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Lin X, Xia L, Zhou Y, Xie J, Tuo Q, Lin L, Liao D. Crosstalk Between Bile Acids and Intestinal Epithelium: Multidimensional Roles of Farnesoid X Receptor and Takeda G Protein Receptor 5. Int J Mol Sci 2025; 26:4240. [PMID: 40362481 PMCID: PMC12072030 DOI: 10.3390/ijms26094240] [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: 03/16/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders.
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Affiliation(s)
| | | | | | | | | | | | - Duanfang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; (X.L.); (L.X.); (Y.Z.); (J.X.); (Q.T.); (L.L.)
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Mayer AMS, Mayer VA, Swanson-Mungerson M, Pierce ML, Rodríguez AD, Nakamura F, Taglialatela-Scafati O. Marine Pharmacology in 2019-2021: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action. Mar Drugs 2024; 22:309. [PMID: 39057418 PMCID: PMC11278370 DOI: 10.3390/md22070309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/22/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
The current 2019-2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019-2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural product pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral mechanism-of-action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities that also affected the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019-2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanisms of action as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories.
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Affiliation(s)
- Alejandro M. S. Mayer
- Department of Pharmacology, College of Graduate Studies, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA;
| | - Veronica A. Mayer
- Department of Nursing Education, School of Nursing, Aurora University, 347 S. Gladstone Ave., Aurora, IL 60506, USA;
| | - Michelle Swanson-Mungerson
- Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA;
| | - Marsha L. Pierce
- Department of Pharmacology, College of Graduate Studies, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA;
| | - Abimael D. Rodríguez
- Molecular Sciences Research Center, University of Puerto Rico, 1390 Ponce de León Avenue, San Juan, PR 00926, USA;
| | - Fumiaki Nakamura
- Research Institute for Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku 169-8555, Tokyo, Japan;
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Lun W, Yan Q, Guo X, Zhou M, Bai Y, He J, Cao H, Che Q, Guo J, Su Z. Mechanism of action of the bile acid receptor TGR5 in obesity. Acta Pharm Sin B 2024; 14:468-491. [PMID: 38322325 PMCID: PMC10840437 DOI: 10.1016/j.apsb.2023.11.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/17/2023] [Accepted: 10/24/2023] [Indexed: 02/08/2024] Open
Abstract
G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.
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Affiliation(s)
- Weijun Lun
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qihao Yan
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xinghua Guo
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Minchuan Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jincan He
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
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Zhu J, Jin J, Qi Q, Li L, Zhou J, Cao L, Wang L. The association of gut microbiome with recurrent pregnancy loss: A comprehensive review. Drug Discov Ther 2023; 17:157-169. [PMID: 37357394 DOI: 10.5582/ddt.2023.01010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
The steady-state gut microbiome not only promotes the metabolism and absorption of nutrients that are difficult to digest by the host itself, but also participates in systemic metabolism. Once the dynamic balance is disturbed, the gut microbiome may lead to a variety of diseases. Recurrent pregnancy loss (RPL) affects 1-2% of women of reproductive age, and its prevalence has increased in recent years. According to the literature review, the gut microbiome is a new potential driver of the pathophysiology of recurrent abortion, and the gut microbiome has emerged as a new candidate for clinical prevention and treatment of RPL. However, few studies have concentrated on the direct correlation between RPL and the gut microbiome, and the mechanisms by which the gut microbiome influences recurrent miscarriage need further investigation. In this review, the effects of the gut microbiome on RPL were discussed and found to be associated with inflammatory response, the disruption of insulin signaling pathway and the formation of insulin resistance, maintenance of immunological tolerance at the maternal-fetal interface due to the interference with the immune imbalance of Treg/Th17 cells, and obesity.
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Affiliation(s)
- Jun Zhu
- The Affiliated Wenling Hospital of Wenzhou Medical University, Zhejiang, China
| | - Jiaxi Jin
- The Affiliated Wenling Hospital of Wenzhou Medical University, Zhejiang, China
| | - Qing Qi
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Lisha Li
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Jing Zhou
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
| | - Liwen Cao
- Center for Reproductive Medicine, Zhoushan Women and Children Hospital, Zhejiang, China
| | - Ling Wang
- Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- The Academy of Integrative Medicine of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
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Ho TM, Arman HD, Yoshimoto FK. Synthesis of Hyocholic Acid and Its Derivatization with Sodium Periodate to Distinguish It from Cholic Acid by Mass Spectrometry. Steroids 2023:109260. [PMID: 37336340 DOI: 10.1016/j.steroids.2023.109260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
Low concentrations of hyocholic acid in human serum has been linked to diabetes. Due to its important role in human health, we were interested in synthesizing hyocholic acid to explore potential biochemical properties of this bile acid. Here, a synthesis of hyocholic acid is reported from chenodeoxycholic acid. The key step was a Rubottom oxidation of a silyl enol ether intermediate to directly incorporate the oxygen at C6. Furthermore, the synthesized hyocholic acid product was treated with NaIO4 to cleave the C6-C7 bond to yield a hemiacetal at C6. This C-C bond cleavage reaction using NaIO4 was used to develop an ultra-performance liquid chromatography mass spectrometry method to distinguish between a 1 to 1 mixture of hyocholic acid and cholic acid (a 12α-hydroxylated bile acid), two bile acid regioisomers with identical masses. Upon treatment of the mixture with NaIO4, hyocholic acid was selectively cleaved in the B ring (C6-C7 bond) to yield the hemiacetal that formed between the C3-hydroxy and the C6-aldehyde moiety with an m/z 405 while cholic acid remained intact with an m/z 407 in the negative electrospray ionization mode. Subsequently, a commercially available ox bile extract was treated with NaIO4 to detect bile acid derivatives by mass spectrometry. Two possible hyocholic acid derivatives conjugated to serine and gamma-glutamic semialdehyde were detected in electrospray ionization positive mode, which oxidatively cleaved with NaIO4 (m/z 496 and 522 to m/z 494 and 520, respectively).
