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Liu S, Chen X, Chen D, Yu B, Zheng P, Luo Y, He J, Huang Z. Oleanolic acid inhibits appetite through the TGR5/cAMP signaling pathway. J Nutr Biochem 2025; 138:109844. [PMID: 39842616 DOI: 10.1016/j.jnutbio.2025.109844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/23/2024] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
Inhibition of appetite is an effective approach to fight obesity. Recently, bile acids have been reported to suppress appetite and alleviate obesity via the Takeda G protein-coupled receptor 5 (TGR5). However, whether the downstream signaling molecule cyclic adenosine monophosphate (cAMP) of TGR5 is involved in this process remains unclear. Oleanolic acid (OA) is a plant analogue of bile acids. The study aimed to explore the effect of dietary OA supplementation on appetite and to examine the role of TGR5/cAMP signaling in this process. In our study, mice were divided into four treatment groups: basal diet, 50mg/kg OA-supplemented diet, 100mg/kg OA-supplemented diet, and 30mg/kg tauroursodeoxycholic acid (TUDCA)-supplemented diet. Our results showed that dietary supplementation of OA and TUDCA both suppressed appetite. Additionally, OA and TUDCA downregulated the expression of appetite-stimulating factors while upregulating appetite-suppressing factors in the hypothalamus. Furthermore, OA was found to activate TGR5 signaling in the hypothalamus. Mechanistic studies using N38 cells revealed that OA reduced the expression and secretion of agouti-related peptide (AgRP), while inhibition of TGR5 and cAMP attenuated this effect of OA. In conclusion, our findings suggest that OA may suppress appetite through activation of the TGR5/cAMP signaling pathway in the hypothalamus.
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Affiliation(s)
- Shuang Liu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China.
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Zhang Z, Zhang Y, Peng H, Yu Q, Kang X, Liu Y, Zheng Y, Cheng F, Wang X, Li F. Decoding TGR5: A comprehensive review of its impact on cerebral diseases. Pharmacol Res 2025; 213:107671. [PMID: 39988005 DOI: 10.1016/j.phrs.2025.107671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Currently, unraveling the enigmatic realm of drug targets for cerebral disorders poses a formidable challenge. Takeda G protein-coupled receptor 5 (TGR5), also known as G protein-coupled bile acid receptor 1, is a specific bile acid receptor. Widely distributed across various tissues, TGR5 orchestrates a myriad of biological functions encompassing inflammation, energy metabolism, fatty acid metabolism, immune responses, cellular proliferation, apoptosis, and beyond. Alongside its well-documented implications in liver diseases, obesity, type 2 diabetes, tumors, and cardiovascular diseases, a growing body of evidence accentuates the pivotal role of TGR5 in cerebral diseases. Thus, this comprehensive review aimed to scrutinize the current insights into the pathological mechanisms involving TGR5 in cerebral diseases, while contemplating its potential as a promising therapeutic target for cerebral diseases.
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Affiliation(s)
- Zehan Zhang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Yifei Zhang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Hongye Peng
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Qingqian Yu
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Xiangdong Kang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Ying Liu
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Yuxiao Zheng
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Fafeng Cheng
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Xueqian Wang
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
| | - Feng Li
- Beijing University of Chinese Medicine, The northeast corner of the intersection of Sunshine South Street and Baiyang East Road, Beijing 102488, China.
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Liu M, Xie WJ, Zhang X, Wu W, Li G, Wang L. Sodium butyrate regulates macrophage polarization by TGR5/β-arrestin2 in vitro. Mol Med 2025; 31:31. [PMID: 39881219 PMCID: PMC11781001 DOI: 10.1186/s10020-025-01096-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/20/2025] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Macrophages play an important role in the pathogenesis of ulcerative colitis (UC). We will explore the effects of sodium butyrate (SB) on macrophage function. METHODS The targets of butyric acid were identified using SwissTargetPrediction database and surface plasmon resonance (SPR). Limited proteolysis mass spectrometry (Lip-MS) was used to further investigate the binding sites of butyric acid with its targets and molecular docking was employed to simulate their binding modes. Macrophage polarization model was established with lipopolysaccharide (LPS) in vitro. Takeda G protein-coupled receptor 5 (TGR5) and β-arrestin2 expression and macrophage polarization markers were detected with or without SB. RESULTS TGR5 was identified as the target of butyric acid. Moreover, the amino acid regions 275-286 and 321-330 of TGR5 (GPBAR1 [275-286] and GPBAR1 [321-330]) were the potential binding regions for butyric acid. Based on molecular docking analysis, butyric acid formed effective hydrogen-bonding interactions with ASP-284 and TYR-287 of TGR5. In cell experiments, LPS inhibited the expression of TGR5, β-arrestin2, IL-10, ARG1, and CD206 and increased the expression of IL-1β, iNOS, and CD86, while SB reversed the effect of LPS. SBI-115, a TGR5 antagonist, and knockdown of β-arrestin2 inhibited the effect of sodium butyrate. INT-777, a TGR5 agonist, reversed the inhibitory effect of knockdown of β-arrestin2. CONCLUSION SB inhibited M1-like polarization and promoted M2-like polarization induced by LPS via TGR5/β-arrestin2 in RAW264.7 cells and TGR5 was the target of SB.
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Affiliation(s)
- Miao Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Wen-Jie Xie
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, Hubei, China
| | - Xu Zhang
- Central laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Wei Wu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, Hubei, China
| | - Guang Li
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, Hubei, China
| | - Lu Wang
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, Hubei, China.
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Enejoh OA, Okonkwo CH, Nortey H, Kemiki OA, Moses A, Mbaoji FN, Yusuf AS, Awe OI. Machine learning and molecular dynamics simulations predict potential TGR5 agonists for type 2 diabetes treatment. Front Chem 2025; 12:1503593. [PMID: 39850718 PMCID: PMC11754275 DOI: 10.3389/fchem.2024.1503593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 12/13/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Treatment of type 2 diabetes (T2D) remains a significant challenge because of its multifactorial nature and complex metabolic pathways. There is growing interest in finding new therapeutic targets that could lead to safer and more effective treatment options. Takeda G protein-coupled receptor 5 (TGR5) is a promising antidiabetic target that plays a key role in metabolic regulation, especially in glucose homeostasis and energy expenditure. TGR5 agonists are attractive candidates for T2D therapy because of their ability to improve glycemic control. This study used machine learning-based models (ML), molecular docking (MD), and molecular dynamics simulations (MDS) to explore novel small molecules as potential TGR5 agonists. Methods Bioactivity data for known TGR5 agonists were obtained from the ChEMBL database. The dataset was cleaned and molecular descriptors based on Lipinski's rule of five were selected as input features for the ML model, which was built using the Random Forest algorithm. The optimized ML model was used to screen the COCONUT database and predict potential TGR5 agonists based on their molecular features. 6,656 compounds predicted from the COCONUT database were docked within the active site of TGR5 to calculate their binding energies. The four top-scoring compounds with the lowest binding energies were selected and their activities were compared to those of the co-crystallized ligand. A 100 ns MDS was used to assess the binding stability of the compounds to TGR5. Results Molecular docking results showed that the lead compounds had a stronger affinity for TGR5 than the cocrystallized ligand. MDS revealed that the lead compounds were stable within the TGR5 binding pocket. Discussion The combination of ML, MD, and MDS provides a powerful approach for predicting new TGR5 agonists that can be optimised for T2D treatment.
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Affiliation(s)
- Ojochenemi A. Enejoh
- Genetics, Genomics and Bioinformatics Department, National Biotechnology Research and Development Agency, Abuja, Nigeria
| | | | - Hector Nortey
- Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Science, University of Ghana, Accra, Ghana
| | - Olalekan A. Kemiki
- Molecular and Tissue Culture Laboratory, Babcock University, Ilisan-remo, Ogun State, Nigeria
| | - Ainembabazi Moses
- African Centers of Excellence in Bioinformatics and data intensive sciences, Department of Immunology and Microbiology, Makerere University, Makerere, Uganda
- Infectious Disease Institute (IDI), Makerere University, Kampala, Uganda
| | - Florence N. Mbaoji
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu, Nigeria
| | - Abdulrazak S. Yusuf
- Department of Biochemistry, Faculty of Basic Health Science, Bayero University, Kano, Nigeria
| | - Olaitan I. Awe
- African Society for Bioinformatics and Computational Biology, Cape Town, South Africa
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Darmanto AG, Yen TL, Jan JS, Linh TTD, Taliyan R, Yang CH, Sheu JR. Beyond metabolic messengers: Bile acids and TGR5 as pharmacotherapeutic intervention for psychiatric disorders. Pharmacol Res 2025; 211:107564. [PMID: 39733841 DOI: 10.1016/j.phrs.2024.107564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.
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Affiliation(s)
- Arief Gunawan Darmanto
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; School of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia
| | - Ting-Lin Yen
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Department of Medical Research, Cathay General Hospital, Taipei 22174, Taiwan, ROC
| | - Jing-Shiun Jan
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC
| | - Tran Thanh Duy Linh
- Family Medicine Training Center, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Viet Nam
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Chih-Hao Yang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Joen-Rong Sheu
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
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Fang Y, Qin M, Zheng Q, Wang K, Han X, Yang Q, Sang X, Cao G. Role of Bile Acid Receptors in the Development and Function of Diabetic Nephropathy. Kidney Int Rep 2024; 9:3116-3133. [PMID: 39534198 PMCID: PMC11551060 DOI: 10.1016/j.ekir.2024.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/25/2024] [Accepted: 08/04/2024] [Indexed: 11/16/2024] Open
Abstract
Diabetic nephropathy (DN) is a prevalent microvascular complication that occurs often in individuals with diabetes. It significantly raises the mortality rate of affected patients. Therefore, there is an urgent need to identify therapeutic targets for controlling and preventing the occurrence and development of DN. Bile acids (BAs) are now recognized as intricate metabolic integrators and signaling molecules. The activation of BAs has great promise as a therapeutic approach for preventing DN, renal damage caused by obesity, and nephrosclerosis. The nuclear receptors (NRs), farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR); and the G protein-coupled BA receptor, Takeda G-protein-coupled receptor 5 (TGR5) have important functions in controlling lipid, glucose, and energy metabolism, inflammation, as well as drug metabolism and detoxification. Over the past 10 years, there has been advancement in comprehending the biology and processes of BA receptors in the kidney, as well as in the creation of targeted BA receptor agonists. In this review, we discuss the role of BA receptors, FXR, PXR, VDR, and TGR5 in DN and their role in renal physiology, as well as the development and application of agonists that activate BA receptors for the treatment of kidney diseases.
