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Jiao Y, Ren J, Xie S, Yuan N, Shen J, Yin H, Wang J, Guo H, Cao J, Wang X, Wu D, Zhou Z, Qi X. Raffinose-metabolizing bacteria impair radiation-associated hematopoietic recovery via the bile acid/FXR/NF-κB signaling pathway. Gut Microbes 2025; 17:2488105. [PMID: 40192235 PMCID: PMC11980471 DOI: 10.1080/19490976.2025.2488105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/23/2025] [Accepted: 03/28/2025] [Indexed: 04/11/2025] Open
Abstract
Radiation-associated hematopoietic recovery (RAHR) is critical for mitigating lethal complications of acute radiation syndrome (ARS), yet therapeutic strategies remain limited. Through integrated multi-omics analysis of a total body irradiation (TBI) mouse model, we identify Bacteroides acidifaciens-dominated gut microbiota as key mediators of RAHR impairment. 16S ribosomal rRNA sequencing revealed TBI-induced dysbiosis characterized by Bacteroidaceae enrichment, while functional metagenomics identified raffinose metabolism as the most significantly perturbed pathway. Notably, raffinose supplementation (10% w/v) recapitulated radiation-induced microbiota shifts and delayed bone marrow recovery. Fecal microbiota transplantation (FMT) revealed a causative role for raffinose-metabolizing microbiota, particularly Bacteroides acidifaciens, in delaying RAHR progression. Mechanistically, B. acidifaciens-mediated bile acid deconjugation activated FXR, subsequently suppressing NF-κB-dependent hematopoietic recovery. Therapeutic FXR inhibition via ursodeoxycholic acid (UDCA) had been shown to be a viable method for rescuing RAHR. Our results delineated a microbiome-bile acid-FXR axis as a master regulator of post-irradiation hematopoiesis. Targeting B. acidifaciens or its metabolic derivatives could represent a translatable strategy to mitigate radiation-induced hematopoietic injury.
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Affiliation(s)
- Yang Jiao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou, China
| | - Jiawei Ren
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Shichang Xie
- Key Laboratory of Alkene-Carbon Fibers-Based Technology & Application for Detection of Major Infectious Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, China
| | - Nan Yuan
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Jiaqi Shen
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
| | - Huafang Yin
- The Affiliated Jiangyin People’s Hospital of Nantong University, Jiangyin, China
| | - Jian Wang
- The Affiliated Jiangyin People’s Hospital of Nantong University, Jiangyin, China
| | - Hongjuan Guo
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Jianping Cao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China
| | - Xin Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products & Institute of Food Sciences, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Depei Wu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou, China
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
| | - Zhemin Zhou
- Key Laboratory of Alkene-Carbon Fibers-Based Technology & Application for Detection of Major Infectious Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Cancer Institute, Suzhou Medical College, Soochow University, Suzhou, China
- Cancer Institute, Suzhou Medical College, The Second Affiliated Hospital of Soochow University, Suzhou, China
- National Center of Technology Innovation for Biopharmaceuticals, Suzhou Biomedical Industry Innovation Center, Suzhou, China
| | - Xiaofei Qi
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Suzhou, China
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
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Zhou Z, Xu D, Huang L, Cui Y, Chen H, Tang J. Farnesoid X Receptor Regulated Sepsis-Induced Abnormal Bile Acid Metabolism via the Fibroblast Growth Factor 15/Fibroblast Growth Factor Receptor 4 Pathway. Immun Inflamm Dis 2025; 13:e70155. [PMID: 40192065 PMCID: PMC11973727 DOI: 10.1002/iid3.70155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 01/06/2025] [Accepted: 01/30/2025] [Indexed: 04/10/2025] Open
Abstract
OBJECTIVE The study aims to investigate the mechanism of Farnesoid X receptor (FXR) activation in sepsis-induced abnormal bile acid metabolism and the metabolism status of each bile acid type. METHODS The sepsis mouse model was developed via lipopolysaccharide intraperitoneal injection and confirmed via hematoxylin and eosin (H&E) staining. FXR agonist activated the FXR/fibroblast growth factor (FGF)15/FGFR pathway via quantitative real-time polymerase chain reaction and Western blot. Consequently, metabolomics and bioinformatics analysis were conducted to identify the alterations in each kind of bile acid content following FXR agonist/inhibitor intervention. RESULTS The H&E staining indicated that FXR activation alleviates the liver injury of the sepsis mouse model. The increased FGF15 and FXFR expression levels and decreased CYP7A1 demonstrated FXR/FGF15/FGFR pathway activation following FXR agonist treatment. Furthermore, total bile acid, interleukin (IL)-6, and tumor necrosis factor-α concentrations were downregulated after FXR activation, whereas IL-10 concentration was upregulated, indicating the alleviated effect of FXR agonist in sepsis. Consequently, metabolomics and bioinformatics analysis determined that T-a-MCA were downregulated in both FXR agonist and inhibitor groups, whereas six bile acid types were altered in the control group. CONCLUSION FXR activation was crucial in alleviating sepsis-induced hepatic injury and cholestasis through the FGF15/FGFR signaling pathway, and FXR may act as a potential preventive and intervention target of sepsis.
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Affiliation(s)
- Ziyang Zhou
- Trauma‐Emergency & Critical Care Medicine CenterShanghai Fifth People's Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Dan Xu
- Trauma‐Emergency & Critical Care Medicine CenterShanghai Fifth People's Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Liou Huang
- Trauma‐Emergency & Critical Care Medicine CenterShanghai Fifth People's Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Yuhui Cui
- Trauma‐Emergency & Critical Care Medicine CenterShanghai Fifth People's Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Hui Chen
- Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life ScienceEast China Normal UniversityShanghaiChina
| | - Jianguo Tang
- Trauma‐Emergency & Critical Care Medicine CenterShanghai Fifth People's Hospital Affiliated to Fudan UniversityShanghaiChina
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Harrouche K, Boutaoui N, Saidi KM, Stiti MZ, Khelafi A, Khelili S. Design, Synthesis, and Biological Evaluation of New Ureido (Thioureido) Anthranilic Acid Isosteres: Molecular Docking, In Silico ADMET Predictions, and In Vivo Anti-Inflammatory Activity. Chem Biodivers 2025:e202500374. [PMID: 40128116 DOI: 10.1002/cbdv.202500374] [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: 01/29/2025] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 03/26/2025]
Abstract
A novel series of anthranilic acid isosteres were designed and synthesized as antiinflammatory agents. The in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted a favorable pharmacokinetic profile and respect for Lipinski's rule of five. Density functional theory (DFT) calculations revealed an improvement in some target compounds' electronic parameters compared to diclofenac (DCF) and aspirin (ASA), predicting an improvement in their biological activity. Docking investigations demonstrated a strong affinity toward the cyclooxygenase (COX)-1 and COX-2 enzymes, with a relative preference for COX-2, predicting antiinflammatory activity. The MolDock scores were between -140.59 and -91.81 kcal/mol for COX-1 and between -148.10 and -108.9 kcal/mol for COX-2. The experimental pharmacological investigation confirmed these theoretical findings. Indeed, target compounds demonstrated a significant inhibition of the carrageenan-induced paw edema in rats and probable inhibition of COX. Particularly, compounds 4e and 4h devoid of COOH group, which provoke serious gastrointestinal irritation, exhibited antiinflammatory activity comparable to that of salicylic acid (ASA) and surpassed the effectiveness of DCF. Cpmpounds 4e and 4h showed 91.72% inhibition after 3h, against 91.03% and 83.44% for ASA and DCF, respectively, with a greater onset effect, and also surpassing the reference compounds after 1 and 2 h. The results also indicate good pharmacokinetic profile of the target compounds similar to ASA and DCF.
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Affiliation(s)
- Kamel Harrouche
- Team of Chemistry of Heterocyclic Compounds, Laboratory of Phytochemistry and Pharmacology, University of Jijel, Jijel, Algeria
| | - Nassima Boutaoui
- Team of Chemistry of Heterocyclic Compounds, Laboratory of Phytochemistry and Pharmacology, University of Jijel, Jijel, Algeria
| | - Katia Mohand Saidi
- Team of Pharmaceutical Chemistry, Analysis and Drug Quality Control, Laboratory of Phytochemistry and Pharmacology, University of Jijel, Jijel, Algeria
| | - Mohamed Zakaria Stiti
- Team of Pharmaceutical Chemistry, Analysis and Drug Quality Control, Laboratory of Phytochemistry and Pharmacology, University of Jijel, Jijel, Algeria
| | - Asma Khelafi
- Team of Chemistry of Heterocyclic Compounds, Laboratory of Phytochemistry and Pharmacology, University of Jijel, Jijel, Algeria
| | - Smail Khelili
- Team of Pharmaceutical Chemistry, Analysis and Drug Quality Control, Laboratory of Phytochemistry and Pharmacology, University of Jijel, Jijel, Algeria
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Xu X, Pu S, Jiang M, Hu X, Wang Q, Yu J, Chu J, Wei G, Wang L. Knockout of nuclear receptor HR38 gene impairs pupal-adult development in silkworm Bombyx mori. INSECT MOLECULAR BIOLOGY 2024; 33:29-40. [PMID: 37738573 DOI: 10.1111/imb.12876] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/30/2023] [Indexed: 09/24/2023]
Abstract
Nuclear receptors are ligand-regulated transcription factors that play important role in regulating insect metamorphosis through the ecdysone signalling pathway. In this study, we investigated the nuclear receptor HR38 gene in Bombyx mori (BmHR38), belonging to the NR4A subfamily. BmHR38 mRNA was highly expressed in the head and epidermis at the pupal stage. The expression of the BmHR38 gene was influenced by different doses of 20E at different times. A BmHR38 deletion mutant silkworm was generated using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Compared with the wild-type B. mori, the BmHR38 deletion mutant resulted in abnormal development during the pupal stage, leading to either failed eclosion or the formation of abnormal adult wings. After silencing of BmHR38 in the pupal stage, the phenotype of pupa or moth had no significant change, but it did result in reduced egg production. The mRNA levels of USP, E75 and E74 were significantly increased, while the transcript levels of FTZ-F1 were suppressed after RNA interference. Furthermore, interference with BmHR38 also inhibited the expressions of chitin metabolism genes, including Chs1, Chs2, Chi, Chi-h and CDA. Our results suggest that BmHR38 is essential for pupal development and pupa-adult metamorphosis in B. mori by regulating the expression of NRs and chitin metabolism genes.
