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Zheng XQ, Wang DB, Jiang YR, Song CL. Gut microbiota and microbial metabolites for osteoporosis. Gut Microbes 2025; 17:2437247. [PMID: 39690861 DOI: 10.1080/19490976.2024.2437247] [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: 07/11/2024] [Revised: 11/13/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024] Open
Abstract
Osteoporosis is an age-related bone metabolic disease. As an essential endocrine organ, the skeletal system is intricately connected with extraosseous organs. The crosstalk between bones and other organs supports this view. In recent years, the link between the gut microecology and bone metabolism has become an important research topic, both in preclinical studies and in clinical trials. Many studies have shown that skeletal changes are accompanied by changes in the composition and structure of the gut microbiota (GM). At the same time, natural or artificial interventions targeting the GM can subsequently affect bone metabolism. Moreover, microbiome-related metabolites may have important effects on bone metabolism. We aim to review the relationships among the GM, microbial metabolites, and bone metabolism and to summarize the potential mechanisms involved and the theory of the gut‒bone axis. We also describe existing bottlenecks in laboratory studies, as well as existing challenges in clinical settings, and propose possible future research directions.
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Affiliation(s)
- Xuan-Qi Zheng
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Ding-Ben Wang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Yi-Rong Jiang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Chun-Li Song
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Spinal Disease Research, Beijing, China
- Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China
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2
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Ke Z, Lu Z, Li F, Zhao Q, Jiang X, Hu Z, Sun F, He Z, Tang Y, Li Q, van Oostendorp S, Chen X, He Q, Wang Y, Zhu Z, Tong W. Gut microbiota alterations induced by Roux-en-Y gastric bypass result in glucose-lowering by enhancing intestinal glucose excretion. Gut Microbes 2025; 17:2473519. [PMID: 40028693 PMCID: PMC11881838 DOI: 10.1080/19490976.2025.2473519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/05/2025] Open
Abstract
Roux-en-Y gastric bypass (RYGB) results in glucose-lowering in patients with type 2 diabetes mellitus (T2DM) and may be associated with increased intestinal glucose excretion. However, the contribution of intestinal glucose excretion to glycemic control after RYGB and its underlying mechanisms are not fully elucidated. Here, we confirmed that intestinal glucose excretion significantly increased in obese rats after RYGB, which was negatively correlated with postoperative blood glucose levels. Moreover, we also found that the contribution of Biliopancreatic limb length, an important factor affecting glycemic control after RYGB, to the improvement of glucose metabolism after RYGB attributed to the enhancement of intestinal glucose excretion. Subsequently, we further determined through multiple animal models that intestinal glucose excretion is physiological rather than pathological and plays a crucial role in maintaining glucose homeostasis in the body. Finally, we employed germ-free mice colonized with fecal samples from patients and rats to demonstrate that enhanced intestinal glucose excretion after RYGB is directly modulated by the surgery-induced changes in the gut microbiota. These results indicated that the gut microbiota plays a direct causal role in the hypoglycemic effect of RYGB by promoting intestinal glucose excretion, which may provide new insights for developing gut microbiota-based therapies for T2DM.
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Affiliation(s)
- Zhigang Ke
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zongshi Lu
- Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China
| | - Fan Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Qingyuan Zhao
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Xianhong Jiang
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhihao Hu
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Fang Sun
- Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China
| | - Zongcheng He
- Department of Digestive Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yi Tang
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Qing Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Stefan van Oostendorp
- Department of Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Qiuyue He
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Yong Wang
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China
| | - Weidong Tong
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Li J, Qiao J, Li Y, Qin G, Xu Y, Lao K, Wang Y, Fan Y, Tang P, Han L. Metabolic disorders in polycystic ovary syndrome: from gut microbiota biodiversity to clinical intervention. Front Endocrinol (Lausanne) 2025; 16:1526468. [PMID: 40357203 PMCID: PMC12066289 DOI: 10.3389/fendo.2025.1526468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/31/2025] [Indexed: 05/15/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent gynecologic endocrine disorder characterized by menstrual irregularities, elevated androgen levels, and ovulatory dysfunction. Its etiology is multifactorial. Emerging evidence indicates that PCOS patients exhibit diminished gut microbiota (GM) diversity and altered microbial ratios, contributing to the metabolic derangements observed in these individuals. This review elucidates the role of GM in the pathogenesis and metabolic disorders of PCOS, encompassing insulin resistance (IR), hormonal imbalances, bile acid metabolic disorders, Interleukin-22-mediated immune dysregulation, and brain-gut axis disturbances. Additionally, it synthesizes current therapeutic strategies targeting the GM, aiming to furnish a theoretical framework for prospective clinical interventions.
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Affiliation(s)
- Jiyuan Li
- The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Jiashen Qiao
- The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Yihan Li
- The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Gaofeng Qin
- Department of Traditional Chinese Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yingjiang Xu
- Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Kaixue Lao
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yanlin Wang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yang Fan
- Department of Clinical Nutrition, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Peiyi Tang
- Department of Clinical Nutrition, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Lei Han
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
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Daliri EBM, Megur A, Mingaila J, Vijaya AK, Balnionytė T, Sakar D, Carnicero-Mayo Y, Behrends V, Costabile A, Burokas A. Fermented beetroot modulates gut microbial carbohydrate metabolism in prediabetes and prevents high-fat diet induced hyperglycemia in a prediabetic model. Curr Res Food Sci 2025; 10:101052. [PMID: 40290372 PMCID: PMC12022487 DOI: 10.1016/j.crfs.2025.101052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/26/2025] [Accepted: 04/11/2025] [Indexed: 04/30/2025] Open
Abstract
The global increase in prevalence of (pre-)diabetes demands immediate intervention strategies. In our earlier work, we demonstrated in vitro antidiabetic potential of a fermented beetroot product (PN39). Here, we examined the impact of PN39 on glucose tolerance and gut microbiota in C57BL/6J male mice and on prediabetic (PD) subjects' stool microbiota. In mice, high-fat diet (HFD) consumption for 9 weeks resulted in hyperglycemia and impaired glucose tolerance (GT) while concomitant consumption of PN39 and HFD (PN39+HFD) prevented GT impairment. Meanwhile, feeding the mice with HFD for 5 weeks to induce PD and later administering them with PN39 for 4 weeks (PD + PN39) neither improved fasting blood glucose nor GT. Relative to control groups, the gut microbiota of both PD mice and humans were characterized by decreased Clostridia UCG-014 and Lactobacilli as well as significantly altered gut microbial carbohydrate metabolism. Feeding PN39 together with HFD preserved Clostridia UCG-014 and Lactobacilli, increased short chain fatty acid production relative to mice fed with HFD only. Treating gut microbiota of PD subjects with PN39 however increased Clostridia UCG-014 and Lactobacilli populations and increased short chain fatty acids concentrations in the stools. In both mice and humans, PN39 treatment rectified the altered microbial carbohydrate metabolism observed in their PD counterparts. This suggests that the gut microbial modulatory effects of PN39 coupled with its capacity to regulate gut microbial glucose metabolism, likely played a role in preventing PD in mice receiving PN39+HFD. Taken together, our results indicate that PN39 could act as a potent antidiabetic functional food for preventing diabetes and its associated dysbiosis.
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Affiliation(s)
- Eric Banan-Mwine Daliri
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio Ave. 7, LT-10257, Vilnius, Lithuania
| | - Ashwinipriyadarshini Megur
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio Ave. 7, LT-10257, Vilnius, Lithuania
| | - Jonas Mingaila
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio Ave. 7, LT-10257, Vilnius, Lithuania
| | - Akshay Kumar Vijaya
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio Ave. 7, LT-10257, Vilnius, Lithuania
| | - Toma Balnionytė
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio Ave. 7, LT-10257, Vilnius, Lithuania
| | - Debalina Sakar
- School of Life and Health Sciences, University of Roehampton, London, SW15 4JD, UK
| | - Yaiza Carnicero-Mayo
- Área de Microbiología, Facultad de Ciencias Biológicas y Ambientales, Universidad de León, 24007, León, Spain
| | - Volker Behrends
- School of Life and Health Sciences, University of Roehampton, London, SW15 4JD, UK
- School of Medicine and Biosciences, University of West London, St Mary's Road, Ealing, London, W5 5RF, UK
| | - Adele Costabile
- School of Life and Health Sciences, University of Roehampton, London, SW15 4JD, UK
| | - Aurelijus Burokas
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio Ave. 7, LT-10257, Vilnius, Lithuania
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5
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Aljumaah MR, Roach J, Hu Y, Gunstad J, Azcarate-Peril MA. Microbial dipeptidyl peptidases of the S9B family as host-microbe isozymes. SCIENCE ADVANCES 2025; 11:eads5721. [PMID: 40173242 PMCID: PMC11964003 DOI: 10.1126/sciadv.ads5721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/26/2025] [Indexed: 04/04/2025]
Abstract
Human dipeptidyl peptidase 4 (hDPP-4) has been a pharmacological target for metabolic diseases, particularly diabetes, since the early 2000s. As a ubiquitous enzyme found in both prokaryotic and eukaryotic organisms, hDPP-4 plays crucial roles in host homeostasis and disease progression. While many studies have explored hDPP-4's properties, research on gut microbially derived DPP-4 (mDPP-4) remains limited. This review discusses the significance of mDPP-4 and its health implications, analyzing crystal structures of mDPP-4 in comparison to human counterparts. We examine how hDPP-4 inhibitors could influence gut microbiome composition and mDPP-4 activity. Additionally, this review connects ongoing discussions regarding DPP-4 substrate specificity and potential access routes for mDPP-4, emphasizing the urgent need for further research on mDPP-4's role in health and improve the precision of DPP-4 inhibitor therapies.
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Affiliation(s)
- Mashael R. Aljumaah
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
- Department of Plant and Microbial Biology, North Carolina State University, Raleigh, NC, USA
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Jeffery Roach
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
| | - Yunan Hu
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
| | - John Gunstad
- Department of Psychological Sciences, Kent State University, Kent, OH, USA
| | - M. Andrea Azcarate-Peril
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
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6
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Ma H, Wang K, Jiang C. Two competing guilds as barometers of host health. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-025-2854-9. [PMID: 40172760 DOI: 10.1007/s11427-025-2854-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 01/23/2025] [Indexed: 04/04/2025]
Affiliation(s)
- Haohan Ma
- Department of Physiology and Pathophysiology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Kai Wang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China.
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
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7
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Huang A, Ma J, Zhu H, Qi Y, Jin Y, Zhang M, Yin L, Luo M, Chen S, Xie C, Huang H. Blood metabolites mediate causal inference studies on the effect of gut microbiota on the risk of vascular calcification. J Adv Res 2025:S2090-1232(25)00198-5. [PMID: 40139524 DOI: 10.1016/j.jare.2025.03.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Emerging evidence indicates a notable connection between gut microbiota and Vascular Calcification (VC). Gut microbiota influences various disease processes through host metabolic pathways; however, the causative link between gut microbiota and VC, along with the potential mediating role of metabolites, is still not well understood. METHODS We leveraged data from the largest Genome-Wide Association Studies (GWAS) concerning gut microbiota, blood metabolites, and VC. To explore the causal relationships among these variables, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses. Furthermore, mediation analyses were conducted to determine if metabolites act as an intermediary in the impact of gut microbiota on VC. In addition, we recruited CKD patients for mass spectrometry and CT examination, and performed a correlation analysis between the expression of blood metabolites and VC score. Finally, we experimentally validated the effects of intermediate metabolites on VC. RESULTS We identified 19 positive gut microbiota species and 52 positive blood metabolites with causal effects on VC. Additionally, the onset of VC was found to induce changes in the abundance of 24 gut microbiota species and 56 metabolites. Further analyses revealed that up to 13 positive gut microbiota species regulate the expression of 20 positive metabolites. Mediation analysis suggests that the gut microbiota g_KLE1615 promotes VC by downregulating the methionine-to-phosphate ratio. Mass spectrometry results indicate that over half of the metabolites identified through MR analysis show altered expression during CKD progression. Among them, 7 metabolites were significantly associated with the progression of VC. Further in vitro experiments confirmed the inhibitory effect of the intermediate metabolite methionine on VC. CONCLUSION Gut microbiota and blood metabolites are causally linked to VC. These findings provide a theoretical basis for microbiome- and metabolome-based therapeutic strategies for targeting VC and enhances our comprehension of the gut-vascular axis.
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Affiliation(s)
- Aoran Huang
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Jianshuai Ma
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Huijin Zhu
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Yanli Qi
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Yang Jin
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Mingxuan Zhang
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Li Yin
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Minhong Luo
- Department of Nephrology, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China
| | - Sifan Chen
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000, China
| | - Chen Xie
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China.
| | - Hui Huang
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518033, China.
