
| | - Lanuza A.P. Faccioli
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Pittsburgh Liver Research Center, Human Synthetic Liver Biology Core, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Zhang Y, Fang XM. The pan-liver network theory: From traditional chinese medicine to western medicine. CHINESE J PHYSIOL 2023; 66:401-436. [PMID: 38149555 DOI: 10.4103/cjop.cjop-d-22-00131] [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] [Indexed: 12/28/2023] Open
Abstract
In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.
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Affiliation(s)
- Yaxing Zhang
- Department of Physiology; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong; Issue 12th of Guangxi Apprenticeship Education of Traditional Chinese Medicine (Shi-Cheng Class of Guangxi University of Chinese Medicine), College of Continuing Education, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xian-Ming Fang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine (Guangxi Hospital of Integrated Chinese Medicine and Western Medicine, Ruikang Clinical Faculty of Guangxi University of Chinese Medicine), Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Di Ciaula A, Bonfrate L, Khalil M, Portincasa P. The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease. Intern Emerg Med 2023; 18:2181-2197. [PMID: 37515676 PMCID: PMC10635993 DOI: 10.1007/s11739-023-03343-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 06/08/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy.
| | - Mohamad Khalil
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri" and Division Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University "Aldo Moro" Medical School, Policlinico Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
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Jiang L, Xu J, Cheng SY, Wang Y, Cai W. The gut microbiome and intestinal failure-associated liver disease. Hepatobiliary Pancreat Dis Int 2023; 22:452-457. [PMID: 37453856 DOI: 10.1016/j.hbpd.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Intestinal failure-associated liver disease (IFALD) is a common hepatobiliary complication resulting from long-term parenteral nutrition (PN) in patients with intestinal failure. The spectrum of IFALD ranges from cholestasis, steatosis, portal fibrosis, to cirrhosis. Development of IFALD is a multifactorial process, in which gut dysbiosis plays a critical role in its initiation and progression in conjunction with increased intestinal permeability, activation of hepatic immune responses, and administration of lipid emulsion. Gut microbiota manipulation including pre/probiotics, fecal microbiota transplantation, and antibiotics has been studied in IFALD with varying success. In this review, we summarize current knowledge on the taxonomic and functional changes of gut microbiota in preclinical and clinical studies of IFALD. We also review the function of microbial metabolites and associated signalings in the context of IFALD. By providing microbiota-targeted interventions aiming to optimize PN-induced liver injury, our review provides perspectives for future basic and translational investigations in the field.
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Affiliation(s)
- Lu Jiang
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Juan Xu
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Si-Yang Cheng
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China; Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
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Ferri N, Corsini A. Mechanism of bempedoic acid induced cholelithiasis: A role for statins to limit this adverse effect? Pharmacol Res 2023; 196:106900. [PMID: 37652280 DOI: 10.1016/j.phrs.2023.106900] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/02/2023]
Affiliation(s)
- Nicola Ferri
- Department of Medicine (DIMED), University of Padova, 35129 Padova, Italy; Veneto Institute of Molecular Medicine (VIMM), 35129 Padua, Italy.
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
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Qin T, Hasnat M, Wang Z, Hassan HM, Zhou Y, Yuan Z, Zhang W. Geniposide alleviated bile acid-associated NLRP3 inflammasome activation by regulating SIRT1/FXR signaling in bile duct ligation-induced liver fibrosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 118:154971. [PMID: 37494875 DOI: 10.1016/j.phymed.2023.154971] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/14/2023] [Accepted: 07/15/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Geniposide (GE), the active compound derived from Gardeniae Fructus, possesses valuable bioactivity for liver diseases, but GE effects on bile duct ligation (BDL)-induced cholestasis remain unclear. This study aimed to elucidate the influence of GE on BDL-induced liver fibrosis and to investigate the underlying mechanisms. METHODS GE (25 or 50 mg/kg) were intragastrical administered to C57BL/6 J mice for two weeks to characterize the hepatoprotective effect of GE on BDL-induced liver fibrosis. NLRP3 inflammasome activation was detected in vivo, and BMDMs were isolated to explore whether GE directly inhibited NLRP3 inflammasome activation. Serum bile acid (BA) profiles were assessed utilizing UPLC-MS/MS, and the involvement of SIRT1/FXR pathways was identified to elucidate the role of SIRT1/FXR in the hepaprotective effect of GE. The veritable impact of SIRT1/FXR signaling was further confirmed by administering the SIRT1 inhibitor EX527 (10 mg/kg) to BDL mice treated with GE. RESULTS GE treatment protected mice from BDL-induced liver fibrosis, with NLRP3 inflammasome inhibition. However, development in vitro experiments revealed that GE could not directly inhibit NLRP3 activation under ATP, monosodium urate, and nigericin stimulation. Further mechanistic data showed that GE activated SIRT1, which subsequently deacetylated FXR and restored CDCA, TUDCA, and TCDCA levels, thereby contributing to the observed hepaprotective effect of GE. Notably, EX527 treatment diminished the hepaprotective effect of GE on BDL-induced liver fibrosis. CONCLUSION This study first proved the hepaprotective effect of GE on liver fibrosis in BDL mice, which was closely associated with the restoration of BA homeostasis and NLRP3 inflammasome inhibition. The activation of SIRT1 and the subsequent FXR deacetylation restored the BA profiles, especially CDCA, TUDCA, and TCDCA contents, which was the main contributor to NLRP3 inhibition and the hepaprotective effect of GE. Overall, our work provides novel insights that GE as well as Gardeniae Fructus might be the potential attractive candidate for ameliorating BDL-induced liver fibrosis.