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Affiliation(s)
- Xinyue Xu
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Shangkun Pu
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Mouzhen Jiang
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Xiaoxuan Hu
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Qing Wang
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Jun Yu
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Jianghong Chu
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Guoqing Wei
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Lei Wang
- Anhui Key Laboratory of Resource Insect Biology and Innovative Utilization, School of Life Sciences, Anhui Agricultural University, Hefei, China
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Takimoto Y, Chu PS, Nakamoto N, Hagihara Y, Mikami Y, Miyamoto K, Morikawa R, Teratani T, Taniki N, Fujimori S, Suzuki T, Koda Y, Ishihara R, Ichikawa M, Honda A, Kanai T. Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience 2023; 26:106220. [PMID: 36876136 PMCID: PMC9982274 DOI: 10.1016/j.isci.2023.106220] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 08/25/2022] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.
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Affiliation(s)
- Yoichi Takimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuya Hagihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kentaro Miyamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Sota Fujimori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Rino Ishihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Ibaraki 300-0395, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Batiha GES, Al-kuraishy HM, Al-Gareeb AI, Youssef FS, El-Sherbeni SA, Negm WA. A perspective study of the possible impact of obeticholic acid against SARS-CoV-2 infection. Inflammopharmacology 2023; 31:9-19. [PMID: 36484974 PMCID: PMC9735105 DOI: 10.1007/s10787-022-01111-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022]
Abstract
The causative agent of CoV disease 2019 is a new coronavirus CoV type 2, affecting the respiratory tract with severe manifestations (SARS-CoV-2). Covid-19 is mainly symptomless, with slight indications in about 85% of the affected cases. Many efforts were done to face this pandemic by testing different drugs and agents to make treatment protocols in different countries. However, the use of these proposed drugs is associated with the development of adverse events. Remarkably, the successive development of SARS-CoV-2 variants which could affect persons even they were vaccinated, prerequisite wide search to find efficient and safe agents to face SARS-CoV-2 infection. Obeticholic acid (OCA), which has anti-inflammatory effects, may efficiently treat Covid-19. Thus, the goal of this perspective study is to focus on the possible medicinal effectiveness in managing Covid-19. OCA is a powerful farnesoid X receptor (FXR) agonist possessing marked antiviral and anti-inflammatory effects. FXR is dysregulated in Covid-19 resulting in hyper-inflammation with concurrent occurrence of hypercytokinemia. Interestingly, OCA inhibits the reaction between this virus and angiotensin-converting enzyme type 2 (ACE2) receptors. FXR agonists control the expression of ACE2 and the inflammatory signaling pathways in this respiratory syndrome, which weakens the effects of Covid-19 disease and accompanied complications. Taken together, FXR agonists like OCA may reveal both direct and indirect impacts in the modulation of immune reaction in SARS-CoV-2 conditions. It is highly recommended to perform many investigations regarding different phases of the discovery of new drugs.
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Affiliation(s)
- Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511 AlBeheira Egypt
| | - Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Fadia S. Youssef
- Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Abbasia, Cairo, 11566 Egypt
| | - Suzy A. El-Sherbeni
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta, 31527 Egypt
| | - Walaa A. Negm
- Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta, 31527 Egypt
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Yakıştıran B, Tanaçan A, Altınboğa O, Elbayiyev S, Canpolat FE, Yücel A. Fetal pulmonary artery Doppler parameters in pregnancies complicated with intrahepatic cholestasis of pregnancy: a prospective case-control study. J Turk Ger Gynecol Assoc 2022; 23:249-254. [DOI: 10.4274/jtgga.galenos.2021.2021-9-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Marotta C, Ahmad A, Luo E, Oosterhaven J, van Marle S, Adda N. EDP-297: A novel, farnesoid X receptor agonist-Results of a phase I study in healthy subjects. Clin Transl Sci 2022; 16:338-351. [PMID: 36369848 PMCID: PMC9926082 DOI: 10.1111/cts.13453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/21/2022] [Accepted: 10/31/2022] [Indexed: 11/13/2022] Open
Abstract
EDP-297 is a farnesoid X receptor agonist under development for treating nonalcoholic steatohepatitis. The pharmacokinetic (PK), pharmacodynamic (PD), food effect, and safety were evaluated in a single ascending dose (SAD) and multiple ascending dose (MAD) phase I study. Healthy subjects received single EDP-297 doses of 20-600 μg or once daily doses of 5-90 μg for 14 days. Safety, PKs, and PDs were assessed, including fibroblast growth factor 19 (FGF-19) and 7-α-hydroxy-4-cholesten-3-one (C4). Among 82 subjects, EDP-297 was generally well-tolerated. Pruritus was observed in four subjects in the SAD phase and seven subjects in the MAD phase; four severe cases occurred at 90 μg in the MAD phase, including one that led to drug discontinuation. A grade 2 elevation in alanine aminotransferase occurred with 90 μg. Mean lipid values remained within normal range. Plasma exposures of EDP-297 increased with SADs and MADs, with mean half-life following multiple doses of 9-12.5 h. No food effect was observed. Mean FGF-19 increased and C4 decreased up to 95% and 92%, respectively. EDP-297 was generally well-tolerated up to 60 μg MAD, with linear PKs suitable for once daily oral dosing, target engagement, and no food effect.
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Affiliation(s)
| | - Alaa Ahmad
- Enanta Pharmaceuticals, Inc.WatertownMassachusettsUSA
| | - Ed Luo
- Enanta Pharmaceuticals, Inc.WatertownMassachusettsUSA
| | | | | | - Nathalie Adda
- Enanta Pharmaceuticals, Inc.WatertownMassachusettsUSA
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9
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Zheng Y, Sun W, Wang Z, Liu J, Shan C, He C, Li B, Hu X, Zhu W, Liu L, Lan F, Jiang C, Zhao C, Li X, Sun N. Activation of Pancreatic Acinar FXR Protects against Pancreatitis via Osgin1-Mediated Restoration of Efficient Autophagy. RESEARCH (WASHINGTON, D.C.) 2022; 2022:9784081. [PMID: 36405253 PMCID: PMC9667885 DOI: 10.34133/2022/9784081] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/29/2022] [Indexed: 07/30/2023]
Abstract
Pancreatitis is the leading cause of hospitalization in gastroenterology, and no medications are available for treating this disease in current clinical practice. FXR plays an anti-inflammatory role in diverse inflammatory diseases, while its function in pancreatitis remains unknown. In this study, we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients with pancreatitis. Deleting the FXR in pancreatic acinar cells (FXRacinarΔ/Δ ) led to more severe pancreatitis in mouse models of caerulein-induced acute and chronic pancreatitis, while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis. FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids (PEOs) in vitro. Utilizing RNA-seq and ChIP-seq of PEOs, we identified Osgin1 as a direct target of FXR in the exocrine pancreas, which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues. Pancreatic knockdown of Osgin1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis, whereas pancreatic overexpression of Osgin1 effectively alleviated caerulein-induced pancreatitis. Mechanistically, we found that the FXR-OSGIN1 axis stimulated autophagic flux in the pancreatic tissues and cell lines, which was considered as the intrinsic mechanisms through which FXR-OSGIN1 protecting against pancreatitis. Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.
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Affiliation(s)
- Yufan Zheng
- Wuxi School of Medicine, Jiangnan University, Jiangsu, China
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wenrui Sun
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhengyang Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiaying Liu
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Cong Shan
- Wuxi School of Medicine, Jiangnan University, Jiangsu, China
| | - Chenxi He
- Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Borui Li
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiao Hu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenjia Zhu
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Liyan Liu
- General Practice/International Medical Care Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Lan
- Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Chao Zhao
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaobo Li
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ning Sun
- Wuxi School of Medicine, Jiangnan University, Jiangsu, China
- Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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10
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Ng SC, Peng Y, Zhang L, Mok CK, Zhao S, Li A, Ching JY, Liu Y, Yan S, Chan DLS, Zhu J, Chen C, Fung AC, Wong KK, Hui DS, Chan FK, Tun HM. Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events. Gut 2022; 71:1106-1116. [PMID: 35140064 PMCID: PMC8844967 DOI: 10.1136/gutjnl-2021-326563] [Citation(s) in RCA: 113] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/16/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty). DESIGN We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA. RESULTS We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05). CONCLUSION Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.