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Affiliation(s)
- Yuanyuan Fang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Minjing Qin
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qitong Zheng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kuilong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Han
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiao Yang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xia'nan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
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Zhao S, Wang L, Huang X, Xiao Y, Li M, Huang X, Chen X, Li S, Xie J, Liu P, Wang YD, Chen WD. Design, Synthesis, and Biological Evaluation of Covalently Mucoadhesive Derivatives as Nonsystemic Intestine-Targeted TGR5 Agonists. J Med Chem 2024; 67:17701-17712. [PMID: 39321318 DOI: 10.1021/acs.jmedchem.4c01637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
Takeda G-protein-coupled receptor 5 (TGR5) is considered a promising therapeutic target for treating type 2 diabetes mellitus (T2DM), obesity, and other metabolism-related diseases. Although many TGR5 agonists have been identified, they might cause some side effects in the gallbladder and the heart. To reduce these side effects and improve glucose-lowering capability, we first designed and synthesized a series of 4-phenoxynicotinamide intestine-targeted TGR5 agonist derivatives containing maleimides in the side chains with different linker lengths. All of the target compounds demonstrated significant TGR5 agonistic activity, among which compound 22b displayed the best TGR5 agonistic activity. Additionally, compound 22b displayed low Caco-2 cell permeability and strong mucoadhesion to mucin and the rat intestine. In C57BL/6J, diet-induced obese, and db/db mice, compound 22b demonstrated a robust and prolonged hypoglycemic effect along with an acceptable safety profile.
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Affiliation(s)
- Shizhen Zhao
- The First Affiliated Hospital of Henan University, Kaifeng 475000, China
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China
| | - Le Wang
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China
| | - Xiaotong Huang
- The First Affiliated Hospital of Henan University, Kaifeng 475000, China
| | - Yali Xiao
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China
| | - Mengqi Li
- The First Affiliated Hospital of Henan University, Kaifeng 475000, China
| | - Xueyuan Huang
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China
| | - Xueyu Chen
- The First Affiliated Hospital of Henan University, Kaifeng 475000, China
| | - Shengjie Li
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China
| | - Jing Xie
- The First Affiliated Hospital of Henan University, Kaifeng 475000, China
| | - Peng Liu
- Hebi Key Laboratory of Cardiovascular Diseases, Hebi Key Laboratory of Energy Metabolism, People's Hospital of Hebi, Henan University, Kaifeng 475000, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010110, China
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Boutaj H. A Comprehensive Review of Moroccan Medicinal Plants for Diabetes Management. Diseases 2024; 12:246. [PMID: 39452489 PMCID: PMC11507334 DOI: 10.3390/diseases12100246] [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: 09/06/2024] [Revised: 09/29/2024] [Accepted: 10/02/2024] [Indexed: 10/26/2024] Open
Abstract
Moroccan flora, renowned for its diverse medicinal plant species, has long been used in traditional medicine to manage diabetes. This review synthesizes ethnobotanical surveys conducted during the last two decades. Among these plants, 10 prominent Moroccan medicinal plants are evaluated for their phytochemical composition and antidiabetic properties through both in vitro and in vivo studies. The review encompasses a comprehensive analysis of the bioactive compounds identified in these plants, including flavonoids, phenolic acids, terpenoids, and alkaloids. Phytochemical investigations revealed a broad spectrum of secondary metabolites contributing to their therapeutic efficacy. In vitro assays demonstrated the significant inhibition of key enzymes α-amylase and α-glucosidase, while in vivo studies highlighted their potential in reducing blood glucose levels and enhancing insulin secretion. Among the ten plants, notable examples include Trigonella foenum-graecum, Nigella Sativa, and Artemisia herba-alba, each showcasing distinct mechanisms of action, such as enzymatic inhibition and the modulation of glucose metabolism pathways. This review underscores the necessity for further chemical, pharmacological, and clinical research to validate the antidiabetic efficacy of these plants and their active compounds, with a view toward their potential integration into therapeutic practices.
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Affiliation(s)
- Hanane Boutaj
- Laboratory of Life and Health Sciences, FMP, Abdelmalek Essaadi University, Tetouan 93000, Morocco;
- Centre d’Agrobiotechnologie et de Bioingénierie, Unité de Recherche Labellisée CNRST (Centre AgroBiotech-URL-CNRST-05), Équipe “Physiologie des Stress Abiotiques”, Faculté de Sciences et Tecchniques, Université Cadi Ayyad, Marrakesh 40000, Morocco
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9
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Mashaal A, El-Yamany HY, Mansour HAEH. Systemic/Immune-Modulation of Olea europaea Leaf Extract in Fetuses of Alloxan-Induced T1 Diabetic Rats. J Med Food 2024; 27:981-992. [PMID: 38979597 DOI: 10.1089/jmf.2024.0021] [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: 07/10/2024] Open
Abstract
Maternal glucose is the principal macronutrient that sustains fetal growth. Prolonged exposure of the fetus to hyperglycemia from the early stages of pregnancy accelerates the maturation of the stimulus-secretion coupling mechanism in β cell autoimmunity, which leads to early hyperinsulinemia in type 1 diabetes mellitus (T1DM). Nowadays, diabetes mellitus (DM) is the most common medical complication of pregnancy, and among young women, the prevalence of overt diabetes and undiagnosed hyperglycemia is rising. Even though conventional medication is effective in treating DM, it is expensive and has harmful side effects. Herbal medicine will thus incorporate alternative therapy and be more effective and less toxic. Due to their bioactive components, olive leaves (Olea europaea) are frequently used medicinally; however, little is known about how this plant affects the immune system when it comes to diabetes. The current study used a pregnant mother rat model of alloxan-induced T1DM to examine the antidiabetic properties and embryonic safety of olive leaves. Forty adult female Sprague Dawley rats were split up into four groups as follows: nondiabetic, diabetic, olive, and diabetic-olive groups. All the mother rats were sacrificed on the 20th day of pregnancy, and fetuses were collected for further investigations. In diabetic pregnant mothers, fetuses had systemic modulation-negative effects. These effects were significantly reversed when the diabetic groups were supplemented with extracts from olive leaves. The findings showed that the olive leaf extract inhibits the diabetogenic effect mediated by alloxan with effective and protective systemic immunomodulation during embryonic development.
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Affiliation(s)
- Alya Mashaal
- Immunology Zoology and Entomology Department , Faculty of Science (for Girls), Al-Azhar University, Cairo, Egypt
| | - Heba Y El-Yamany
- Histology and Cell Biology, Histology Department, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt
| | - Hend Abd El-Halim Mansour
- Embryology, Zoology and Entomology Department, Faculty of Science (for Girls), Al-Azhar University, Cairo, Egypt
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Bhimanwar RS, Mittal A, Chaudhari S, Sharma V. Recent advancements in the structural exploration of TGR5 agonists for diabetes treatment. RSC Med Chem 2024; 15:3026-3037. [PMID: 39309359 PMCID: PMC11411620 DOI: 10.1039/d4md00473f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 07/16/2024] [Indexed: 09/25/2024] Open
Abstract
TGR5, a receptor that interacts with bile acids on cell surfaces, has become a promising therapeutic target for type II diabetes due to its ability to regulate energy expenditure and blood sugar levels. While several TGR5 agonists have been identified, only a few are currently in clinical trials. This article reviews the promising TGR5 agonists discovered in recent years, highlighting the chemical structure and pharmacological profile of the most effective compounds. With the limited number of effective drugs available for treating type II diabetes, the search for a potent TGR5 agonist with high efficacy and fewer side effects continues. The goal of this article is to provide an overview of the latest advancements in TGR5 agonists and offer insights for the future development of novel, potent TGR5 agonists for diabetes treatment. A noteworthy aspect addressed in the discussion is the common side effect associated with TGR5 agonist treatment - gallbladder filling. The review also explores potential strategies to mitigate this side effect, with the goal of improving the overall safety and tolerability of TGR5-targeted therapies.
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Affiliation(s)
- Rachana S Bhimanwar
- Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research Pimpri Pune Maharashtra-411018 India
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University Jalandhar-Delhi G.T. Road (NH-1) Phagwara Punjab-144411 India
| | - Amit Mittal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University Jalandhar-Delhi G.T. Road (NH-1) Phagwara Punjab-144411 India
| | - Snehal Chaudhari
- Department of Biochemistry, University of Wisconsin-Madison Madison WI-53706 USA
| | - Vikas Sharma
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University Jalandhar-Delhi G.T. Road (NH-1) Phagwara Punjab-144411 India
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11
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Herrmann M, Rodriguez-Blanco G, Balasso M, Sobolewska K, Semeraro MD, Alonso N, Herrmann W. The role of bile acid metabolism in bone and muscle: from analytics to mechanisms. Crit Rev Clin Lab Sci 2024; 61:510-528. [PMID: 38488591 DOI: 10.1080/10408363.2024.2323132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/09/2024] [Accepted: 02/21/2024] [Indexed: 08/25/2024]
Abstract
Osteoporosis and sarcopenia are both common age-related disorders that are associated with increased morbidity and mortality. Bone and muscle are metabolically very active tissues that require large amounts of energy. Bile acids (BAs), a group of liver-derived steroid compounds, are primarily known as emulsifiers that facilitate the resorption of dietary fat and lipids. In addition, they have pleiotropic metabolic functions in lipoprotein and glucose metabolism, inflammation, and intestinal bacterial growth. Through these effects, they are related to metabolic diseases, such as diabetes, hypertriglyceridemia, atherosclerosis, and nonalcoholic steatohepatitis. BAs mediate their metabolic effects through receptor dependent and receptor-independent mechanisms. Emerging evidence suggests that BAs are also involved in bone and muscle metabolism. Under normal circumstances, BAs support bone health by shifting the delicate equilibrium of bone turnover toward bone formation. In contrast, low or excessive amounts of BAs promote bone resorption. In cholestatic liver disease, BAs accumulate in the liver, reach toxic concentrations in the circulation, and thus may contribute to bone loss and muscle wasting. In addition, the measurement of BAs is in rapid evolution with modern mass spectrometry techniques that allow for the detection of a continuously growing number of BAs. This review provides a comprehensive overview of the biochemistry, physiology and measurement of bile acids. Furthermore, it summarizes the existing literature regarding their role in bone and muscle.