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8
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Faucher FF, Lovell S, Bertolini M, Blažková K, Cosco ED, Bogyo M, Barniol-Xicota M. Macrocyclic phage display for identification of selective protease substrates. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.13.643185. [PMID: 40161698 PMCID: PMC11952493 DOI: 10.1101/2025.03.13.643185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Traditional methods for identifying selective protease substrates have primarily relied on synthetic libraries of linear peptides, which offer limited sequence and structural diversity. Here, we present an approach that leverages phage display technology to screen large libraries of chemically modified cyclic peptides, enabling the identification of highly selective substrates for a protease of interest. Our method uses a reactive chemical linker to cyclize peptides on the phage surface, while simultaneously incorporating an affinity tag and a fluorescent reporter. The affinity tag enables capture of the phage library and subsequent release of phages expressing optimal substrates upon incubation with a protease of interest. The addition of a turn-on fluorescent reporter allows direct quantification of cleavage efficiency throughout each selection round. The resulting identified substrates can then be chemically synthesized, optimized and validated using recombinant enzymes and cells. We demonstrate the utility of this approach using Fibroblast Activation Protein alpha (FAPα) and the related proline-specific protease, dipeptidyl peptidase-4 (DPP4), as targets. Phage selection and subsequent optimization identified substrates with selectivity for each target that have the potential to serve as valuable tools for applications in basic biology and fluorescence image-guided surgery (FIGS). Overall, our strategy provides a rapid and unbiased platform for effectively discovering highly selective, non-natural protease substrates, overcoming key limitations of existing methods.
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Affiliation(s)
- Franco F. Faucher
- Department of Chemistry, Stanford University, Stanford, CA 94305, United States
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Scott Lovell
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
- Department of Life Sciences, University of Bath, Bath, BA2 7AX, United Kingdom
| | - Matilde Bertolini
- Department of Genetics, School of Medicine, Stanford University, California 94305, United States
| | - Kristýna Blažková
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Emily D. Cosco
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Matthew Bogyo
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, United States
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Marta Barniol-Xicota
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
- Department of Medicine and Life Sciences, Biomedical Research Park (PRBB), Universitat Pompeu Fabra, 08003 Barcelona
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9
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Xu J, Chen N, Li Z, Liu Y. Gut microbiome and liver diseases. FUNDAMENTAL RESEARCH 2025; 5:890-901. [PMID: 40242515 PMCID: PMC11997574 DOI: 10.1016/j.fmre.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 04/18/2025] Open
Abstract
Symbiotic microbiota plays a crucial role in the education, development, and maintenance of the host immune system, significantly contributing to overall health. Through the gut-liver axis, the gut microbiota and liver have a bidirectional relationship that is becoming increasingly evident as more research highlights the translocation of the gut microbiota and its metabolites. The focus of this narrative review is to examine and discuss the importance of the gut-liver axis and the enterohepatic barrier in maintaining overall health. Additionally, we emphasize the crucial role of the gut microbiome in liver diseases and explore potential therapeutic strategies for liver diseases by manipulating the microbiota.
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Affiliation(s)
- Jun Xu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Ning Chen
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Zhou Li
- Beijing Key Laboratory of Micro-nano Energy and Sensor, Beijing Institute of Nanoenergy and Nanosystems Chinese Academy of Sciences, Beijing 101400, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing 100044, China
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10
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Yang DD, Chutiwitoonchai N, Wang F, Tian P, Sureram S, Lei X, Mahidol C, Ruchirawat S, Kittakoop P. Effects of organic salts of virucidal and antiviral compounds from Nelumbo nucifera and Kaempferia parviflora against SARS-CoV-2. Sci Rep 2025; 15:6380. [PMID: 39984611 PMCID: PMC11845762 DOI: 10.1038/s41598-025-89736-0] [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: 12/11/2024] [Accepted: 02/07/2025] [Indexed: 02/23/2025] Open
Abstract
The present work investigates virucidal and antiviral compounds in the extracts of seed embryos of a lotus, Nelumbo nucifera, and a Thai ginseng, Kaempferia parviflora. Separation of the extracts led to the identification of antiviral compounds against SARS-CoV-2. Neferine (1) and nuciferine (3) from N. nucifera, as well as their respective HCl salts (2 and 4), exhibited virucidal and antiviral activities against SARS-CoV-2. Virucidal activity of neferine salt (2) (EC50 4.78 µM) was 7.5 times better than its free-base, neferine (1) (EC50 36.01 µM), and the salt (2) also improved the selectivity index (SI), showing less cytotoxicity than 1. This work demonstrates that organic salts have an impact on biological activities. A crude extract of K. parviflora rhizomes displayed virucidal activity (EC50 42.11 µg/mL) and antiviral activity (EC50 39.28 µg/mL). Isolation of a crude extract of K. parviflora rhizomes led to the identification of nine flavonoids (5-13). Among these flavonoids, only 5,7,4'-trimethoxyflavone (8) was found to show virucidal (EC50 437.90 µM) and antiviral (EC50 50.97 µM) activities against SARS-CoV-2. However, flavonoids (5-13) did not inhibit SARS-CoV-2 3CLpro enzyme at the concentrations of 10 µM and 100 µM. In conclusion, our data underscores the therapeutic potential of N. nucifera and K. parviflora derived bioactive compounds against SARS-CoV-2.
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Affiliation(s)
- Dan-Dan Yang
- Chulabhorn Graduate Institute, Program in Chemical Sciences, Laksi, Bangkok, 10210, Thailand
| | - Nopporn Chutiwitoonchai
- Virology and Cell Technology Research Team, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Phahonyothin Rd, Pathumthani, 12120, Thailand.
| | - Feng Wang
- The Research Center of Chiral Drugs, China-Thailand Joint Research Institute of Natural Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, 201203, Shanghai, China
| | - Ping Tian
- The Research Center of Chiral Drugs, China-Thailand Joint Research Institute of Natural Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, 201203, Shanghai, China
| | - Sanya Sureram
- Chulabhorn Research Institute, Kamphaeng Phet 6, Talat Bang Khen, Lak Si, 10210, Bangkok, Thailand
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China
| | - Chulabhorn Mahidol
- Chulabhorn Research Institute, Kamphaeng Phet 6, Talat Bang Khen, Lak Si, 10210, Bangkok, Thailand
| | - Somsak Ruchirawat
- Chulabhorn Graduate Institute, Program in Chemical Sciences, Laksi, Bangkok, 10210, Thailand
- Chulabhorn Research Institute, Kamphaeng Phet 6, Talat Bang Khen, Lak Si, 10210, Bangkok, Thailand
- Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Science, Research and Innovation, Ministry of Higher Education, 10400, Bangkok, Thailand
| | - Prasat Kittakoop
- Chulabhorn Graduate Institute, Program in Chemical Sciences, Laksi, Bangkok, 10210, Thailand.
- Chulabhorn Research Institute, Kamphaeng Phet 6, Talat Bang Khen, Lak Si, 10210, Bangkok, Thailand.
- Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Science, Research and Innovation, Ministry of Higher Education, 10400, Bangkok, Thailand.
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11
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Dhieb D, Mustafa D, Hassiba M, Alasmar M, Elsayed MH, Musa A, Zirie M, Bastaki K. Harnessing Pharmacomultiomics for Precision Medicine in Diabetes: A Comprehensive Review. Biomedicines 2025; 13:447. [PMID: 40002860 PMCID: PMC11853021 DOI: 10.3390/biomedicines13020447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/08/2024] [Accepted: 12/11/2024] [Indexed: 02/27/2025] Open
Abstract
Type 2 diabetes (T2D) is the fastest-growing non-communicable disease worldwide, accounting for around 90% of all diabetes cases and imposing a significant health burden globally. Due to its phenotypic heterogeneity and composite genetic underpinnings, T2D requires a precision medicine approach personalized to individual molecular profiles, thereby shifting away from the traditional "one-size-fits-all" medical methods. This review advocates for a thorough pharmacomultiomics approach to enhance precision medicine for T2D. It emphasizes personalized treatment strategies that enhance treatment efficacy while minimizing adverse effects by integrating data from genomics, proteomics, metabolomics, transcriptomics, microbiomics, and epigenomics. We summarize key findings on candidate genes impacting diabetic medication responses and explore the potential of pharmacometabolomics in predicting drug efficacy. The role of pharmacoproteomics in prognosis and discovering new therapeutic targets is discussed, along with transcriptomics' contribution to understanding T2D pathophysiology. Additionally, pharmacomicrobiomics is explored to understand gut microbiota interactions with antidiabetic drugs. Emerging evidence on utilizing epigenomic profiles in improving drug efficacy and personalized treatment is also reviewed, illustrating their implications in personalized medicine. In this paper, we discuss the integration of these layers of omics data, examining recently developed paradigms that leverage complex data to deepen our understanding of diabetes. Such integrative approaches advance precision medicine strategies to tackle the disease by better understanding its complex biology.
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Affiliation(s)
- Dhoha Dhieb
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - Dana Mustafa
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - Maryam Hassiba
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - May Alasmar
- Hamad Medical Corporation, Doha P.O. Box 3050, Qatar; (M.A.); (M.Z.)
| | - Mohamed Haitham Elsayed
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - Ameer Musa
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Mahmoud Zirie
- Hamad Medical Corporation, Doha P.O. Box 3050, Qatar; (M.A.); (M.Z.)
| | - Kholoud Bastaki
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
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12
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Zhang Y, Xu D, Cai X, Xing X, Shao X, Yin A, Zhao Y, Wang M, Fan Y, Liu B, Yang H, Zhou W, Li P. Gut Commensal Barnesiella Intestinihominis Ameliorates Hyperglycemia and Liver Metabolic Disorders. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2411181. [PMID: 39741391 PMCID: PMC11848638 DOI: 10.1002/advs.202411181] [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: 09/12/2024] [Revised: 12/19/2024] [Indexed: 01/03/2025]
Abstract
Recent studies have highlighted the role of the gut microbiota in type 2 diabetes (T2D). Improving gut microbiota dysbiosis can be a potential strategy for the prevention and management of T2D. Here, this work finds that the abundance of Barnesiella intestinihominis is significantly decreased in the fecal of T2D patients from 2-independent centers. Oral treatment of live B. intestinihominis (LBI) considerably ameliorates hyperglycemia and liver metabolic disorders in HFD/STZ-induced T2D models and db/db mice. LBI-derived acetate has similar protective effects against T2D. Mechanistically, acetate enhances fibroblast growth factor 21 (FGF21) through inhibition of histone deacetylase 9 (HDAC9) to increase H3K27 acetylation at the FGF21 promoter. The screening puerarin from Gegen Qinlian decoction in a gut microbiota-dependent manner improved hyperglycemia and liver metabolic disorders by promoting the growth of B. intestinihominis. This study suggests that gut commensal B. intestinihominis and puerarin, respectively have the potential as a probiotic and prebiotic in the treatment of T2D.
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Affiliation(s)
- Ye Zhang
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Dong Xu
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Xuyi Cai
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Xue Xing
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Xin Shao
- Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineNanjing210022China
| | - Ailing Yin
- Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese MedicineNanjing210022China
| | - Yanyan Zhao
- Department of EndocrinologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China
| | - Mengyuan Wang
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Yu‐nuo Fan
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Boao Liu
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Hua Yang
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Wei Zhou
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
| | - Ping Li
- State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing211198China
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13
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He X, Dou L, Wang J, Xia L, Miao J, Yan Y. Nobiletin regulates the proliferation and migration of ovarian cancer A2780 cells via DPP4 and TXNIP. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1483-1495. [PMID: 39102034 DOI: 10.1007/s00210-024-03334-x] [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: 04/28/2024] [Accepted: 07/24/2024] [Indexed: 08/06/2024]
Abstract
Nobiletin is an active compound extracted from citrus fruits. Research has indicated that nobiletin has a potential inhibitory effect on ovarian cancer (OV). However, the mechanism of action remains unclear. The OV A2780 cells were treated using nobiletin, cell viability was examined using a cell counting kit-8 experiment, and cell migration was examined with a wound healing experiment. Nobiletin targets were retrieved from target databases. Differentially expressed genes (DEG) and weighted gene co-expression network analysis (WGCNA) were conducted on GSE26712 (OV). The intersection of the critical genes for nobiletin's action on OV and gene enrichment and immune infiltration analyses were performed. The Cancer Genome Atlas-OV data and molecular docking helped validate the findings. After adding nobiletin, cell viability and migration significantly decreased (P < 0.01). A total of 88 nobiletin targets and 1288 DEG were identified. The intersection genes were enriched inflammatory response and response to hypoxia. The most related module obtained from WGCNA contained 414 genes (correlation coefficient = 0.77, P < 0.01). DPP4 and TXNIP were recognized as the hub genes. The abundance of macrophages M2 and mast cells activated significantly enhanced with increased DPP4 expression (P < 0.05). The binding energy between DPP4/TXNIP and nobiletin was - 7.012/ - 7.184 kcal/mol, forming 5/2 hydrogen bonds. Nobiletin effectively suppresses the viability and migration of OV A2780 cells. In this process, DPP4 and TXNIP are the key target, immune regulation, and oxidative stress playing significant roles.