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Affiliation(s)
- Siew C Ng
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ye Peng
- HKU-Pasteur Research Pole, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Lin Zhang
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University Hong Kong, Hong Kong SAR, China
| | - Chris Kp Mok
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shilin Zhao
- HKU-Pasteur Research Pole, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Amy Li
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jessica Yl Ching
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yingzhi Liu
- Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University Hong Kong, Hong Kong SAR, China
| | - Shuai Yan
- Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University Hong Kong, Hong Kong SAR, China
| | - Dream L S Chan
- Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jie Zhu
- HKU-Pasteur Research Pole, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Chunke Chen
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Adrian Ch Fung
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kenneth Ky Wong
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - David Sc Hui
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Francis Kl Chan
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Microbiota I-Center (MagIC), The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hein M Tun
- HKU-Pasteur Research Pole, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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11
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Pfister ED, Dröge C, Liebe R, Stalke A, Buhl N, Ballauff A, Cantz T, Bueltmann E, Stindt J, Luedde T, Baumann U, Keitel V. Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review. Liver Int 2022; 42:1084-1096. [PMID: 35184362 DOI: 10.1111/liv.15200] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
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Affiliation(s)
- Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
| | - Roman Liebe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Amelie Stalke
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Buhl
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Antje Ballauff
- Department of Paediatrics, Helios Hospital, Krefeld, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Eva Bueltmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
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12
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New Kids on the Block: Bile Salt Conjugates of Microbial Origin. Metabolites 2022; 12:metabo12020176. [PMID: 35208250 PMCID: PMC8876647 DOI: 10.3390/metabo12020176] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 02/04/2023] Open
Abstract
Biotransformation of host bile salts by gut microbes results in generation of secondary bile salt species that have biological and physicochemical properties that are distinct from the parent compounds. There is increased awareness that a bile salt–gut microbiome axis modulates various processes in the host, including innate and adaptive immunity, by interaction of microbial bile salt metabolites with host receptors. Omics and targeted approaches have vastly expanded the number and repertoire of secondary bile salt species. A new class of microbial bile salt metabolites was reported in 2020 and comprises bile salts that are conjugated by microbial enzymes. Amino acids other than those employed by host enzymes (glycine and taurine) are used as substrates in the formation of these microbial bile salt conjugates (MBSCs). Leucocholic acid, phenylalanocholic acid and tyrosocholic acid were the first MBSCs identified in mice and humans. The number of distinct MBSCs is now approaching 50, with variation both at the level of bile salt and amino acid employed for conjugation. Evidence is emerging that MBSC generation is a common feature of human gut bacteria, and initial links with disease states have been reported. In this review, we discuss this intriguing new class of secondary bile salts, with yet enigmatic function.
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13
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She J, Gu T, Pang X, Liu Y, Tang L, Zhou X. Natural Products Targeting Liver X Receptors or Farnesoid X Receptor. Front Pharmacol 2022; 12:772435. [PMID: 35069197 PMCID: PMC8766425 DOI: 10.3389/fphar.2021.772435] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/22/2021] [Indexed: 12/18/2022] Open
Abstract
Nuclear receptors (NRs) are a superfamily of transcription factors induced by ligands and also function as integrators of hormonal and nutritional signals. Among NRs, the liver X receptors (LXRs) and farnesoid X receptor (FXR) have been of significance as targets for the treatment of metabolic syndrome-related diseases. In recent years, natural products targeting LXRs and FXR have received remarkable interests as a valuable source of novel ligands encompassing diverse chemical structures and bioactive properties. This review aims to survey natural products, originating from terrestrial plants and microorganisms, marine organisms, and marine-derived microorganisms, which could influence LXRs and FXR. In the recent two decades (2000-2020), 261 natural products were discovered from natural resources such as LXRs/FXR modulators, 109 agonists and 38 antagonists targeting LXRs, and 72 agonists and 55 antagonists targeting FXR. The docking evaluation of desired natural products targeted LXRs/FXR is finally discussed. This comprehensive overview will provide a reference for future study of novel LXRs and FXR agonists and antagonists to target human diseases, and attract an increasing number of professional scholars majoring in pharmacy and biology with more in-depth discussion.
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Affiliation(s)
- Jianglian She
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.,College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Tanwei Gu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaoyan Pang
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China
| | - Yonghong Liu
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.,College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing, China.,Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
| | - Lan Tang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xuefeng Zhou
- CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
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14
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Cai Z, Wang B, Zhou Z, Zhao X, Hu L, Ren Q, Deng L, Li Z, Wang G. Discovery of a novel and orally active Farnesoid X receptor agonist for the protection of acetaminophen-induced hepatotoxicity. Chem Biol Drug Des 2021; 99:483-495. [PMID: 34936214 DOI: 10.1111/cbdd.14014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/01/2021] [Accepted: 12/19/2021] [Indexed: 12/31/2022]
Abstract
Acetaminophen (APAP) overdose is a leading cause of acute hepatic failure and liver transplantation, while the existing treatments are poorly effective. Therefore, it is necessary to develop effective therapeutic drugs for APAP-induced hepatotoxicity. Farnesoid X receptor (FXR) is a potential target for the treatment of liver disease, and the activation of FXR protects mice against APAP-induced hepatotoxicity. Compound 5, a glycine-conjugated derivative of FXR agonist 4, was designed to extend the chemical space of existing FXR agonists. Molecular modeling study indicated that compound 5 formed hydrogen bond network with key residues of FXR. Moreover, compound 5 (10 mg/kg) revealed better protective effects against APAP-induced hepatotoxicity than parent compound 4 (30 mg/kg). Further mechanical research indicated that compound 5 regulated the expressions of genes related to FXR and oxidative stress. These findings suggest that compound 5 is a promising FXR agonist suitable for further research, and it is the first time to verify that the glycine-conjugated derivative five exerted better protective effects than its parent compound.
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Affiliation(s)
- Zongyu Cai
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Bin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zongtao Zhou
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xin Zhao
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.,School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Lijun Hu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qiang Ren
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, China
| | - Liming Deng
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.,Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, China
| | - Guangji Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.,State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
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15
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Anderson KM, Gayer CP. The Pathophysiology of Farnesoid X Receptor (FXR) in the GI Tract: Inflammation, Barrier Function and Innate Immunity. Cells 2021; 10:cells10113206. [PMID: 34831429 PMCID: PMC8624027 DOI: 10.3390/cells10113206] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
Abstract
The Farnesoid-X Receptor, FXR, is a nuclear bile acid receptor. Its originally described function is in bile acid synthesis and regulation within the liver. More recently, however, FXR has been increasingly appreciated for its breadth of function and expression across multiple organ systems, including the intestine. While FXR’s role within the liver continues to be investigated, increasing literature indicates that FXR has important roles in responding to inflammation, maintaining intestinal epithelial barrier function, and regulating immunity within the gastrointestinal (GI) tract. Given the complicated and multi-factorial nature of intestinal barrier dysfunction, it is not surprising that FXR’s role appears equally complicated and not without conflicting data in different model systems. Recent work has suggested translational applications of FXR modulation in GI pathology; however, a better understanding of FXR physiology is necessary for these treatments to gain widespread use in human disease. This review aims to discuss current scientific work on the role of FXR within the GI tract, specifically in its role in intestinal inflammation, barrier function, and immune response, while also exploring areas of controversy.
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Affiliation(s)
- Kemp M. Anderson
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Christopher P. Gayer
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
- Correspondence: ; Tel.: +1-323-361-4974
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16
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Kumari A, Mittal L, Srivastava M, Pathak DP, Asthana S. Conformational Characterization of the Co-Activator Binding Site Revealed the Mechanism to Achieve the Bioactive State of FXR. Front Mol Biosci 2021; 8:658312. [PMID: 34532338 PMCID: PMC8439381 DOI: 10.3389/fmolb.2021.658312] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
FXR bioactive states are responsible for the regulation of metabolic pathways, which are modulated by agonists and co-activators. The synergy between agonist binding and ‘co-activator’ recruitment is highly conformationally driven. The characterization of conformational dynamics is essential for mechanistic and therapeutic understanding. To shed light on the conformational ensembles, dynamics, and structural determinants that govern the activation process of FXR, molecular dynamic (MD) simulation is employed. Atomic insights into the ligand binding domain (LBD) of FXR revealed significant differences in inter/intra molecular bonding patterns, leading to structural anomalies in different systems of FXR. The sole presence of an agonist or ‘co-activator’ fails to achieve the essential bioactive conformation of FXR. However, the presence of both establishes the bioactive conformation of FXR as they modulate the internal wiring of key residues that coordinate allosteric structural transitions and their activity. We provide a precise description of critical residue positioning during conformational changes that elucidate the synergy between its binding partners to achieve an FXR activation state. Our study offers insights into the associated modulation occurring in FXR at bound and unbound forms. Thereafter, we also identified hot-spots that are critical to arrest the activation mechanism of FXR that would be helpful for the rational design of its agonists.
