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Li B, Gao H, Xiao H, He H, Ni Q, Li Q, Wang H, Chen L. Abnormal chenodexycholic acid metabolism programming promotes cartilage matrix degradation in male adult offspring rats induced by prenatal caffeine exposure. Toxicol Res (Camb) 2025; 14:tfaf063. [PMID: 40331087 PMCID: PMC12051868 DOI: 10.1093/toxres/tfaf063] [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: 11/18/2024] [Revised: 04/01/2025] [Accepted: 04/18/2025] [Indexed: 05/08/2025] Open
Abstract
Epidemiological evidence links osteoarthritis to fetal origins. Our study shows prenatal caffeine exposure (PCE) in rats predisposes adult offspring to osteoarthritis, associated with elevated intrauterine glucocorticoid levels. Previous research indicates that chenodeoxycholic acid (CDCA), a bile acid, can slow osteoarthritis progression when administered intra-articularly. This study explored if disrupted bile acid metabolism in cartilage affects osteoarthritis risk in adult offspring with PCE. Our findings indicate that the expression of MMP3/MMP13 was upregulated, while endogenous CDCA levels were reduced in the cartilage of PCE-exposed offspring. Furthermore, we observed a persistent reduction in H3K27ac levels at the CYP7B1 promoter and its expression in the cartilage of PCE offspring from fetus to adulthood. Moreover, a sub-physiological level of CDCA promoted NF-κB phosphorylation and the expression of MMP3/MMP13 in chondrocytes in vitro. High levels of glucocorticoids reduced H3K27ac levels and CYP7B1 expression in the promoter region of CYP7B1 through the glucocorticoid receptor and histone deacetylase 4, consequently leading to decreased CDCA levels. In summary, our findings suggest that intrauterine low-expression programming of CYP7B1, induced by elevated glucocorticoid levels, reduces local CDCA levels in the cartilage of PCE offspring, ultimately leading to increased matrix degradation and susceptibility to osteoarthritis.
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Affiliation(s)
- Bin Li
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China
| | - Hui Gao
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hao Xiao
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China
| | - Hangyuan He
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Qubo Ni
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Qingxian Li
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hui Wang
- Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China
- Department of Pharmacology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan 430071, China
| | - Liaobin Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China
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2
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Daghistani H, Hegazy GA, Alkhalofah M, Alsobeihy A, Nasser S, Gad H, Shamrani T, Mufrrih M, Alyousfi D. Long noncoding RNAs in familial hypercholesterolemia: biomarkers, therapeutics, and AI in precision medicine. Lipids Health Dis 2025; 24:182. [PMID: 40399983 PMCID: PMC12093904 DOI: 10.1186/s12944-025-02605-7] [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] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 05/08/2025] [Indexed: 05/23/2025] Open
Abstract
Long noncoding RNAs (lncRNAs) have emerged as critical regulators of lipid metabolism, playing pivotal roles in cholesterol biosynthesis, transport, and efflux. Familial Hypercholesterolemia (FH), a genetic disorder characterized by excessive low-density lipoprotein cholesterol (LDL-C) levels, remains a significant contributor to premature cardiovascular disease (CVD). Traditional diagnostic methods, including lipid profiling and genetic testing, have limitations in sensitivity and accessibility, highlighting the need for novel molecular biomarkers. This review delves into the mechanistic involvement of lncRNAs in FH pathogenesis, shedding light on their potential as non-invasive biomarkers and therapeutic targets. Key lncRNAs such as LeXis, CHROME, and H19 have been implicated in cholesterol regulation and atherosclerosis progression, making them attractive candidates for precision medicine applications. Additionally, advancements in AI-driven lncRNA discovery and single-cell transcriptomics are paving the way for innovative diagnostic and therapeutic strategies. Emerging RNA-based therapeutics, including antisense oligonucleotides, small interfering RNAs (siRNAs), and CRISPR-based gene-editing tools, hold promise for modulating lncRNA function to restore lipid homeostasis. However, challenges such as biomarker validation, efficient RNA delivery, and regulatory approval must be addressed for clinical translation. The integration of lncRNA-based approaches into FH management offers new possibilities for early detection, targeted therapy, and personalized cardiovascular risk assessment, underscoring the need for continued research in this rapidly evolving field.