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Affiliation(s)
- Xiuzhen He
- Department of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing, 404120, China
- Key Laboratory, Chongqing Three Gorges Medical College, Chongqing, 404120, China
| | - Lu Dou
- Department of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing, 404120, China
- Key Laboratory, Chongqing Three Gorges Medical College, Chongqing, 404120, China
| | - Jie Wang
- Department of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing, 404120, China
- Key Laboratory, Chongqing Three Gorges Medical College, Chongqing, 404120, China
| | - Lili Xia
- The Third Surgery, Chongqing City Wanzhou District Shanghai Hospital, Chongqing, 404120, China
| | - Jiawei Miao
- Department of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing, 404120, China
- Key Laboratory, Chongqing Three Gorges Medical College, Chongqing, 404120, China
| | - Yongbo Yan
- Pharmacy Department, The People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing Three Gorges Medical College, No. 27, Guoben Road, Wanzhou District, Chongqing, 404197, China.
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14
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Chen Z, Zhou J, Zheng X, Xie H, Hao H. Metabolic insights into gut microbiota in the pharmacology of natural medicines. Chin J Nat Med 2025; 23:158-168. [PMID: 39986692 DOI: 10.1016/s1875-5364(25)60820-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/12/2024] [Accepted: 10/24/2024] [Indexed: 02/24/2025]
Abstract
Natural medicines (NMs) demonstrate distinct advantages in the clinical management of chronic diseases. Recent years have seen growing recognition of the gut microbiota's role in the efficacy and synergy of NMs, providing new impetus for elucidating the material basis and mechanisms of NMs and their path toward modernization. A fundamental question that has emerged is how NM-microbiota interactions integrate into the multi-target holistic mechanisms of NMs, the answer to which may also illuminate new avenues for drug discovery. Metabolic regulation via small-molecule metabolites has been increasingly implicated in host-microbe interaction. This review presents an integral metabolic perspective on NMs-microbiota interaction in host health and disease. It highlights the emerging understanding of gut microbiota-related metabolic signals implicated in NM components' local and systemic actions. Additionally, it discusses key issues and prospects related to drug development and the translational study of NMs.
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Affiliation(s)
- Zixin Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Junchi Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiao Zheng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Xie
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Laboratory of Metabolic Regulation and Drug Target Discovery, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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15
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Wang ZY, Ren YM, Hu SW, Zhang NX, Dong MX, Li Y, Yang Y, Guo ZJ, Xu SS, Chen J, Goh AH, Chen XY. 19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans. Acta Pharmacol Sin 2025; 46:489-499. [PMID: 39349765 PMCID: PMC11747505 DOI: 10.1038/s41401-024-01393-7] [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: 05/26/2024] [Accepted: 09/05/2024] [Indexed: 01/30/2025]
Abstract
Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using 19F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma. Of the administered dose, 55.4% (54.3% of M0) was recovered in urine, while 36.7% (4.57% of M0) was excreted in feces. UPLC/Q-TOF MS was used to identify metabolites in human plasma, urine and feces. Notably, oxidative metabolites catalyzed by CYP3A were scarcely detected in these matrixes. The amide hydrolyzed metabolite M9 and the cyano hydrolyzed metabolite M10 were recognized as the predominant metabolites, with the main excretion being through feces (19.0% and 12.7% of the administered dose, respectively). In vitro experiments indicated that M10 is primarily formed in the duodenum and jejunum, with further metabolism to M9 by microbiota in the large intestine. Overall, the co-administration of simnotrelvir with ritonavir led to predominant metabolism by intestinal enzymes or microbiota, resulting in hydrolyzed metabolites. These findings highlight the critical role of intestinal metabolism in the pharmacokinetics of simnotrelvir and emphasize the need to consider interactions with antibiotics and individual differences of intestinal microbiota.
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Affiliation(s)
- Ze-Yu Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yong-Mei Ren
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Shu-Wei Hu
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Nai-Xia Zhang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Meng-Xiao Dong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yun Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yang Yang
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
- Simcere Zaiming Pharmaceutical Co. Ltd., Nanjing, 210042, China
| | - Zi-Jia Guo
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
- Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210042, China
| | - Shan-Sen Xu
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
- Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210042, China
| | - Jia Chen
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
- Simcere Zaiming Pharmaceutical Co. Ltd., Nanjing, 210042, China
| | - Aik Han Goh
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
- Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210042, China
| | - Xiao-Yan Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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16
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Zhang M, He S, Han C, Wu Y, Cui J, Feng L, Huo X, Li D, Chen Q, Ma X, Wang C. High-Throughput Screening of DPPIV Inhibitors Antagonizing GLP-1 Degradation Using an Enzymatic Activated Fluorescent Probe. Anal Chem 2025; 97:262-270. [PMID: 39733350 DOI: 10.1021/acs.analchem.4c04093] [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: 12/31/2024]
Abstract
Dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) is an exopeptidase widely expressed on various cell surfaces that selectively cleaves N-terminal dipeptides from diverse substrates. In recent years, DPPIV inhibitors have been extensively utilized in the treatment of hepatitis mellitus (DM). In this study, we designed a far-red fluorescent probe, DBX-AP, through molecular docking simulations and by leveraging the functional characteristics of DPPIV. This probe enables rapid, highly selective, and real-time monitoring of DPPIV activity both in vitro and in vivo. Using DBX-AP, we developed a visual high-throughput screening technique for the detection of DPPIV inhibitors. From a library of 4828 compounds, three inhibitors (K784-2660, 6484-0066, and E699-0153) were identified for their strong inhibitory effects on DPPIV. These inhibitors not only suppressed DPPIV activity in the ileum of mice, thereby reducing GLP-1 degradation, but also effectively inhibited DPPIV activity in gut microbiota. The successful application of DBX-AP in visual detection technology highlights its potential for evaluating DPPIV activity and identifying novel DPPIV inhibitors for diabetes mellitus treatment.
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Affiliation(s)
- Ming Zhang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
- Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Shengui He
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Chaoyan Han
- First Affiliated Hospital, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Yuzhuo Wu
- Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Jingnan Cui
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Lei Feng
- Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
| | - Xiaokui Huo
- Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Dawei Li
- First Affiliated Hospital, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Qinhua Chen
- Bao'an Authentic TCM Therapy Hospital, Shenzhen 518102, China
| | - Xiaochi Ma
- Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China
- Bao'an Authentic TCM Therapy Hospital, Shenzhen 518102, China
| | - Chao Wang
- First Affiliated Hospital, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian 116044, China
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17
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Wang J, Zhao J, Yu Z, Wang S, Guo F, Yang J, Gao L, Lei X. Concise and Modular Chemoenzymatic Total Synthesis of Bisbenzylisoquinoline Alkaloids. Angew Chem Int Ed Engl 2025; 64:e202414340. [PMID: 39305151 DOI: 10.1002/anie.202414340] [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: 07/29/2024] [Indexed: 11/03/2024]
Abstract
The bisbenzylisoquinoline alkaloids (bisBIAs) have attracted tremendous attention from the synthetic community due to their diverse and intriguing biological activities. Herein, we report the convergent and modular chemoenzymatic syntheses of eight bisBIAs bearing various substitutes and linkages in 5-7 steps. The gram-scale synthesis of various well-designed enantiopure benzylisoquinoline monomers was accomplished through an enzymatic stereoselective Pictet-Spengler reaction, followed by regioselective enzymatic methylation or chemical functionalization in a sequential one-pot process. A modified intermolecular copper-mediated Ullmann coupling enabled the concise and efficient total synthesis of five different linear bisBIAs with either head-to-tail or tail-to-tail linkage. A biomimetic oxidative phenol dimerization selectively formed the sterically hindered, electron-rich diaryl ether bond, and subsequent intramolecular Suzuki-Miyaura domino reaction or Ullmann coupling facilitated the first enantioselective total synthesis of three macrocyclic bisBIAs, including ent-isogranjine, tetrandrine and O-methylrepandine. This study highlights the great potential of chemoenzymatic strategies in the total synthesis of diverse bisBIAs and paves the way to further explore the biological functions of these natural products.
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Affiliation(s)
- Jin Wang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, People's Republic of China
| | - Jianxiong Zhao
- Peking-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, People's Republic of China
| | - Zhenyang Yu
- Department of Chemistry, National University of Singapore, Singapore, Republic of, Singapore
| | - Siyuan Wang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, People's Republic of China
| | - Fusheng Guo
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, People's Republic of China
| | - Jun Yang
- Peking-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, People's Republic of China
| | - Lei Gao
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, People's Republic of China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, People's Republic of China
- Peking-Tsinghua Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, People's Republic of China
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18
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Cai R, Liu J, Wang X, An T, Zhang L. Identification of daurisoline metabolites in rats via the UHPLC-Q-exactive orbitrap mass spectrometer. J Pharm Biomed Anal 2025; 252:116482. [PMID: 39321490 DOI: 10.1016/j.jpba.2024.116482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/26/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
Daurisoline, a bisbenzylisoquinoline alkaloid extracted from the rhizomes of Menispermum dauricum, exhibits diverse biological activities, encompassing antiplatelet, anti-inflammatory, neuroprotective, and antitumor properties. However, previous investigations have not comprehensively elucidated the metabolic profile and pathways of daurisoline in vivo. Using Ultra-High-Performance Liquid Chromatography with Q-Exactive Orbitrap Mass Spectrometry technology, we comprehensively investigated the metabolites of daurisoline in Sprague-Dawley rats, following intragastric administration. Data collection and analysis were enhanced through Full Scan MS/dd-MS2, in conjunction with parallel reaction monitoring, extracted ion chromatography, and diagnostic fragment ions. Sixty-three metabolites were detected and characterized, including sixty-two novel metabolites and coclaurine. This investigation elucidated the cleavage patterns and tissue distribution characteristics of the metabolism of daurisoline. Furthermore, in vivo reactions, including dehydrogenation, hydroxylation, methylation, sulfation and glucuronidation, were thoroughly examined. Investigating the metabolites of daurisoline in rats has deepened our understanding of its metabolism in vivo, aiding in elucidating its metabolic and pharmacological actions. This provides a valuable foundation for further research into its therapeutic efficacy.
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Affiliation(s)
- Ruijun Cai
- Department of Pharmacy, Shanghai General Hospital Jiuquan Hospital (The People's Hospital of Jiuquan), Jiuquan, GanSu 735000, China
| | - Jing Liu
- Department of Pharmacy, Shanghai General Hospital Jiuquan Hospital (The People's Hospital of Jiuquan), Jiuquan, GanSu 735000, China
| | - Xuefang Wang
- Department of Pharmacy, Shanghai General Hospital Jiuquan Hospital (The People's Hospital of Jiuquan), Jiuquan, GanSu 735000, China
| | - Tao An
- Department of Pharmacy, Shanghai General Hospital Jiuquan Hospital (The People's Hospital of Jiuquan), Jiuquan, GanSu 735000, China
| | - Ling Zhang
- Department of Pharmacy, Shanghai General Hospital Jiuquan Hospital (The People's Hospital of Jiuquan), Jiuquan, GanSu 735000, China.
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19
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Fu Y, Gou W, Zhong H, Tian Y, Zhao H, Liang X, Shuai M, Zhuo LB, Jiang Z, Tang J, Ordovas JM, Chen YM, Zheng JS. Diet-gut microbiome interaction and its impact on host blood glucose homeostasis: a series of nutritional n-of-1 trials. EBioMedicine 2025; 111:105483. [PMID: 39647263 PMCID: PMC11667054 DOI: 10.1016/j.ebiom.2024.105483] [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: 07/05/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 12/10/2024] Open
Abstract
BACKGROUND The interplay between diet and gut microbiome substantially influences host metabolism, but uncertainties remain regarding their relationships tailored for each subject given the huge inter-individual variability. Here we aim to investigate diet-gut microbiome interaction at single-subject resolution and explore its effects on blood glucose homeostasis. METHODS We conducted a series of nutritional n-of-1 trials (NCT04125602), in which 30 participants were assigned high-carbohydrate (HC) and low-carbohydrate (LC) diets in a randomized sequence across 3 pair of cross-over periods lasting 72 days. We used shotgun metagenomic sequencing and continuous glucose monitoring systems to profile the gut microbiome and blood glucose, respectively. An independent cohort of 1219 participants with available metagenomics data are included as a validation cohort. FINDINGS We demonstrated that the gut microbiome exhibited both intra-individually dynamic and inter-individually personalized signatures during the interventions. At the single-subject resolution, we observed person-specific response patterns of gut microbiota to interventional diets. Furthermore, we discovered a personal gut microbial signature represented by a carb-sensitivity score, which was closely correlated with glycemic phenotypes during the HC intervention, but not LC intervention. We validate the role of this score in the validation cohort and find that it reflects host glycemic sensitivity to the personal gut microbiota profile when sensing the dietary carbohydrate inputs. INTERPRETATION Our finding suggests that the HC diet modulates gut microbiota in a person-specific manner and facilitates the connection between gut microbiota and glycemic sensitivity. This study represents a new paradigm for investigating the diet-microbiome interaction in the context of precision nutrition. FUNDING This work was supported by the National Key R&D Program of China, National Natural Science Foundation of China and Zhejiang Provincial Natural Science Foundation of China.