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Affiliation(s)
- Tingting Qin
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, PR China
| | - Muhammad Hasnat
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China; Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Ziwei Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China
| | - Hozeifa Mohamed Hassan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, PR China
| | - Yang Zhou
- Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou University, Zhengzhou, PR China
| | - Ziqiao Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China.
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, PR China.
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Liu X, Wang J, Li M, Qiu J, Li X, Qi L, Liu J, Liu P, Xie G, Wang X. Farnesoid X receptor is an important target for the treatment of disorders of bile acid and fatty acid metabolism in mice with nonalcoholic fatty liver disease combined with cholestasis. J Gastroenterol Hepatol 2023; 38:1438-1446. [PMID: 37415275 DOI: 10.1111/jgh.16279] [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: 05/08/2023] [Revised: 06/07/2023] [Accepted: 06/20/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND AND AIM The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rising globally. NAFLD patients combined with cholestasis have more obvious liver fibrosis, impaired bile acid (BA), and fatty acid (FA) metabolism and severer liver injury; however, its therapeutic options are limited, and the underlying metabolic mechanisms are understood. Here, we aimed to investigate the effects of farnesoid X receptor (FXR) on BA and FA metabolism in NAFLD combined with cholestasis and related signaling pathways. METHODS A mouse model of NAFLD combined with cholestasis was established by joint intervention with high-fat diet (HFD) and alpha-naphthylisothiocyanate. The effects of FXR on BA and FA metabolism were evaluated by serum biochemical analysis. Liver damage was identified by histopathology. The expression of nuclear hormone receptor, membrane receptor, FA transmembrane transporter, and BA transporter protein in mice were measured by western blot. RESULTS NAFLD mice combined with cholestasis developed more severe cholestasis and dysregulated BA and FA metabolism. Meanwhile, the expression of FXR protein was decreased in NAFLD mice combined with cholestasis compared to the controls. Fxr-/- mice showed liver injury. HFD aggravated the liver injury with decreased BSEP expression, increased expression of NTCP, LXRα, SREBP-1c, FAS, ACC1, and CD36, and significantly increased BA and FA accumulation. CONCLUSION All the results suggested that FXR plays a key role in both FA and BA metabolism in NAFLD combined with cholestasis and thus may be a potential target for the treatment of disorders of BA and FA metabolism in NAFLD combined with cholestasis.
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Affiliation(s)
- Xinzhu Liu
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jiaxuan Wang
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Maogang Li
- Human Metabolomics Institute, Inc., Shenzhen, 518109, Guangdong, China
| | - Jiannan Qiu
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xingying Li
- South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Li Qi
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jia Liu
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ping Liu
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Institute of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Guoxiang Xie
- Human Metabolomics Institute, Inc., Shenzhen, 518109, Guangdong, China
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China
| | - Xiaoning Wang
- Basic Research Center of Traditional Chinese Medicine Prescription and Syndrome, Institute of Interdisciplinary Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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Tittarelli A, Barría O, Sanders E, Bergqvist A, Brange DU, Vidal M, Gleisner MA, Vergara JR, Niechi I, Flores I, Pereda C, Carrasco C, Quezada-Monrás C, Salazar-Onfray F. Co-Expression of Immunohistochemical Markers MRP2, CXCR4, and PD-L1 in Gallbladder Tumors Is Associated with Prolonged Patient Survival. Cancers (Basel) 2023; 15:3440. [PMID: 37444550 DOI: 10.3390/cancers15133440] [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: 06/06/2023] [Revised: 06/10/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Gallbladder cancer (GBC) is a rare pathology in Western countries. However, it constitutes a relevant health problem in Asia and Latin America, with a high mortality in middle-aged Chilean women. The limited therapeutic options for GBC require the identification of targetable proteins with prognostic value for improving clinical management support. We evaluated the expression of targetable proteins, including three epithelial tumor markers, four proteins associated with multidrug and apoptosis resistance, and eleven immunological markers in 241 primary gallbladder adenocarcinomas. We investigated correlations between tumor marker expression, the primary tumor staging, and GBC patients' survival using automated immunohistochemistry, a semi-automatic method for image analysis, univariate and multivariate statistical analyses, and machine learning algorithms. Our data show a significant association between the expression of MRP2 (p = 0.0028), CXCR4 (p = 0.0423), and PD-L1 (p = 0.0264), and a better prognosis for patients with late-stage primary tumors. The expression of the MRP2/CXCR4/PD-L1 cluster of markers discriminates among short-, medium-, and long-term patient survival, with an ROC of significant prognostic value (AUC = 0.85, p = 0.0012). Moreover, a high MRP2/CXCR4/PD-L1 co-expression is associated with increased survival time (30 vs. 6 months, p = 0.0025) in GBC patients, regardless of tumor stage. Hence, our results suggest that the MRP2/CXCR4/PD-L1 cluster could potentially be a prognostic marker for GBC.