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Affiliation(s)
- Markus Herrmann
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Giovanny Rodriguez-Blanco
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Marco Balasso
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Katarzyna Sobolewska
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Maria Donatella Semeraro
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Nerea Alonso
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Wolfgang Herrmann
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
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12
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Gu P, Zhao J, Zhang W, Ruan X, Hu L, Zeng Y, Hou X, Zheng X, Gao M, Chi J. An Inducible CRISPR-dCas9-Based Transcriptional Repression System for Cancer Therapy. SMALL METHODS 2024; 8:e2301310. [PMID: 38164884 DOI: 10.1002/smtd.202301310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/12/2023] [Indexed: 01/03/2024]
Abstract
Gene therapy has been adapted for improving malignant tumor treatment. However, pharmacotherapies targeting cancer remain limited and are generally inapplicable for rare disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment for many disorders. Here, the congruent pharmacological activities of OA and CRISPR-dCas9 in targeting AURKA or KDM1A and improving disease-specific prognosis and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs are utilized. In particular, the OA-triggered CRISPR-dCas9 transcriptional repression system rapidly and simultaneously attenuated lung and thyroid cancer. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficiencies of single therapeutics.
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Affiliation(s)
- Pengfei Gu
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jie Zhao
- Department of Orthopedics, Tianjin University Tianjin Hospital, Tianjin, 300211, China
| | - Wei Zhang
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xianhui Ruan
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Linfei Hu
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yu Zeng
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xiukun Hou
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xiangqian Zheng
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Ming Gao
- Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- Tianjin Key Laboratory of General Surgery in construction, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Jiadong Chi
- Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
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13
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Wang Y, Liu K. Therapeutic potential of oleanolic acid in liver diseases. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4537-4554. [PMID: 38294504 DOI: 10.1007/s00210-024-02959-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 01/15/2024] [Indexed: 02/01/2024]
Abstract
Liver-associated diseases affect millions of individuals worldwide. In developed countries, the incidence of viral hepatitis is reducing due to advancements in disease prevention, diagnosis, and treatment. However, with improvements in living standards, the prevalence of metabolic liver diseases, such as non-alcoholic fatty liver disease and alcohol-related liver disease, is expected to increase; notably, this rise in the prevalence of metabolic liver disease can lead to the development of more severe liver diseases, including liver failure, cirrhosis, and liver cancer. The growing demand for natural alternative therapies for chronic diseases has highlighted the importance of studying the pharmacology of bioactive compounds in plants. One such compound is oleanolic acid (OA), a pentacyclic triterpenoid known for its antioxidant, anti-inflammatory, anti-ulcer, antibacterial, antiviral, antihypertensive, anti-obesity, anticancer, anti-diabetic, cardioprotective, hepatoprotective, and anti-neurodegenerative properties. Recent studies have demonstrated that OA treatment can reduce the risk of pathological liver damage, ultimately alleviating liver dysregulation and restoring overall liver function. This review aims to explore the latest research on the biological effects of OA and its derivatives. Notably, it explores the mechanisms of action of these compounds in both in vitro and in vivo research models and, ultimately, highlights OA as a promising candidate for alternative therapies in the treatment and management of chronic liver disease.
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Affiliation(s)
- Yongxin Wang
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China.
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14
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Regolo L, Giampieri F, Battino M, Armas Diaz Y, Mezzetti B, Elexpuru-Zabaleta M, Mazas C, Tutusaus K, Mazzoni L. From by-products to new application opportunities: the enhancement of the leaves deriving from the fruit plants for new potential healthy products. Front Nutr 2024; 11:1083759. [PMID: 38895662 PMCID: PMC11184148 DOI: 10.3389/fnut.2024.1083759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 05/03/2024] [Indexed: 06/21/2024] Open
Abstract
In the last decades, the world population and demand for any kind of product have grown exponentially. The rhythm of production to satisfy the request of the population has become unsustainable and the concept of the linear economy, introduced after the Industrial Revolution, has been replaced by a new economic approach, the circular economy. In this new economic model, the concept of "the end of life" is substituted by the concept of restoration, providing a new life to many industrial wastes. Leaves are a by-product of several agricultural cultivations. In recent years, the scientific interest regarding leaf biochemical composition grew, recording that plant leaves may be considered an alternative source of bioactive substances. Plant leaves' main bioactive compounds are similar to those in fruits, i.e., phenolic acids and esters, flavonols, anthocyanins, and procyanidins. Bioactive compounds can positively influence human health; in fact, it is no coincidence that the leaves were used by our ancestors as a natural remedy for various pathological conditions. Therefore, leaves can be exploited to manufacture many products in food (e.g., being incorporated in food formulations as natural antioxidants, or used to create edible coatings or films for food packaging), cosmetic and pharmaceutical industries (e.g., promising ingredients in anti-aging cosmetics such as oils, serums, dermatological creams, bath gels, and other products). This review focuses on the leaves' main bioactive compounds and their beneficial health effects, indicating their applications until today to enhance them as a harvesting by-product and highlight their possible reuse for new potential healthy products.
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Affiliation(s)
- Lucia Regolo
- Dipartimento di Scienze Agrarie, Alimentari ed Ambientali – Università Politecnica delle Marche, Ancona, Italy
| | - Francesca Giampieri
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Maurizio Battino
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Product Processing, Jiangsu University, Zhenjiang, China
| | - Yasmany Armas Diaz
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Bruno Mezzetti
- Dipartimento di Scienze Agrarie, Alimentari ed Ambientali – Università Politecnica delle Marche, Ancona, Italy
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
| | - Maria Elexpuru-Zabaleta
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
| | - Cristina Mazas
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
- Universidad Internacional Iberoamericana, Campeche, Mexico
| | - Kilian Tutusaus
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
- Research Center for Foods, Nutritional Biochemistry and Health, Universidade Internacional do Cuanza, Cuito, Angola
| | - Luca Mazzoni
- Dipartimento di Scienze Agrarie, Alimentari ed Ambientali – Università Politecnica delle Marche, Ancona, Italy
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15
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Fryer E, Guha S, Rogel-Hernandez LE, Logan-Garbisch T, Farah H, Rezaei E, Mollhoff IN, Nekimken AL, Xu A, Seyahi LS, Fechner S, Druckmann S, Clandinin TR, Rhee SY, Goodman MB. A high-throughput behavioral screening platform for measuring chemotaxis by C. elegans. PLoS Biol 2024; 22:e3002672. [PMID: 38935621 PMCID: PMC11210793 DOI: 10.1371/journal.pbio.3002672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 05/11/2024] [Indexed: 06/29/2024] Open
Abstract
Throughout history, humans have relied on plants as a source of medication, flavoring, and food. Plants synthesize large chemical libraries and release many of these compounds into the rhizosphere and atmosphere where they affect animal and microbe behavior. To survive, nematodes must have evolved the sensory capacity to distinguish plant-made small molecules (SMs) that are harmful and must be avoided from those that are beneficial and should be sought. This ability to classify chemical cues as a function of their value is fundamental to olfaction and represents a capacity shared by many animals, including humans. Here, we present an efficient platform based on multiwell plates, liquid handling instrumentation, inexpensive optical scanners, and bespoke software that can efficiently determine the valence (attraction or repulsion) of single SMs in the model nematode, Caenorhabditis elegans. Using this integrated hardware-wetware-software platform, we screened 90 plant SMs and identified 37 that attracted or repelled wild-type animals but had no effect on mutants defective in chemosensory transduction. Genetic dissection indicates that for at least 10 of these SMs, response valence emerges from the integration of opposing signals, arguing that olfactory valence is often determined by integrating chemosensory signals over multiple lines of information. This study establishes that C. elegans is an effective discovery engine for determining chemotaxis valence and for identifying natural products detected by the chemosensory nervous system.
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Affiliation(s)
- Emily Fryer
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
- Department of Plant Biology, Carnegie Institution for Science, Stanford, California, United States of America
| | - Sujay Guha
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
| | - Lucero E. Rogel-Hernandez
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
| | - Theresa Logan-Garbisch
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
- Neurosciences Graduate Program, Stanford University, Stanford, California, United States of America
| | - Hodan Farah
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
- Department of Plant Biology, Carnegie Institution for Science, Stanford, California, United States of America
| | - Ehsan Rezaei
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
| | - Iris N. Mollhoff
- Department of Biology, Stanford University, Stanford, California, United States of America
| | - Adam L. Nekimken
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
- Department of Mechanical Engineering, Stanford University, Stanford, California, United States of America
| | - Angela Xu
- Department of Plant Biology, Carnegie Institution for Science, Stanford, California, United States of America
| | - Lara Selin Seyahi
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
- Department of Plant Biology, Carnegie Institution for Science, Stanford, California, United States of America
| | - Sylvia Fechner
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
| | - Shaul Druckmann
- Department of Neurobiology, Stanford University, Stanford, California, United States of America
| | - Thomas R. Clandinin
- Department of Neurobiology, Stanford University, Stanford, California, United States of America
| | - Seung Y. Rhee
- Department of Plant Biology, Carnegie Institution for Science, Stanford, California, United States of America
| | - Miriam B. Goodman
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, United States of America
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16
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Wasim M, Bergonzi MC. Unlocking the Potential of Oleanolic Acid: Integrating Pharmacological Insights and Advancements in Delivery Systems. Pharmaceutics 2024; 16:692. [PMID: 38931816 PMCID: PMC11206505 DOI: 10.3390/pharmaceutics16060692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/16/2024] [Accepted: 05/19/2024] [Indexed: 06/28/2024] Open
Abstract
The growing interest in oleanolic acid (OA) as a triterpenoid with remarkable health benefits prompts an emphasis on its efficient use in pharmaceutical research. OA exhibits a range of pharmacological effects, including antidiabetic, anti-inflammatory, immune-enhancing, gastroprotective, hepatoprotective, antitumor, and antiviral properties. While OA demonstrates diverse pharmacological effects, optimizing its therapeutic potential requires overcoming significant challenges. In the field of pharmaceutical research, the exploration of efficient drug delivery systems is essential to maximizing the therapeutic potential of bioactive compounds. Efficiently delivering OA faces challenges, such as poor aqueous solubility and restricted bioavailability, and to unlock its full therapeutic efficacy, novel formulation strategies are imperative. This discussion thoroughly investigates different approaches and advancements in OA drug delivery systems with the aim of enhancing the biopharmaceutical features and overall efficacy in diverse therapeutic contexts.