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Affiliation(s)
- Yuanqing Fu
- Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China; Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China
| | - Wanglong Gou
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China
| | - Haili Zhong
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Yunyi Tian
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China
| | - Hui Zhao
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China
| | - Xinxiu Liang
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China
| | - Menglei Shuai
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China
| | - Lai-Bao Zhuo
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Zengliang Jiang
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China; Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
| | - Jun Tang
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China; Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
| | - Jose M Ordovas
- Nutrition and Genomics Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; Nutritional Genomics and Epigenomics Group, Precision Nutrition and Obesity Program, IMDEA Food, CEI UAM + CSIC, Madrid, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Institute of Health Carlos III, Madrid, Spain
| | - Yu-Ming Chen
- Department of Epidemiology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, China.
| | - Ju-Sheng Zheng
- Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China; Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, School of Medicine and School of Life Sciences, Westlake University, Hangzhou, China; Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.
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20
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Jia M, Fan Y, Ma Q, Yang D, Wang Y, He X, Zhao B, Zhan X, Qi Z, Ren Y, Dong Z, Zhu F, Wang W, Gao Y, Ma X. Gut microbiota dysbiosis promotes cognitive impairment via bile acid metabolism in major depressive disorder. Transl Psychiatry 2024; 14:503. [PMID: 39719433 DOI: 10.1038/s41398-024-03211-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 12/05/2024] [Accepted: 12/16/2024] [Indexed: 12/26/2024] Open
Abstract
Evidence suggests that complex interactions among the gut microbiome, metabolic abnormalities, and brain have important etiological and therapeutic implications in major depressive disorder (MDD). However, the influence of microbiome-gut-brain cross-talk on cognitive impairment in MDD remains poorly characterized. We performed serum metabolomic profiling on 104 patients with MDD and 77 healthy controls (HCs), and also performed fecal metagenomic sequencing on a subset of these individuals, including 79 MDD patients and 60 HCs. The findings were validated in a separate cohort that included 40 patients with MDD and 40 HCs using serum-targeted metabolomics. Abnormal bile acid metabolism was observed in patients with MDD, which is related to cognitive dysfunction. The following gut microbiota corresponded to changes in bile acid metabolism and enzyme activities involved in the bile acid metabolic pathway, including Lachnospiraceae (Blautia_massiliensis, Anaerostipes_hadrus, Dorea_formicigenerans, and Fusicatenibacter_saccharivorans), Ruminococcaceae (Ruminococcus_bromii, Flavonifractor_plautii, and Ruthenibacterium_lactatiformans), and Escherichia_coli. Furthermore, a combinatorial marker classifier that robustly differentiated patients with MDD from HCs was identified. In conclusion, this study provides insights into the gut-brain interactions in the cognitive phenotype of MDD, indicating a potential therapeutic strategy for MDD-associated cognitive impairment by targeting the gut microbiota and bile acid metabolism.
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Affiliation(s)
- Min Jia
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yajuan Fan
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qingyan Ma
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ding Yang
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yunpeng Wang
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoyan He
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Binbin Zhao
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xianyan Zhan
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhiyang Qi
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yifan Ren
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ziqing Dong
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Feng Zhu
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wei Wang
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Gao
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Xiancang Ma
- Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Shaanxi Belt and Road Joint Laboratory of Precision Medicine in Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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21
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Bredefeld CL, Choi P, Cullen T, Nicolich-Henkin SJ, Waters L. Statin Use and Hyperglycemia: Do Statins Cause Diabetes? Curr Atheroscler Rep 2024; 27:18. [PMID: 39699704 DOI: 10.1007/s11883-024-01266-8] [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] [Accepted: 12/06/2024] [Indexed: 12/20/2024]
Abstract
PURPOSE OF REVIEW Atherosclerotic cardiovascular disease (ASCVD) and diabetes are leading causes of morbidity and mortality in the United States and globally. Statin medications, a cornerstone of ASCVD prevention and treatment strategies, have been demonstrated to cause hyperglycemia and new onset diabetes mellitus (NODM). The purpose of this review is to summarize existing and emerging knowledge around the intersection of statins and these two important clinical problems. RECENT FINDINGS Since initial reporting of statin-induced hyperglycemia and NODM, the totality of available data corroborates an association between incident diabetes and statin use. A consensus that high-intensity statin and individuals with obesity or glycemic parameters approximating diabetes thresholds constitute the majority of risk exists. Alterations in insulin signaling, glucose transport and gastrointestinal microbiota are leading hypotheses underlying the mechanisms of statin-induced hyperglycemia. The probability of NODM based on an individual's risk factors and statin specific properties can be anticipated. This risk needs to be contextualized with the risk of ASCVD. In order to effectively adjudicate the risk of NODM, improvement in formulating and ultimately conveying a comprehensive ASCVD risk assessment to patients is necessary.
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Affiliation(s)
- Cindy L Bredefeld
- Department of Medicine, New York University Grossman Long Island School of Medicine, NYU Langone Hospital-Long Island, Garden City, NY, 11530, USA.
- Department of Foundations of Medicine, New York University Grossman Long Island School of Medicine, NYU Langone Hospital-Long Island, Mineola, NY, 11501, USA.
| | - Paula Choi
- Department of Medicine, New York University Grossman Long Island School of Medicine, NYU Langone Hospital-Long Island, Garden City, NY, 11530, USA
| | - Tiffany Cullen
- Department of Medicine, New York University Grossman Long Island School of Medicine, NYU Langone Hospital-Long Island, Garden City, NY, 11530, USA
| | - Sophie J Nicolich-Henkin
- Department of Medicine, New York University Grossman Long Island School of Medicine, NYU Langone Hospital-Long Island, Garden City, NY, 11530, USA
| | - Lauren Waters
- Department of Medicine, New York University Grossman Long Island School of Medicine, NYU Langone Hospital-Long Island, Garden City, NY, 11530, USA
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22
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Chen WB, Hu GA, Dong BC, Sun HY, Lu DZ, Ru MY, Yu YL, Wang H, Wei B. Insights into the modulatory effects of host-gut microbial xanthine co-metabolism on high-fat diet-fed mice. Biochem Pharmacol 2024; 230:116596. [PMID: 39481656 DOI: 10.1016/j.bcp.2024.116596] [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: 03/07/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 11/02/2024]
Abstract
Gut microbiota-mediated endobiotic and xenobiotic metabolism play crucial roles in disease progression, and drug therapy/toxicity. Our recent study suggested that gut microbiota-mediated xanthine metabolism is correlated with resistance to high-fat diet (HFD)-induced obesity. Here, we explored the role of host-gut microbial xanthine co-metabolism in the prevention and treatment of HFD-induced obesity by orally administration of Bifidobacterium longum, xanthine, and a xanthine oxidase inhibitor (topiroxostat). The findings indicate that xanthine exhibits a significantly protective effect against HFD-induced obesity. While B. longum, xanthine, and topiroxostat did not alleviate the dysbiosis of the weight and glucose metabolism of HFD-induced obesity (DIO) and obesity resistance (DIR) mice. 16S rRNA sequencing analyses revealed that treatments with B. longum significantly altered gut microbiota composition in HFD-fed and DIO mice. Microbial interaction network analysis revealed several Bacteroidetes species, such as Amulumruptor caecigallinarius and Muribaculum intestinale, as keystone taxa that were notably enriched by B. longum. Untargeted metabolomics analysis implied that xanthine might serve as a crucial molecule in regulating body weight, exerting a preventive effect on HFD-induced obesity. This study offers new perspectives on the influence of host-gut microbial xanthine co-metabolism on HFD-fed mice and emphasizes the promising role of xanthine in promoting weight loss.
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Affiliation(s)
- Wei-Bing Chen
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Gang-Ao Hu
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Bing-Cheng Dong
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Huai-Ying Sun
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Dong-Ze Lu
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Meng-Ying Ru
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Yan-Lei Yu
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China
| | - Hong Wang
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China; Binjiang Institute of Artificial Intelligence, ZJUT, Hangzhou 310056, China.
| | - Bin Wei
- College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou 310014, China; Binjiang Institute of Artificial Intelligence, ZJUT, Hangzhou 310056, China.
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23
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Gomes SF, Valois A, Estevinho MM, Santiago M, Magro F. Association of Gut Microbiome and Dipeptidyl Peptidase 4 in Immune-Mediated Inflammatory Bowel Disease: A Rapid Literature Review. Int J Mol Sci 2024; 25:12852. [PMID: 39684563 PMCID: PMC11641704 DOI: 10.3390/ijms252312852] [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: 10/12/2024] [Revised: 11/23/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Immune-mediated inflammatory diseases (IMIDs) are characterized by dysregulated immune responses and chronic tissue inflammation. In the setting of inflammatory bowel disease (IBD), dipeptidyl peptidase 4 (DPP4) and gut microorganisms have been proved to interplay, potentially influenced by dietary factors. This rapid review aimed to study the DPP4-gut microbiome link in IBD. A search across five databases and two gray literature sources identified seven relevant studies reporting data on DPP4 and gut microbiome in patients with IBD-related IMIDs or in vitro or in vivo models: one cross-sectional, one in vitro, and five in vivo studies. The findings revealed a significant impact of DPP4 and its substrates, i.e., glucagon-like peptide-1/2 (GLP-1/2), on the composition of gut microbiome and on the development of dysbiosis. Increased DPP4 activity is associated with decreased GLP-1/2; increased pathogenic bacterial phyla such as Actinobacteria, Bacteroidetes, Deferribacteres, Firmicutes, Fusobacteriota, Proteobacteria, and Verrucomicrobia; and decreased alpha diversity of beneficial gut microbes, including Clostridiaceae, Lachnospiraceae, and Ruminococcaceae families and short-chain fatty acid-producing bacteria like Odoribacter and Butryvibrio spp., with exacerbation of intestinal inflammation. This overview revealed that understanding the DPP4-gut microbiome association is critical for the development of DPP4-targeted therapeutic strategies to guarantee gut microbiome balance and modulation of immune response in IBD.
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Affiliation(s)
- Sandra F. Gomes
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal; (S.F.G.); (M.M.E.)
- Unit of Medical Education, Department of Public Health and Forensic Sciences and Medical Education, Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, 4200-450 Porto, Portugal
- RISE-Health, Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal
| | - André Valois
- Unit of Clinical Pharmacology, São João University Hospital Center, 4200-319 Porto, Portugal;
| | - Maria Manuela Estevinho
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal; (S.F.G.); (M.M.E.)
- Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, 4200-450 Porto, Portugal
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, 4434-502 Vila Nova de Gaia, Portugal
| | - Mafalda Santiago
- Portuguese Study Group of Inflammatory Bowel Disease (GEDII), 4200-450 Porto, Portugal;
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal; (S.F.G.); (M.M.E.)
- RISE-Health, Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal
- Unit of Clinical Pharmacology, São João University Hospital Center, 4200-319 Porto, Portugal;
- Portuguese Study Group of Inflammatory Bowel Disease (GEDII), 4200-450 Porto, Portugal;
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto (FMUP), 4200-450 Porto, Portugal
- Department of Gastroenterology, São João University Hospital Center, 4200-319 Porto, Portugal
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24
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Yang X, Hang HC. Chemical genetic approaches to dissect microbiota mechanisms in health and disease. Science 2024; 386:eado8548. [PMID: 39541443 DOI: 10.1126/science.ado8548] [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: 05/08/2024] [Accepted: 10/04/2024] [Indexed: 11/16/2024]
Abstract
Advances in genomics, proteomics, and metabolomics have revealed associations between specific microbiota species in health and disease. However, the precise mechanism(s) of action for many microbiota species and molecules have not been fully elucidated, limiting the development of microbiota-based diagnostics and therapeutics. In this Review, we highlight innovative chemical and genetic approaches that are enabling the dissection of microbiota mechanisms and providing causation in health and disease. Although specific microbiota molecules and mechanisms have begun to emerge, new approaches are still needed to go beyond phenotypic associations and translate microbiota discoveries into actionable targets and therapeutic leads to prevent and treat diseases.