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Affiliation(s)
- Andrés Tittarelli
- Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica Metropolitana, Santiago 8940577, Chile
| | - Omar Barría
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Evy Sanders
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Anna Bergqvist
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Daniel Uribe Brange
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Mabel Vidal
- Molecular and Traslational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Pharmacy Faculty, Universidad de Concepción, Concepción 4070386, Chile
- Computer Science Department, Universidad de Concepción, Concepción 4070386, Chile
| | - María Alejandra Gleisner
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Jorge Ramón Vergara
- Departamento de Informática y Computación, Universidad Tecnológica Metropolitana, Santiago 7800002, Chile
| | - Ignacio Niechi
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Iván Flores
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Cristián Pereda
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Cristian Carrasco
- Subdepartamento de Anatomía Patológica, Hospital Base de Valdivia, Valdivia 5090000, Chile
| | - Claudia Quezada-Monrás
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Laboratorio de Biología Tumoral, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia 5090000, Chile
| | - Flavio Salazar-Onfray
- Millennium Institute on Immunology and Immunotherapy, Santiago 8380453, Chile
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
- Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden
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Zhu F, Zheng S, Zhao M, Shi F, Zheng L, Wang H. The regulatory role of bile acid microbiota in the progression of liver cirrhosis. Front Pharmacol 2023; 14:1214685. [PMID: 37416060 PMCID: PMC10320161 DOI: 10.3389/fphar.2023.1214685] [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: 05/02/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023] Open
Abstract
Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.
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Affiliation(s)
- Feng Zhu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Gastroenterology, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haiqiang Wang
- Department of Gastroenterology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Rusch JA, Layden BT, Dugas LR. Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol (Lausanne) 2023; 14:1130689. [PMID: 37404311 PMCID: PMC10316519 DOI: 10.3389/fendo.2023.1130689] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/25/2023] [Indexed: 07/06/2023] Open
Abstract
Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
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Affiliation(s)
- Jody A. Rusch
- Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town, South Africa
- C17 Chemical Pathology Laboratory, Groote Schuur Hospital, National Health Laboratory Service, Cape Town, South Africa
| | - Brian T. Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States
| | - Lara R. Dugas
- Division of Epidemiology and Biostatistics, School of Public Health, University of Cape Town, Cape Town, South Africa
- Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, IL, United States
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Walter Bock K. Aryl hydrocarbon receptor (AHR): towards understanding intestinal microbial ligands including vitamin B12 and folic acid as natural antagonists. Biochem Pharmacol 2023:115658. [PMID: 37336251 DOI: 10.1016/j.bcp.2023.115658] [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: 04/17/2023] [Revised: 06/08/2023] [Accepted: 06/09/2023] [Indexed: 06/21/2023]
Abstract
AHR has been identified as ligand-modulated transcription factor and environmental sensor. However, explanation of its multiple agonistic and antagonistic ligands is far from complete. Studies of AHR's role in host-microbiome interaction are currently a fruitful area of research. Microbial products and virulence factors have been identified as AHR agonists. In steady state they are involved in safeguarding intestinal barrier integrity. When virulence factors from pathogenic bacteria are identified by AHR of intestinal immune cells, anti-microbial defense mechanisms are activated by generating reactive oxygen species (ROS) in intestinal epithelial cells and recruited immune cells. ROS production has to be strictly controlled, and anti-inflammatory responses have to be initiated timely in the resolution phase of inflammation to avoid tissue damage and chronic inflammatory responses. Surprisingly, bacteria-generated vitamin B12/cobalamin and vitamin B9/folic acid have been identified as natural AHR antagonists, stimulating the interest of biochemists. Hints for AHR-cobalamin antagonism are pointing to cobalamin-dependent enzymes leading to alterations of TCA cycle intermediates, and TCDD-mediated loss of serum cobalamin. Although we are still at the beginning to understand mechanisms, it is likely that scientific efforts are on a rewarding path to understand novel AHR functions.
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Affiliation(s)
- Karl Walter Bock
- Institute of Experimental and Clinical Pharmacology, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
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