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Affiliation(s)
- Hussam Daghistani
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- King Fahad Medical Research Centre, Regenerative Medicine Unit, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Gehan A Hegazy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Manal Alkhalofah
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Afaf Alsobeihy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sara Nasser
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hoda Gad
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Taghreed Shamrani
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Nutrition and Lifestyle Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Mufrrih
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Special Infectious Agents Unit BSL-3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Dareen Alyousfi
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
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3
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He Y, Shaoyong W, Chen Y, Li M, Gan Y, Sun L, Liu Y, Wang Y, Jin M. The functions of gut microbiota-mediated bile acid metabolism in intestinal immunity. J Adv Res 2025:S2090-1232(25)00307-8. [PMID: 40354934 DOI: 10.1016/j.jare.2025.05.015] [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: 02/14/2025] [Revised: 04/19/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation. AIM OF REVIEW This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Yanmin He
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Weike Shaoyong
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yanli Chen
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Menglin Li
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yujie Gan
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Lu Sun
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yalin Liu
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yizhen Wang
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Mingliang Jin
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China.
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Wei H, Suo C, Gu X, Shen S, Lin K, Zhu C, Yan K, Bian Z, Chen L, Zhang T, Yan R, Yang Z, Yu Y, Li Z, Liu R, He J, He Q, Zhong X, Jia W, Wong CM, Dong Z, Cao J, Sun L, Zhang H, Gao P. AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity. Cell Metab 2025; 37:1103-1118.e7. [PMID: 40010348 DOI: 10.1016/j.cmet.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 07/31/2024] [Accepted: 01/14/2025] [Indexed: 02/28/2025]
Abstract
Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of Bacteroidetes ovatus (B. ovatus), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by B. ovatus might be a promising strategy to activate NK cell cytotoxicity to treat HCC.
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Affiliation(s)
- Haoran Wei
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Caixia Suo
- Department of Colorectal Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Xuemei Gu
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Shengqi Shen
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Kashuai Lin
- Department of Colorectal Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Chuxu Zhu
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Kai Yan
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhenhua Bian
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Liang Chen
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Tong Zhang
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ronghui Yan
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhiyi Yang
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Yingxuan Yu
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhikun Li
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Rui Liu
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Junming He
- School of Medicine and Institute for Immunology, Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China
| | - Qiwei He
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiuying Zhong
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Weidong Jia
- Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, the First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Chun-Ming Wong
- State Key Laboratory of Liver Research, Department of Pathology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China
| | - Zhongjun Dong
- School of Medicine and Institute for Immunology, Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China
| | - Jie Cao
- Department of Colorectal Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Linchong Sun
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Huafeng Zhang
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China; Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, the First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
| | - Ping Gao
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China.
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5
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Zhang B, Lin Y, Song S, Guo H. Exploring the Vital Role of Microbiota Metabolites in Early-Life Health. J Nutr 2025:S0022-3166(25)00270-6. [PMID: 40324527 DOI: 10.1016/j.tjnut.2025.04.025] [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: 12/15/2024] [Revised: 04/23/2025] [Accepted: 04/29/2025] [Indexed: 05/07/2025] Open
Abstract
Early-life gut microbiota metabolites profoundly influence gut homeostasis, neurodevelopment, metabolic regulation, and immune system maturation. However, there is still a lack of comprehensive summaries and discussions regarding gut microbiota metabolites during early-life stages. This review systematically analyzes microbiota metabolites, including short-chain fatty acids, secondary bile acids, tryptophan metabolites, and branched-chain fatty acids, and delves into their production mechanisms and temporal dynamics. Additionally, the review highlights how maternal factors, breastfeeding, complementary feeding, and environmental influences shape the composition and metabolic functions of the early-life gut microbiota, emphasizing that early life is a crucial window for lifelong health interventions. By integrating the latest research findings and identifying knowledge gaps, this review emphasizes the molecular mechanisms of gut microbiota metabolites and their role in addressing common early-life diseases, including their potential as early biomarkers for screening, prevention, improvement, and even treatment of early diseases, as well as predicting their potential related diseases. On the basis of these insights, this review lays the foundation for future research and practical applications, aiming to promote optimal health from infancy to childhood.