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Affiliation(s)
- Xinglin Yang
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA
| | - Howard C Hang
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA
- Department of Chemistry, Scripps Research Institute, La Jolla, CA, USA
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25
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Wang A, Guan B, Yu L, Liu Q, Hou Y, Li Z, Sun D, Xu H. Palmatine protects against atherosclerosis by gut microbiota and phenylalanine metabolism. Pharmacol Res 2024; 209:107413. [PMID: 39293583 DOI: 10.1016/j.phrs.2024.107413] [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: 05/01/2024] [Revised: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 09/20/2024]
Abstract
Accumulating evidence illuminated that gut microbiota directly modulates the development of atherosclerosis (AS) through interactions with metaflammation. The natural bioactive isoquinoline alkaloid palmatine (PAL), which is extracted from one of the herbs (Coptis chinensis) of the anti-AS formular, is of particular interest due to its pharmacological properties. ApoE-/- mice were administered PAL or vehicle; plaque areas, and stability were assessed by histopathological and immunohistochemistry analysis, serum glycolysis and lipid levels, and inflammation levels were also evaluated. 16S rRNA sequencing and metabolomics analysis were employed to evaluate microbial composition and serum metabolites. Microbial culture experiments were designed to reveal the target microbiota and associated metabolites. Cell culture and transcriptome were performed to elucidate the function of microbial metabolites on THP-1. PAL reduced the area of plaque and necrotic core, improving inflammatory infiltration within plaques, improving glycolipid metabolism, and reducing the levels of serum inflammatory cytokines in a dose-dependent manner. PAL treatment reshaped the composition of the gut microbiota, especially, reducing the relative abundance of Desulfovibrio piger (D. piger) in a dose-dependent manner and serum level of hippuric acid (HA). D. piger was able to convert phenylalanine into 3-phenylpropionic acid (precursor of HA). Finally, we verified HA accelerated the progression of AS and increased the secretions of inflammatory cytokines in vivo and in vitro. In conclusion, PAL exhibited anti-AS effects by regulating the gut microbiota-phenylalanine metabolism axis.
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Affiliation(s)
- Anlu Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Baoyi Guan
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Linghua Yu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qiyu Liu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yuanlong Hou
- Laboratory of Metabolism and Drug Target Discovery, State Key Laboratory of Natural Medicines, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ziguang Li
- Laboratory of Metabolism and Drug Target Discovery, State Key Laboratory of Natural Medicines, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Daming Sun
- Laboratory of Metabolism and Drug Target Discovery, State Key Laboratory of Natural Medicines, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Xu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China.
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26
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Ke Z, Ma Q, Ye X, Wang Y, Jin Y, Zhao X, Su Z. Peptide GLP-1 receptor agonists: From injection to oral delivery strategies. Biochem Pharmacol 2024; 229:116471. [PMID: 39127152 DOI: 10.1016/j.bcp.2024.116471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/20/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
Peptide glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective drugs for treating type 2 diabetes (T2DM) and have been proven to benefit the heart and kidney. Apart from oral semaglutide, which does not require injection, other peptide GLP-1RAs need to be subcutaneously administered. However, oral semaglutide also faces significant challenges, such as low bioavailability and frequent gastrointestinal discomfort. Thus, it is imperative that advanced oral strategies for peptide GLP-1RAs need to be explored. This review mainly compares the current advantages and disadvantages of various oral delivery strategies for peptide GLP-1RAs in the developmental stage and discusses the latest research progress of peptide GLP-1RAs, providing a useful guide for the development of new oral peptide GLP-1RA drugs.
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Affiliation(s)
- Zhiqiang Ke
- Protein Engineering and Biopharmaceuticals Science, Hubei University of Technology, Wuhan 430068, China; Hubei Key Laboratory of Diabetes and Angiopathy, National Demonstration Center for Experimental General Medicine Education, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, China
| | - Qianqian Ma
- Protein Engineering and Biopharmaceuticals Science, Hubei University of Technology, Wuhan 430068, China; School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi 830017, China
| | - Xiaonan Ye
- Protein Engineering and Biopharmaceuticals Science, Hubei University of Technology, Wuhan 430068, China
| | - Yanlin Wang
- Protein Engineering and Biopharmaceuticals Science, Hubei University of Technology, Wuhan 430068, China
| | - Yan Jin
- Protein Engineering and Biopharmaceuticals Science, Hubei University of Technology, Wuhan 430068, China
| | - Xinyuan Zhao
- Hubei Key Laboratory of Diabetes and Angiopathy, National Demonstration Center for Experimental General Medicine Education, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, China.
| | - Zhengding Su
- Protein Engineering and Biopharmaceuticals Science, Hubei University of Technology, Wuhan 430068, China; School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi 830017, China.
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27
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Si ZL, Wang HY, Wang T, Cao YZ, Li QZ, Liu K, Huang Z, Liu HL, Tan YJ, Wang YY, Huang FQ, Ma GX, Alolga RN, Yan M, Chen C, Li JH, Li J, Liu HW, Zhang ZH. Gut Bacteroides ovatus ameliorates renal fibrosis by promoting the production of HDCA through upregulation of Clostridium scindens. Cell Rep 2024; 43:114830. [PMID: 39392759 DOI: 10.1016/j.celrep.2024.114830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/14/2024] [Accepted: 09/19/2024] [Indexed: 10/13/2024] Open
Abstract
Renal fibrosis, inflammation, and gut dysbiosis are all linked to chronic kidney disease (CKD). Here we show that Bacteroides ovatus protects against renal fibrosis. Mechanistically, B. ovatus enhances intestinal hyodeoxycholic acid (HDCA) levels by upregulating a strain of intestinal bacteria, Clostridium scindens, that has the capacity for direct HDCA production in mice. HDCA significantly promoted GLP-1 secretion by upregulating the expression of TGR5 and downregulating the expression of farnesoid X receptor (FXR) in the gut. Activation of renal GLP-1R attenuates renal fibrosis while delaying the subsequent development of CKD. In addition, HDCA can also protect against renal fibrosis by directly upregulating renal TGR5. The natural product neohesperidin (NHP) was found to exert its anti-renal fibrotic effects by promoting the growth of B. ovatus. Our findings provide mechanistic insights into the therapeutic potential of B. ovatus, C. scindens, and HDCA in treating CKD.
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Affiliation(s)
- Zi-Lin Si
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Han-Yu Wang
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Tao Wang
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No. 1 Beichenxi Road, Chaoyang District, Beijing 100101, P.R. China
| | - Yi-Zhi Cao
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Qing-Zhen Li
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Kang Liu
- Department of Nephrology, Jiangsu Province Hospital (The First Affiliated Hospital of Nanjing Medical University), Nanjing 210029, China
| | - Zhou Huang
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Hui-Ling Liu
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
| | - Ya-Jie Tan
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yin-Yin Wang
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Feng-Qing Huang
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Gao-Xiang Ma
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Raphael N Alolga
- State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Miao Yan
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Cheng Chen
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jun-Hui Li
- Putuo People's Hospital, Tongji University, Shanghai 200060, China
| | - Jing Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
| | - Hong-Wei Liu
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, No. 1 Beichenxi Road, Chaoyang District, Beijing 100101, P.R. China
| | - Zhi-Hao Zhang
- Key Laboratory of Tropical Biological Resources of the Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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Zhang J, Zhu YD, Li CQ, Fan YM, Huo H, Sun CG, Zhou J, Sun L, Qian XK, Zou LW. A sensitive fluorescence assay of serum dipeptidyl peptidase IV activity to predict the suitability of its inhibitors in patients with type 2 diabetes mellitus. J Pharm Biomed Anal 2024; 249:116382. [PMID: 39098293 DOI: 10.1016/j.jpba.2024.116382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/23/2024] [Accepted: 07/25/2024] [Indexed: 08/06/2024]
Abstract
DPP-IV inhibitors, which are close to the natural hypoglycemic pathway of human physiology and have few side effects, have been extensively employed in the management of type 2 diabetes mellitus (T2DM). However, there are currently no specific blood indicators that can indicate or predict a patient's suitability for DPP-IV inhibitors. In this study, based on the self-developed high-specificity fluorescent substrate glycyl-prolyl-N-butyl-4-amino-1, 8-naphthimide (GP-BAN), a detection method of human serum DPP-IV activity was established and optimized. The method demonstrates a favorable lower limit of detection (LOD) at 0.32 ng/mL and a satisfactory lower limit of quantification (LOQ) of 1.12 ng/mL, and can be used for the detection of DPP-IV activity in trace serum (2 μL). In addition, Vitalliptin and Sitagliptin showed similar IC50 values when human recombinant DPP-IV and human serum were used as enzyme sources, and the intra-day and inter-day precision obtained by the microplate analyzer were less than 15 %. These results indicate that the microplate reader based detection technique has good accuracy, repeatability and reproducibility. A total of 700 volunteers were recruited, and 646 serum samples were tested for DPP-IV activity. The results showed that serum DPP-IV activity was higher in patients with T2DM than in controls (P < 0.01). However, the statistical data of family history of diabetes, gender and age of diabetic patients showed no statistical significance, and there was no contrast difference. The DPP-IV activity of serum in T2DM patients ranged from 2.4 μmol/min/L to 78.6 μmol/min/L, with a huge difference of up to 32-fold. These results suggest that it is necessary to test DPP-IV activity in patients with T2DM when taking DPP-IV inhibitors to determine the applicability of DPP-IV inhibitors in T2DM patients. These results suggest that it is necessary to detect the activity of DPP-IV in blood before taking DPP-IV inhibitors in patients with T2DM to judge the applicability of DPP-IV inhibitors in patients with T2DM.
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Affiliation(s)
- Jing Zhang
- Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou 550025, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ya-Di Zhu
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Ci-Qin Li
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi-Ming Fan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong Huo
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Cheng-Gong Sun
- The Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Jing Zhou
- Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Lei Sun
- The Second Hospital of Dalian Medical University, Dalian 116023, China.
| | - Xing-Kai Qian
- Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou 550025, China; Department of Cardiac Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China.
| | - Li-Wei Zou
- Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou 550025, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Tong M, Xu J, Li W, Jiang K, Yang Y, Chen Z, Jiao X, Meng X, Wang M, Hong J, Long H, Liu SJ, Lim B, Gao X. A highly conserved SusCD transporter determines the import and species-specific antagonism of Bacteroides ubiquitin homologues. Nat Commun 2024; 15:8794. [PMID: 39389974 PMCID: PMC11467351 DOI: 10.1038/s41467-024-53149-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
Efficient interbacterial competitions and diverse defensive strategies employed by various bacteria play a crucial role in acquiring a hold within a dense microbial community. The gut symbiont Bacteroides fragilis secretes an antimicrobial ubiquitin homologue (BfUbb) that targets an essential periplasmic PPIase to drive intraspecies bacterial competition. However, the mechanisms by which BfUbb enters the periplasm and its potential for interspecies antagonism remain poorly understood. Here, we employ transposon mutagenesis and identify a highly conserved TonB-dependent transporter SusCD (designated as ButCD) in B. fragilis as the BfUbb transporter. As a putative protein-related nutrient utilization system, ButCD is widely distributed across diverse Bacteroides species with varying sequence similarity, resulting in distinct import efficiency of Bacteroides ubiquitin homologues (BUbb) and thereby determining the species-specific toxicity of BUbb. Cryo-EM structural and functional investigations of the BfUbb-ButCD complex uncover distinctive structural features of ButC that are crucial for its targeting by BfUbb. Animal studies further demonstrate the specific and efficient elimination of enterotoxigenic B. fragilis (ETBF) in the murine gut by BfUbb, suggesting its potential as a therapeutic against ETBF-associated inflammatory bowel disease and colorectal cancer. Our findings provide a comprehensive elucidation of the species-specific toxicity exhibited by BUbb and explore its potential applications.
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Affiliation(s)
- Ming Tong
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Jinghua Xu
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Weixun Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Kun Jiang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Yan Yang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Zhe Chen
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Xuyao Jiao
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Xiangfeng Meng
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Mingyu Wang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
| | - Jie Hong
- NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, 200001, China
| | - Hongan Long
- Institute of Evolution and Marine Biodiversity, KLMME, Ocean University of China, Qingdao, 266003, China
| | - Shuang-Jiang Liu
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Bentley Lim
- Department of Microbial Pathogenesis and Microbial Sciences Institute, Yale University School of Medicine, New Haven, CT, 06536, USA
| | - Xiang Gao
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
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De La Torre S, Cuesta SA, Calle L, Mora JR, Paz JL, Espinoza-Montero PJ, Flores-Sumoza M, Márquez EA. Computational approaches for lead compound discovery in dipeptidyl peptidase-4 inhibition using machine learning and molecular dynamics techniques. Comput Biol Chem 2024; 112:108145. [PMID: 39002224 DOI: 10.1016/j.compbiolchem.2024.108145] [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: 02/25/2024] [Revised: 07/01/2024] [Accepted: 07/08/2024] [Indexed: 07/15/2024]
Abstract
The prediction of possible lead compounds from already-known drugs that may present DPP-4 inhibition activity imply a advantage in the drug development in terms of time and cost to find alternative medicines for the treatment of Type 2 Diabetes Mellitus (T2DM). The inhibition of dipeptidyl peptidase-4 (DPP-4) has been one of the most explored strategies to develop potential drugs against this condition. A diverse dataset of molecules with known experimental inhibitory activity against DPP-4 was constructed and used to develop predictive models using different machine-learning algorithms. Model M36 is the most promising one based on the internal and external performance showing values of Q2CV = 0.813, and Q2EXT = 0.803. The applicability domain evaluation and Tropsha's analysis were conducted to validate M36, indicating its robustness and accuracy in predicting pIC50 values for organic molecules within the established domain. The physicochemical properties of the ligands, including electronegativity, polarizability, and van der Waals volume were relevant to predict the inhibition process. The model was then employed in the virtual screening of potential DPP4 inhibitors, finding 448 compounds from the DrugBank and 9 from DiaNat with potential inhibitory activity. Molecular docking and molecular dynamics simulations were used to get insight into the ligand-protein interaction. From the screening and the favorable molecular dynamic results, several compounds including Skimmin (pIC50 = 3.54, Binding energy = -8.86 kcal/mol), bergenin (pIC50 = 2.69, Binding energy = -13.90 kcal/mol), and DB07272 (pIC50 = 3.97, Binding energy = -25.28 kcal/mol) seem to be promising hits to be tested and optimized in the treatment of T2DM. This results imply a important reduction in cost and time on the application of this drugs because all the information about the its metabolism is already available.