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Affiliation(s)
- Anita Kumari
- Translational Health Science and Technology Institute (THSTI), Faridabad, India.,Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India
| | - Lovika Mittal
- Translational Health Science and Technology Institute (THSTI), Faridabad, India
| | - Mitul Srivastava
- Translational Health Science and Technology Institute (THSTI), Faridabad, India
| | - Dharam Pal Pathak
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India.,Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), New Delhi, India
| | - Shailendra Asthana
- Translational Health Science and Technology Institute (THSTI), Faridabad, India
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17
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Orozco-Aguilar J, Simon F, Cabello-Verrugio C. Redox-Dependent Effects in the Physiopathological Role of Bile Acids. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4847941. [PMID: 34527174 PMCID: PMC8437588 DOI: 10.1155/2021/4847941] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/17/2021] [Indexed: 12/17/2022]
Abstract
Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.
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Affiliation(s)
- Josué Orozco-Aguilar
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8370146, Chile
- Laboratory of Integrative Physiopathology, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
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18
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Mooranian A, Foster T, Ionescu CM, Walker D, Jones M, Wagle SR, Kovacevic B, Chester J, Johnston E, Wong E, Atlas MD, Mikov M, Al-Salami H. Enhanced Bilosomal Properties Resulted in Optimum Pharmacological Effects by Increased Acidification Pathways. Pharmaceutics 2021; 13:pharmaceutics13081184. [PMID: 34452145 PMCID: PMC8398365 DOI: 10.3390/pharmaceutics13081184] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Recent studies in our laboratory have shown that some bile acids, such as chenodeoxycholic acid (CDCA), can exert cellular protective effects when encapsulated with viable β-cells via anti-inflammatory and anti-oxidative stress mechanisms. However, to explore their full potential, formulating such bile acids (that are intrinsically lipophilic) can be challenging, particularly if larger doses are required for optimal pharmacological effects. One promising approach is the development of nano gels. Accordingly, this study aimed to examine biological effects of various concentrations of CDCA using various solubilising nano gel systems on encapsulated β-cells. METHODS Using our established cellular encapsulation system, the Ionic Gelation Vibrational Jet Flow technology, a wide range of CDCA β-cell capsules were produced and examined for morphological, biological, and inflammatory profiles. RESULTS AND CONCLUSION Capsules' morphology and topographic characteristics remained similar, regardless of CDCA or nano gel concentrations. The best pharmacological, anti-inflammatory, and cellular respiration, metabolism, and energy production effects were observed at high CDCA and nano gel concentrations, suggesting dose-dependent cellular protective and positive effects of CDCA when incorporated with high loading nano gel.
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Affiliation(s)
- Armin Mooranian
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Thomas Foster
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Corina M. Ionescu
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Daniel Walker
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Melissa Jones
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Susbin Raj Wagle
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Bozica Kovacevic
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Jacqueline Chester
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Edan Johnston
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Elaine Wong
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Marcus D. Atlas
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21101 Novi Sad, Serbia;
| | - Hani Al-Salami
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; (A.M.); (T.F.); (C.M.I.); (D.W.); (M.J.); (S.R.W.); (B.K.); (J.C.); (E.J.)
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Perth, WA 6009, Australia; (E.W.); (M.D.A.)
- Correspondence: ; Tel.: +61-8-9266-9816; Fax: +61-8-9266-2769
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Girisa S, Henamayee S, Parama D, Rana V, Dutta U, Kunnumakkara AB. Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer. MOLECULAR BIOMEDICINE 2021; 2:21. [PMID: 35006466 PMCID: PMC8607382 DOI: 10.1186/s43556-021-00035-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the lethal diseases that arise due to the molecular alterations in the cell. One of those alterations associated with cancer corresponds to differential expression of Farnesoid X receptor (FXR), a nuclear receptor regulating bile, cholesterol homeostasis, lipid, and glucose metabolism. FXR is known to regulate several diseases, including cancer and cardiovascular diseases, the two highly reported causes of mortality globally. Recent studies have shown the association of FXR overexpression with cancer development and progression in different types of cancers of breast, lung, pancreas, and oesophagus. It has also been associated with tissue-specific and cell-specific roles in various cancers. It has been shown to modulate several cell-signalling pathways such as EGFR/ERK, NF-κB, p38/MAPK, PI3K/AKT, Wnt/β-catenin, and JAK/STAT along with their targets such as caspases, MMPs, cyclins; tumour suppressor proteins like p53, C/EBPβ, and p-Rb; various cytokines; EMT markers; and many more. Therefore, FXR has high potential as novel biomarkers for the diagnosis, prognosis, and therapy of cancer. Thus, the present review focuses on the diverse role of FXR in different cancers and its agonists and antagonists.
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Affiliation(s)
- Sosmitha Girisa
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Sahu Henamayee
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Dey Parama
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Varsha Rana
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam, 781001, India.
| | - Ajaikumar B Kunnumakkara
- Department of Biosciences and Bioengineering, Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
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20
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Wang LX, Frey MR, Kohli R. The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling. Front Endocrinol (Lausanne) 2021; 12:799648. [PMID: 35116006 PMCID: PMC8804323 DOI: 10.3389/fendo.2021.799648] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. Bile acids are ligands that can bind to several receptors, including the nuclear receptor farnesoid X receptor (FXR) in ileal enterocytes. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acid-related disorders.
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21
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Hernandez-Quiles M, Broekema MF, Kalkhoven E. PPARgamma in Metabolism, Immunity, and Cancer: Unified and Diverse Mechanisms of Action. Front Endocrinol (Lausanne) 2021; 12:624112. [PMID: 33716977 PMCID: PMC7953066 DOI: 10.3389/fendo.2021.624112] [Citation(s) in RCA: 247] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/08/2021] [Indexed: 12/20/2022] Open
Abstract
The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation-where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα-is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression-where PPARγ alters gene expression independent of DNA binding-is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ's target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.
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Affiliation(s)
- Miguel Hernandez-Quiles
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Marjoleine F. Broekema
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Eric Kalkhoven
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- *Correspondence: Eric Kalkhoven,
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22
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Berardo C, Di Pasqua LG, Cagna M, Richelmi P, Vairetti M, Ferrigno A. Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research. Int J Mol Sci 2020; 21:ijms21249646. [PMID: 33348908 PMCID: PMC7766139 DOI: 10.3390/ijms21249646] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in parallel with a worldwide increase in the recurrence rate of diabetes and metabolic syndrome. It has been estimated that NASH cirrhosis may surpass viral hepatitis C and become the leading indication for liver transplantation in the next decades. The broadening of the knowledge about NASH pathogenesis and progression is of pivotal importance for the discovery of new targeted and more effective therapies; aim of this review is to offer a comprehensive and updated overview on NAFLD and NASH pathogenesis, the most recommended treatments, drugs under development and new drug targets. The most relevant in vitro and in vivo models of NAFLD and NASH will be also reviewed, as well as the main molecular pathways involved in NAFLD and NASH development.
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Affiliation(s)
| | | | | | | | | | - Andrea Ferrigno
- Correspondence: (L.G.D.P.); (A.F.); Tel.: +39-0382-986-451 (L.G.D.P.)
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23
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Hu L, Ren Q, Deng L, Zhou Z, Cai Z, Wang B, Li Z. Design, synthesis, and biological studies of novel 3-benzamidobenzoic acid derivatives as farnesoid X receptor partial agonist. Eur J Med Chem 2020; 211:113106. [PMID: 33360559 DOI: 10.1016/j.ejmech.2020.113106] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/01/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022]
Abstract
Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, regulates the metabolism of bile acid and lipids as well as maintains the stability of internal environment. FXR was considered as a therapeutic target of liver disorders, such as drug-induced liver injury, fatty liver and cholestasis. The previous reported FXR partial agonist 6 was a suitable lead compound in terms of its high potent and low molecular size, while the docking study of compound 6 suggested a large unoccupied hydrophobic pocket, which might be provided more possibility of structure-activity relationship (SAR) study. In this study, we have performed comprehensive SAR and molecular modeling studies based on lead compound 6. All of these efforts resulted in the identification of a novel series of FXR partial agonists. In this series, compound 41 revealed the best activity and strong interaction with binding pocket of FXR. Moreover, compound 41 protected mice against acetaminophen-induced hepatotoxicity by the regulation of FXR-related gene expression and improving antioxidant capacity. In summary, these results suggest that compound 41 is a promising FXR partial agonist suitable for further investigation.
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Affiliation(s)
- Lijun Hu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Qiang Ren
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Liming Deng
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Zongtao Zhou
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Zongyu Cai
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Bin Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Zheng Li
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
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24
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Gupta S, Gupta P. Etiopathogenesis, Challenges and Remedies Associated With Female Genital Tuberculosis: Potential Role of Nuclear Receptors. Front Immunol 2020; 11:02161. [PMID: 33178178 PMCID: PMC7593808 DOI: 10.3389/fimmu.2020.02161] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 08/07/2020] [Indexed: 12/16/2022] Open
Abstract
Extra-pulmonary tuberculosis (EPTB) is recognized mainly as a secondary manifestation of a primary tuberculosis (TB) infection in the lungs contributing to a high incidence of morbidity and mortality. The TB bacilli upon reactivation maneuver from the primary site disseminating to other organs. Diagnosis and treatment of EPTB remains challenging due to the abstruse positioning of the infected organs and the associated invasiveness of sample acquisition as well as misdiagnosis, associated comorbidities, and the inadequacy of biomarkers. Female genital tuberculosis (FGTB) represents the most perilous form of EPTB leading to poor uterine receptivity (UR), recurrent implantation failure and infertility in females. Although the number of TB cases is reducing, FGTB cases are not getting enough attention because of a lack of clinical awareness, nonspecific symptoms, and inappropriate diagnostic measures. This review provides an overview for EPTB, particularly FGTB diagnostics and treatment challenges. We emphasize the need for new therapeutics and highlight the need for the exaction of biomarkers as a point of care diagnostic. Nuclear receptors have reported role in maintaining UR, immune modulation, and TB modulation; therefore, we postulate their role as a therapeutic drug target and biomarker that should be explored in FGTB.