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Affiliation(s)
- Baoyi Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yingying Lin
- Key Laboratory of Functional Dairy, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Sijia Song
- Key Laboratory of Functional Dairy, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Huiyuan Guo
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China; Key Laboratory of Functional Dairy, Department of Nutrition and Health, China Agricultural University, Beijing, China.
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6
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Ghaffari MH, Ostendorf CS, Hemmert KJ, Schuchardt S, Koch C, Sauerwein H. Longitudinal characterization of plasma and fecal bile acids in dairy heifers from birth to first calving in response to transition milk feeding. J Dairy Sci 2025; 108:5475-5488. [PMID: 40216228 DOI: 10.3168/jds.2025-26307] [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: 01/13/2025] [Accepted: 02/27/2025] [Indexed: 05/03/2025]
Abstract
This study aimed to characterize plasma bile acid changes from birth to first calving and evaluate the effects of early transition milk (TM) feeding versus milk replacer (MR) during key stages. Fecal bile acids in TM-fed calves were also analyzed, offering insights into bile acid metabolism. Thirty female Holstein calves were fed TM or MR for the first 5 d, followed by 12 L/d MR. From d 14, calves were fed MR and starter with gradual weaning between wk 8 and 14. Blood samples were collected at 7 time points: 30 min and 12 h after birth, preweaning (wk 2, 6), weaning (wk 14), 8 mo, 13 mo, 3 wk before calving, at calving, and 3 wk after calving. Fecal samples were collected from a subset of TM-fed calves (n = 10) at birth, wk 6, wk 14, 8 mo, and calving. Samples were analyzed for bile acids using the Biocrates MxP Quant 500 kit. Cholic acid (CA) in plasma showed significant time-treatment interactions, with higher levels in TM-fed calves at weaning. Taurine- and glycine-conjugated bile acids had no treatment or time-treatment interactions, but all plasma bile acids showed significant time effects. Principal component analysis revealed that bile acid profiles at birth and after colostrum intake were tightly clustered. Plasma bile acid profiles showed greater dispersion during milk feeding and weaning, with tighter clustering observed postweaning, particularly at 13 mo, and in the transition period. Significant effects were observed for CA, deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), with CA showing a notable interaction and being higher in TM-fed calves at weaning than in MR-fed calves. Bile acid levels increased toward weaning, peaked at wk 14, and decreased after weaning. Glycine-conjugated bile acids changed over time, with glycocholic acid (GCA) and glycodeoxycholic acid (GDCA) peaking at weaning, and glycochenodeoxycholic acid (GCDCA) being elevated before weaning, decreasing thereafter, and increasing again at calving. Taurine-conjugated bile acids also showed temporal changes, peaking at wk 6. The shifts in bile acid composition from birth to postcalving, with taurolithocholic acid (TLCA), GDCA, and taurocholic acid (TCA) initially dominating, CA increasing at weaning, and GDCA and DCA dominating at calving, with CA increasing again postcalving. During the transition to calving, CA decreased whereas glycine-conjugated bile acids increased relative to taurine-conjugated bile acids in plasma, irrespective of treatment. Fecal bile acid profiles in TM-fed calves clustered distinctly at birth, evolving through pre- to postweaning and calving, with increasing profile overlap over time. Most fecal bile acids, except DCA and CA, were abundant at birth but declined over time. Both DCA and CA increased postweaning, mirroring plasma trends. From wk 6 to calving, DCA was the dominant bile acid, accounting for the highest percentage of total bile acids excreted in feces. Spearman's correlation analysis was performed to assess the relationship between plasma and fecal bile acids in TN-fed calves. A significant positive correlation was observed only for GCDCA (Spearman's rank correlation coefficient [rho] = 0.35), whereas all other bile acids were not correlated. These results illustrate the complex dynamics of bile acid profiles during calf development.