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Affiliation(s)
| | - Maria Camilla Bergonzi
- Department of Chemistry, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Italy;
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17
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Jin W, Zheng M, Chen Y, Xiong H. Update on the development of TGR5 agonists for human diseases. Eur J Med Chem 2024; 271:116462. [PMID: 38691888 DOI: 10.1016/j.ejmech.2024.116462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/20/2024] [Accepted: 04/27/2024] [Indexed: 05/03/2024]
Abstract
The G protein-coupled bile acid receptor 1 (GPBAR1) or TGR5 is widely distributed across organs, including the small intestine, stomach, liver, spleen, and gallbladder. Many studies have established strong correlations between TGR5 and glucose homeostasis, energy metabolism, immune-inflammatory responses, and gastrointestinal functions. These results indicate that TGR5 has a significant impact on the progression of tumor development and metabolic disorders such as diabetes mellitus and obesity. Targeting TGR5 represents an encouraging therapeutic approach for treating associated human ailments. Notably, the GLP-1 receptor has shown exceptional efficacy in clinical settings for diabetes management and weight loss promotion. Currently, numerous TGR5 agonists have been identified through natural product-based approaches and virtual screening methods, with some successfully progressing to clinical trials. This review summarizes the intricate relationships between TGR5 and various diseases emphasizing recent advancements in research on TGR5 agonists, including their structural characteristics, design tactics, and biological activities. We anticipate that this meticulous review could facilitate the expedited discovery and optimization of novel TGR5 agonists.
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Affiliation(s)
- Wangrui Jin
- Institute for Advanced Study, and College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China; Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Mingyue Zheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yihua Chen
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, China; Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Hai Xiong
- Institute for Advanced Study, and College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China.
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18
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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19
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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20
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Labani N, Gbahou F, Lian S, Liu J, Jockers R. 2023 Julius Axelrod Symposium: Plant-Derived Molecules Acting on G Protein-Coupled Receptors. Mol Pharmacol 2024; 105:328-347. [PMID: 38458772 DOI: 10.1124/molpharm.123.000854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/12/2024] [Accepted: 02/20/2024] [Indexed: 03/10/2024] Open
Abstract
Plant extracts have played a significant role in traditional medicine for centuries, contributing to improved health and the treatment of various human illnesses. G protein-coupled receptors (GPCRs) are crucial in numerous physiologic functions, and there is growing evidence suggesting their involvement in the therapeutic effects of many plant extracts. In recent years, scientists have identified an expanding number of isolated molecules responsible for the biologic activity of these extracts, with many believed to act on GPCRs. This article critically reviews the evidence supporting the modulation of GPCR function by these plant-derived molecules through direct binding. Structural information is now available for some of these molecules, allowing for a comparison of their binding mode with that of endogenous GPCR ligands. The final section explores future trends and challenges, focusing on the identification of new plant-derived molecules with both orthosteric and allosteric binding modes, as well as innovative strategies for designing GPCR ligands inspired by these plant-derived compounds. In conclusion, plant-derived molecules are anticipated to play an increasingly vital role as therapeutic drugs and serve as templates for drug design. SIGNIFICANCE STATEMENT: This minireview summarizes the most pertinent publications on isolated plant-derived molecules interacting with G protein-coupled receptors (GPCRs) and comments on available structural information on GPCR/plant-derived ligand pairs. Future challenges and trends for the isolation and characterization of plant-derived molecules and drug design are discussed.
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Affiliation(s)
- Nedjma Labani
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China (N.L., J.L.) and Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France (N.L., F.G., S.L., R.J.)
| | - Florence Gbahou
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China (N.L., J.L.) and Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France (N.L., F.G., S.L., R.J.)
| | - Shuangyu Lian
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China (N.L., J.L.) and Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France (N.L., F.G., S.L., R.J.)
| | - Jianfeng Liu
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China (N.L., J.L.) and Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France (N.L., F.G., S.L., R.J.)
| | - Ralf Jockers
- Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China (N.L., J.L.) and Université Paris Cité, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France (N.L., F.G., S.L., R.J.)
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21
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Fryer E, Guha S, Rogel-Hernandez LE, Logan-Garbisch T, Farah H, Rezaei E, Mollhoff IN, Nekimken AL, Xu A, Selin Seyahi L, Fechner S, Druckmann S, Clandinin TR, Rhee SY, Goodman MB. An efficient behavioral screening platform classifies natural products and other chemical cues according to their chemosensory valence in C. elegans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.06.02.542933. [PMID: 37333363 PMCID: PMC10274637 DOI: 10.1101/2023.06.02.542933] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Throughout history, humans have relied on plants as a source of medication, flavoring, and food. Plants synthesize large chemical libraries and release many of these compounds into the rhizosphere and atmosphere where they affect animal and microbe behavior. To survive, nematodes must have evolved the sensory capacity to distinguish plant-made small molecules (SMs) that are harmful and must be avoided from those that are beneficial and should be sought. This ability to classify chemical cues as a function of their value is fundamental to olfaction, and represents a capacity shared by many animals, including humans. Here, we present an efficient platform based on multi-well plates, liquid handling instrumentation, inexpensive optical scanners, and bespoke software that can efficiently determine the valence (attraction or repulsion) of single SMs in the model nematode, Caenorhabditis elegans. Using this integrated hardware-wetware-software platform, we screened 90 plant SMs and identified 37 that attracted or repelled wild-type animals, but had no effect on mutants defective in chemosensory transduction. Genetic dissection indicates that for at least 10 of these SMs, response valence emerges from the integration of opposing signals, arguing that olfactory valence is often determined by integrating chemosensory signals over multiple lines of information. This study establishes that C. elegans is an effective discovery engine for determining chemotaxis valence and for identifying natural products detected by the chemosensory nervous system.
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Affiliation(s)
- Emily Fryer
- Department of Plant Biology, Carnegie Institution for Science
- Department of Molecular and Cellular Physiology, Stanford University
| | - Sujay Guha
- Department of Molecular and Cellular Physiology, Stanford University
| | | | - Theresa Logan-Garbisch
- Department of Molecular and Cellular Physiology, Stanford University
- Neurosciences Graduate Program, Stanford University
| | - Hodan Farah
- Department of Plant Biology, Carnegie Institution for Science
- Department of Molecular and Cellular Physiology, Stanford University
| | - Ehsan Rezaei
- Department of Molecular and Cellular Physiology, Stanford University
| | - Iris N. Mollhoff
- Department of Plant Biology, Carnegie Institution for Science
- Department of Molecular and Cellular Physiology, Stanford University
- Department of Biology, Stanford University
| | - Adam L. Nekimken
- Department of Molecular and Cellular Physiology, Stanford University
- Department of Mechanical Engineering, Stanford University
| | - Angela Xu
- Department of Plant Biology, Carnegie Institution for Science
| | - Lara Selin Seyahi
- Department of Plant Biology, Carnegie Institution for Science
- Department of Molecular and Cellular Physiology, Stanford University
| | - Sylvia Fechner
- Department of Molecular and Cellular Physiology, Stanford University
| | | | | | - Seung Y. Rhee
- Department of Plant Biology, Carnegie Institution for Science
| | - Miriam B. Goodman
- Department of Molecular and Cellular Physiology, Stanford University
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22
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Luo Q, Wei Y, Lv X, Chen W, Yang D, Tuo Q. The Effect and Mechanism of Oleanolic Acid in the Treatment of Metabolic Syndrome and Related Cardiovascular Diseases. Molecules 2024; 29:758. [PMID: 38398510 PMCID: PMC10892503 DOI: 10.3390/molecules29040758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/31/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
Metabolic syndromes (MetS) and related cardiovascular diseases (CVDs) pose a serious threat to human health. MetS are metabolic disorders characterized by obesity, dyslipidemia, and hypertension, which increase the risk of CVDs' initiation and development. Although there are many availabile drugs for treating MetS and related CVDs, some side effects also occur. Considering the low-level side effects, many natural products have been tried to treat MetS and CVDs. A five-cyclic triterpenoid natural product, oleanolic acid (OA), has been reported to have many pharmacologic actions such as anti-hypertension, anti-hyperlipidemia, and liver protection. OA has specific advantages in the treatment of MetS and CVDs. OA achieves therapeutic effects through a variety of pathways, attracting great interest and playing a vital role in the treatment of MetS and CVDs. Consequently, in this article, we aim to review the pharmacological actions and potential mechanisms of OA in treating MetS and related CVDs.
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Affiliation(s)
- Quanye Luo
- Key Laboratory of Vascular Biology and Translational Medicine, Medical School, Hunan University of Chinese Medicine, Changsha 410208, China; (Q.L.); (Y.W.); (W.C.)
| | - Yu Wei
- Key Laboratory of Vascular Biology and Translational Medicine, Medical School, Hunan University of Chinese Medicine, Changsha 410208, China; (Q.L.); (Y.W.); (W.C.)
| | - Xuzhen Lv
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, The School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China;
| | - Wen Chen
- Key Laboratory of Vascular Biology and Translational Medicine, Medical School, Hunan University of Chinese Medicine, Changsha 410208, China; (Q.L.); (Y.W.); (W.C.)
| | - Dongmei Yang
- Key Laboratory of Vascular Biology and Translational Medicine, Medical School, Hunan University of Chinese Medicine, Changsha 410208, China; (Q.L.); (Y.W.); (W.C.)
| | - Qinhui Tuo
- Key Laboratory of Vascular Biology and Translational Medicine, Medical School, Hunan University of Chinese Medicine, Changsha 410208, China; (Q.L.); (Y.W.); (W.C.)