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Affiliation(s)
- Tu M Ho
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, TX 78249
| | - Hadi D Arman
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, TX 78249
| | - Francis K Yoshimoto
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, TX 78249
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Abstract
Covering: January to December 2021This review covers the literature published in 2021 for marine natural products (MNPs), with 736 citations (724 for the period January to December 2021) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1425 in 416 papers for 2021), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of the number of authors, their affiliations, domestic and international collection locations, focus of MNP studies, citation metrics and journal choices is discussed.
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Affiliation(s)
- Anthony R Carroll
- School of Environment and Science, Griffith University, Gold Coast, Australia. .,Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia
| | - Brent R Copp
- School of Chemical Sciences, University of Auckland, Auckland, New Zealand
| | - Rohan A Davis
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia.,School of Enivironment and Science, Griffith University, Brisbane, Australia
| | - Robert A Keyzers
- Centre for Biodiscovery, and School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
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Ackerman HD, Gerhard GS. Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile. Pharmaceuticals (Basel) 2023; 16:174. [PMID: 37259326 PMCID: PMC9963315 DOI: 10.3390/ph16020174] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 09/24/2024] Open
Abstract
Increasing evidence supports a neuroprotective role for bile acids in major neurodegenerative disorders. We studied major human bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), as potential neurotrophic agents. Using quantitative image analysis, we found that 20 μM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 μM retinoic acid (RA), with lesser effects observed for chenodexoycholic acid (CDCA) at 20 μM, and similar though less robust neurite outgrowth in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, we found that TGR5 agonism was comparable to DCA stimulation and stronger than RA, and that neither FXR nor liver X receptor (LXR) inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.
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Affiliation(s)
- Hayley D Ackerman
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Glenn S Gerhard
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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Zhang MY, Zhu L, Zheng X, Xie TH, Wang W, Zou J, Li Y, Li HY, Cai J, Gu S, Yao Y, Wei TT. TGR5 Activation Ameliorates Mitochondrial Homeostasis via Regulating the PKCδ/Drp1-HK2 Signaling in Diabetic Retinopathy. Front Cell Dev Biol 2022; 9:759421. [PMID: 35096809 PMCID: PMC8795816 DOI: 10.3389/fcell.2021.759421] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/07/2021] [Indexed: 01/07/2023] Open
Abstract
Background: Diabetic retinopathy (DR) is one of the most important microvascular diseases of diabetes. Our previous research demonstrated that bile acid G-protein-coupled membrane receptor (TGR5), a novel cell membrane receptor of bile acid, ameliorates the vascular endothelial cell dysfunction in DR. However, the precise mechanism leading to this alteration remains unknown. Thus, the mechanism of TGR5 in the progress of DR should be urgently explored. Methods: In this study, we established high glucose (HG)-induced human retinal vascular endothelial cells (RMECs) and streptozotocin-induced DR rat in vitro and in vivo. The expression of TGR5 was interfered through the specific agonist or siRNA to study the effect of TGR5 on the function of endothelial cell in vitro. Western blot, immunofluorescence and fluorescent probes were used to explore how TGR5 regulated mitochondrial homeostasis and related molecular mechanism. The adeno-associated virus serotype 8-shTGR5 (AAV8-shTGR5) was performed to evaluate retinal dysfunction in vivo and further confirm the role of TGR5 in DR by HE staining, TUNEL staining, PAS staining and Evans Blue dye. Results: We found that TGR5 activation alleviated HG-induced endothelial cell apoptosis by improving mitochondrial homeostasis. Additionally, TGR5 signaling reduced mitochondrial fission by suppressing the Ca2+-PKCδ/Drp1 signaling and enhanced mitophagy through the upregulation of the PINK1/Parkin signaling pathway. Furthermore, our result indicated that Drp1 inhibited mitophagy by facilitating the hexokinase (HK) 2 separation from the mitochondria and HK2-PINK1/Parkin signaling. In vivo, intraretinal microvascular abnormalities, including retinal vascular leakage, acellular capillaries and apoptosis, were poor in AAV8-shTGR5-treated group under DR, but this effect was reversed by pretreatment with the mitochondrial fission inhibitor Mdivi-1 or autophagy agonist Rapamycin. Conclusion: Overall, our findings indicated that TGR5 inhibited mitochondrial fission and enhanced mitophagy in RMECs by regulating the PKCδ/Drp1-HK2 signaling pathway. These results revealed the molecular mechanisms underlying the protective effects of TGR5 and suggested that activation of TGR5 might be a potential therapeutic strategy for DR.
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Affiliation(s)
- Meng-Yuan Zhang
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Lingpeng Zhu
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Xinhua Zheng
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Tian-Hua Xie
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Wenjuan Wang
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jian Zou
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yan Li
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Hong-Ying Li
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jiping Cai
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Shun Gu
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yong Yao
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.,Department of Ophthalmology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Ting-Ting Wei
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
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