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Affiliation(s)
- M H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| | - C S Ostendorf
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | - K J Hemmert
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - S Schuchardt
- Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
| | - C Koch
- Educational and Research Centre for Animal Husbandry, Hofgut Neumühle, 67728 Münchweiler an der Alsenz, Germany
| | - H Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
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7
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Yamamura R, Okubo R, Ukawa S, Nakamura K, Okada E, Nakagawa T, Imae A, Kimura T, Tamakoshi A. Increased fecal glycocholic acid levels correlate with obesity in conjunction with the depletion of archaea: The Dosanco Health Study. J Nutr Biochem 2025; 139:109846. [PMID: 39863085 DOI: 10.1016/j.jnutbio.2025.109846] [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: 07/22/2024] [Revised: 12/30/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
Recent studies have focused on the relationship between obesity and gut microbiota. This study aims to identify fecal components and gut bacterial species associated with different BMI categories. In this study, 538 participants aged ≥18 years were categorized into underweight, normal, and obese groups based on BMI (cutoffs: 18.5 and 25.0 kg/m²). We compared 30 fecal components among these groups and calculated correlation coefficients between each component and BMI. Participants were then divided into quartiles based on fecal component levels correlated with BMI, and the prevalence ratio (PR) of obesity was calculated, adjusted for confounding factors. We also analyzed the composition and diversity of gut microbiota and bacterial gene expression among the quartiles for each fecal component. Fecal glycocholic acid (GCA) showed a significant positive correlation with BMI. The PR for obesity in the highest quartile of fecal GCA was 3.30 (95% CI, 1.21-9.54), indicating a significantly higher risk of obesity compared to the lowest quartile. Gut microbiota analysis revealed significant differences in the abundance of Ruminococcaceae Incertae Sedis, Faecalibacterium, and Methanobrevibacter, with Methanobrevibacter being absent in the higher quartiles of fecal GCA. Additionally, gene expression for enzymes involved in the deconjugation of conjugated bile acids, including GCA, was downregulated in the highest quartile. Increased fecal GCA levels are positively correlated with obesity, alongside a depletion of archaea.
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Affiliation(s)
- Ryodai Yamamura
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
| | - Ryo Okubo
- Department of Neuropsychiatry, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Shigekazu Ukawa
- Osaka Metropolitan University Graduate School of Human Life and Ecology, Sumiyoshi, Osaka, Japan; Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Koshi Nakamura
- Department of Public Health and Epidemiology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan; Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Emiko Okada
- The Health Care Science Institute, Minato-ku, Tokyo, Japan; Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | | | - Akihiro Imae
- The Hokkaido Centre for Family Medicine, Sapporo, Japan
| | - Takashi Kimura
- Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Akiko Tamakoshi
- Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan
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Huang Y, Yu F, Ding Y, Zhang H, Li X, Wang X, Wu X, Xu J, Wang L, Tian C, Jiang M, Zhang R, Yan C, Song Y, Huang H, Xu G, Ding Q, Ye X, Lu Y, Hu C. Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver. Hepatology 2025; 81:1564-1582. [PMID: 38985984 PMCID: PMC11999092 DOI: 10.1097/hep.0000000000000998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/08/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND AND AIMS An imbalance in lipid metabolism is the main cause of NAFLD. While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of IL-22 protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. APPROACH AND RESULTS This study shows that hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly 3 beta-hydroxy-5-cholestenoic acid (3β HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3β HCA deposition through the activating transcription factor 3/oxysterol 7 alpha-hydroxylase axis. Notably, 3β HCA facilitates lipogenesis in mouse primary hepatocytes and human liver organoids by activating liver X receptor-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring oxysterol 7 alpha-hydroxylase or silencing hepatic activating transcription factor 3 reduces both hepatic 3β HCA and lipid contents in hepatocyte-specific Il22ra1 knockout mice. CONCLUSIONS These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an activating transcription factor 3/oxysterol 7 alpha-hydroxylase-dependent manner and establish a link between 3β HCA and hepatic lipid homeostasis.
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Affiliation(s)
- