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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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Callewaert E, Louisse J, Kramer N, Sanz-Serrano J, Vinken M. Adverse Outcome Pathways Mechanistically Describing Hepatotoxicity. Methods Mol Biol 2025; 2834:249-273. [PMID: 39312169 DOI: 10.1007/978-1-0716-4003-6_12] [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] [Indexed: 10/15/2024]
Abstract
Adverse outcome pathways (AOPs) describe toxicological processes from a dynamic perspective by linking a molecular initiating event to a specific adverse outcome via a series of key events and key event relationships. In the field of computational toxicology, AOPs can potentially facilitate the design and development of in silico prediction models for hazard identification. Various AOPs have been introduced for several types of hepatotoxicity, such as steatosis, cholestasis, fibrosis, and liver cancer. This chapter provides an overview of AOPs on hepatotoxicity, including their development, assessment, and applications in toxicology.
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Affiliation(s)
- Ellen Callewaert
- Department of Pharmaceutical and Pharmacological Sciences, Entity of In vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Nynke Kramer
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands
- Toxicology Division, Wageningen University, Wageningen, Netherlands
| | - Julen Sanz-Serrano
- Department of Pharmaceutical and Pharmacological Sciences, Entity of In vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Entity of In vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
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Garcia M, Holota H, De Haze A, Saru JP, Sanchez P, Battistelli E, Thirouard L, Monrose M, Benoit G, Volle DH, Beaudoin C. Alternative splicing is an FXRα loss-of-function mechanism and impacts energy metabolism in hepatocarcinoma cells. J Biol Chem 2025; 301:108022. [PMID: 39608717 PMCID: PMC11758954 DOI: 10.1016/j.jbc.2024.108022] [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: 07/14/2024] [Revised: 11/02/2024] [Accepted: 11/13/2024] [Indexed: 11/30/2024] Open
Abstract
Farnesoid X receptor α (FXRα, NR1H4) is a bile acid-activated nuclear receptor that regulates the expression of glycolytic and lipogenic target genes by interacting with the 9-cis-retinoic acid receptor α (RXRα, NR2B1). Along with cofactors, the FXRα proteins reported thus far in humans and rodents have been observed to regulate both isoform (α1-4)- and tissue-specific gene expression profiles to integrate energy balance and metabolism. Here, we studied the biological functions of an FXRα naturally occurring spliced exon 5 isoform (FXRαse5) lacking the second zinc-binding module of the DNA-binding domain. We demonstrate spliced exon 5 FXRα expression in all FXRα-expressing human and mouse tissues and cells, and that it is unable to bind to its response element or activate FXRα dependent transcription. In parallel, this spliced variant displays differential interaction capacities with its obligate heterodimer partner retinoid X receptor α that may account for silencing of this permissive dimer for signal transduction. Finally, deletion of exon 5 by gene edition in HepG2 cells leads to FXRα loss-of-function, increased expression of LRH1 metabolic sensor and CD36 fatty acid transporter in conjunction with changes in glucose and triglycerides homeostasis. Together, these findings highlight a novel mechanism by which alternative splicing may regulate FXRα gene function to fine-tune adaptive and/or metabolic responses. This finding deepens our understanding on the role of splicing events in hindering FXRα activity to regulate specific transcriptional programs and their contribution in modifying energy metabolism in normal tissues and metabolic diseases.
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Affiliation(s)
- Manon Garcia
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Hélène Holota
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Angélique De Haze
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Jean-Paul Saru
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Phelipe Sanchez
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Edwige Battistelli
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Laura Thirouard
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Mélusine Monrose
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Gérard Benoit
- Université de Rennes 1, CNRS UMR6290, INSERM U1305, IGDR, Rennes Cedex, France
| | - David H Volle
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France.
| | - Claude Beaudoin
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France.
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Guo Z, Wang H, Sun J, Ma Y, Cui X, Kou S, Jiang Z, Zhang L, Wang X, Wang T, Sun L, Huang X. The intestinal absorption of triptolide for the treatment of rheumatoid arthritis is mediated by transporters. Int Immunopharmacol 2024; 143:113440. [PMID: 39471693 DOI: 10.1016/j.intimp.2024.113440] [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: 12/29/2023] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 11/01/2024]
Abstract
Tripterygium wilfordii Hook. f. is a traditional Chinese herb that is used to treat rheumatoid arthritis (RA). Triptolide (TP), an epoxidized diterpene lactone extracted from this herb, has been suggested to be the primary active and toxic component. In this work, the material basis and molecular mechanism of toxicity induced by T. wilfordii preparations in RA were investigated. Female rats with collagen-induced arthritis were given 500 μg·kg-1 TP intragastrically or intravenously. Compared with that in the control group, the AUClast in the CIA group was 1.7-fold greater after intragastric administration, while this value decreased 22.6 % after intravenous administration, suggesting that the absorption of TP was significantly greater in the CIA group. The results from RT-PCR and probe substrate perfusion indicated that Oatp1a5 expression was upregulated while P-glycoprotein (P-gp) expression was downregulated in the duodenums of CIA rats. Naringin, an inhibitor of Oatp1a5, decreased the Peff of TP in the rat duodenum by 27.9 %, whereas verapamil hydrochloride, an inhibitor of P-gp, increased the Peff by 50.8 %, suggesting that Oatp1a5 and P-gp mediate the uptake and efflux of TP in the rat duodenum, respectively. Furthermore, among the upstream nuclear receptors, the mRNA expression levels and protein expression levels of FXR and VDR were noticeably decreased. In the present study, the absorption of TP in the duodenums of CIA rats significantly increased due to the upregulation of Oatp1a5 expression and the downregulation of P-gp expression, leading to an increase in TP plasma exposure after intragastric administration. The altered expression of Oatp1a5 and P-gp may be related to FXR and VDR.
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Affiliation(s)
- Ziyu Guo
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, Guangdong 518057, China
| | - Hefei Wang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Juan Sun
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ying Ma
- Foreign Language Teaching Department, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xueyang Cui
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Shanshan Kou
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zhenzhou Jiang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Luyong Zhang
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinzhi Wang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Tao Wang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Lixin Sun
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Xin Huang
- New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
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Hossam Abdelmonem B, Abdelaal NM, Anwer EKE, Rashwan AA, Hussein MA, Ahmed YF, Khashana R, Hanna MM, Abdelnaser A. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines 2024; 12:1467. [PMID: 39062040 PMCID: PMC11275228 DOI: 10.3390/biomedicines12071467] [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: 04/16/2024] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 07/28/2024] Open
Abstract
Cytochrome P450 (CYP450) is a group of enzymes that play an essential role in Phase I metabolism, with 57 functional genes classified into 18 families in the human genome, of which the CYP1, CYP2, and CYP3 families are prominent. Beyond drug metabolism, CYP enzymes metabolize endogenous compounds such as lipids, proteins, and hormones to maintain physiological homeostasis. Thus, dysregulation of CYP450 enzymes can lead to different endocrine disorders. Moreover, CYP450 enzymes significantly contribute to fatty acid metabolism, cholesterol synthesis, and bile acid biosynthesis, impacting cellular physiology and disease pathogenesis. Their diverse functions emphasize their therapeutic potential in managing hypercholesterolemia and neurodegenerative diseases. Additionally, CYP450 enzymes are implicated in the onset and development of illnesses such as cancer, influencing chemotherapy outcomes. Assessment of CYP450 enzyme expression and activity aids in evaluating liver health state and differentiating between liver diseases, guiding therapeutic decisions, and optimizing drug efficacy. Understanding the roles of CYP450 enzymes and the clinical effect of their genetic polymorphisms is crucial for developing personalized therapeutic strategies and enhancing drug responses in diverse patient populations.