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Affiliation(s)
- Shalini Gupta
- Department of Molecular Biology, CSIR-Institute of Microbial Technology, Chandigarh, India
| | - Pawan Gupta
- Department of Molecular Biology, CSIR-Institute of Microbial Technology, Chandigarh, India
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25
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Li T, Chiang JYL. Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease. Hepatobiliary Surg Nutr 2020; 9:152-169. [PMID: 32355674 PMCID: PMC7188552 DOI: 10.21037/hbsn.2019.09.03] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/26/2019] [Indexed: 12/12/2022]
Abstract
Bile acids are synthesized from cholesterol only in hepatocytes. Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine. Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor TGR5. FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis. In addition, bile acid-activated cellular signaling pathways regulate metabolic homeostasis, immunity, and cell proliferation in various metabolically active organs. In the small and large intestine, gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects. In turn, bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity. Currently, bile acid-based therapies including systemic and intestine-restricted FXR agonists, TGR5 agonists, fibroblast growth factor 19 analogue, intestine FXR antagonists, and intestine apical sodium-bile acid transporter (ASBT) inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis (NASH). These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest. More recently, human and experimental alcoholic liver disease (ALD) has been associated with disrupted bile acid homeostasis. In additional, new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
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Affiliation(s)
- Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - John Y. L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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26
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Ding Y, Yanagi K, Cheng C, Alaniz RC, Lee K, Jayaraman A. Interactions between gut microbiota and non-alcoholic liver disease: The role of microbiota-derived metabolites. Pharmacol Res 2019; 141:521-529. [PMID: 30660825 PMCID: PMC6392453 DOI: 10.1016/j.phrs.2019.01.029] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 02/07/2023]
Abstract
There is increasing evidence that the intestinal microbiota plays a mechanistic role in the etiology of non-alcoholic fatty liver disease (NAFLD). Animal and human studies have linked small molecule metabolites produced by commensal bacteria in the gut contribute to not only intestinal inflammation, but also to hepatic inflammation. These immunomodulatory metabolites are capable of engaging host cellular receptors, and may mediate the observed association between gut dysbiosis and NAFLD. This review focuses on the effects and potential mechanisms of three specific classes of metabolites that synthesized or modified by gut bacteria: short chain fatty acids, amino acid catabolites, and bile acids. In particular, we discuss their role as ligands for cell surface and nuclear receptors regulating metabolic and inflammatory pathways in the intestine and liver. Studies reveal that the metabolites can both agonize and antagonize their cognate receptors to reduce or exacerbate liver steatosis and inflammation, and that the effects are metabolite- and context-specific. Further studies are warranted to more comprehensively understand bacterial metabolite-mediated gut-liver in NAFLD. This understanding could help identify novel therapeutics and therapeutic targets to intervene in the disease through the gut microbiota.
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Affiliation(s)
- Yufang Ding
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Karin Yanagi
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, 02155, USA
| | - Clint Cheng
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77807, USA
| | - Robert C Alaniz
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77807, USA
| | - Kyongbum Lee
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, 02155, USA.
| | - Arul Jayaraman
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA; Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77807, USA; Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas, 77843, USA.
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27
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van de Wiel SMW, Bijsmans ITGW, van Mil SWC, van de Graaf SFJ. Identification of FDA-approved drugs targeting the Farnesoid X Receptor. Sci Rep 2019; 9:2193. [PMID: 30778102 PMCID: PMC6379390 DOI: 10.1038/s41598-019-38668-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 12/21/2018] [Indexed: 12/25/2022] Open
Abstract
The farnesoid X receptor (FXR) belongs to the nuclear receptor family and is activated by bile acids. Multiple, chemically rather diverse, FXR agonists have been developed and several of these compounds are currently tested in clinical trials for NAFLD and cholestasis. Here, we investigated possible FXR-agonism or antagonism of existing FDA/EMA-approved drugs. By using our recently developed FRET-sensor, containing the ligand binding domain of FXR (FXR-LBD), 1280 FDA-approved drugs were screened for their ability to activate FXR in living cells using flow cytometry. Fifteen compounds induced the sensor for more than twenty percent above background. Real-time confocal microscopy confirmed that avermectin B1a, gliquidone, nicardipine, bepridil and triclosan activated the FRET sensor within two minutes. These compounds, including fluticasone, increased mRNA expression of FXR target genes OSTα and OSTβ in Huh7 cells, and in most cases also of MRP2, SHP and FGF19. Finally, avermectin B1a, gliquidone, nicardipine and bepridil significantly increased IBABP promoter activity in a luciferase reporter assay in a dose-dependent manner. In conclusion, six FDA/EMA-approved drugs currently used in the clinical practice exhibit moderate agonistic FXR activity. This may on the one hand explain (undesired) side-effects, but on the other hand may form an opportunity for polypharmacology.
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Affiliation(s)
- Sandra M W van de Wiel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ingrid T G W Bijsmans
- Center for Molecular Medicine, UMC Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Saskia W C van Mil
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Center for Molecular Medicine, UMC Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
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28
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Donkers JM, Roscam Abbing RLP, van de Graaf SFJ. Developments in bile salt based therapies: A critical overview. Biochem Pharmacol 2018; 161:1-13. [PMID: 30582898 DOI: 10.1016/j.bcp.2018.12.018] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 12/20/2018] [Indexed: 01/06/2023]
Abstract
Bile acids, amphipathic molecules known for their facilitating role in fat absorption, are also recognized as signalling molecules acting via nuclear and membrane receptors. Of the bile acid-activated receptors, the Farnesoid X Receptor (FXR) and the G protein-coupled bile acid receptor-1 (Gpbar1 or TGR5) have been studied most extensively. Bile acid signaling is critical in the regulation of bile acid metabolism itself, but it also plays a significant role in glucose, lipid and energy metabolism. Activation of FXR and TGR5 leads to reduced hepatic bile salt load, improved insulin sensitivity and glucose regulation, increased energy expenditure, and anti-inflammatory effects. These beneficial effects render bile acid signaling an interesting therapeutic target for the treatment of diseases such as cholestasis, non-alcoholic fatty liver disease, and diabetes. Here, we summarize recent findings on bile acid signaling and discuss potential and current limitations of bile acid receptor agonist and modulators of bile acid transport as future therapeutics for a wide-spectrum of diseases.
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Affiliation(s)
- Joanne M Donkers
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands
| | - Reinout L P Roscam Abbing
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands
| | - Stan F J van de Graaf
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands.
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29
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Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases. Int J Mol Sci 2018; 19:ijms19113630. [PMID: 30453651 PMCID: PMC6274770 DOI: 10.3390/ijms19113630] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 02/06/2023] Open
Abstract
Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.
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30
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Massafra V, Pellicciari R, Gioiello A, van Mil SW. Progress and challenges of selective Farnesoid X Receptor modulation. Pharmacol Ther 2018; 191:162-177. [DOI: 10.1016/j.pharmthera.2018.06.009] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Schubert K, Olde Damink SWM, von Bergen M, Schaap FG. Interactions between bile salts, gut microbiota, and hepatic innate immunity. Immunol Rev 2018; 279:23-35. [PMID: 28856736 DOI: 10.1111/imr.12579] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed.
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Affiliation(s)
- Kristin Schubert
- Department of Molecular Systems Biology, Helmholtz Center for Environmental Research, Leipzig, Germany
| | - Steven W M Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.,Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Center for Environmental Research, Leipzig, Germany.,Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany
| | - Frank G Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.,Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
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32
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Giancristofaro A, Barbosa AJM, Ammazzalorso A, Amoia P, De Filippis B, Fantacuzzi M, Giampietro L, Maccallini C, Amoroso R. Discovery of new FXR agonists based on 6-ECDCA binding properties by virtual screening and molecular docking. MEDCHEMCOMM 2018; 9:1630-1638. [PMID: 30393515 PMCID: PMC6194413 DOI: 10.1039/c8md00272j] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 06/28/2018] [Indexed: 01/03/2023]
Abstract
FXR is a member of the nuclear receptor superfamily, which regulates the expression of various genes involved in bile acid, lipid and glucose metabolism. Targeting FXR with small molecules has been exploited to treat lipid-related disorders and diseases such as cholestasis, gallstones and hepatic disorders. In this work, we expand the existing pool of known FXR agonists using a fast hit-to-lead structure-based pharmacophore and docking screening protocol. A set of 25 molecules was selected after screening a large database of commercial chemicals, and experimental tests were carried out to demonstrate their ability to activate FXR. Three novel FXR agonists are reported, namely, one full agonist, more efficient than the endogenous ligand chenodeoxycholic acid, and two partial agonists.