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Affiliation(s)
- Sandra De La Torre
- Grupo de Química Computacional y Teórica (QCT-USFQ), Departamento de Ingeniería Química, Universidad San Francisco de Quito, Diego de Robles y Vía Interoceánica, Quito 170901, Ecuador
| | - Sebastián A Cuesta
- Grupo de Química Computacional y Teórica (QCT-USFQ), Departamento de Ingeniería Química, Universidad San Francisco de Quito, Diego de Robles y Vía Interoceánica, Quito 170901, Ecuador; Department of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
| | - Luis Calle
- Facultad de Ciencias Médicas, Instituto de Investigación e Innovación en Salud Integral, Universidad Católica Santiago de Guayaquil, Guayaquil 09013493, Ecuador
| | - José R Mora
- Grupo de Química Computacional y Teórica (QCT-USFQ), Departamento de Ingeniería Química, Universidad San Francisco de Quito, Diego de Robles y Vía Interoceánica, Quito 170901, Ecuador.
| | - Jose L Paz
- Departamento Académico de Química Inorgánica, Facultad de Química e Ingeniería Química, Universidad Nacional Mayor de San Marcos, Lima, Peru
| | | | - Máryury Flores-Sumoza
- Facultad de Ciencias Básicas y Biomédicas, Programa de Química y Farmacia, Universidad Simón Bolívar, carrera 59 N° 59-65, Barranquilla 080002, Colombia
| | - Edgar A Márquez
- Grupo de Investigaciones en Química y Biología, Departamento de Química y Biología, Facultad de Ciencias Básicas, Universidad del Norte, Carrera 51B, Km 5, vía Puerto Colombia, Barranquilla 081007, Colombia
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Lin Y, Dong Y, Li X, Cai J, Cai L, Zhang G. Enzymatic production of xylooligosaccharide from lignocellulosic and marine biomass: A review of current progress, challenges, and its applications in food sectors. Int J Biol Macromol 2024; 277:134014. [PMID: 39047995 DOI: 10.1016/j.ijbiomac.2024.134014] [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: 09/18/2023] [Revised: 04/03/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024]
Abstract
Over the last decade, xylooligosaccharides (XOS) have attracted great attentions because of their unique chemical properties and excellent prebiotic effects. Among the current strategies for XOS production, enzymatic hydrolysis is preferred due to its green and safe process, simplicity in equipment, and high control of the degrees of polymerization. This paper comprehensively summarizes various lignocellulosic biomass and marine biomass employed in enzymatic production of XOS. The importance and advantages of enzyme immobilization in XOS production are also discussed. Many novel immobilization techniques for xylanase are presented. In addition, bioinformatics techniques for the mining and designing of new xylanase are also described. Moreover, XOS has exhibited great potential applications in the food industry as diverse roles, such as a sugar replacer, a fat replacer, and cryoprotectant. This review systematically summarizes the current research progress on the applications of XOS in food sectors, including beverages, bakery products, dairy products, meat products, aquatic products, food packaging film, wall materials, and others. It is anticipated that this paper will act as a reference for the further development and application of XOS in food sectors and other fields.
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Affiliation(s)
- Yuanqing Lin
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen 361024, Fujian, China
| | - Yuting Dong
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen 361024, Fujian, China; Department of Bioengineering and Biotechnology, Huaqiao University, Xiamen 361021, Fujian, China
| | - Xiangling Li
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, United States
| | - Jinzhong Cai
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen 361024, Fujian, China
| | - Lixi Cai
- Department of Bioengineering and Biotechnology, Huaqiao University, Xiamen 361021, Fujian, China; College of Basic Medicine, Putian University, Putian 351100, Fujian, China.
| | - Guangya Zhang
- Department of Bioengineering and Biotechnology, Huaqiao University, Xiamen 361021, Fujian, China.
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32
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Ma Z, Zuo T, Frey N, Rangrez AY. A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation. Signal Transduct Target Ther 2024; 9:237. [PMID: 39307902 PMCID: PMC11418828 DOI: 10.1038/s41392-024-01946-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/03/2024] [Accepted: 08/01/2024] [Indexed: 09/26/2024] Open
Abstract
The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the 'innate and adaptive genomes', which enhance genetic and evolutionary comprehension of the human genome. The 'germ-free syndrome' challenges the traditional 'microbes as pathogens' view, advocating for the necessity of microbes for health. The 'slave tissue' concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. 'Acquired microbial immunity' positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The 'homeostatic reprogramming hypothesis' integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The 'cell-microbe co-ecology model' elucidates the symbiotic regulation affecting cellular balance, while the 'meta-host model' broadens the host definition to include symbiotic microbes. The 'health-illness conversion model' encapsulates the innate and adaptive genomes' interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.
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Affiliation(s)
- Ziqi Ma
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
| | - Tao Zuo
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
| | - Ashraf Yusuf Rangrez
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
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Byndloss M, Devkota S, Duca F, Niess JH, Nieuwdorp M, Orho-Melander M, Sanz Y, Tremaroli V, Zhao L. The gut microbiota and diabetes: research, translation, and clinical applications - 2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. Diabetologia 2024; 67:1760-1782. [PMID: 38910152 PMCID: PMC11410996 DOI: 10.1007/s00125-024-06198-1] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/23/2024] [Indexed: 06/25/2024]
Abstract
This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.
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Affiliation(s)
- Mariana Byndloss
- Vanderbilt University Medical Center, Nashville, TN, USA
- Howard Hughes Medical Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Suzanne Devkota
- Cedars-Sinai Medical Center, Human Microbiome Research Institute, Los Angeles, CA, USA
| | | | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, University Digestive Healthcare Center, Clarunis, Basel, Switzerland
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Amsterdam Diabeter Center, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Marju Orho-Melander
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - Yolanda Sanz
- Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain.
| | - Valentina Tremaroli
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Liping Zhao
- Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ, USA
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Jin FX, Wang Y, Li MN, Li RJ, Guo JT. Intestinal glucagon-like peptide-1: A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice. World J Diabetes 2024; 15:1764-1777. [PMID: 39192849 PMCID: PMC11346100 DOI: 10.4239/wjd.v15.i8.1764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/03/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic reactions. However, the patho-genesis of hypoglycaemic counterregulation is still unclear. Glucagon-like peptide-1 (GLP-1) and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus (T1DM). The role of GLP-1 in counterregulatory dys-function during hypoglycaemia in patients with T1DM has not been reported. AIM To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice. METHODS T1DM was induced in C57BL/6J mice using streptozotocin, followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia (DH5). Immunofluorescence, Western blot, and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon (GCG) secretion. The GLP-1 receptor agonist GLP-1(7-36) or the antagonist exendin (9-39) were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model mice. RESULTS The expression levels of intestinal GLP-1 and its receptor (GLP-1R) were significantly increased in DH5 mice. Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex, leading to dysfunction of adrenal counterregulation during hypoglycaemia. DH5 mice showed increased pancreatic δ-cell mass, cAMP levels in δ cells, and plasma somatostatin concentrations, while cAMP levels in pancreatic α cells and plasma GCG levels decreased. Furthermore, GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group. Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway. CONCLUSION Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and GCG during hypo-glycaemia.
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Affiliation(s)
- Fang-Xin Jin
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Yan Wang
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Min-Ne Li
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Ru-Jiang Li
- Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
| | - Jun-Tang Guo
- Department of Pathological Physiology, Shandong Second Medical University, Weifang 261053, Shandong Province, China
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35
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Baars DP, Fondevila MF, Meijnikman AS, Nieuwdorp M. The central role of the gut microbiota in the pathophysiology and management of type 2 diabetes. Cell Host Microbe 2024; 32:1280-1300. [PMID: 39146799 DOI: 10.1016/j.chom.2024.07.017] [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: 06/17/2024] [Revised: 07/15/2024] [Accepted: 07/18/2024] [Indexed: 08/17/2024]
Abstract
The inhabitants of our intestines, collectively called the gut microbiome, comprise fungi, viruses, and bacterial strains. These microorganisms are involved in the fermentation of dietary compounds and the regulation of our adaptive and innate immune systems. Less known is the reciprocal interaction between the gut microbiota and type 2 diabetes mellitus (T2DM), as well as their role in modifying therapies to reduce associated morbidity and mortality. In this review, we aim to discuss the existing literature on gut microbial strains and their diet-derived metabolites involved in T2DM. We also explore the potential diagnostics and therapeutic avenues the gut microbiota presents for targeted T2DM management. Personalized treatment plans, driven by diet and medication based on the patient's microbiome and clinical markers, could optimize therapy.
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Affiliation(s)
- Daniel P Baars
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands
| | - Marcos F Fondevila
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Abraham S Meijnikman
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands
| | - Max Nieuwdorp
- Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands; Diabetes Center Amsterdam, Amsterdam, the Netherlands.
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Sun R, Fei F, Jin D, Yang H, Xu Z, Cao B, Li J. The integrated analysis of gut microbiota and metabolome revealed steroid hormone biosynthesis is a critical pathway in liver regeneration after 2/3 partial hepatectomy. Front Pharmacol 2024; 15:1407401. [PMID: 39188944 PMCID: PMC11345278 DOI: 10.3389/fphar.2024.1407401] [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: 03/26/2024] [Accepted: 07/23/2024] [Indexed: 08/28/2024] Open
Abstract
Introduction: The liver is the only organ capable of full regeneration in mammals. However, the exact mechanism of gut microbiota and metabolites derived from them relating to liver regeneration has not been fully elucidated. Methods: To demonstrate how the gut-liver axis contributes to liver regeneration, using an LC-QTOF/MS-based metabolomics technique, we examine the gut microbiota-derived metabolites in the gut content of C57BL/6J mice at various points after 2/3 partial hepatectomy (PHx). Compound identification, multivariate/univariate data analysis and pathway analysis were performed subsequently. The diversity of the bacterial communities in the gastrointestinal content was measured using 16S rRNA gene sequencing. Then, the integration analysis of gut microbiota and metabolome was performed. Results: After 2/3 PHx, the residual liver proliferated quickly in the first 3 days and had about 90% of its initial weight by the seventh day. The results of PLS-DA showed that a significant metabolic shift occurred at 6 h and 36 h after 2/3 PHx that was reversed at the late phase of liver regeneration. The α and β-diversity of the gut microbiota significantly changed at the early stage of liver regeneration. Specifically, Escherichia Shigella, Lactobacillus, Akkermansia, and Muribaculaceae were the bacteria that changed the most considerably during liver regeneration. Further pathway analysis found the most influenced co-metabolized pathways between the host and gut bacteria including glycolysis, the TCA cycle, arginine metabolism, glutathione metabolism, tryptophan metabolism, and purine and pyrimidine metabolism. Specifically, steroid hormone biosynthesis is the most significant pathway of the host during liver regeneration. Discussion: These findings revealed that during liver regeneration, there was a broad modification of gut microbiota and systemic metabolism and they were strongly correlated. Targeting specific gut bacterial strains, especially increasing the abundance of Akkermansia and decreasing the abundance of Enterobacteriaceae, may be a promising beneficial strategy to modulate systemic metabolism such as amino acid and nucleotide metabolism and promote liver regeneration.