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23
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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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24
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Groenen C, Nguyen TA, Paulusma C, van de Graaf S. Bile salt signaling and bile salt-based therapies in cardiometabolic disease. Clin Sci (Lond) 2024; 138:1-21. [PMID: 38180064 PMCID: PMC10767275 DOI: 10.1042/cs20230934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/23/2023] [Accepted: 12/05/2023] [Indexed: 01/06/2024]
Abstract
Bile salts have an established role in the emulsification and intestinal absorption of dietary lipids, and their homeostasis is tightly controlled by various transporters and regulators in the enterohepatic circulation. Notably, emerging evidence points toward bile salts as major modulators of cardiometabolic disease (CMD), an umbrella disease of disorders affecting the heart and blood vessels that is caused by systemic metabolic diseases such as Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), the latter encompassing also metabolic dysfunction-associated steatohepatitis (MASH). The underlying mechanisms of protective effects of bile salts are their hormonal properties, enabling them to exert versatile metabolic effects by activating various bile salt-responsive signaling receptors with the nuclear farnesoid X receptor (FXR) and the Takeda G-protein-coupled receptor 5 (TGR5) as most extensively investigated. Activation of FXR and TGR5 is involved in the regulation of glucose, lipid and energy metabolism, and inflammation. Bile salt-based therapies directly targeting FXR and TGR5 signaling have been evaluated for their therapeutic potential in CMD. More recently, therapeutics targeting bile salt transporters thereby modulating bile salt localization, dynamics, and signaling, have been developed and evaluated in CMD. Here, we discuss the current knowledge on the contribution of bile salt signaling in the pathogenesis of CMD and the potential of bile salt-based therapies for the treatment of CMD.
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Affiliation(s)
- Claire C.J. Groenen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
| | - Thuc-Anh Nguyen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
| | - Coen C. Paulusma
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, The Netherlands
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25
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Liu S, Chen X, He J, Luo Y, Zheng P, Yu B, Chen D, Huang Z. Oleanolic acid promotes skeletal muscle fiber type transformation by activating TGR5-mediated CaN signaling pathway. J Nutr Biochem 2024; 123:109507. [PMID: 37890712 DOI: 10.1016/j.jnutbio.2023.109507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/27/2023] [Accepted: 10/24/2023] [Indexed: 10/29/2023]
Abstract
In recent years, the impact of bile acids and their representative G protein-coupled bile acid receptor 1 Takeda-G-protein-receptor-5 (TGR5) signaling pathway on muscle function and metabolic health has gained considerable interest. Increasing the content of slow muscle fibers has been recognized as an effective strategy to improve metabolic health. Oleanolic acid (OA) is a naturally occurring triterpenoid compound derived from plants, which can activate TGR5. The aim of this study was to investigate the effect of OA and TGR5 on muscle fiber types and further explore the underlying TGR5-dependent mechanisms. In this study, mice were divided into three groups and dietary supplementation with 0, 50, or 100 mg/kg OA. In addition, C2C12 cells were treated with OA at concentrations of 0, 5, 10, and 20 µM. Our studies revealed that OA promoted the conversion of fast to slow muscle fibers. In addition, it was found that OA activated the TGR5-mediated calcineurin (CaN)/nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. Further mechanistic investigations demonstrated that inhibiting TGR5 and CaN abolished the effects of OA on muscle fiber types transformation. In conclusion, this study found that OA promotes the transformation of fast muscle fibers to slow muscle fibers through the TGR5-mediated CaN/NFATc1 signaling pathway.
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Affiliation(s)
- Shuang Liu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Jun He
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Yuheng Luo
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Ping Zheng
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China
| | - Zhiqing Huang
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, Sichuan, PR China.
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26
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R K, S M, Igk I, J S, S V. Analyzing the Antihyperglycemic Effect of Cissus quadrangularis and Bacopa monnieri on 3T3-L1 Cell Lines. Cureus 2024; 16:e52661. [PMID: 38380214 PMCID: PMC10877220 DOI: 10.7759/cureus.52661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/21/2024] [Indexed: 02/22/2024] Open
Abstract
Background Cissus quadrangularis is a perennial shrub of the grape family. Other names for it include devil's backbone, veld grape, and pirandai (Tamil). Bacopa monnieri, a perennial plant, is native to wetlands in eastern and southern India. The 3T3-L1 cell line, which was created from 3T3 cells, was used in the scientific study. The current study's purpose is to evaluate the antihyperglycemic benefits of B. monnieri and C. quadrangularis, which will be added to the current arsenal of efficient herbal hypoglycemic medications. Aim To analyze and compare the anti-hyperglycaemic effects of the two plant extracts, C. quadrangularis and B. monnieri using a 3T3-L1 cell line. Materials and methods C. quadrangularis seeds were gathered, and extraction was conducted. The B. monnieri plant was harvested, and a rotary evaporator was used to extract the flower. Adipocyte cells were obtained from NCCS, Pune. A CO2 incubator was used to incubate the cells. The MTT assay and gene expression analysis were done on the cell line samples. Results The antihyperglycemic effects of C. quadrangularis IRS mRNA levels of 0.7 and AKT mRNA levels of 0.7 are compared to B. monnieri IRS1 mRNA levels of 0.6 and AKT mRNA levels of 0.6 to build better diabetic treatments. The antihyperglycemic benefits of C. quadrangularis levels of IRS mRNA and AKT mRNA are compared to the influence of B. monnieri IRS1 mRNA and AKT mRNA on the development of better diabetic drugs. Conclusion Comparing the effects of C. quadrangularis and B. monnieri on the 3T3 cell line by gene expression of IRS mRNA and AKT mRNA suggests that the particular AKT downregulation shows that insulin suppresses gluconeogenesis and C. quadrangularis inhibits hyperglycemia in 3T3-L1 cells, while research on in vitro rats suggests that B. monnieri may minimize the signs and symptoms of diabetes via enhancing IRS1/AKT signaling.
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Affiliation(s)
- Katheeja R
- Department of Physiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University, Chennai, IND
| | - Manish S
- Department of Physiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University, Chennai, IND
| | - Ilangovar Igk
- Department of Physiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University, Chennai, IND
| | - Selvaraj J
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University, Chennai, IND
| | - Vasugi S
- Department of Physiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University, Chennai, IND
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Brahma S, Goyal AK, Dhamodhar P, Kumari MR, Jayashree S, Usha T, Middha SK. Can Polyherbal Medicine be used for the Treatment of Diabetes? - A Review of Historical Classics, Research Evidence and Current Prevention Programs. Curr Diabetes Rev 2024; 20:e140323214600. [PMID: 36918778 DOI: 10.2174/1573399819666230314093721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/05/2023] [Accepted: 01/17/2023] [Indexed: 03/16/2023]
Abstract
Diabetes mellitus (DM), a chronic medical condition, has attained a global pandemic status over the last few decades affecting millions of people. Despite a variety of synthetic drugs available in the market, the use of herbal medicines for managing diabetes is gaining importance because of being comparatively safer. This article reviews the result of a substantial literature search on polyherbal formulations (PHFs) developed and evaluated with potential for DM. The accumulated data in the literature allowed us to enlist 76PHFs consisting of different parts of 147 plant species belonging to 58 botanical families. The documented plant species are laden with bioactive components with anti-diabetic properties and thus draw attention. The most favoured ingredient for PHFs was leaves of Gymnema sylvestre and seeds of Trigonella foenum-graecum used in 27 and 22 formulations, respectively. Apart from herbs, shilajit (exudates from high mountain rocks) formed an important component of 9 PHFs, whereas calcined Mytilus margaritiferus and goat pancreas were used in Dolabi, the most commonly used tablet form of PHF in Indian markets. The healing properties of PHFs against diabetes have been examined in both pre-clinical studies and clinical trials. However, the mechanism(s) of action of PHFs are still unclear and considered the pitfalls inherent in understanding the benefits of PHFs. From the information available based on experimental systems, it could be concluded that plant-derived medicines will have a considerable role to play in the control of diabetes provided the challenges related to their bioavailability, bioefficacy, optimal dose, lack of characterization, ambiguous mechanism of action, and clinical efficiency are addressed.
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Affiliation(s)
- Sudem Brahma
- Department of Biotechnology, Bodoland University, Kokrajhar-783370, BTR, Assam, India
| | - Arvind Kumar Goyal
- Department of Biotechnology, Bodoland University, Kokrajhar-783370, BTR, Assam, India
| | - Prakash Dhamodhar
- Department of Biotechnology, M.S. Ramaiah Institute of Technology, Bangaluru-560054, Karnataka, India
| | - Mani Reema Kumari
- Department of Botany, Maharani Lakshmi Ammanni College for Women, Bengaluru-560012, Karnataka, India
| | - S Jayashree
- School of Allied Health Sciences, REVA University, Bengaluru-560064, Karnataka, India
| | - Talambedu Usha
- Department of Biochemistry, Maharani Lakshmi Ammanni College for Women, Bengaluru-560012, Karnataka, India
| | - Sushil Kumar Middha
- Department of Biochemistry, Maharani Lakshmi Ammanni College for Women, Bengaluru-560012, Karnataka, India
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28
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Stelling-Férez J, Cappellacci I, Pandolfi A, Gabaldón JA, Pipino C, Nicolás FJ. Oleanolic acid rescues critical features of umbilical vein endothelial cells permanently affected by hyperglycemia. Front Endocrinol (Lausanne) 2023; 14:1308606. [PMID: 38192424 PMCID: PMC10773851 DOI: 10.3389/fendo.2023.1308606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/23/2023] [Indexed: 01/10/2024] Open
Abstract
Skin wound healing is a physiological process that involves several cell types. Among them, endothelial cells are required for inflammation resolution and neo-angiogenesis, both necessary for tissue restoration after injury. Primary human umbilical vein endothelial cells (C-HUVECs) are derived from the umbilical cord. When women develop gestational diabetes, chronic exposure to hyperglycemia induces epigenetic modifications in these cells (GD-HUVECs), leading to a permanent pro-inflammatory phenotype and impaired angiogenesis in contrast to control cells. Oleanolic acid (OA) is a bioactive triterpenoid known for its epithelial cell migration promotion stimulation and higher tensile strength of wounds. However, the potentially anti-inflammatory and pro-angiogenic properties of OA are still under investigation. We tested OA on C- and GD-HUVECs under inflammatory conditions induced by low levels of the inflammatory cytokine TNF-α. Reduced expression of adhesion molecules VCAM1, ICAM1, and SELE was obtained in OA-pre-treated C- and GD-HUVECs. Additionally, protein VCAM1 levels were also decreased by OA. Coherently, monocyte adhesion assays showed that a lower number of monocytes adhered to GD-HUVEC endothelium under OA pre-treatment when compared to untreated ones. It is noteworthy that OA improved angiogenesis parameters in both phenotypes, being especially remarkable in the case of GD-HUVECs, since OA strongly rescued their poor tube formation behavior. Moreover, endothelial cell migration was improved in C- and GD-HUVECs in scratch assays, an effect that was further confirmed by focal adhesion (FA) remodeling, revealed by paxillin staining on immunocytochemistry assays. Altogether, these results suggest that OA could be an emergent wound healing agent due to its capacity to rescue endothelial malfunction caused by hyperglycemia.