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Affiliation(s)
- Basma Hossam Abdelmonem
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (B.H.A.); (M.A.H.); (Y.F.A.); (R.K.); (M.M.H.)
- Department of Microbiology and Immunology, Faculty of Pharmacy, October University for Modern Sciences & Arts (MSA), Giza 12451, Egypt
| | - Noha M. Abdelaal
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (N.M.A.); (E.K.E.A.); (A.A.R.)
| | - Eman K. E. Anwer
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (N.M.A.); (E.K.E.A.); (A.A.R.)
- Department of Microbiology and Immunology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 4411601, Egypt
| | - Alaa A. Rashwan
- Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (N.M.A.); (E.K.E.A.); (A.A.R.)
| | - Mohamed Ali Hussein
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (B.H.A.); (M.A.H.); (Y.F.A.); (R.K.); (M.M.H.)
| | - Yasmin F. Ahmed
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (B.H.A.); (M.A.H.); (Y.F.A.); (R.K.); (M.M.H.)
| | - Rana Khashana
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (B.H.A.); (M.A.H.); (Y.F.A.); (R.K.); (M.M.H.)
| | - Mireille M. Hanna
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (B.H.A.); (M.A.H.); (Y.F.A.); (R.K.); (M.M.H.)
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University in Cairo, New Cairo 11835, Egypt; (B.H.A.); (M.A.H.); (Y.F.A.); (R.K.); (M.M.H.)
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Song Y, Lau HCH, Zhang X, Yu J. Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma. Cancer Biol Med 2023; 21:j.issn.2095-3941.2023.0394. [PMID: 38148326 PMCID: PMC10884537 DOI: 10.20892/j.issn.2095-3941.2023.0394] [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: 10/09/2023] [Accepted: 11/28/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and aggressive liver malignancy. The interplay between bile acids (BAs) and the gut microbiota has emerged as a critical factor in HCC development and progression. Under normal conditions, BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs. The gut microbiota plays a critical role in BA metabolism, and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis. Of note, dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis, thereby leading to liver inflammation and fibrosis, and ultimately contributing to HCC development. Therefore, understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis. In this review, we comprehensively explore the roles and functions of BA metabolism, with a focus on the interactions between BAs and gut microorganisms in HCC. Additionally, therapeutic strategies targeting BA metabolism and the gut microbiota are discussed, including the use of BA agonists/antagonists, probiotic/prebiotic and dietary interventions, fecal microbiota transplantation, and engineered bacteria. In summary, understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.
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Affiliation(s)
- Yang Song
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
- Department of Gastroenterology, Zhongshan Hospital Xiamen University, Xiamen 361004, China
| | - Harry CH Lau
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiang Zhang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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Witkowska AM, Salem JE. Pharmacological and Nutritional Modulation of Metabolome and Metagenome in Cardiometabolic Disorders. Biomolecules 2023; 13:1340. [PMID: 37759740 PMCID: PMC10526920 DOI: 10.3390/biom13091340] [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: 07/24/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Cardiometabolic disorders are major causes of morbidity and mortality worldwide. A growing body of research indicates that the gut microbiota, whether it interacts favorably or not, plays an important role in host metabolism. Elucidating metabolic pathways may be crucial in preventing and treating cardiometabolic diseases, and omics methods are key to studying the interaction between the fecal microbiota and host metabolism. This review summarizes available studies that combine metabolomic and metagenomic approaches to describe the effects of drugs, diet, nutrients, and specific foods on cardiometabolic health and to identify potential targets for future research.
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Affiliation(s)
- Anna Maria Witkowska
- Department of Food Biotechnology, Faculty of Health Sciences, Medical University of Bialystok, Szpitalna 37, 15-295 Białystok, Poland
| | - Joe-Elie Salem
- Department of Pharmacology, Pitié-Salpêtrière Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center (CIC-1901), Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, 75013 Paris, France;
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8
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van Ertvelde J, Verhoeven A, Maerten A, Cooreman A, Santos Rodrigues BD, Sanz-Serrano J, Mihajlovic M, Tripodi I, Teunis M, Jover R, Luechtefeld T, Vanhaecke T, Jiang J, Vinken M. Optimization of an adverse outcome pathway network on chemical-induced cholestasis using an artificial intelligence-assisted data collection and confidence level quantification approach. J Biomed Inform 2023; 145:104465. [PMID: 37541407 DOI: 10.1016/j.jbi.2023.104465] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/19/2023] [Accepted: 07/31/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND Adverse outcome pathway (AOP) networks are versatile tools in toxicology and risk assessment that capture and visualize mechanisms driving toxicity originating from various data sources. They share a common structure consisting of a set of molecular initiating events and key events, connected by key event relationships, leading to the actual adverse outcome. AOP networks are to be considered living documents that should be frequently updated by feeding in new data. Such iterative optimization exercises are typically done manually, which not only is a time-consuming effort, but also bears the risk of overlooking critical data. The present study introduces a novel approach for AOP network optimization of a previously published AOP network on chemical-induced cholestasis using artificial intelligence to facilitate automated data collection followed by subsequent quantitative confidence assessment of molecular initiating events, key events, and key event relationships. METHODS Artificial intelligence-assisted data collection was performed by means of the free web platform Sysrev. Confidence levels of the tailored Bradford-Hill criteria were quantified for the purpose of weight-of-evidence assessment of the optimized AOP network. Scores were calculated for biological plausibility, empirical evidence, and essentiality, and were integrated into a total key event relationship confidence value. The optimized AOP network was visualized using Cytoscape with the node size representing the incidence of the key event and the edge size indicating the total confidence in the key event relationship. RESULTS This resulted in the identification of 38 and 135 unique key events and key event relationships, respectively. Transporter changes was the key event with the highest incidence, and formed the most confident key event relationship with the adverse outcome, cholestasis. Other important key events present in the AOP network include: nuclear receptor changes, intracellular bile acid accumulation, bile acid synthesis changes, oxidative stress, inflammation and apoptosis. CONCLUSIONS This process led to the creation of an extensively informative AOP network focused on chemical-induced cholestasis. This optimized AOP network may serve as a mechanistic compass for the development of a battery of in vitro assays to reliably predict chemical-induced cholestatic injury.
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Affiliation(s)
- Jonas van Ertvelde
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Anouk Verhoeven
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Amy Maerten
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Axelle Cooreman
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bruna Dos Santos Rodrigues
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Julen Sanz-Serrano
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Milos Mihajlovic
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Marc Teunis
- Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences Utrecht, Utrecht, The Netherlands
| | - Ramiro Jover
- Joint Research Unit in Experimental Hepatology, University of Valencia, Health Research Institute Hospital La Fe & CIBER of Hepatic and Digestive Diseases, Spain
| | | | - Tamara Vanhaecke
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jian Jiang
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium.