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Affiliation(s)
- Runbin Sun
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Fei
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Jin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haoyi Yang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhi Xu
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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Liu X, Liang XQ, Lu TC, Feng Z, Zhang M, Liao NQ, Zhang FL, Wang B, Wang LS. Leech Poecilobdella manillensis protein extract ameliorated hyperuricemia by restoring gut microbiota dysregulation and affecting serum metabolites. World J Gastroenterol 2024; 30:3488-3510. [PMID: 39156502 PMCID: PMC11326090 DOI: 10.3748/wjg.v30.i29.3488] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 06/20/2024] [Accepted: 07/19/2024] [Indexed: 07/29/2024] Open
Abstract
BACKGROUND Hyperuricemia (HUA) is a public health concern that needs to be solved urgently. The lyophilized powder of Poecilobdella manillensis has been shown to significantly alleviate HUA; however, its underlying metabolic regulation remains unclear. AIM To explore the underlying mechanisms of Poecilobdella manillensis in HUA based on modulation of the gut microbiota and host metabolism. METHODS A mouse model of rapid HUA was established using a high-purine diet and potassium oxonate injections. The mice received oral drugs or saline. Additionally, 16S rRNA sequencing and ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics were performed to identify changes in the microbiome and host metabolome, respectively. The levels of uric acid transporters and epithelial tight junction proteins in the renal and intestinal tissues were analyzed using an enzyme-linked immunosorbent assay. RESULTS The protein extract of Poecilobdella manillensis lyophilized powder (49 mg/kg) showed an enhanced anti-trioxypurine ability than that of allopurinol (5 mg/kg) (P < 0.05). A total of nine bacterial genera were identified to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which included the genera of Prevotella, Delftia, Dialister, Akkermansia, Lactococcus, Escherichia_Shigella, Enterococcus, and Bacteroides. Furthermore, 22 metabolites in the serum were found to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which correlated to the Kyoto Encyclopedia of Genes and Genomes pathways of cysteine and methionine metabolism, sphingolipid metabolism, galactose metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. Correlation analysis found that changes in the gut microbiota were significantly related to these metabolites. CONCLUSION The proteins in Poecilobdella manillensis powder were effective for HUA. Mechanistically, they are associated with improvements in gut microbiota dysbiosis and the regulation of sphingolipid and galactose metabolism.
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Affiliation(s)
- Xia Liu
- Medical College, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
- Department of Traditional Chinese Medicine, HIV/AIDS Clinical Treatment Center of Guangxi (Nanning), The Fourth People’s Hospital of Nanning, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Xing-Qiu Liang
- Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - Tian-Cai Lu
- General Manager’s Office, Guangxi Fuxinyi Biological Technology Co. Ltd., Pingnan 537300, Guangxi Zhuang Autonomous Region, China
| | - Zhe Feng
- Department of Joint and Sports Medicine, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - Min Zhang
- Department of Gerontology, Nanning Social Welfare Hospital, Nanning 530004, Guangxi Zhuang Autonomous Region, China
| | - Nan-Qing Liao
- Medical College, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
| | - Feng-Lian Zhang
- Medical College, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
| | - Bo Wang
- Medical College, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
| | - Li-Sheng Wang
- Medical College, Guangxi University, Nanning 530004, Guangxi Zhuang Autonomous Region, China
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Shekarabi A, Qureishy I, Puglisi CH, Dalseth M, Vuong HE. Host-microbe interactions: communication in the microbiota-gut-brain axis. Curr Opin Microbiol 2024; 80:102494. [PMID: 38824840 PMCID: PMC11323153 DOI: 10.1016/j.mib.2024.102494] [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: 12/04/2023] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/04/2024]
Abstract
Animals harbor a diverse array of symbiotic micro-organisms that coexist in communities across different body sites. These microbes maintain host homeostasis and respond to environmental insults to impact host physiological processes. Trillions of indigenous microbes reside in the gastrointestinal tract and engage with the host central nervous system (microbiota-gut-brain axis) by modulating immune responses, interacting with gut intrinsic and extrinsic nervous system, and regulating neuromodulators and biochemicals. These gut microbiota to brain signaling pathways are constantly informed by each other and are hypothesized to mediate brain health across the lifespan. In this review, we will examine the crosstalk of gut microbiota to brain communications in neurological pathologies, with an emphasis on microbial metabolites and neuromodulators, and provide a discussion of recent advances that help elucidate the microbiota as a therapeutic target for treating brain and behavioral disorders.
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Affiliation(s)
- Aryan Shekarabi
- University of Minnesota Twin-Cities, Department of Pediatrics, Neonatology Division, USA
| | - Izhan Qureishy
- University of Minnesota Twin-Cities, Department of Pediatrics, Neonatology Division, USA
| | - Chloe H Puglisi
- University of Minnesota Twin-Cities, Department of Pediatrics, Neonatology Division, USA
| | - Marge Dalseth
- University of Minnesota Twin-Cities, Department of Pediatrics, Neonatology Division, USA
| | - Helen E Vuong
- University of Minnesota Twin-Cities, Department of Pediatrics, Neonatology Division, USA.
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Olivares M, Hernández-Calderón P, Cárdenas-Brito S, Liébana-García R, Sanz Y, Benítez-Páez A. Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation. Genome Biol 2024; 25:174. [PMID: 38961511 PMCID: PMC11221189 DOI: 10.1186/s13059-024-03325-4] [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: 12/18/2023] [Accepted: 06/26/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. RESULTS We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. CONCLUSIONS Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.
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Affiliation(s)
- Marta Olivares
- Institute of Agrochemistry and Food Technology, Microbiome, Nutrition and Health Research Unit, Spanish National Research Council, IATA-CSIC, 46980, Paterna-Valencia, Spain
| | - Paula Hernández-Calderón
- Principe Felipe Research Center (CIPF), Host-Microbe Interactions in Metabolic Health Laboratory, 46012, Valencia, Spain
| | - Sonia Cárdenas-Brito
- Principe Felipe Research Center (CIPF), Host-Microbe Interactions in Metabolic Health Laboratory, 46012, Valencia, Spain
| | - Rebeca Liébana-García
- Institute of Agrochemistry and Food Technology, Microbiome, Nutrition and Health Research Unit, Spanish National Research Council, IATA-CSIC, 46980, Paterna-Valencia, Spain
| | - Yolanda Sanz
- Institute of Agrochemistry and Food Technology, Microbiome, Nutrition and Health Research Unit, Spanish National Research Council, IATA-CSIC, 46980, Paterna-Valencia, Spain.
| | - Alfonso Benítez-Páez
- Institute of Agrochemistry and Food Technology, Microbiome, Nutrition and Health Research Unit, Spanish National Research Council, IATA-CSIC, 46980, Paterna-Valencia, Spain.
- Principe Felipe Research Center (CIPF), Host-Microbe Interactions in Metabolic Health Laboratory, 46012, Valencia, Spain.
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Zhang Z, Wang K, Jiang C. Gut microbial-host-isozymes are new targets for diseases. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1525-1527. [PMID: 38644445 DOI: 10.1007/s11427-024-2551-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 02/28/2024] [Indexed: 04/23/2024]
Affiliation(s)
- Zhiwei Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Peking University, Beijing, 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Peking University, Beijing, 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Peking University, Beijing, 100191, China.
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
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He J, Liu X, Zhang J, Wang R, Cao X, Liu G. Gut microbiome-derived hydrolases-an underrated target of natural product metabolism. Front Cell Infect Microbiol 2024; 14:1392249. [PMID: 38915922 PMCID: PMC11194327 DOI: 10.3389/fcimb.2024.1392249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/16/2024] [Indexed: 06/26/2024] Open
Abstract
In recent years, there has been increasing interest in studying gut microbiome-derived hydrolases in relation to oral drug metabolism, particularly focusing on natural product drugs. Despite the significance of natural product drugs in the field of oral medications, there is a lack of research on the regulatory interplay between gut microbiome-derived hydrolases and these drugs. This review delves into the interaction between intestinal microbiome-derived hydrolases and natural product drugs metabolism from three key perspectives. Firstly, it examines the impact of glycoside hydrolases, amide hydrolases, carboxylesterase, bile salt hydrolases, and epoxide hydrolase on the structure of natural products. Secondly, it explores how natural product drugs influence microbiome-derived hydrolases. Lastly, it analyzes the impact of interactions between hydrolases and natural products on disease development and the challenges in developing microbial-derived enzymes. The overarching goal of this review is to lay a solid theoretical foundation for the advancement of research and development in new natural product drugs and personalized treatment.
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Affiliation(s)
- Jiaxin He
- People’s Hospital of Ningxia Hui Autonomous Region, Pharmacy Department, Yinchuan, China
| | - Xiaofeng Liu
- People’s Hospital of Ningxia Hui Autonomous Region, Pharmacy Department, Yinchuan, China
| | - Junming Zhang
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Rong Wang
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Xinyuan Cao
- People’s Hospital of Ningxia Hui Autonomous Region, Pharmacy Department, Yinchuan, China
- Ningxia Medical University, School of Basic Medicine, Yinchuan, China
| | - Ge Liu
- Ningxia Medical University, School of Basic Medicine, Yinchuan, China
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Zhang X, Wang J, Liu Y, Wang H, Li B, Li Q, Wang Y, Zong Y, Wang J, Meng Q, Wu S, Hao R, Li X, Chen R, Chen H. In situ profiling reveals spatially metabolic injury in the initiation of polystyrene nanoplastic-derived intestinal epithelial injury in mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 927:172037. [PMID: 38575003 DOI: 10.1016/j.scitotenv.2024.172037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/22/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024]
Abstract
Despite increasing concerns regarding the harmful effects of plastic-induced gut injury, mechanisms underlying the initiation of plastic-derived intestinal toxicity remain unelucidated. Here, mice were subjected to long-term exposure to polystyrene nanoplastics (PS-NPs) of varying sizes (80, 200, and 1000 nm) at doses relevant to human dietary exposure. PS-NPs exposure did not induce a significant inflammatory response, histopathological damage, or intestinal epithelial dysfunction in mice at a dosage of 0.5 mg/kg/day for 28 days. However, PS-NPs were detected in the mouse intestine, coupled with observed microstructural changes in enterocytes, including mild villous lodging, mitochondrial membrane rupture, and endoplasmic reticulum (ER) dysfunction, suggesting that intestinal-accumulating PS-NPs resulted in the onset of intestinal epithelial injury in mice. Mechanistically, intragastric PS-NPs induced gut microbiota dysbiosis and specific bacteria alterations, accompanied by abnormal metabolic fingerprinting in the plasma. Furthermore, integrated data from mass spectrometry imaging-based spatial metabolomics and metallomics revealed that PS-NPs exposure led to gut dysbiosis-associated host metabolic reprogramming and initiated intestinal injury. These findings provide novel insights into the critical gut microbial-host metabolic remodeling events vital to nanoplastic-derived-initiated intestinal injury.
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Affiliation(s)
- Xianan Zhang
- School of Public Health, Capital Medical University, Beijing 100069, China; Yanjing Medical College, Capital Medical University, Beijing 101300, China
| | - Jing Wang
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Yuansheng Liu
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Hemin Wang
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Bin Li
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Qing Li
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Yi Wang
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Yuru Zong
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Jiajia Wang
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Qingtao Meng
- School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing 100069, China
| | - Shenshen Wu
- School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing 100069, China
| | - Rongzhang Hao
- School of Public Health, Capital Medical University, Beijing 100069, China
| | - Xiaobo Li
- School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing 100069, China.
| | - Rui Chen
- School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing 100069, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China; Department of Occupational and Environmental Health, Fourth Military Medical University, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Xi'an 710032, China.
| | - Hanqing Chen
- School of Public Health, Capital Medical University, Beijing 100069, China; Department of Nutrition & Food Hygiene, Capital Medical University, Beijing 100069, China.
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Yasuda T, Harada N, Inagaki N. Effects of dipeptidyl peptidase-4 inhibition in vivo: Dipeptidyl peptidase-4 inhibitor/gut microbiome crosstalk suggests novel therapeutic options for diabetes management. J Diabetes Investig 2024; 15:704-706. [PMID: 38323861 PMCID: PMC11143409 DOI: 10.1111/jdi.14157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 01/19/2024] [Accepted: 01/24/2024] [Indexed: 02/08/2024] Open
Abstract
Wang et al. report that clinical dipeptidyl peptidase-4 (DPP-4) inhibitors show little effect on microbial DPP-4 produced by Bacteroides genus. Furthermore, oral administration of microbial DPP-4 to high-fat diet-fed mice was found to reduce plasma active glucagon-like peptide-1 levels through an increase in extraluminal intestinal tissular DPP-4 activity, resulting in reduced glucose-induced insulin levels and exacerbated glucose tolerance.