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Affiliation(s)
- Javier Stelling-Férez
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Murcia, Spain
- Regeneration, Molecular Oncology, and TGF-β, IMIB-Pascual Parrilla, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Ilaria Cappellacci
- Department of Medical, Oral and Biotechnological Sciences, StemTeCh Group, Center for Advanced Studies and Technology-CAST (ex CeSI-MeT), University G. D’Annunzio Chieti-Pescara, Chieti, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, StemTeCh Group, Center for Advanced Studies and Technology-CAST (ex CeSI-MeT), University G. D’Annunzio Chieti-Pescara, Chieti, Italy
| | - José Antonio Gabaldón
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Murcia, Spain
| | - Caterina Pipino
- Department of Medical, Oral and Biotechnological Sciences, StemTeCh Group, Center for Advanced Studies and Technology-CAST (ex CeSI-MeT), University G. D’Annunzio Chieti-Pescara, Chieti, Italy
| | - Francisco José Nicolás
- Regeneration, Molecular Oncology, and TGF-β, IMIB-Pascual Parrilla, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
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29
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Hong W, Fu W, Zhao Q, Xue C, Cai W, Dong N, Shan A. Effects of oleanolic acid on acute liver injury triggered by lipopolysaccharide in broiler chickens. Br Poult Sci 2023; 64:697-709. [PMID: 37697900 DOI: 10.1080/00071668.2023.2251119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 06/21/2023] [Accepted: 07/03/2023] [Indexed: 09/13/2023]
Abstract
1. Infectious injury caused by lipopolysaccharide (LPS), a metabolite of gram-negative bacteria, can induce stress responses in animals and is a significant cause of morbidity and mortality in young birds. The purpose of this study was to investigate the effects of dietary supplementation with oleanolic acid (OA) on acute liver injury in broiler chickens challenged with LPS.2. In total, 120 broiler chickens were randomly divided into six groups and fed a basal diet containing 0, 50, 100, or 200 mg/kg OA or 100 mg/kg aureomycin. On d 15, broiler chickens were injected with either LPS or an equivalent volume of normal saline. Six hours after LPS injection, two broiler chicks were randomly selected for sampling in each replicate.3. The results indicated that dietary aureomycin was ineffective in alleviating LSP-associated liver injury, but protected broiler chickens from LPS-induced liver damage. This promoted a significant reduction in the levels of malondialdehyde and an increase in the levels of superoxide dismutase in liver. In addition, OA was found to cause significant reductions in the relative expression of IL-1β, IL-6, and TNF-α in broiler liver tissues, whereas the relative expression of IL-10 was significantly increased.4. In conclusion, oleanolic acid can alleviate oxidative stress and injury in the livers of broiler chickens induced by lipopolysaccharide. Consequently, oleanolic acid has potential utility as a novel anti-inflammatory and antioxidant feed additive.
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Affiliation(s)
- W Hong
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
| | - W Fu
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
| | - Q Zhao
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
| | - C Xue
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
| | - W Cai
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
| | - N Dong
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
| | - A Shan
- The Laboratory of Molecular Nutrition and Immunity, College of Animal Science and Technology, Northeast Agricultural University, Harbin, P. R. China
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Radwan MO, Kadasah SF, Aljubiri SM, Alrefaei AF, El-Maghrabey MH, El Hamd MA, Tateishi H, Otsuka M, Fujita M. Harnessing Oleanolic Acid and Its Derivatives as Modulators of Metabolic Nuclear Receptors. Biomolecules 2023; 13:1465. [PMID: 37892147 PMCID: PMC10604226 DOI: 10.3390/biom13101465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/25/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.
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Affiliation(s)
- Mohamed O. Radwan
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
| | - Sultan F. Kadasah
- Department of Biology, Faculty of Science, University of Bisha, Bisha 61922, Saudi Arabia;
| | - Salha M. Aljubiri
- Department of Chemistry, College of Science, University of Bisha, Bisha 61922, Saudi Arabia;
| | | | - Mahmoud H. El-Maghrabey
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Mohamed A. El Hamd
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt
| | - Hiroshi Tateishi
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
| | - Masami Otsuka
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
- Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan
| | - Mikako Fujita
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
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31
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Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1169624. [PMID: 37560311 PMCID: PMC10407565 DOI: 10.3389/fendo.2023.1169624] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Affiliation(s)
| | - Van B. Lu
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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32
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Assar DH, Ragab AE, Abdelsatar E, Salah AS, Salem SMR, Hendam BM, Al Jaouni S, Al Wakeel RA, AbdEl-Kader MF, Elbialy ZI. Dietary Olive Leaf Extract Differentially Modulates Antioxidant Defense of Normal and Aeromonas hydrophila-Infected Common Carp ( Cyprinus carpio) via Keap1/Nrf2 Pathway Signaling: A Phytochemical and Biological Link. Animals (Basel) 2023; 13:2229. [PMID: 37444027 DOI: 10.3390/ani13132229] [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: 05/12/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Olive leaves are an immense source of antioxidant and antimicrobial bioactive constituents. This study investigated the effects of dietary incorporation of olive leaf extract (OLE) on the growth performance, hematobiochemical parameters, immune response, antioxidant defense, histopathological changes, and some growth- and immune-related genes in the common carp (Cyprinus carpio). A total of 180 fish were allocated into four groups with triplicate each. The control group received the basal diet without OLE, while the other three groups were fed a basal diet with the OLE at 0.1, 0.2, and 0.3%, respectively. The feeding study lasted for 8 weeks, then fish were challenged with Aeromonas hydrophila. The results revealed that the group supplied with the 0.1% OLE significantly exhibited a higher final body weight (FBW), weight gain (WG%), and specific growth rate (SGR) with a decreased feed conversion ratio (FCR) compared to the other groups (p < 0.05). An increase in immune response was also observed in the fish from this group, with higher lysosome activity, immunoglobulin (IgM), and respiratory burst than nonsupplemented fish, both before and after the A. hydrophila challenge (p < 0.05). Similarly, the supplementation of the 0.1% OLE also promoted the C. carpio's digestive capacity pre- and post-challenge, presenting the highest activity of protease and alkaline phosphatase (p < 0.05). In addition, this dose of the OLE enhanced fish antioxidant capacity through an increase in the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and decreased hepatic lipid peroxidation end products (malondialdehyde-MDA), when compared to the control group, both pre- and post-infection (p < 0.05). Concomitantly with the superior immune response and antioxidant capacity, the fish fed the 0.1% OLE revealed the highest survival rate after the challenge with A. hydrophila (p < 0.05). A significant remarkable upregulation of the hepatic sod, nrf2, and protein kinase C transcription levels was detected as a vital approach for the prevention of both oxidative stress and inflammation compared to the infected unsupplied control group (p < 0.05). Interestingly, HPLC and UPLC-ESI-MS/MS analyses recognized that oleuropein is the main constituent (20.4%) with other 45 compounds in addition to tentative identification of two new compounds, namely oleuroside-10-carboxylic acid (I) and demethyl oleuroside-10-carboxylic acid (II). These constituents may be responsible for the OLE exerted potential effects. To conclude, the OLE at a dose range of 0.66-0.83 g/kg w/w can be included in the C. carpio diet to improve the growth, antioxidant capacity, and immune response under normal health conditions along with regulating the infection-associated pro-inflammatory gene expressions, thus enhancing resistance against A. hydrophila.
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Affiliation(s)
- Doaa H Assar
- Clinical Pathology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Amany E Ragab
- Pharmacognosy Department, Faculty of Pharmacy, Tanta University, Tanta 32527, Egypt
| | - Essam Abdelsatar
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Abdallah S Salah
- Department of Aquaculture, Faculty of Aquatic and Fisheries Sciences, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK
| | - Shimaa M R Salem
- Department of Animal Nutrition and Nutritional Deficiency Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Basma M Hendam
- Department of Animal Wealth Development, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Soad Al Jaouni
- Department of Hematology/Pediatric Oncology, Yousef Abdulatif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Rasha A Al Wakeel
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Marwa F AbdEl-Kader
- Department of Fish Health and Management, Sakha Aquaculture Research Unit, Central Laboratory for Aquaculture Research, A.R.C., Kafrelsheikh 33516, Egypt
| | - Zizy I Elbialy
- Department of Fish Processing and Biotechnology, Faculty of Aquatic and Fisheries Sciences, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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33
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de la Peña I, Afable T, Dahilig-Talan VR, Cruz P. Review of Plant Extracts and Active Components: Mechanisms of Action for the Treatment of Obesity-Induced Cognitive Impairment. Brain Sci 2023; 13:929. [PMID: 37371407 DOI: 10.3390/brainsci13060929] [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: 05/17/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Obesity has been shown to negatively impact cognitive functions, but effective treatments for obesity-induced cognitive impairment are lacking. Natural dietary and plant products, functional foods, and plant-derived compounds have gained attention as potential remedies in part due to the nootropic properties of plants and certain plant-derived agents. This review discusses plant extracts and plant-derived substances that have been shown to ameliorate obesity-induced cognitive impairment in animal models. Mechanistic evaluations of their therapeutic effects are also summarized. A literature search was conducted using PubMed and Google Scholar databases, resulting in the review of 27 English language articles meeting the inclusion criteria. The nine plants (e.g., Ashwagandha, Adzuki bean, and olive) and 18 plant-derived substances (e.g., curcumin, Huperzine A, and Roxburgh's jewel orchid polysaccharides) included in this review improved obesity-induced cognitive impairment through several mechanisms, including attenuation of neuroinflammation, improvement in both central and peripheral insulin resistance, enhancement of neuroprotection and neurogenesis, and modulation of the synthesis and release of cognition-associated neurotransmitters. Based on these findings, plants and plant-derived substances may hold promise for the prevention and treatment of obesity-induced cognitive impairment. Further research is warranted to explore the clinical potential of these plant-derived treatments and to elucidate their underlying molecular mechanisms.
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Affiliation(s)
- Ike de la Peña
- Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University, Loma Linda, CA 92350, USA
| | - Timothy Afable
- Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University, Loma Linda, CA 92350, USA
| | | | - Philip Cruz
- Herbanext Laboratories, Inc., Negros South Road, Bago City 6101, Philippines
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Ehtezazi T, Rahman K, Davies R, Leach AG. The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease. J Alzheimers Dis Rep 2023; 7:173-211. [PMID: 36994114 PMCID: PMC10041467 DOI: 10.3233/adr-220071] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments.