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9
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Mezhibovsky E, Tveter KM, Villa-Rodriguez JA, Bacalia K, Kshatriya D, Desai N, Cabales A, Wu Y, Sui K, Duran RM, Bello NT, Roopchand DE. Grape Polyphenols May Prevent High-Fat Diet-Induced Dampening of the Hypothalamic-Pituitary-Adrenal Axis in Male Mice. J Endocr Soc 2023; 7:bvad095. [PMID: 37538101 PMCID: PMC10396072 DOI: 10.1210/jendso/bvad095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Indexed: 08/05/2023] Open
Abstract
Context Chronic high-fat diet (HFD) consumption causes obesity associated with retention of bile acids (BAs) that suppress important regulatory axes, such as the hypothalamic-pituitary-adrenal axis (HPAA). HFD impairs nutrient sensing and energy balance due to a dampening of the HPAA and reduced production and peripheral metabolism of corticosterone (CORT). Objective We assessed whether proanthocyanidin-rich grape polyphenol (GP) extract can prevent HFD-induced energy imbalance and HPAA dysregulation. Methods Male C57BL6/J mice were fed HFD or HFD supplemented with 0.5% w/w GPs (HFD-GP) for 17 weeks. Results GP supplementation reduced body weight gain and liver fat while increasing circadian rhythms of energy expenditure and HPAA-regulating hormones, CORT, leptin, and PYY. GP-induced improvements were accompanied by reduced mRNA levels of Il6, Il1b, and Tnfa in ileal or hepatic tissues and lower cecal abundance of Firmicutes, including known BA metabolizers. GP-supplemented mice had lower concentrations of circulating BAs, including hydrophobic and HPAA-inhibiting BAs, but higher cecal levels of taurine-conjugated BAs antagonistic to farnesoid X receptor (FXR). Compared with HFD-fed mice, GP-supplemented mice had increased mRNA levels of hepatic Cyp7a1 and Cyp27a1, suggesting reduced FXR activation and more BA synthesis. GP-supplemented mice also had reduced hepatic Abcc3 and ileal Ibabp and Ostβ, indicative of less BA transfer into enterocytes and circulation. Relative to HFD-fed mice, CORT and BA metabolizing enzymes (Akr1d1 and Srd5a1) were increased, and Hsd11b1 was decreased in GP supplemented mice. Conclusion GPs may attenuate HFD-induced weight gain by improving hormonal control of the HPAA and inducing a BA profile with less cytotoxicity and HPAA inhibition, but greater FXR antagonism.
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Affiliation(s)
- Esther Mezhibovsky
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Kevin M Tveter
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Jose A Villa-Rodriguez
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Karen Bacalia
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Dushyant Kshatriya
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Nikhil Desai
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Alrick Cabales
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Ke Sui
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Rocio M Duran
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Nicholas T Bello
- Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Department of Food Science and NJ Institute for Food Nutrition and Health (Rutgers Center for Lipid Research; Center for Nutrition Microbiome and Health), Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Nutritional Sciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
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10
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Zhao L, Jin L, Yang B. Protocatechuic acid inhibits LPS-induced mastitis in mice through activating the pregnane X receptor. J Cell Mol Med 2023; 27:2321-2327. [PMID: 37328960 PMCID: PMC10424283 DOI: 10.1111/jcmm.17812] [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: 03/30/2023] [Revised: 05/28/2023] [Accepted: 06/05/2023] [Indexed: 06/18/2023] Open
Abstract
Mastitis refers to the inflammation in the mammary gland caused by various reasons. Protocatechuic acid (PCA) exerts anti-inflammatory effect. However, no studies have shown the protective role of PCA on mastitis. We investigated the protective effect of PCA on LPS-induced mastitis in mice and elucidated its possible mechanism. LPS-induced mastitis model was established by injection of LPS into the mammary gland. The pathology of mammary gland, MPO activity and inflammatory cytokine production were detected to evaluate the effects of PCA on mastitis. In vivo, PCA significantly attenuated LPS-induced mammary pathological changes, MPO activity, TNF-α and IL-1β production. In vitro, the production of inflammatory cytokines TNF-α and IL-1β was significantly reduced by PCA. Furthermore, LPS-induced NF-κB activation was also inhibited by PCA. In addition, PCA was found to activate pregnane X receptor (PXR) transactivation and PCA dose-dependently increased the expression of PXR downstream molecule CYP3A4. In addition, the inhibitory effect of PCA on inflammatory cytokine production was also reversed when PXR was knocked down. In conclusion, the protective effects of PCA on LPS-induced mastitis in mice through regulating PXR.
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Affiliation(s)
- Lihua Zhao
- Department of Breast SurgeryChina‐Japan Union Hospital of Jilin UniversityJilinChina
| | - Lei Jin
- Department of AnesthesiologyChina‐Japan Union Hospital of Jilin UniversityJilinChina
| | - Bin Yang
- Department of Breast SurgeryChina‐Japan Union Hospital of Jilin UniversityJilinChina
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11
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Tveter KM, Mezhibovsky E, Wu Y, Roopchand DE. Bile acid metabolism and signaling: Emerging pharmacological targets of dietary polyphenols. Pharmacol Ther 2023; 248:108457. [PMID: 37268113 PMCID: PMC10528343 DOI: 10.1016/j.pharmthera.2023.108457] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/03/2023] [Accepted: 05/22/2023] [Indexed: 06/04/2023]
Abstract
Beyond their role as emulsifiers of lipophilic compounds, bile acids (BAs) are signaling endocrine molecules that show differential affinity and specificity for a variety of canonical and non-canonical BA receptors. Primary BAs (PBAs) are synthesized in the liver while secondary BAs (SBAs) are gut microbial metabolites of PBA species. PBAs and SBAs signal to BA receptors that regulate downstream pathways of inflammation and energy metabolism. Dysregulation of BA metabolism or signaling has emerged as a feature of chronic disease. Dietary polyphenols are non-nutritive plant-derived compounds associated with decreased risk of metabolic syndrome, type-2 diabetes, hepatobiliary and cardiovascular disease. Evidence suggests that the health promoting effects of dietary polyphenols are linked to their ability to alter the gut microbial community, the BA pool, and BA signaling. In this review we provide an overview of BA metabolism and summarize studies that link the cardiometabolic improvements of dietary polyphenols to their modulation of BA metabolism and signaling pathways, and the gut microbiota. Finally, we discuss approaches and challenges in deciphering cause-effect relationships between dietary polyphenols, BAs, and gut microbes.
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Affiliation(s)
- Kevin M Tveter
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Esther Mezhibovsky
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA.
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12
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Fritsche K, Ziková-Kloas A, Marx-Stoelting P, Braeuning A. Metabolism-Disrupting Chemicals Affecting the Liver: Screening, Testing, and Molecular Pathway Identification. Int J Mol Sci 2023; 24:ijms24032686. [PMID: 36769005 PMCID: PMC9916672 DOI: 10.3390/ijms24032686] [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: 12/14/2022] [Revised: 01/26/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed.
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Affiliation(s)
- Kristin Fritsche
- German Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
| | - Andrea Ziková-Kloas
- German Federal Institute for Risk Assessment, Department Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
| | - Philip Marx-Stoelting
- German Federal Institute for Risk Assessment, Department Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
| | - Albert Braeuning
- German Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
- Correspondence: ; Tel.: +49-(0)30-18412-25100
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13
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Qin Y, Tan J, Han X, Wang N, Zhai X, Lu Y. Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo. Biol Pharm Bull 2023; 46:1810-1819. [PMID: 38044100 DOI: 10.1248/bpb.b23-00580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsA-induced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.
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Affiliation(s)
- Yanjie Qin
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
| | - Jingxuan Tan
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
| | - Xuemei Han
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
| | - Nanxi Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
| | - Xuejia Zhai
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province Clinical Research Centre for Precision Medicine for Critical Illness
| | - Yongning Lu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
- Hubei Province Clinical Research Centre for Precision Medicine for Critical Illness
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14
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Interactions governing transcriptional activity of nuclear receptors. Biochem Soc Trans 2022; 50:1941-1952. [DOI: 10.1042/bst20220338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
The key players in transcriptional regulation are transcription factors (TFs), proteins that bind specific DNA sequences. Several mechanisms exist to turn TFs ‘on’ and ‘off’, including ligand binding which induces conformational changes within TFs, subsequently influencing multiple inter- and intramolecular interactions to drive transcriptional responses. Nuclear receptors are a specific family of ligand-regulated TFs whose activity relies on interactions with DNA, coregulator proteins and other receptors. These multidomain proteins also undergo interdomain interactions on multiple levels, further modulating transcriptional outputs. Cooperation between these distinct interactions is critical for appropriate transcription and remains an intense area of investigation. In this review, we report and summarize recent findings that continue to advance our mechanistic understanding of how interactions between nuclear receptors and diverse partners influence transcription.