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Affiliation(s)
- Antonella Giancristofaro
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Arménio J M Barbosa
- Chemistry Department , Faculdade de Ciências e Tecnologia , Universidade Nova de Lisboa , 2829-516 Caparica , Portugal
| | - Alessandra Ammazzalorso
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Pasquale Amoia
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Barbara De Filippis
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Marialuigia Fantacuzzi
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Letizia Giampietro
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Cristina Maccallini
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
| | - Rosa Amoroso
- Department of Pharmacy , University of Chieti "G. d'Annunzio" , via dei vestini 31 , 66100 Chieti , Italy .
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33
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Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer. Signal Transduct Target Ther 2018; 3:19. [PMID: 30013796 PMCID: PMC6043541 DOI: 10.1038/s41392-018-0017-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 02/05/2018] [Accepted: 03/21/2018] [Indexed: 02/07/2023] Open
Abstract
Protein methyltransferases have been shown to methylate histone and non-histone proteins, leading to regulation of several biological processes that control cell homeostasis. Over the past few years, the histone-lysine N-methyltransferase SETD7 (SETD7; also known as SET7/9, KIAA1717, KMT7, SET7, SET9) has emerged as an important regulator of at least 30 non-histone proteins and a potential target for the treatment of several human diseases. This review discusses current knowledge of the structure and subcellular localization of SETD7, as well as its function as a histone and non-histone methyltransferase. This work also underlines the putative contribution of SETD7 to the regulation of gene expression, control of cell proliferation, differentiation and endoplasmic reticulum stress, which indicate that SETD7 is a candidate for novel targeted therapies with the aim of either stimulating or inhibiting its activity, depending on the cell signaling context.
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34
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Liu X, Guo GL, Kong B, Hilburn DB, Hubchak SC, Park S, LeCuyer B, Hsieh A, Wang L, Fang D, Green RM. Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice. Hepatology 2018; 68:304-316. [PMID: 29377207 PMCID: PMC6033648 DOI: 10.1002/hep.29815] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 12/20/2017] [Accepted: 01/16/2018] [Indexed: 12/19/2022]
Abstract
UNLABELLED Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1α (p-IRE1α) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p-IRE1α protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and p-IRE1α protein expression. Co-immunoprecipitation (Co-IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)-SHP and FLAG-IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression. CONCLUSION FXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances p-IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (Hepatology 2018;68:304-316).
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Affiliation(s)
- Xiaoying Liu
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ
| | - Bo Kong
- Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ
| | - David B. Hilburn
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
| | - Susan C. Hubchak
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
| | - Seong Park
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
| | - Brian LeCuyer
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
| | - Antony Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
| | - Li Wang
- Department of Physiology and Neurobiology, and the Institute for Systems Genomics, University of Connecticut, Storrs, CT,Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT,Veterans Affairs Connecticut Healthcare System, West Haven, CT
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Richard M. Green
- Division of Gastroenterology and Hepatology, Department of Medicine, Chicago, IL
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Broekema MF, Hollman DAA, Koppen A, van den Ham HJ, Melchers D, Pijnenburg D, Ruijtenbeek R, van Mil SWC, Houtman R, Kalkhoven E. Profiling of 3696 Nuclear Receptor-Coregulator Interactions: A Resource for Biological and Clinical Discovery. Endocrinology 2018; 159:2397-2407. [PMID: 29718163 DOI: 10.1210/en.2018-00149] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/24/2018] [Indexed: 12/13/2022]
Abstract
Nuclear receptors (NRs) are ligand-inducible transcription factors that play critical roles in metazoan development, reproduction, and physiology and therefore are implicated in a broad range of pathologies. The transcriptional activity of NRs critically depends on their interaction(s) with transcriptional coregulator proteins, including coactivators and corepressors. Short leucine-rich peptide motifs in these proteins (LxxLL in coactivators and LxxxIxxxL in corepressors) are essential and sufficient for NR binding. With 350 different coregulator proteins identified to date and with many coregulators containing multiple interaction motifs, an enormous combinatorial potential is present for selective NR-mediated gene regulation. However, NR-coregulator interactions have often been determined experimentally on a one-to-one basis across diverse experimental conditions. In addition, NR-coregulator interactions are difficult to predict because the molecular determinants that govern specificity are not well established. Therefore, many biologically and clinically relevant NR-coregulator interactions may remain to be discovered. Here, we present a comprehensive overview of 3696 NR-coregulator interactions by systematically characterizing the binding of 24 nuclear receptors with 154 coregulator peptides. We identified unique ligand-dependent NR-coregulator interaction profiles for each NR, confirming many well-established NR-coregulator interactions. Hierarchical clustering based on the NR-coregulator interaction profiles largely recapitulates the classification of NR subfamilies based on the primary amino acid sequences of the ligand-binding domains, indicating that amino acid sequence is an important, although not the only, molecular determinant in directing and fine-tuning NR-coregulator interactions. This NR-coregulator peptide interactome provides an open data resource for future biological and clinical discovery as well as NR-based drug design.
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Affiliation(s)
- Marjoleine F Broekema
- Molecular Cancer Research and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, CG Utrecht, Netherlands
| | - Danielle A A Hollman
- Molecular Cancer Research and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, CG Utrecht, Netherlands
| | - Arjen Koppen
- Molecular Cancer Research and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, CG Utrecht, Netherlands
| | | | - Diana Melchers
- PamGene International B. V., BJ 's-Hertogenbosch, Netherlands
| | - Dirk Pijnenburg
- PamGene International B. V., BJ 's-Hertogenbosch, Netherlands
| | - Rob Ruijtenbeek
- PamGene International B. V., BJ 's-Hertogenbosch, Netherlands
| | - Saskia W C van Mil
- Molecular Cancer Research and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, CG Utrecht, Netherlands
| | - René Houtman
- PamGene International B. V., BJ 's-Hertogenbosch, Netherlands
| | - Eric Kalkhoven
- Molecular Cancer Research and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, CG Utrecht, Netherlands
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de Boer JF, Bloks VW, Verkade E, Heiner-Fokkema MR, Kuipers F. New insights in the multiple roles of bile acids and their signaling pathways in metabolic control. Curr Opin Lipidol 2018; 29:194-202. [PMID: 29553998 DOI: 10.1097/mol.0000000000000508] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW There is a growing awareness that individual bile acid species exert different physiological functions, beyond their classical roles in bile formation and fat absorption, due to differential stimulatory effects on the bile-acid-activated receptors farnesoid X receptor (FXR) and takeda G receptor 5 (TGR5). This review integrates recent findings on the role of individual bile acids and their receptors in metabolic control, with special emphasis on cholesterol homeostasis. RECENT FINDINGS The consequences of altered bile acid metabolism, for example, in type 2 diabetes and during aging, on metabolic control is increasingly recognized but full impact hereof remains to be elucidated. These effects interact with those of newly developed pharmacological FXR and TGR5 modulators that aim to improve metabolic health. Studies in genetically modified mice have provided important new insights, for example, establishment of the role of intestinal FXR in control of the transintestinal cholesterol excretion pathway. However, translation from mice to men is hampered by the presence of rodent-specific bile acid species with special features. SUMMARY Specific bile acids and their signaling pathways play important roles in control of (cholesterol) metabolism. Deeper insight into the interactions between endogenous (i.e., bile acids) and pharmacological modulators of FXR and TGR5 is needed to optimize therapeutic benefit of the latter. The recent identification of cytochrome P450 2C70 as key enzyme in the formation of rodent-specific hydrophilic muricholic acids allows for the development of adequate mouse models for this purpose.