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Affiliation(s)
- Touraj Ehtezazi
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Khalid Rahman
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Rhys Davies
- The Walton Centre, NHS Foundation Trust, Liverpool, UK
| | - Andrew G Leach
- School of Pharmacy, University of Manchester, Manchester, UK
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35
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Smaling A, Romero-Ramírez L, Mey J. Is TGR5 a therapeutic target for the treatment of spinal cord injury? J Neurochem 2023; 164:454-467. [PMID: 36409000 DOI: 10.1111/jnc.15727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/03/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022]
Abstract
Bile acids, which are synthesized in liver and colon, facilitate the digestion of dietary lipids. In addition to this metabolic function, they also act as molecular signals with activities in the nervous system. These are mediated primarily by a G-protein-coupled bile acid receptor (known as TGR5). Preceded by a long tradition in Chinese medicine, bile acids are now being investigated as therapeutic options in several neuropathologies. Specifically, one bile acid, tauroursodeoxycholic acid (TUDCA), which passes the blood-brain barrier and shows anti-inflammatory and anti-apoptotic effects, has been tested in animal models of spinal cord injury (SCI). In this review, we discuss the evidence for a therapeutic benefit in these preclinical experiments. At the time of writing, 12 studies with TGR5 agonists have been published that report functional outcomes with rodent models of SCI. Most investigations found cytoprotective effects and benefits regarding the recovery of sensorimotor function in the subacute phase. When TUDCA was applied in a hydrogel into the lesion site, a significant improvement was obtained at 2 weeks after SCI. However, no lasting improvements with TUDCA treatment were found, when animals were assessed in later, chronic stages. A combination of TUDCA with stem cell injection failed to improve the effect of the cellular treatment. We conclude that the evidence does not support the use of TUDCA as a treatment of SCI. Nevertheless, cytoprotective effects suggest that different modes of application or combinatorial therapies might still be explored.
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Affiliation(s)
- Anna Smaling
- School of Mental Health and Neuroscience and EURON Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands
| | | | - Jörg Mey
- School of Mental Health and Neuroscience and EURON Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands.,Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain
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36
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Bile acids and their receptors in regulation of gut health and diseases. Prog Lipid Res 2023; 89:101210. [PMID: 36577494 DOI: 10.1016/j.plipres.2022.101210] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/26/2022]
Abstract
It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.
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37
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Romero-Juárez PA, Visco DB, Manhães-de-Castro R, Urquiza-Martínez MV, Saavedra LM, González-Vargas MC, Mercado-Camargo R, Aquino JDS, Toscano AE, Torner L, Guzmán-Quevedo O. Dietary flavonoid kaempferol reduces obesity-associated hypothalamic microglia activation and promotes body weight loss in mice with obesity. Nutr Neurosci 2023; 26:25-39. [PMID: 34905445 DOI: 10.1080/1028415x.2021.2012629] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Obesity results from an unbalance in the ingested and burned calories. Energy balance (EB) is critically regulated by the hypothalamic arcuate nucleus (ARC) by promoting appetite or anorectic actions. Hypothalamic inflammation, driven by high activation of the microglia, has been reported as a key mechanism involved in the development of diet-induced obesity. Kaempferol (KF), a flavonoid-type polyphenol present in a large number of fruits and vegetables, was shown to regulate both energy metabolism and inflammation. OBJECTIVES In this work, we studied the effects of both the central and peripheral treatment with KF on hypothalamic inflammation and EB regulation in mice with obesity. METHODS Obese adult mice were chronically (40 days) treated with KF (0.5 mg/kg/day, intraperitoneally). During the treatment, body weight, food intake (FI), feed efficiency (FE), glucose tolerance, and insulin sensitivity were determined. Analysis of microglia activation in the ARC of the hypothalamus at the end of the treatment was also performed. Body weight, FI, and FE changes were also evaluated in response to 5µg KF, centrally administrated. RESULTS Chronic administration of KF decreased ∼43% of the density, and ∼30% of the ratio, of activated microglia in the arcuate nucleus. These changes were accompanied by body weight loss, decreased FE, reduced fasting blood glucose, and a tendency to improve insulin sensitivity. Finally, acute central administration of KF reproduced the effects on EB triggered by peripheral administration. CONCLUSION These findings suggest that KF might fight obesity by regulating central processes related to EB regulation and hypothalamic inflammation.
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Affiliation(s)
- Pedro A Romero-Juárez
- Instituto Tecnológico Superior de Tacámbaro, Michoacán, México.,Facultad de Químico-Farmacobiología, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México.,Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México
| | - Diego Bulcão Visco
- Instituto Tecnológico Superior de Tacámbaro, Michoacán, México.,Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México.,Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brasil.,Unidade de Estudos em Nutrição e Plasticidade Fenotípica do Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brazil
| | - Raul Manhães-de-Castro
- Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brasil.,Unidade de Estudos em Nutrição e Plasticidade Fenotípica do Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brazil
| | - Mercedes V Urquiza-Martínez
- Facultad de Químico-Farmacobiología, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México.,Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México
| | - Luis Miguel Saavedra
- Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México
| | - Mari C González-Vargas
- Instituto Tecnológico Superior de Tacámbaro, Michoacán, México.,Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México
| | - Rosalio Mercado-Camargo
- Facultad de Químico-Farmacobiología, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México
| | - Jailane de Souza Aquino
- Laboratório de Nutrição Experimental, Departamento de Nutrição, Universidade Federal da Paraíba, João Pessoa, Brazil
| | - Ana E Toscano
- Unidade de Estudos em Nutrição e Plasticidade Fenotípica do Departamento de Nutrição, Universidade Federal de Pernambuco, Recife, Brazil.,Departmento de Enfermagem, Universidade Federal de Pernambuco, Recife, Brasil.,Pós-Graduação em Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco, Recife, Brasil
| | - Luz Torner
- Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México
| | - Omar Guzmán-Quevedo
- Instituto Tecnológico Superior de Tacámbaro, Michoacán, México.,Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, México.,Pós-Graduação em Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco, Recife, Brasil
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38
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Renoprotective effects of oleanolic acid and its possible mechanisms in rats with diabetic kidney disease. Biochem Biophys Res Commun 2022; 636:1-9. [DOI: 10.1016/j.bbrc.2022.10.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 11/19/2022]
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Giannini C, Mastromauro C, Scapaticci S, Gentile C, Chiarelli F. Role of bile acids in overweight and obese children and adolescents. Front Endocrinol (Lausanne) 2022; 13:1011994. [PMID: 36531484 PMCID: PMC9747777 DOI: 10.3389/fendo.2022.1011994] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/07/2022] [Indexed: 12/05/2022] Open
Abstract
Bile acids (BAs) are amphipathic molecules synthetized in the liver. They are primarily involved in the digestion of nutrients. Apart from their role in dietary lipid absorption, BAs have progressively emerged as key regulators of systemic metabolism and inflammation. In the last decade, it became evident that BAs are particularly important for the regulation of glucose, lipid, and energy metabolism. Indeed, the interest in role of BA in metabolism homeostasis is further increased due to the global public health increase in obesity and related complications and a large number of research postulating that there is a close mutual relationship between BA and metabolic disorders. This strong relationship seems to derive from the role of BAs as signaling molecules involved in the regulation of a wide spectrum of metabolic pathways. These actions are mediated by different receptors, particularly nuclear farnesoid X receptor (FXR) and Takeda G protein coupled receptor 5 (TGR5), which are probably the major effectors of BA actions. These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in BA, lipid and carbohydrate metabolism, energy expenditure, and inflammation. The large correlation between BAs and metabolic disorders offers the possibility that modulation of BAs could be used as a therapeutic approach for the treatment of metabolic diseases, including obesity itself. The aim of this review is to describe the main physiological and metabolic actions of BA, focusing on its signaling pathways, which are important in the regulation of metabolism and might provide new BA -based treatments for metabolic diseases.
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Affiliation(s)
- Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
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40
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Tamai Y, Eguchi A, Shigefuku R, Kitamura H, Tempaku M, Sugimoto R, Kobayashi Y, Iwasa M, Takei Y, Nakagawa H. Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans. eLife 2022; 11:80638. [PMID: 36206032 PMCID: PMC9545520 DOI: 10.7554/elife.80638] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate; however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-chain amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition. Methods: The correlation between serum BA levels and psoas muscle mass index (PMI) was examined in 73 CLD patients. Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy. Results: In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist. Conclusions: Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival. Funding: This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115. Maintaining cirrhotic rats were partially supported by Otsuka Pharmaceutical Company.
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Affiliation(s)
- Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Ryuta Shigefuku
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Hiroshi Kitamura
- Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - Mina Tempaku
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Ryosuke Sugimoto
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Yoshinao Kobayashi
- Center for Physical and mental health, Mie University Graduate School of Medicine, Tsu, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, Graduate school of medicine, Mie University, Tsu, Japan
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Antidiabetic Potential and Antioxidant Activity of Olea europaea subsp. Cuspidata (Indian Olive) Seed Extracts. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5164985. [PMID: 36217432 PMCID: PMC9547684 DOI: 10.1155/2022/5164985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/24/2022] [Accepted: 09/18/2022] [Indexed: 11/07/2022]
Abstract
The aim of the present study was to evaluate the antioxidant and antidiabetic potential of Indian olive seed extracts. Plant seeds were sequentially extracted with n-hexane, chloroform, methanol, and water. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging and alpha-amylase inhibitory activities of extracts were carried out. Olea europaea methanolic extract (MEOE) and aqueous extract (AEOE) were orally administered to normoglycemic and alloxan-treated diabetic rats so as to determine their hypoglycemic effect. High-performance liquid chromatography (HPLC) analysis showed gallic acid, ferulic acid, quercetin, and vanillic acid in MEOE. It was found that the methanolic and aqueous extracts exhibited the maximum DPPH and alpha-amylase inhibition activities, respectively. MEOE and AEOE exerted a significant decline in the fasting blood sugar in diabetic animals (p < 0.05); however, they did not cause hypoglycemia in nondiabetic animals. Treatment with MEOE and AEOE reduced the aggravated liver and kidney function biomarkers. Aggravated levels of oxidative stress biomarkers including superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and malondialdehyde (MDA) were restored by treatment with MEOE. Moreover, MEOE improved the count of islets of Langerhans in the pancreas, fatty changes, and enlarged sinusoidal spaces in the liver and necrosis of the glomerulus and tubular cells of the kidney in diabetic rats. This study showed that the African olive seed extract effectively managed experimental diabetes and restored the normal functions and histology of the liver and kidney in diabetic rats through the reduction of oxidative stress.