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15
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Shansky Y, Bespyatykh J. Bile Acids: Physiological Activity and Perspectives of Using in Clinical and Laboratory Diagnostics. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27227830. [PMID: 36431930 PMCID: PMC9692537 DOI: 10.3390/molecules27227830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022]
Abstract
Bile acids play a significant role in the digestion of nutrients. In addition, bile acids perform a signaling function through their blood-circulating fraction. They regulate the activity of nuclear and membrane receptors, located in many tissues. The gut microbiota is an important factor influencing the effects of bile acids via enzymatic modification. Depending on the rate of healthy and pathogenic microbiota, a number of bile acids may support lipid and glucose homeostasis as well as shift to more toxic compounds participating in many pathological conditions. Thus, bile acids can be possible biomarkers of human pathology. However, the chemical structure of bile acids is similar and their analysis requires sensitive and specific methods of analysis. In this review, we provide information on the chemical structure and the biosynthesis of bile acids, their regulation, and their physiological role. In addition, the review describes the involvement of bile acids in various diseases of the digestive system, the approaches and challenges in the analysis of bile acids, and the prospects of their use in omics technologies.
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Affiliation(s)
- Yaroslav Shansky
- Department of Molecular Medicine, Center of Molecular Medicine and Diagnostics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Malaya Pirogovskaya Str., 1a, 119435 Moscow, Russia
- Correspondence:
| | - Julia Bespyatykh
- Department of Molecular Medicine, Center of Molecular Medicine and Diagnostics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Malaya Pirogovskaya Str., 1a, 119435 Moscow, Russia
- Department of Expertise in Doping and Drug Control, Mendeleev University of Chemical Technology of Russia, Miusskaya Square, 9, 125047 Moscow, Russia
- Department of Public Health and Health Care, Federal Scientific State Budgetary Institution «N.A. Semashko National Research Institute of Public Health», Vorontsovo Pole Str., 12-1, 105064 Moscow, Russia
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16
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Klyushova LS, Perepechaeva ML, Grishanova AY. The Role of CYP3A in Health and Disease. Biomedicines 2022; 10:2686. [PMID: 36359206 PMCID: PMC9687714 DOI: 10.3390/biomedicines10112686] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics (including drugs); almost the only common characteristic of these compounds is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in human organs and tissues, and consequences of these enzymes' activities play a major role both in normal regulation of physiological levels of endogenous compounds and in various pathological conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological conditions and their involvement in the initiation and progression of diseases.
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Affiliation(s)
| | - Maria L. Perepechaeva
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, 630117 Novosibirsk, Russia
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Xiao T, Guo Z, Fu M, Huang J, Wang X, Zhao Y, Tao L, Shen X. Amelioration of Alcoholic Liver Disease by Activating PXR-Cytochrome P450s Axis with Blackberry Extract. SEPARATIONS 2022; 9:321. [DOI: 10.3390/separations9100321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2025] Open
Abstract
Blackberry is widely used in diets for its rich biological phytochemicals and health benefits. However, the relationship between the effect of blackberry extract (BBE) on ameliorating alcoholic liver disease (ALD) and the PXR-Cytochrome P450s axis in vivo and in vitro is unknown. In this study, 50% and 30% ethanol by gavage were used to establish acute and subacute ALD. Male mice were intragastrically administered BBE with 25, 50, and 100 mg/kg BW in the treatment groups. In the experiment, samples were collected, and related indices and histopathological observation were measured. In addition, the potential mechanism was predicted by network and docking studies, which were verified by qRT-PCR analysis, the detection of apoptosis, the measurement of mitochondrial membrane potential, the detection of ROS levels, and Western blotting in liver tissues and HepG2 cells. The acute and subacute ALD experiments indicated BBE ameliorated liver indices, AST, ALT, SOD, and MDA in serum, and the histopathology changed, as observed via H&E, Sirius red, and oil red O staining. The potential mechanism was predicted by network and docking studies, which were verified by experiments. Western blotting suggested BBE reduced the protein expression of NF-κB, TGF-β, IL-6, and α-SMA, and enhanced PXR and CAR in livers. In addition, qRT-PCR showed BBE significantly elevated the mRNA levels of PXR, CAR, CYP3A25, CYP3A11, and CYP2B10. In the experiment of the ethanol-induced apoptosis of HepG2 cells, BBE reduced the apoptosis of HepG2 cells by boosting mitochondrial membrane potential, reducing the apoptotic rate and ROS content, lessening the expression of Bax, and inducing the expression of PXR. For the first time, this study demonstrated BBE’s preventive effects on ALD, which are associated with the antioxidation and stimulation of the PXR-Cytochrome P450s axis. In addition, BBE is available as a nutritional agent.
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Affiliation(s)
- Ting Xiao
- The State Key Laboratory of Functions and Applications of Medicinal Plants, The Department of Pharmaceutic Preparation of Chinse Medicine, The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Zhenghong Guo
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
| | - Min Fu
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Jiaoyan Huang
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Xiaowei Wang
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Yuqing Zhao
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ling Tao
- The State Key Laboratory of Functions and Applications of Medicinal Plants, The Department of Pharmaceutic Preparation of Chinse Medicine, The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Xiangchun Shen
- The State Key Laboratory of Functions and Applications of Medicinal Plants, The Department of Pharmaceutic Preparation of Chinse Medicine, The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China
- The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
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18
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Wang Y, Ai Z, Xing X, Fan Y, Zhang Y, Nan B, Li X, Wang Y, Liu J. The ameliorative effect of probiotics on diet-induced lipid metabolism disorders: A review. Crit Rev Food Sci Nutr 2022; 64:3556-3572. [PMID: 36218373 DOI: 10.1080/10408398.2022.2132377] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
High-fat diet induces lipid metabolism disorders that has become one of the grievous public health problems and imposes a serious economic and social burden worldwide. Safety probiotics isolated from nature are regarded as a novel supplementary strategy for preventing and improving diet-induced lipid metabolism disorders and related chronic diseases. The present review summarized the latest researches of probiotics in high fat diet induced lipid metabolism disorders to provide a critical perspective on the regulatory function of probiotics for future research. Furthermore, the screening criteria and general sources of probiotics with lipid-lowering ability also outlined to enlarge microbial species resource bank instantly, which promoted the development of functional foods with lipid-lowering strains from nature. After critically reviewing the lipid-lowering potential of probiotics both in vitro and in vivo and even in clinical data of humans, we provided a perspective that probiotics activated AMPK signaling pathway to regulate fat synthesis and decomposition, as well as affected positively the gut microbiota structure, intestinal barrier function and systemic inflammatory response, then these beneficial effects are amplified along Gut-liver axis, which regulated intestinal flora metabolites such as SCFAs and BAs by HMGCR/FXR/SHP signaling pathway to improve high fat diet induced lipid metabolism disorders effectively.