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Affiliation(s)
- Jan Freark de Boer
- Department of Pediatrics
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | | | - M Rebecca Heiner-Fokkema
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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37
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Allosteric modulation of the farnesoid X receptor by a small molecule. Sci Rep 2018; 8:6846. [PMID: 29717168 PMCID: PMC5931576 DOI: 10.1038/s41598-018-25158-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 04/17/2018] [Indexed: 11/25/2022] Open
Abstract
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
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38
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Wu G, Wen M, Sun L, Li H, Liu Y, Li R, Wu F, Yang R, Lin Y. Mechanistic insights into geniposide regulation of bile salt export pump (BSEP) expression. RSC Adv 2018; 8:37117-37128. [PMID: 35557817 PMCID: PMC9089303 DOI: 10.1039/c8ra06345a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/17/2018] [Indexed: 12/14/2022] Open
Abstract
Geniposide (GE) is a major component isolated from Gardenia jasminoides Ellis, which has been used to treat cholestasis liver diseases. Our previous study has shown that GE could notably increase mRNA and protein expressions of BSEP in cholestatic rats. BSEP plays a critical role in maintenance of the enterohepatic circulation of bile acids. BSEP could be regulated by the transactivation pathway of farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor (Nrf2). Here the mechanisms for BSEP regulation by GE were investigated. GE induced the mRNA levels of BSEP in HepG2 cells and cholestatic mice, and knockdown of FXR and Nrf2 reduced the mRNA expression of BSEP at varying degrees after treatment of GE. FXR acts as the major regulator of BSEP transcription. The involvement of FXR regulated BSEP expression by GE was further investigated. An enhancement was observed in FXR-dependent BSEP promoter activation using luciferase assay. ChIP assay further confirmed the interaction between FXR and BSEP after GE treatment. Using siRNA and ChIP assays, we demonstrated that peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) and co-activator-associated arginine methyltransferase 1 (CARM1) were predominantly recruited to the BSEP promoter upon FXR activation by GE. In conclusion, GE regulated the expression of BSEP through FXR and Nrf2 signaling pathway. The FXR transactivation pathway was enhanced by increasing recruitment of coactivators PGC-1α and CARM1 upon GE treatment, coupled with an increased binding of FXR to the BSEP promoter. PGC-1α and CARM1 interact with FXR to increase FXR-dependent BSEP expression upon GE treatment.![]()
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Affiliation(s)
- Guixin Wu
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Min Wen
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Lin Sun
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Huitao Li
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Yubei Liu
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Rui Li
- School of Pharmacy
- Nanjing Medical University
- Nanjing 211166
- P. R. China
| | - Feihua Wu
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Rong Yang
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
| | - Yining Lin
- School of Traditional Chinese Pharmacy
- China Pharmaceutical University
- Nanjing 211198
- P. R. China
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Massafra V, van Mil SWC. Farnesoid X receptor: A "homeostat" for hepatic nutrient metabolism. Biochim Biophys Acta Mol Basis Dis 2017; 1864:45-59. [PMID: 28986309 DOI: 10.1016/j.bbadis.2017.10.003] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/27/2017] [Accepted: 10/02/2017] [Indexed: 02/06/2023]
Abstract
The Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids (BAs). BAs are amphipathic molecules that serve as fat solubilizers in the intestine under postprandial conditions. In the post-absorptive state, BAs bind FXR in the hepatocytes, which in turn provides feedback signals on BA synthesis and transport and regulates lipid, glucose and amino acid metabolism. Therefore, FXR acts as a homeostat of all three classes of nutrients, fats, sugars and proteins. Here we re-analyze the function of FXR in the perspective of nutritional metabolism, and discuss the role of FXR in liver energy homeostasis in postprandial, post-absorptive and fasting/starvation states. FXR, by regulating nutritional metabolism, represses autophagy in conditions of nutrient abundance, and controls the metabolic needs of proliferative cells. In addition, FXR regulates inflammation via direct effects and via its impact on nutrient metabolism. These functions indicate that FXR is an attractive therapeutic target for liver diseases.
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Affiliation(s)
- Vittoria Massafra
- Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands
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40
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Li YF, Wu JS, Li YY, Dai Y, Zheng M, Zeng JK, Wang GF, Wang TM, Li WK, Zhang XY, Gu M, Huang C, Yang L, Wang ZT, Ma YM. Chicken bile powder protects against α-naphthylisothiocyanate-induced cholestatic liver injury in mice. Oncotarget 2017; 8:97137-97152. [PMID: 29228599 PMCID: PMC5722551 DOI: 10.18632/oncotarget.21385] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 07/26/2017] [Indexed: 12/19/2022] Open
Abstract
This study explored the effects of chicken bile powder (CBP), a 2000-year-old Chinese medicine, on α-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. CBP treatment for 14 days significantly ameliorated ANIT-induced changes in serum alanine aminotransferase, aspartate aminotransferase, bile acids, bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase, and liver tissue morphology. Serum metabolomics showed changes in 24 metabolites in ANIT-exposed mice; 16 of these metabolites were reversed by CBP treatment via two main pathways (bile acid biosynthesis and arachidonic acid metabolism). Additionally, CBP administration markedly increased fecal and biliary bile acid excretion, and reduced total and hydrophobic bile acid levels in the livers of cholestatic mice. Moreover, CBP increased liver expression of bile acid efflux transporters and metabolic enzymes. It also attenuated ANIT-induced increases in hepatic nuclear factor-κB-mediated inflammatory signaling, and increased liver expression of the nuclear farnesoid X receptor (FXR) in cholestatic mice. CBP also activated FXR in vitro in HEK293T cells expressing mouse Na+-taurocholate cotransporting polypeptide. It did not ameliorate the ANIT-induced liver injuries in FXR-knockout mice. These results suggested that CBP provided protection from cholestatic liver injury by restoring bile acid homeostasis and reducing inflammation in a FXR-dependent manner.
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Affiliation(s)
- Yi-Fei Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Sheng Wu
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuan-Yuan Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan Dai
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Min Zheng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Kai Zeng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guo-Feng Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tian-Ming Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wen-Kai Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xue-Yan Zhang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ming Gu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- Research Centre for Traditional Chinese Medicine of Complexity Systems, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zheng-Tao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue-Ming Ma
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.,Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Xie S, Guo C, Chi Z, Huang B, Wu Y, Wang D, Xia D. A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism. FEBS Lett 2017; 591:2836-2847. [PMID: 28787755 DOI: 10.1002/1873-3468.12782] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 07/11/2017] [Accepted: 07/25/2017] [Indexed: 12/12/2022]
Abstract
GW4064 is a small molecule known to be an agonist of the nuclear farnesoid X receptor (FXR). We found that GW4064 inhibits the NLR family CARD domain containing 3 (NLRP3) inflammasome activation in an FXR-independent manner as evidenced by its similar inhibitory effect on NLRP3 inflammasome activation in FXR-deficient macrophages. Interestingly, GW4064 decreases the nigericin-induced oligomerization and ubiquitination of ASC which is critical for the NLRP3 inflammasome activation. In vivo results indicate that GW4064 could partially rescue the symptoms of NLRP3-dependent inflammatory disease models. These results not only necessitate cautious interpretation of the biological function of GW4064 as an FXR agonist, but also provide a potential therapeutic approach using GW4064 in the treatment of NLRP3-related diseases.
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Affiliation(s)
- Shujun Xie
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, China
| | - Chuansheng Guo
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhexu Chi
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bo Huang
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, China
| | - Yihua Wu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, China
| | - Di Wang
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China
| | - Dajing Xia
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, China
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Flesch D, Cheung SY, Schmidt J, Gabler M, Heitel P, Kramer J, Kaiser A, Hartmann M, Lindner M, Lüddens-Dämgen K, Heering J, Lamers C, Lüddens H, Wurglics M, Proschak E, Schubert-Zsilavecz M, Merk D. Nonacidic Farnesoid X Receptor Modulators. J Med Chem 2017; 60:7199-7205. [PMID: 28749691 DOI: 10.1021/acs.jmedchem.7b00903] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
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Affiliation(s)
- Daniel Flesch
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Sun-Yee Cheung
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Jurema Schmidt
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Matthias Gabler
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Pascal Heitel
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Jan Kramer
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Astrid Kaiser
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Markus Hartmann
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Mara Lindner
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME , Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany
| | - Kerstin Lüddens-Dämgen
- Department of Psychiatry and Psychotherapy, University Medical Center Mainz , D-55131 Mainz, Germany
| | - Jan Heering
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME , Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany
| | - Christina Lamers
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Hartmut Lüddens
- Department of Psychiatry and Psychotherapy, University Medical Center Mainz , D-55131 Mainz, Germany
| | - Mario Wurglics
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Ewgenij Proschak
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Manfred Schubert-Zsilavecz
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
| | - Daniel Merk
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany
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Bilodeau S, Caron V, Gagnon J, Kuftedjian A, Tremblay A. A CK2-RNF4 interplay coordinates non-canonical SUMOylation and degradation of nuclear receptor FXR. J Mol Cell Biol 2017; 9:195-208. [PMID: 28201649 PMCID: PMC5907841 DOI: 10.1093/jmcb/mjx009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 12/18/2016] [Accepted: 02/14/2017] [Indexed: 01/20/2023] Open
Abstract
Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that plays a central role in regulating genes involved in bile acid homeostasis, and fat and glucose metabolism. Here, we demonstrate a post-translational interplay between FXR phosphorylation, SUMOylation, and ubiquitination that directs the receptor into an activation-degradation pathway in hepatocytes. We identify a non-canonical SUMOylation motif termed pSuM that conjugates SUMO2 at Lys-325 of FXR under the direct control of casein kinase 2 (CK2), which provides the required negative charge for Ubc9 and PIAS1 to perform SUMOylation, by phosphorylating Ser-327. Lys-325 SUMOylation is indispensable to the promotion of efficient ligand activation and transcriptional coactivation of FXR. Constitutive pSuM activation using a phospho-mimic Ser-327 mutant or catalytic CK2 expression strongly induces SUMO2 conjugation, which directs FXR ubiquitination and proteasome-dependent degradation. We also determine that such SUMOylation-dependent ubiquitination of FXR is mediated by the E3 ubiquitin ligase RNF4, which is required to achieve maximal induction of FXR and optimal up- or downregulation of responsive genes involved in bile acid homeostasis and liver regeneration. Our findings identify a highly regulated atypical SUMO conjugation motif that serves to coordinate FXR transcriptional competence, thereby expanding the intricate dynamics of the SUMOylation process used by incoming signals to govern metabolic gene regulation.