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Affiliation(s)
- Takuma Yasuda
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Nobuya Inagaki
- P.I.I.F. Tazuke‐Kofukai Medical Research Institute KITANO HOSPITALOsakaJapan
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Liu T, Zhang C, Zhang H, Jin J, Li X, Liang S, Xue Y, Yuan F, Zhou Y, Bian X, Wei H. A new evaluation system for drug-microbiota interactions. IMETA 2024; 3:e199. [PMID: 38898986 PMCID: PMC11183188 DOI: 10.1002/imt2.199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 06/21/2024]
Abstract
The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism. Additionally, individual differences in gut microbiota create a unique metabolic environment that influences the in vivo processes underlying drug absorption, distribution, metabolism, and excretion (ADME). Here, we discuss how gut microbiota, shaped by both genetic and environmental factors, affects the host's ADME microenvironment within a new evaluation system for drug-microbiota interactions. Furthermore, we propose a new top-down research approach to investigate the intricate nature of drug-microbiota interactions in vivo. This approach utilizes germ-free animal models, providing foundation for the development of a new evaluation system for drug-microbiota interactions.
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Affiliation(s)
- Tian‐Hao Liu
- Yu‐Yue Pathology Scientific Research CenterChongqingChina
- Department of PathologyArmy Medical UniversityChongqingChina
- Department of GastroenterologyAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Chen‐Yang Zhang
- Department of GastroenterologyAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
- Institute of Integrated traditional Chinese and Western MedicineAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Hang Zhang
- College of Animal Science and Technology, College of Animal MedicineHuazhong Agricultural UniversityWuhanHubeiChina
| | - Jing Jin
- Department of PathologyArmy Medical UniversityChongqingChina
| | - Xue Li
- Wuxi Hospital Affiliated to Nanjing University of Chinese MedicineWuxiJiangsuChina
| | - Shi‐Qiang Liang
- College of Animal Science and Technology, College of Animal MedicineHuazhong Agricultural UniversityWuhanHubeiChina
| | - Yu‐Zheng Xue
- Department of GastroenterologyAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Feng‐Lai Yuan
- Institute of Integrated traditional Chinese and Western MedicineAffiliated Hospital of Jiangnan UniversityWuxiChina
| | - Ya‐Hong Zhou
- Wuxi Hospital Affiliated to Nanjing University of Chinese MedicineWuxiJiangsuChina
| | - Xiu‐Wu Bian
- Yu‐Yue Pathology Scientific Research CenterChongqingChina
- Department of PathologyArmy Medical UniversityChongqingChina
| | - Hong Wei
- Yu‐Yue Pathology Scientific Research CenterChongqingChina
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Balleza-Alejandri LR, Peña-Durán E, Beltrán-Ramírez A, Reynoso-Roa AS, Sánchez-Abundis LD, García-Galindo JJ, Suárez-Rico DO. Decoding the Gut Microbiota-Gestational Diabetes Link: Insights from the Last Seven Years. Microorganisms 2024; 12:1070. [PMID: 38930451 PMCID: PMC11205738 DOI: 10.3390/microorganisms12061070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/04/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
The human microbiome, a complex ecosystem of bacteria, viruses, and protozoans living in symbiosis with the host, plays a crucial role in human health, influencing everything from metabolism to immune function. Dysbiosis, or an imbalance in this ecosystem, has been linked to various health issues, including diabetes and gestational diabetes (GD). In diabetes, dysbiosis affects the function of adipose tissue, leading to the release of adipokines and cytokines, which increase inflammation and insulin resistance. During pregnancy, changes to the microbiome can exacerbate glucose intolerance, a common feature of GD. Over the past years, burgeoning insights into the gut microbiota have unveiled its pivotal role in human health. This article comprehensively reviews literature from the last seven years, highlighting the association between gut microbiota dysbiosis and GD, as well as the metabolism of antidiabetic drugs and the potential influences of diet and probiotics. The underlying pathophysiological mechanisms discussed include the impact of dysbiosis on systemic inflammation and the interplay with genetic and environmental factors. By focusing on recent studies, the importance of considering microbial health in the prevention and treatment of GD is emphasized, providing insights into future research directions and clinical applications to improve maternal-infant health outcomes.
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Affiliation(s)
- Luis Ricardo Balleza-Alejandri
- Doctorado en Farmacología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.-A.); (A.S.R.-R.)
| | - Emiliano Peña-Durán
- Licenciatura en Médico Cirujano y Partero, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Mexico;
| | - Alberto Beltrán-Ramírez
- Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Calle Sierra Mojada 950, Independencia Oriente, Guadalajara 44340, Mexico; (A.B.-R.); (J.J.G.-G.)
| | - Africa Samantha Reynoso-Roa
- Doctorado en Farmacología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.-A.); (A.S.R.-R.)
| | - Luis Daniel Sánchez-Abundis
- Hospital Civil de Guadalajara, Fray Antonio Alcalde, Instituto de Patología Infecciosa y Experimental, Guadalajara 44200, Mexico;
| | - Jesús Jonathan García-Galindo
- Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Calle Sierra Mojada 950, Independencia Oriente, Guadalajara 44340, Mexico; (A.B.-R.); (J.J.G.-G.)
| | - Daniel Osmar Suárez-Rico
- Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Calle Sierra Mojada 950, Independencia Oriente, Guadalajara 44340, Mexico; (A.B.-R.); (J.J.G.-G.)
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Carpio LE, Olivares M, Benítez-Paez A, Serrano-Candelas E, Barigye SJ, Sanz Y, Gozalbes R. Comparative Binding Study of Gliptins to Bacterial DPP4-like Enzymes for the Treatment of Type 2 Diabetes Mellitus (T2DM). Int J Mol Sci 2024; 25:5744. [PMID: 38891933 PMCID: PMC11171585 DOI: 10.3390/ijms25115744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including Segatella copri, Phocaeicola vulgatus, Bacteroides uniformis, Parabacteroides merdae, and Alistipes sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.
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Affiliation(s)
- Laureano E. Carpio
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
- MolDrug AI Systems SL, 46018 Valencia, Spain
| | - Marta Olivares
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Alfonso Benítez-Paez
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Eva Serrano-Candelas
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
| | | | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Rafael Gozalbes
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
- MolDrug AI Systems SL, 46018 Valencia, Spain
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Zhao Z, Ma R, Ma Y, Zhao L, Wang L, Fang Y, Zhang Y, Wu X, Wang X. Discovery of Nine Dipeptidyl Peptidase-4 Inhibitors from Coptis chinensis Using Virtual Screening, Bioactivity Evaluation, and Binding Studies. Molecules 2024; 29:2304. [PMID: 38792165 PMCID: PMC11123979 DOI: 10.3390/molecules29102304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/07/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
The objective of this study was to identify multiple alkaloids in Coptis chinensis that demonstrate inhibitory activity against DPP-4 and systematically evaluate their activity and binding characteristics. A combined strategy that included molecular docking, a DPP-4 inhibition assay, surface plasmon resonance (SPR), and a molecular dynamics simulation technique was employed. The results showed that nine alkaloids in Coptis chinensis directly inhibited DPP-4, with IC50 values of 3.44-53.73 μM. SPR-based binding studies revealed that these alkaloids display rapid binding and dissociation characteristics when interacting with DPP-4, with KD values ranging from 8.11 to 29.97 μM. A molecular dynamics analysis revealed that equilibrium was rapidly reached by nine DPP-4-ligand systems with minimal fluctuations, while binding free energy calculations showed that the ∆Gbind values for the nine test compounds ranged from -31.84 to -16.06 kcal/mol. The most important forces for the binding of these alkaloids with DPP-4 are electrostatic interactions and van der Waals forces. Various important amino acid residues, such as Arg125, His126, Phe357, Arg358, and Tyr547, were involved in the inhibition of DPP-4 by the compounds, revealing a mechanistic basis for the further optimization of these alkaloids as DPP-4 inhibitors. This study confirmed nine alkaloids as direct inhibitors of DPP-4 and characterized their binding features, thereby providing a basis for further research and development on novel DPP-4 inhibitors.
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Affiliation(s)
- Zixi Zhao
- School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing 100069, China; (Z.Z.); (R.M.); (Y.M.); (L.Z.)
| | - Ruonan Ma
- School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing 100069, China; (Z.Z.); (R.M.); (Y.M.); (L.Z.)
| | - Yuqing Ma
- School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing 100069, China; (Z.Z.); (R.M.); (Y.M.); (L.Z.)
| | - Liqiang Zhao
- School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing 100069, China; (Z.Z.); (R.M.); (Y.M.); (L.Z.)
| | - Lele Wang
- School of Pharmacy, Minzu University of China, Haidian District, Beijing 100081, China; (L.W.); (Y.F.)
| | - Yuzhen Fang
- School of Pharmacy, Minzu University of China, Haidian District, Beijing 100081, China; (L.W.); (Y.F.)
| | - Yuxin Zhang
- School of Pharmacy, Minzu University of China, Haidian District, Beijing 100081, China; (L.W.); (Y.F.)
| | - Xia Wu
- School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing 100069, China; (Z.Z.); (R.M.); (Y.M.); (L.Z.)
| | - Xing Wang
- School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing 100069, China; (Z.Z.); (R.M.); (Y.M.); (L.Z.)
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An Z, Gao R, Chen S, Tian Y, Li Q, Tian L, Zhang W, Kong L, Zheng B, Hao L, Xin T, Yao H, Wang Y, Song W, Hua X, Liu C, Song J, Fan H, Sun W, Chen S, Xu Z. Lineage-Specific CYP80 Expansion and Benzylisoquinoline Alkaloid Diversity in Early-Diverging Eudicots. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309990. [PMID: 38477432 PMCID: PMC11109638 DOI: 10.1002/advs.202309990] [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: 12/19/2023] [Revised: 02/07/2024] [Indexed: 03/14/2024]
Abstract
Menispermaceae species, as early-diverging eudicots, can synthesize valuable benzylisoquinoline alkaloids (BIAs) like bisbenzylisoquinoline alkaloids (bisBIAs) and sinomenines with a wide range of structural diversity. However, the evolutionary mechanisms responsible for their chemo-diversity are not well understood. Here, a chromosome-level genome assembly of Menispermum dauricum is presented and demonstrated the occurrence of two whole genome duplication (WGD) events that are shared by Ranunculales and specific to Menispermum, providing a model for understanding chromosomal evolution in early-diverging eudicots. The biosynthetic pathway for diverse BIAs in M. dauricum is reconstructed by analyzing the transcriptome and metabolome. Additionally, five catalytic enzymes - one norcoclaurine synthase (NCS) and four cytochrome P450 monooxygenases (CYP450s) - from M. dauricum are responsible for the formation of the skeleton, hydroxylated modification, and C-O/C-C phenol coupling of BIAs. Notably, a novel leaf-specific MdCYP80G10 enzyme that catalyzes C2'-C4a phenol coupling of (S)-reticuline into sinoacutine, the enantiomer of morphinan compounds, with predictable stereospecificity is discovered. Moreover, it is found that Menispermum-specific CYP80 gene expansion, as well as tissue-specific expression, has driven BIA diversity in Menispermaceae as compared to other Ranunculales species. This study sheds light on WGD occurrences in early-diverging eudicots and the evolution of diverse BIA biosynthesis.
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Affiliation(s)
- Zhoujie An
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Ranran Gao
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing100700China
| | - Shanshan Chen
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing100700China
| | - Ya Tian
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Qi Li
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Lixia Tian
- School of Pharmaceutical SciencesGuizhou UniversityGuiyang550025China
| | - Wanran Zhang
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Lingzhe Kong
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Baojiang Zheng
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Lijun Hao
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193China
| | - Tianyi Xin
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193China
| | - Hui Yao
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193China
| | - Yu Wang
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193China
| | - Wei Song
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Xin Hua
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Chengwei Liu
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
| | - Jingyuan Song
- Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing100193China
| | - Huahao Fan
- College of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing100029China
| | - Wei Sun
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing100700China
| | - Shilin Chen
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing100700China
- Institute of HerbgenomicsChengdu University of Traditional Chinese MedicineChengdu611137China
| | - Zhichao Xu
- Key Laboratory of Saline‐alkali Vegetation Ecology Restoration (Northeast Forestry University)Ministry of EducationHarbin150040China
- College of Life ScienceNortheast Forestry UniversityHarbin150040China
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Froldi G. View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences. Pharmaceuticals (Basel) 2024; 17:478. [PMID: 38675438 PMCID: PMC11054066 DOI: 10.3390/ph17040478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.
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Affiliation(s)
- Guglielmina Froldi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
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Li Y, Liu Y, Cui J, Zhu M, Wang W, Chen K, Huang L, Liu Y. Oral-gut microbial transmission promotes diabetic coronary heart disease. Cardiovasc Diabetol 2024; 23:123. [PMID: 38581039 PMCID: PMC10998415 DOI: 10.1186/s12933-024-02217-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 03/27/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia-reperfusion injury (MIRI). METHODS We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. RESULTS Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. CONCLUSION Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease.
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Affiliation(s)
- Yiwen Li
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100078, China
| | - Yanfei Liu
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Jing Cui
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Mengmeng Zhu
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wenting Wang
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Keji Chen
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Luqi Huang
- China Academy of Chinese Medical Sciences, Beijing, 100078, China
| | - Yue Liu
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China.
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