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Affiliation(s)
- Yu Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Zhiyi Ai
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Xinyue Xing
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Yuling Fan
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Yue Zhang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Bo Nan
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Xia Li
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Yuhua Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
- National Processing Laboratory for Soybean Industry and Technology, Changchun, China
- National Engineering Research Center for Wheat and Cord Deep Processing, Changchun, China
| | - Jingsheng Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- National Engineering Research Center for Wheat and Cord Deep Processing, Changchun, China
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19
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Wang H, Zhang J, Zhang X, Zhao N, Zhou Z, Tao L, Fu L, Peng S, Chai J. Fluorofenidone ameliorates cholestasis and fibrosis by inhibiting hepatic Erk/-Egr-1 signaling and Tgfβ1/Smad pathway in mice. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166556. [PMID: 36154893 DOI: 10.1016/j.bbadis.2022.166556] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/14/2022] [Accepted: 09/17/2022] [Indexed: 11/15/2022]
Abstract
Cholestasis is characterized by intrahepatic accumulation of bile acids (BAs), resulting in liver injury, fibrosis, and liver failure. To date, only ursodeoxycholic acid and obeticholic acid have been approved for the treatment of cholestasis. As fluorofenidone (AKF-PD) was previously reported to play significant anti-fibrotic and anti-inflammatory roles in various diseases, we investigated whether AKF-PD ameliorates cholestasis. A mouse model of cholestasis was constructed by administering a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet for 14 days. Male C57BL/6 J mice were treated with either AKF-PD or pirfenidone (PD) orally in addition to the DDC diet. Serum and liver tissues were subsequently collected and analyzed. We found that AKF-PD significantly reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile salts (TBA), as well as hepatic bile acids (BAs) levels. Hepatic histological analyses demonstrated that AKF-PD markedly attenuated hepatic inflammation and fibrosis. Further mechanistic analyses revealed that AKF-PD markedly inhibited expression of Cyp7a1, an enzyme key to BAs synthesis, by increasing Fxr nuclear translocation, and decreased hepatic inflammation by attenuating Erk/-Egr-1-mediated expression of inflammatory cytokines and chemokines Tnfα, Il-1β, Il-6, Ccl2, Ccl5 and Cxcl10. Moreover, AKF-PD was found to substantially reduce liver fibrosis via inhibition of Tgfβ1/Smad pathway in our mouse model. Here, we found that AKF-PD effectively attenuates cholestasis and hepatic fibrosis in the mouse model of DDC-induced cholestasis. As such, AKF-PD warrants further investigation as a candidate drug for treatment of cholestasis.
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Affiliation(s)
- Huiwen Wang
- Department of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jian Zhang
- Department of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaoxun Zhang
- Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Nan Zhao
- Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Zongtao Zhou
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Lijian Tao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Lei Fu
- Department of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Shifang Peng
- Department of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Jin Chai
- Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China.
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20
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Xia Y, Xu X, Guo Y, Lin C, Xu X, Zhang F, Fan M, Qi T, Li C, Hu G, Peng L, Wang S, Zhang L, Hai C, Liu R, Yan W, Tao L. Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200431. [PMID: 35780502 PMCID: PMC9404394 DOI: 10.1002/advs.202200431] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 05/14/2022] [Indexed: 06/15/2023]
Abstract
Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI.
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Affiliation(s)
- Yunlong Xia
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Xinyue Xu
- State Key Laboratory of Military StomatologyNational Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced ManufactureDepartment of PeriodontologySchool of StomatologyFourth Military Medical UniversityXi'anShaanxi710032China
| | - Yongzhen Guo
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Chen Lin
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
- CardiologyGeneral Hospital of Eastern Theater Command of Chinese PLANanjing210002China
| | - Xiaoming Xu
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Fuyang Zhang
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Miaomiao Fan
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Tingting Qi
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Congye Li
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Guangyu Hu
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Lu Peng
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Shan Wang
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Ling Zhang
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Chunxu Hai
- Department of ToxicologyShanxi Provincial Key Lab of Free Radical Biology and MedicineMinistry of Education Key Lab of Hazard Assessment and Control in Special Operational EnvironmentSchool of Public HealthFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Rui Liu
- Department of ToxicologyShanxi Provincial Key Lab of Free Radical Biology and MedicineMinistry of Education Key Lab of Hazard Assessment and Control in Special Operational EnvironmentSchool of Public HealthFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Wenjun Yan
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Ling Tao
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
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21
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Alaei Faradonbeh F, Lastuvkova H, Cermanova J, Hroch M, Nova Z, Uher M, Hirsova P, Pavek P, Micuda S. Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats. Front Physiol 2022; 13:859294. [PMID: 35388287 PMCID: PMC8979289 DOI: 10.3389/fphys.2022.859294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/21/2022] [Indexed: 12/23/2022] Open
Abstract
Multidrug resistance-associated protein 2 (Mrp2) mediates biliary secretion of anionic endobiotics and xenobiotics. Genetic alteration of Mrp2 leads to conjugated hyperbilirubinemia and predisposes to the development of intrahepatic cholestasis of pregnancy (ICP), characterized by increased plasma bile acids (BAs) due to mechanisms that are incompletely understood. Therefore, this study aimed to characterize BA metabolomics during experimental Mrp2 deficiency and ICP. ICP was modeled by ethinylestradiol (EE) administration to Mrp2-deficient (TR) rats and their wild-type (WT) controls. Spectra of BAs were analyzed in plasma, bile, and stool using an advanced liquid chromatography–mass spectrometry (LC–MS) method. Changes in BA-related genes and proteins were analyzed in the liver and intestine. Vehicle-administered TR rats demonstrated higher plasma BA concentrations consistent with reduced BA biliary secretion and increased BA efflux from hepatocytes to blood via upregulated multidrug resistance-associated protein 3 (Mrp3) and multidrug resistance-associated protein 4 (Mrp4) transporters. TR rats also showed a decrease in intestinal BA reabsorption due to reduced ileal sodium/bile acid cotransporter (Asbt) expression. Analysis of regulatory mechanisms indicated that activation of the hepatic constitutive androstane receptor (CAR)-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by accumulating bilirubin may be responsible for changes in BA metabolomics in TR rats. Ethinylestradiol administration to TR rats further increased plasma BA concentrations as a result of reduced BA uptake and increased efflux via reduced Slco1a1 and upregulated Mrp4 transporters. These results demonstrate that Mrp2-deficient organism is more sensitive to estrogen-induced cholestasis. Inherited deficiency in Mrp2 is associated with activation of Mrp3 and Mrp4 proteins, which is further accentuated by increased estrogen. Bile acid monitoring is therefore highly desirable in pregnant women with conjugated hyperbilirubinemia for early detection of intrahepatic cholestasis.
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Affiliation(s)
- Fatemeh Alaei Faradonbeh
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Hana Lastuvkova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Jolana Cermanova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Milos Hroch
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Zuzana Nova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Martin Uher
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Stanislav Micuda
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
- *Correspondence: Stanislav Micuda,
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22
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Taubenheim J, Kortmann C, Fraune S. Function and Evolution of Nuclear Receptors in Environmental-Dependent Postembryonic Development. Front Cell Dev Biol 2021; 9:653792. [PMID: 34178983 PMCID: PMC8222990 DOI: 10.3389/fcell.2021.653792] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 05/06/2021] [Indexed: 12/14/2022] Open
Abstract
Nuclear receptors (NRs) fulfill key roles in the coordination of postembryonal developmental transitions in animal species. They control the metamorphosis and sexual maturation in virtually all animals and by that the two main environmental-dependent developmental decision points. Sexual maturation and metamorphosis are controlled by steroid receptors and thyroid receptors, respectively in vertebrates, while both processes are orchestrated by the ecdysone receptor (EcR) in insects. The regulation of these processes depends on environmental factors like nutrition, temperature, or photoperiods and by that NRs form evolutionary conserved mediators of phenotypic plasticity. While the mechanism of action for metamorphosis and sexual maturation are well studied in model organisms, the evolution of these systems is not entirely understood and requires further investigation. We here review the current knowledge of NR involvement in metamorphosis and sexual maturation across the animal tree of life with special attention to environmental integration and evolution of the signaling mechanism. Furthermore, we compare commonalities and differences of the different signaling systems. Finally, we identify key gaps in our knowledge of NR evolution, which, if sufficiently investigated, would lead to an importantly improved understanding of the evolution of complex signaling systems, the evolution of life history decision points, and, ultimately, speciation events in the metazoan kingdom.