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Stelling-Férez J, Gabaldón JA, Nicolás FJ. Oleanolic acid stimulation of cell migration involves a biphasic signaling mechanism. Sci Rep 2022; 12:15065. [PMID: 36064555 PMCID: PMC9445025 DOI: 10.1038/s41598-022-17553-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 07/27/2022] [Indexed: 11/09/2022] Open
Abstract
Cell migration is a critical process for wound healing, a physiological phenomenon needed for proper skin restoration after injury. Wound healing can be compromised under pathological conditions. Natural bioactive terpenoids have shown promising therapeutic properties in wound healing. Oleanolic acid (OA), a triterpenoid, enhances in vitro and in vivo cell migration. However, the underlying signaling mechanisms and pathways triggered by OA are poorly understood. We have previously shown that OA activates epidermal growth factor receptor (EGFR) and downstream effectors such as mitogen-activated protein (MAP) kinase cascade and c-Jun N-terminal kinase (JNK), leading to c-Jun transcription factor phosphorylation, all of which are involved in migration. We performed protein expression or migration front protein subcellular localization assays, which showed that OA induces c-Jun activation and its nuclear translocation, which precisely overlaps at wound-edge cells. Furthermore, c-Jun phosphorylation was independent of EGFR activation. Additionally, OA promoted actin cytoskeleton and focal adhesion (FA) dynamization. In fact, OA induced the recruitment of regulator proteins to FAs to dynamize these structures during migration. Moreover, OA changed paxillin distribution and activated focal adhesion kinase (FAK) at focal adhesions (FAs). The molecular implications of these observations are discussed.
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Affiliation(s)
- Javier Stelling-Férez
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos nº135, Guadalupe, 30107, Murcia, Spain.,Regeneration, Molecular Oncology and TGF-ß, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
| | - José Antonio Gabaldón
- Department of Nutrition and Food Technology, Health Sciences PhD Program, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos nº135, Guadalupe, 30107, Murcia, Spain
| | - Francisco José Nicolás
- Regeneration, Molecular Oncology and TGF-ß, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 150] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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Thirouard L, Holota H, Monrose M, Garcia M, de Haze A, Damon‐Soubeyrand C, Renaud Y, Saru J, Perino A, Schoonjans K, Beaudoin C, Volle DH. Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200626. [PMID: 35435331 PMCID: PMC9189661 DOI: 10.1002/advs.202200626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/09/2022] [Indexed: 06/14/2023]
Abstract
Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well-documented previously. This study investigates how busulfan, an alkylating agent that is often used for chemotherapeutic purposes, affects male fertility. Specifically, the role of the TGR5 pathway is investigated on spermatogonia homeostasis using in vivo, in vitro, and pharmacological methods. In vivo studies are performed using wild-type and Tgr5-deficient mouse models. The results clearly show that Tgr5 deficiency can facilitate restoration of the spermatogonia homeostasis and allow faster resurgence of germ cell lineage after exposure to busulfan. TGR5 modulates the expression of key genes of undifferentiated spermatogonia such as Gfra1 and Fgfr2. At the molecular level, the present data highlight molecular mechanisms underlying the interactions among the TGR5, GLIS2, and TP53 pathways in spermatogonia associated with germ cell apoptosis following busulfan exposure. This study makes a significant contribution to the literature because it shows that TGR5 plays key role on undifferentiated germ cell homeostasis and that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders.
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Affiliation(s)
- Laura Thirouard
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Hélène Holota
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Mélusine Monrose
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Manon Garcia
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Angélique de Haze
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | | | - Yoan Renaud
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteBio‐informatic facilityClermont‐FerrandF‐63037France
| | - Jean‐Paul Saru
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Alessia Perino
- Laboratory of Metabolic SignalingInstitute of BioengineeringSchool of Life SciencesEcole Polytechnique Fédérale de LausanneLausanneCH‐1015Switzerland
| | - Kristina Schoonjans
- Laboratory of Metabolic SignalingInstitute of BioengineeringSchool of Life SciencesEcole Polytechnique Fédérale de LausanneLausanneCH‐1015Switzerland
| | - Claude Beaudoin
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - David H. Volle
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
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Zhou JX, Li CN, Liu YM, Lin SQ, Wang Y, Xie C, Nan FJ. Discovery of 9,11-Seco-Cholesterol Derivatives as Novel FXR Antagonists. ACS OMEGA 2022; 7:17401-17405. [PMID: 35647433 PMCID: PMC9134407 DOI: 10.1021/acsomega.2c01567] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/29/2022] [Indexed: 06/15/2023]
Abstract
The farnesoid X receptor (FXR) plays an important role in the regulation of bile acid, lipid, and glucose homeostasis. Recent findings have shown that the inhibition of FXR is beneficial to improvement of related metabolic diseases and cholestasis. In the present work, 9,11-seco-cholesterol derivatives were designed and synthesized by cleaving the C ring of cholesterol and were identified as novel structures of FXR antagonists. Compound 9a displayed the best FXR antagonistic activity at the cellular level (IC50 = 4.6 μM) and decreased the expression of the target genes of FXR in vivo.
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Affiliation(s)
- Jia-Xu Zhou
- University
of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People’s Republic of China
- State
Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
| | - Cui-Na Li
- State
Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
| | - Ya-Meng Liu
- State
Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
| | - Su-Qin Lin
- School
of Chinese Materia Medica, Nanjing University
of Chinese Medicine, Nanjing 210046, People’s Republic
of China
| | - Ying Wang
- State
Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
| | - Cen Xie
- State
Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
| | - Fa-Jun Nan
- University
of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People’s Republic of China
- State
Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
- Drug
Discovery Shandong Laboratory, Bohai Rim
Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, People’s Republic of China
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Režen T, Rozman D, Kovács T, Kovács P, Sipos A, Bai P, Mikó E. The role of bile acids in carcinogenesis. Cell Mol Life Sci 2022; 79:243. [PMID: 35429253 PMCID: PMC9013344 DOI: 10.1007/s00018-022-04278-2] [Citation(s) in RCA: 132] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/03/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022]
Abstract
AbstractBile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.
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Affiliation(s)
- Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tünde Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
| | - Patrik Kovács
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Adrienn Sipos
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
| | - Péter Bai
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary
- Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary
| | - Edit Mikó
- Department of Medical Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary.
- MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary.
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Anti-parasitic activity of the Olea europaea and Ficus carica on Leishmania major: new insight into the anti-leishmanial agents. Biologia (Bratisl) 2022. [DOI: 10.1007/s11756-022-01066-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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SASAKI T, OKUDA M, HONG TW, WATANABE Y, TAKAHASHI Y, SHIMIZU M, YAMAUCHI Y, SATO R. Sesamin and Hepatic Metabolites Derived from Sesamin and Episesamin Antagonize Farnesoid X Receptor and Reduce the Expression of Gluconeogenesis-Related Genes. J Nutr Sci Vitaminol (Tokyo) 2022; 68:55-64. [DOI: 10.3177/jnsv.68.55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Takashi SASAKI
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Mako OKUDA
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Tzu-Wen HONG
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Yuichi WATANABE
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Yu TAKAHASHI
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Makoto SHIMIZU
- Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Yoshio YAMAUCHI
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Ryuichiro SATO
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
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Zhang F, Xiao X, Li Y, Wu H, Deng X, Jiang Y, Zhang W, Wang J, Ma X, Zhao Y. Therapeutic Opportunities of GPBAR1 in Cholestatic Diseases. Front Pharmacol 2022; 12:805269. [PMID: 35095513 PMCID: PMC8793736 DOI: 10.3389/fphar.2021.805269] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
GPBAR1, a transmembrane G protein-coupled receptor for bile acids, is widely expressed in multiple tissues in humans and rodents. In recent years, GPBAR1 has been thought to play an important role in bile homeostasis, metabolism and inflammation. This review specifically focuses on the function of GPBAR1 in cholestatic liver disease and summarizes the various pathways through which GPBAR1 acts in cholestatic models. GPBAR1 mainly regulates cholestasis in a holistic system of liver-gallbladder-gut formation. In the state of cholestasis, the activation of GPBAR1 could regulate liver inflammation, induce cholangiocyte regeneration to maintain the integrity of the biliary tree, control the hydrophobicity of the bile acid pool and promote the secretion of bile HCO3−. All these functions of GPBAR1 might be clear ways to protect against cholestatic diseases and liver injury. However, the characteristic of GPBAR1-mediated proliferation increases the risk of proliferation of cholangiocarcinoma in malignant transformed cholangiocytes. This dichotomous function of GPBAR1 limits its use in cholestasis. During disease treatment, simultaneous activation of GPBAR1 and FXR receptors often results in improved outcomes, and this strategy may become a crucial direction in the development of bile acid-activated receptors in the future.
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Affiliation(s)
- Fangling Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yong Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hefei Wu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yinxiao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jian Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, China
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50
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Oleanolic Acid: Extraction, Characterization and Biological Activity. Nutrients 2022; 14:nu14030623. [PMID: 35276982 PMCID: PMC8838233 DOI: 10.3390/nu14030623] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/25/2022] [Indexed: 11/28/2022] Open
Abstract
Oleanolic acid, a pentacyclic triterpenoid ubiquitously present in the plant kingdom, is receiving outstanding attention from the scientific community due to its biological activity against multiple diseases. Oleanolic acid is endowed with a wide range of biological activities with therapeutic potential by means of complex and multifactorial mechanisms. There is evidence suggesting that oleanolic acid might be effective against dyslipidemia, diabetes and metabolic syndrome, through enhancing insulin response, preserving the functionality and survival of β-cells and protecting against diabetes complications. In addition, several other functions have been proposed, including antiviral, anti-HIV, antibacterial, antifungal, anticarcinogenic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic and anti-atherosclerotic activities, as well as interfering in several stages of the development of different types of cancer; however, due to its hydrophobic nature, oleanolic acid is almost insoluble in water, which has led to a number of approaches to enhance its biopharmaceutical properties. In this scenario, the present review aimed to summarize the current knowledge and the research progress made in the last years on the extraction and characterization of oleanolic acid and its biological activities and the underlying mechanisms of action.
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