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Affiliation(s)
- Stéphanie Bilodeau
- Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada
| | - Véronique Caron
- Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada
| | - Jonathan Gagnon
- Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada
| | - Alexandre Kuftedjian
- Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada
| | - André Tremblay
- Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada
- Department of Obstetrics & Gynecology, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada
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44
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Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation. Toxicol Appl Pharmacol 2017; 314:39-47. [DOI: 10.1016/j.taap.2016.11.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/07/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022]
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van Mierlo KMC, Schaap FG, Dejong CHC, Olde Damink SWM. Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure. J Hepatol 2016; 65:1217-1231. [PMID: 27312944 DOI: 10.1016/j.jhep.2016.06.006] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 06/03/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatic failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. Despite improved perioperative care, the increasing complexity and extensiveness of surgical interventions, in combination with an expanding number of resections in patients with compromised liver function, still results in an incidence of postresectional liver failure (PLF) of 1-9%. Preventive measures aim to enhance future remnant liver size and function. Numerous non-invasive techniques to assess liver function and predict remnant liver volume are being developed, along with introduction of novel surgical strategies that augment growth of the future remnant liver. Detection of PLF is often too late and treatment is primarily symptomatic. Current therapeutic research focuses on ([bio]artificial) liver function support and regenerative medicine. In this review we discuss the current state and new developments in prediction, prevention and management of PLF, in light of novel insights into the aetiology of this complex syndrome. LAY SUMMARY Liver failure is the main cause of death after partial liver resection for cancer, and is presumably caused by an insufficient quantity and function of the liver remnant. Detection of liver failure is often too late, and current treatment focuses on relieve of symptoms. New research initiatives explore artificial support of liver function and stimulation of regrowth of the remnant liver.
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Affiliation(s)
- Kim M C van Mierlo
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Frank G Schaap
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Steven W M Olde Damink
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Institute of Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
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Chen YH, Hu XG, Zhou Y, Yu Z, Fu L, Zhang GB, Bo QL, Wang H, Zhang C, Xu DX. Obeticholic Acid Protects against Lipopolysaccharide-Induced Fetal Death and Intrauterine Growth Restriction through Its Anti-Inflammatory Activity. THE JOURNAL OF IMMUNOLOGY 2016; 197:4762-4770. [PMID: 27821667 DOI: 10.4049/jimmunol.1601331] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/08/2016] [Indexed: 12/16/2022]
Abstract
Farnesoid X receptor (FXR) is expressed in human and rodent placentas. Nevertheless, its function remains obscure. This study investigated the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, on LPS-induced fetal death and intrauterine growth restriction. All pregnant mice except controls were i.p. injected with LPS (100 μg/kg) daily from gestational day (GD) 15 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD13 to GD17. As expected, placental FXR signaling was activated by OCA. OCA pretreatment protected against LPS-induced fetal death. In addition, OCA pretreatment alleviated LPS-induced reduction of fetal weight and crown-rump length. Additional experiments showed that OCA inhibited LPS-evoked TNF-α in maternal serum and amniotic fluid. Moreover, OCA significantly attenuated LPS-induced upregulation of placental proinflammatory genes including Tnf-α, Il-1β, IL-6, Il-12, Mip-2, Kc, and Mcp-1 By contrast, OCA elevated anti-inflammatory cytokine IL-10 in maternal serum, amniotic fluid, and placenta. Further analysis showed that OCA blocked nuclear translocation of NF-κB p65 and p50 subunits in trophoblast giant cells of the labyrinth zone. These results provide a mechanistic explanation for placental FXR-mediated anti-inflammatory activity. Overall, this study provides evidence for roles of FXR as an important regulator of placental inflammation.
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Affiliation(s)
- Yuan-Hua Chen
- Department of Toxicology, Anhui Medical University, Hefei 230032, China.,Laboratory of Environmental Toxicology, Hefei 230032, China; and.,Department of Histology and Embryology, Anhui Medical University, Hefei 230032, China
| | - Xiao-Guang Hu
- Department of Toxicology, Anhui Medical University, Hefei 230032, China.,Laboratory of Environmental Toxicology, Hefei 230032, China; and
| | - Yan Zhou
- Department of Toxicology, Anhui Medical University, Hefei 230032, China.,Laboratory of Environmental Toxicology, Hefei 230032, China; and
| | - Zhen Yu
- Department of Toxicology, Anhui Medical University, Hefei 230032, China.,Laboratory of Environmental Toxicology, Hefei 230032, China; and
| | - Lin Fu
- Department of Toxicology, Anhui Medical University, Hefei 230032, China
| | - Gui-Bin Zhang
- Department of Toxicology, Anhui Medical University, Hefei 230032, China
| | - Qing-Li Bo
- Department of Toxicology, Anhui Medical University, Hefei 230032, China.,Laboratory of Environmental Toxicology, Hefei 230032, China; and
| | - Hua Wang
- Department of Toxicology, Anhui Medical University, Hefei 230032, China.,Laboratory of Environmental Toxicology, Hefei 230032, China; and
| | - Cheng Zhang
- Department of Toxicology, Anhui Medical University, Hefei 230032, China
| | - De-Xiang Xu
- Department of Toxicology, Anhui Medical University, Hefei 230032, China; .,Laboratory of Environmental Toxicology, Hefei 230032, China; and
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47
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Mousa HS, Carbone M, Malinverno F, Ronca V, Gershwin ME, Invernizzi P. Novel therapeutics for primary biliary cholangitis: Toward a disease-stage-based approach. Autoimmun Rev 2016; 15:870-876. [DOI: 10.1016/j.autrev.2016.07.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 06/01/2016] [Indexed: 12/22/2022]
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48
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Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes. ENVIRONMENTAL HEALTH PERSPECTIVES 2016; 124:1050-61. [PMID: 26662846 PMCID: PMC4937872 DOI: 10.1289/ehp.1510385] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 11/24/2015] [Indexed: 05/21/2023]
Abstract
BACKGROUND Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. OBJECTIVE In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. METHODS We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. RESULTS A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. CONCLUSION Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. CITATION Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061; http://dx.doi.org/10.1289/ehp.1510385.
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Affiliation(s)
- Maxwell C.K. Leung
- Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
- Address correspondence to M.C.K. Leung, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr., Research Triangle Park, NC 27711 USA. Telephone: (919) 541-2721. E-mail: , or T.B. Knudsen, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr., Research Triangle Park, NC 27711 USA. Telephone: (919) 541-9776. E-mail:
| | - Jimmy Phuong
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
| | | | - Nisha S. Sipes
- Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
| | - Gary R. Klinefelter
- National Health and Environmental Effects Research Laboratory, U.S. EPA, Research Triangle Park, North Carolina
| | - Matthew T. Martin
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
| | - Keith W. McLaurin
- Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
| | - R. Woodrow Setzer
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
| | - Sally Perreault Darney
- National Health and Environmental Effects Research Laboratory, U.S. EPA, Research Triangle Park, North Carolina
| | - Richard S. Judson
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
| | - Thomas B. Knudsen
- National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina
- Address correspondence to M.C.K. Leung, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr., Research Triangle Park, NC 27711 USA. Telephone: (919) 541-2721. E-mail: , or T.B. Knudsen, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr., Research Triangle Park, NC 27711 USA. Telephone: (919) 541-9776. E-mail:
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Martin SJ, Sabina EP. Amelioration of anti-tuberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model. Ren Fail 2016; 38:1115-21. [PMID: 27183989 DOI: 10.1080/0886022x.2016.1184940] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Nephrotoxicity is a rare complication caused by anti-tuberculosis therapy-induced oxidative stress. The Cyanobacterium Spirulina fusiformis Voronikhin belonging to Oscillatoriaceae family is used traditionally as a source of antioxidants against oxidative stress. We aimed to investigate the efficacy of S. fusiformis in modifying isoniazid (INH) and rifampicin (RIF)-induced changes in Wistar rat kidneys. Animals were divided into six groups: normal control rats; toxic control (INH & RIF-50 mg/kg b.w./d each; p.o.); INH & RIF + S. fusiformis (400 mg/kg b.w./d); INH & RIF + S. fusiformis (800 mg/kg b.w./d); S. fusiformis (800 mg/kg b.w./d) alone-treated rats; INH & RIF + silymarin (25 mg/kg b.w./d). Study duration was 28 d after which blood and kidneys were analyzed. We also studied the binding and interactions of the transcription factors Liver X Receptor (LXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of S. fusiformis by in silico methods. INH & RIF treatment caused significant (p< 0.05) decrease in antioxidant levels and significant (p< 0.05) increase in the levels of creatinine, urea, and uric acid showing impaired kidney function. Spirulina fusiformis ameliorated these effects in a dose dependent manner. Histological examination of kidneys supported these findings. Results of the in silico analyses showed that selected active components of S. fusiformis interact with LXR and FXR and could be a possible mechanism of action. S. fusiformis rendered protection against anti-tuberculosis drugs-induced oxidative stress in kidney tissues of rats.
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Affiliation(s)
- Sherry Joseph Martin
- a Department of Bio-Medical Sciences, School of Bio Sciences and Technology, VIT University , Vellore , Tamil Nadu , India
| | - Evan Prince Sabina
- a Department of Bio-Medical Sciences, School of Bio Sciences and Technology, VIT University , Vellore , Tamil Nadu , India
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Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches. Int J Mol Sci 2016; 17:536. [PMID: 27070594 PMCID: PMC4848992 DOI: 10.3390/ijms17040536] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 03/29/2016] [Accepted: 04/05/2016] [Indexed: 12/19/2022] Open
Abstract
In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R²(train) = 0.935, R²(test) = 0.902, Q²(LOO) = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC(-)), oprea's lead-like (opr_leadlike), subdivided van der Waal's surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R²(train) = 0.944, R²(test) = 0.892, Q²(LOO) = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC50 values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity.
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