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Affiliation(s)
| | | | - Sebastian Fraune
- Zoology and Organismic Interactions, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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23
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Wu J, Ye Y, Quan J, Ding R, Wang X, Zhuang Z, Zhou S, Geng Q, Xu C, Hong L, Xu Z, Zheng E, Cai G, Wu Z, Yang J. Using nontargeted LC-MS metabolomics to identify the Association of Biomarkers in pig feces with feed efficiency. Porcine Health Manag 2021; 7:39. [PMID: 34078468 PMCID: PMC8170940 DOI: 10.1186/s40813-021-00219-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/11/2021] [Indexed: 12/15/2022] Open
Abstract
Background Improving feed efficiency is economically and environmentally beneficial in the pig industry. A deeper understanding of feed efficiency is essential on many levels for its highly complex nature. The aim of this project is to explore the relationship between fecal metabolites and feed efficiency-related traits, thereby identifying metabolites that may assist in the screening of the feed efficiency of pigs. Results We performed fecal metabolomics analysis on 50 individuals selected from 225 Duroc x (Landrace x Yorkshire) (DLY) commercial pigs, 25 with an extremely high feed efficiency and 25 with an extremely low feed efficiency. A total of 6749 and 5644 m/z features were detected in positive and negative ionization modes by liquid chromatography-mass spectrometry (LC/MS). Regrettably, the PCA could not classify the the samples accurately. To improve the classification, OPLS-DA was introduced. However, the predictive ability of the OPLS-DA model did not perform well. Then, through weighted coexpression network analysis (WGCNA), we found that one module in each positive and negative mode was related to residual feed intake (RFI), and six and three metabolites were further identified. The nine metabolites were found to be involved in multiple metabolic pathways, including lipid metabolism (primary bile acid synthesis, linoleic acid metabolism), vitamin D, glucose metabolism, and others. Then, Lasso regression analysis was used to evaluate the importance of nine metabolites obtained by the annotation process. Conclusions Altogether, this study provides new insights for the subsequent evaluation of commercial pig feed efficiency through small molecule metabolites, but also provide a reference for the development of new feed additives. Supplementary Information The online version contains supplementary material available at 10.1186/s40813-021-00219-w.
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Affiliation(s)
- Jie Wu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Yong Ye
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Jianping Quan
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Rongrong Ding
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Xingwang Wang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Zhanwei Zhuang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Shenping Zhou
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Qian Geng
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Cineng Xu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Linjun Hong
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Zheng Xu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Enqin Zheng
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Gengyuan Cai
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China
| | - Zhenfang Wu
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China. .,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China. .,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangzhou, 510642l, China. .,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, Guangzhou, 510642, China.
| | - Jie Yang
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, 510642, China. .,Guangdong Provincial Laboratory of Lingnan Modern Agricultural Science and Technology, Guangzhou, 510642, China.
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24
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Faradonbeh FA, Sa II, Lastuvkova H, Cermanova J, Hroch M, Faistova H, Mokry J, Nova Z, Uher M, Nachtigal P, Pavek P, Micuda S. Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice. Chem Biol Interact 2021; 345:109525. [PMID: 34058177 DOI: 10.1016/j.cbi.2021.109525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/28/2021] [Accepted: 05/16/2021] [Indexed: 12/12/2022]
Abstract
Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.
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Affiliation(s)
- Fatemeh Alaei Faradonbeh
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Ivone Igreja Sa
- Department of Biological and Medical Sciences, Charles University, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Hana Lastuvkova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Jolana Cermanova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Milos Hroch
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Hana Faistova
- Department of Pathology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Jaroslav Mokry
- Department of Histology and Embryology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Zuzana Nova
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Martin Uher
- Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Petr Nachtigal
- Department of Biological and Medical Sciences, Charles University, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic
| | - Stanislav Micuda
- Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic.
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25
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Paraiso IL, Tran TQ, Magana AA, Kundu P, Choi J, Maier CS, Bobe G, Raber J, Kioussi C, Stevens JF. Xanthohumol ameliorates Diet-Induced Liver Dysfunction via Farnesoid X Receptor-Dependent and Independent Signaling. Front Pharmacol 2021; 12:643857. [PMID: 33959012 PMCID: PMC8093804 DOI: 10.3389/fphar.2021.643857] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/22/2021] [Indexed: 12/20/2022] Open
Abstract
The farnesoid X receptor (FXR) plays a critical role in the regulation of lipid and bile acid (BA) homeostasis. Hepatic FXR loss results in lipid and BA accumulation, and progression from hepatic steatosis to nonalcoholic steatohepatitis (NASH). This study aimed to evaluate the effects of xanthohumol (XN), a hop-derived compound mitigating metabolic syndrome, on liver damage induced by diet and FXR deficiency in mice. Wild-type (WT) and liver-specific FXR-null mice (FXRLiver−/−) were fed a high-fat diet (HFD) containing XN or the vehicle formation followed by histological characterization, lipid, BA and gene profiling. HFD supplemented with XN resulted in amelioration of hepatic steatosis and decreased BA concentrations in FXRLiver−/− mice, the effect being stronger in male mice. XN induced the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and glucocorticoid receptor (GR) gene expression in the liver of FXRLiver−/− mice. These findings suggest that activation of BA detoxification pathways represents the predominant mechanism for controlling hydrophobic BA concentrations in FXRLiver−/− mice. Collectively, these data indicated sex-dependent relationship between FXR, lipids and BAs, and suggest that XN ameliorates HFD-induced liver dysfunction via FXR-dependent and independent signaling.
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Affiliation(s)
- Ines L Paraiso
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States.,Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, United States
| | - Thai Q Tran
- Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, United States
| | - Armando Alcazar Magana
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States.,Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, United States.,Department of Chemistry, Oregon State University, Corvallis, OR, United States
| | - Payel Kundu
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, United States
| | - Jaewoo Choi
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States
| | - Claudia S Maier
- Department of Chemistry, Oregon State University, Corvallis, OR, United States
| | - Gerd Bobe
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States.,Department of Animal and Rangeland Sciences, Oregon State University, Corvallis, OR, United States
| | - Jacob Raber
- Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, United States.,Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, United States.,Department of Neurology, Psychiatry and Radiation Medicine, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Portland, OR, United States
| | - Chrissa Kioussi
- Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, United States
| | - Jan F Stevens
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States.,Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, United States
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26
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Bioinformatis analysis reveals possible molecular mechanism of PXR on regulating ulcerative colitis. Sci Rep 2021; 11:5428. [PMID: 33686088 PMCID: PMC7940411 DOI: 10.1038/s41598-021-83742-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/08/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease of the gastrointestinal (GI) tract. Ulcerative colitis (UC) is a type of IBD. Pregnane X Receptor (PXR) is a member of the nuclear receptor superfamily. In order to deepen understanding and exploration of the molecular mechanism of regulation roles of PXR on UC, biological informatics analysis was performed. First, 878 overlapping differentially expressed genes (DEGs) between UC and normal samples were obtained from the Gene Expression Omnibus (GEO) database (GSE59071 and GSE38713) by using the "limma" R language package. Then WGCNA analysis was performed by 878 DEGs to obtain co-expression modules that were positively and negatively correlated with clinical traits. GSEA analysis of PXR results obtained the signal pathways enriched in the PXR high and low expression group and the active genes of each signal pathway. Then the association of PXR with genes that are both active in high expression group and negatively related to diseases (gene set 1), or both active in low expression group and negatively related to diseases (gene set 2) was analyzed by String database. Finally, carboxylesterase 2 (CES2), ATP binding cassette subfamily G member 2 (ABCG2), phosphoenolpyruvate carboxykinase (PCK1), PPARG coactivator 1 alpha (PPARGC1A), cytochrome P450 family 2 subfamily B member 6 (CYP2B6) from gene set 1 and C-X-C motif chemokine ligand 8 (CXCL8) from gene set 2 were screened out. After the above analysis and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) verification, we speculated that PXR may exert a protective role on UC by promoting CES2, ABCG2, PCK1, PPARGC1A, CYP2B6 expression and inhibiting CXCL8 expression in their corresponding signal pathway in intestinal tissue.
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Abstract
Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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Mocking RJT, Naviaux JC, Li K, Wang L, Monk JM, Bright AT, Figueroa CA, Schene AH, Ruhé HG, Assies J, Naviaux RK. Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence. Transl Psychiatry 2021; 11:37. [PMID: 33431800 PMCID: PMC7801396 DOI: 10.1038/s41398-020-01182-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 12/08/2020] [Accepted: 12/15/2020] [Indexed: 01/29/2023] Open
Abstract
Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69-1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.
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Affiliation(s)
- Roel J T Mocking
- Department of Psychiatry, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Meibergdreef 5, 1105 AZ, Amsterdam, The Netherlands.
| | - Jane C Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
- Department of Neurosciences, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
| | - Kefeng Li
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
| | - Lin Wang
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
| | - Jonathan M Monk
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
| | - A Taylor Bright
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA
- Colt Neck Labs, 838 E High St 202., Lexington, KY, 40503, USA
| | - Caroline A Figueroa
- Department of Psychiatry, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Meibergdreef 5, 1105 AZ, Amsterdam, The Netherlands
- School of Social Welfare, University of California, Berkeley, CA, 94720, USA
| | - Aart H Schene
- Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands
- Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, the Netherlands
| | - Henricus G Ruhé
- Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands
- Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, the Netherlands
| | - Johanna Assies
- Department of Psychiatry, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Meibergdreef 5, 1105 AZ, Amsterdam, The Netherlands.
| | - Robert K Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA.
- Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA.
- Department of Pediatrics, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA.
- Department of Pathology, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, San Diego, CA, 92103-8467, USA.
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Luan Z, Wei Y, Huo X, Sun X, Zhang C, Ming W, Luo Z, Du C, Li Y, Xu H, Lu H, Zheng F, Guan Y, Zhang X. Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice. Biochim Biophys Acta Mol Basis Dis 2020; 1867:165996. [PMID: 33127475 DOI: 10.1016/j.bbadis.2020.165996] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/13/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022]
Abstract
Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many other functions including the regulation of cell proliferation, inflammatory response, and glucose and lipid metabolism. In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity in mice. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α‑carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory gene expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways, especially the PI3K/AKT pathway. In vitro study further revealed that PXR protected against cisplatin-induced apoptosis of cultured proximal tubule cells in a PI3K-dependent manner. Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel protective target for cisplatin-induced nephrotoxicity.
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Affiliation(s)
- Zhilin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Yuanyi Wei
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Xiaoxiao Huo
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Xiaowan Sun
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Cong Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Wenhua Ming
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Zhaokang Luo
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Chunxiu Du
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Yaqing Li
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Hu Xu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Heyuan Lu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Feng Zheng
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
| | - Xiaoyan Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
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Küblbeck J, Niskanen J, Honkakoski P. Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR. Cells 2020; 9:E2306. [PMID: 33076503 PMCID: PMC7602645 DOI: 10.3390/cells9102306] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.
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Affiliation(s)
- Jenni Küblbeck
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
- School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
| | - Jonna Niskanen
- School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
| | - Paavo Honkakoski
- School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Campus Box 7569, Chapel Hill, NC 27599-7569, USA
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Wang M, Tan J, Zhou J, Yi B, Huang Z. Farnesoid X receptor mediates hepatic steatosis induced by PM 2.5. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:34412-34420. [PMID: 32557026 DOI: 10.1007/s11356-020-09676-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 06/09/2020] [Indexed: 06/11/2023]
Abstract
Ambient particulate matter (PM) newly has been regarded as a conceivable hazard for public health. A large number of studies have described that PM, exceptionally PM2.5, is correlated with respiratory, cardiovascular, and metabolic diseases, etc. PM2.5-induced hepatocyte steatosis previously has been uncovered both in cellular and murine models. Nevertheless, less is known about the underlying mechanism. Here, we found that PM2.5 could cause the downregulation of farnesoid X receptor (FXR), a key transcription factor for lipid metabolism. FXR could regulate the accumulation of lipid droplets induced by PM2.5 in vitro. Moreover, FXR-/- mice were exposed to PM2.5 for 2 months to investigate the role of FXR in pathogenesis of PM2.5-induced hepatic steatosis in vivo. The results showed that exposure of wild-type (WT) mice to PM2.5 caused mild liver steatosis compared with the mice exposure to filtered air (FA). Furthermore, the content of triglyceride (TG) and total cholesterol (TC) was elevated in WT mice liver triggered by the inhalation of PM2.5. However, there was no statistical difference in TG and TC content between FXR-/- mice with and without PM2.5 exposure. Overall, our finding suggested FXR mediated PM2.5-induced hepatic steatosis.
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Affiliation(s)
- Mengyao Wang
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Jieqiong Tan
- Center for Medical Genetics, Life Science School, Central South University, Changsha, 410013, China
| | - Ji Zhou
- Typhoon Institute/CMA, Shanghai Key Laboratory of Meteorology and Health, Shanghai, 200030, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Zhijun Huang
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
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Intestinal Inflammation Alters the Expression of Hepatic Bile Acid Receptors Causing Liver Impairment. J Pediatr Gastroenterol Nutr 2020; 71:189-196. [PMID: 32404746 DOI: 10.1097/mpg.0000000000002759] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The gut-liver axis has been recently investigated in depth in relation to intestinal and hepatic diseases. Key actors are bile acid (BA) receptors, as farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR), and G-protein-coupled-receptor (GPCR; TGR5), that control a broad range of metabolic processes as well as inflammation and fibrosis. The present study aims to investigate the impact of intestinal inflammation on liver health with a focus on FXR, PXR, and TGR5 expression. The strategy to improve liver health by reducing gut inflammation is also considered. Modulation of BA receptors in the inflamed colonic tissues of inflammatory bowel disease (IBD) pediatric patients is analyzed. METHODS A dextran sodium sulphate (DSS) colitis animal model was built. Co-cultures with Caco2 and HepG2 cell lines were set up. Modulation of BA receptors in biopsies of IBD pediatric patients was assessed by real-time PCR and immunohistochemistry. RESULTS Histology showed inflammatory cell infiltration in the liver of DSS mice, where FXR and PXR were significantly decreased and oxidative stress was increased. Exposure of Caco2 to inflammatory stimuli resulted in the reduction of BA receptor expression in HepG2. Caco2 treatment with dipotassium glycyrrhizate (DPG) reduced these effects on liver cells. Inflamed colon of patients showed altered FXR, PXR, and TGR5 expression. CONCLUSIONS This study strongly suggests that gut inflammation affects hepatic cells by altering BA receptor levels as well as increasing the production of pro-inflammatory cytokines and oxidative stress. Hence, reducing gut inflammation is needed not only to improve the intestinal disease but also to protect the liver.
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Petrov PD, Fernández-Murga L, Conde I, Martínez-Sena T, Guzmán C, Castell JV, Jover R. Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes. Arch Toxicol 2020; 94:589-607. [PMID: 31894354 DOI: 10.1007/s00204-019-02643-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 12/02/2019] [Indexed: 02/06/2023]
Abstract
Anabolic-androgenic steroids are testosterone derivatives, used by body-builders to increase muscle mass. Epistane (EPI) is an orally administered 17α-alkylated testosterone derivative with 2a-3a epithio ring. We identified four individuals who, after EPI consumption, developed long-lasting cholestasis. The bile acid (BA) profile of three patients was characterized, as well the molecular mechanisms involved in this pathology. The serum BA pool was increased from 14 to 61-fold, basically on account of primary conjugated BA (cholic acid (CA) conjugates), whereas secondary BA were very low. In in vitro experiments with cultured human hepatocytes, EPI caused the accumulation of glycoCA in the medium. Moreover, as low as 0.01 μM EPI upregulated the expression of key BA synthesis genes (CYP7A1, by 65% and CYP8B1, by 67%) and BA transporters (NTCP, OSTA and BSEP), and downregulated FGF19. EPI increased the uptake/accumulation of a fluorescent BA analogue in hepatocytes by 50-70%. Results also evidenced, that 40 μM EPI trans-activated the nuclear receptors LXR and PXR. More importantly, 0.01 μM EPI activated AR in hepatocytes, leading to an increase in the expression of CYP8B1. In samples from a human liver bank, we proved that the expression of AR was positively correlated with that of CYP8B1 in men. Taken together, we conclude that EPI could cause cholestasis by inducing BA synthesis and favouring BA accumulation in hepatocytes, at least in part by AR activation. We anticipate that the large phenotypic variability of BA synthesis enzymes and transport genes in man provide a putative explanation for the idiosyncratic nature of EPI-induced cholestasis.
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Affiliation(s)
- Petar D Petrov
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Leonor Fernández-Murga
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Isabel Conde
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain.,Unidad de Hepatotoxicidad Clínica, Servicio de Medicina Digestiva, Sección Hepatología, Hospital La Fe, Valencia, Spain
| | - Teresa Martínez-Sena
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Carla Guzmán
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - José Vicente Castell
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. .,Departamento de Bioquímica Y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Ramiro Jover
- Unidad Mixta de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, 46026, Valencia, Spain. .,Departamento de Bioquímica Y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
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Li D, Zhu H, Luo X, Ge W. PXR haplotype clusters will affect the pharmacokinetics of ciclosporin in Chinese renal transplant recipients. J Pharm Pharmacol 2019; 72:271-278. [PMID: 31820434 DOI: 10.1111/jphp.13206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 10/26/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE PXR was reported to be the key nuclear receptor regulating the expression of metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of PXR haplotype clusters on ciclosporin concentration in Chinese renal transplant recipients during the early stage after transplantation. METHODS A total of 98 recipients receiving ciclosporin were genotyped by PCR-RFLP, and the ciclosporin concentration was determined by EMIT. KEY FINDINGS The frequency of IVS2+55A>G, IVS2+78A>G, IVS6-17C>T, 1792A>G, 1944T>C and 2654T>C variant alleles was 0.343, 0.332, 0.378, 0.515, 0.520 and 0.393, which fitted Hardy-Weinberg equilibrium. Only the IVS6-17C>T and 2654T>C were significantly associated with the ciclosporin C2 /D during the end of the first month. The mean ciclosporin C2 /D level of the PXR*1B haplotype clusters was 1.3-fold and 1.2-fold higher compared with the *1A and *1C. No significant difference was observed in CsA C2 /D between the PXR*1A and PXR*1C. We found no difference in C0 /D among the six genotypes or the three haplotype clusters. CONCLUSIONS The PXR*1B in Chinese renal transplant patients was associated with ciclosporin concentration. Genetic polymorphisms and specific haplotype clusters in PXR could have significant contributory roles in affecting interethnic variations in drug disposition in the Chinese population.
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Affiliation(s)
- Danying Li
- Pharmacy Department, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
| | - Huaijun Zhu
- Pharmacy Department, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
| | - Xuemei Luo
- Pharmacy Department, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
| | - Weihong Ge
- Pharmacy Department, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
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Garcia M, Thirouard L, Monrose M, Holota H, De Haze A, Caira F, Beaudoin C, Volle DH. Farnesoid X receptor alpha (FXRα) is a critical actor of the development and pathologies of the male reproductive system. Cell Mol Life Sci 2019; 76:4849-4859. [PMID: 31407019 PMCID: PMC11105758 DOI: 10.1007/s00018-019-03247-6] [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: 04/30/2019] [Revised: 07/19/2019] [Accepted: 07/23/2019] [Indexed: 12/01/2022]
Abstract
The farnesoid-X-receptorα (FXRα; NR1H4) is one of the main bile acid (BA) receptors. During the last decades, through the use of pharmalogical approaches and transgenic mouse models, it has been demonstrated that the nuclear receptor FXRα controls numerous physiological functions such as glucose or energy metabolisms. It is also involved in the etiology or the development of several pathologies. Here, we will review the unexpected roles of FXRα on the male reproductive tract. FXRα has been demonstrated to play functions in the regulation of testicular and prostate homeostasis. Even though additional studies are needed to confirm these findings in humans, the reviewed reports open new field of research to better define the effects of bile acid-FXRα signaling pathways on fertility disorders and cancers.
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Affiliation(s)
- Manon Garcia
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Laura Thirouard
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Mélusine Monrose
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Hélène Holota
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Angélique De Haze
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Françoise Caira
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Claude Beaudoin
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France.
| | - David H Volle
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France.
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36
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Warner DR, Warner JB, Hardesty JE, Song YL, King TN, Kang JX, Chen CY, Xie S, Yuan F, Prodhan MAI, Ma X, Zhang X, Rouchka EC, Maddipati KR, Whitlock J, Li EC, Wang GP, McClain CJ, Kirpich IA. Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury. J Lipid Res 2019; 60:2034-2049. [PMID: 31586017 PMCID: PMC6889711 DOI: 10.1194/jlr.ra119000200] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 09/22/2019] [Indexed: 02/07/2023] Open
Abstract
Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 (fat-1) mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and Cxcl1 was attenuated in fat-1 and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including Alpi and Leap2) in fat-1 versus WT mice fed EtOH. fat-1 mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in fat-1 versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.
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Affiliation(s)
- Dennis R Warner
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
| | - Jeffrey B Warner
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
- Department of Medicine Division of Infectious Diseases and Global Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Josiah E Hardesty
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
| | - Ying L Song
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
| | - Taylor N King
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Chih-Yu Chen
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Shanfu Xie
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Fang Yuan
- Department of Chemistry, University of Louisville, Louisville, KY
| | | | - Xipeng Ma
- Department of Chemistry, University of Louisville, Louisville, KY
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, KY
| | - Eric C Rouchka
- Department of Computer Engineering and Computer Science, Speed School of Engineering, University of Louisville, Louisville, KY
| | | | - Joan Whitlock
- Department of Medicine Division of Infectious Diseases and Global Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Eric C Li
- Department of Medicine Division of Infectious Diseases and Global Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Gary P Wang
- Department of Medicine Division of Infectious Diseases and Global Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Craig J McClain
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
- Department of Pharmacology and Toxicology and University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY
- Robley Rex Veterans Medical Center, Louisville, KY
| | - Irina A Kirpich
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY
- Department of Pharmacology and Toxicology and University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY
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Rosenthal SB, Bush KT, Nigam SK. A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis. Sci Rep 2019; 9:11879. [PMID: 31417100 PMCID: PMC6695406 DOI: 10.1038/s41598-019-47798-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023] Open
Abstract
Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network-including SLC and ABC "drug" transporters, "drug" metabolizing enzymes (DMEs), and regulatory genes-is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4α, HNF1α, and PXR. Knockout gene expression data confirmed ~60-70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney "remote sensing and signaling network" consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules.
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Affiliation(s)
- Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California at San Diego, La Jolla, CA, 92093-0693, USA
| | - Kevin T Bush
- Departments of Pediatrics, University of California at San Diego, La Jolla, CA, 92093-0693, USA
| | - Sanjay K Nigam
- Departments of Pediatrics, University of California at San Diego, La Jolla, CA, 92093-0693, USA.
- Departments of Medicine, University of California at San Diego, La Jolla, CA, 92093-0693, USA.
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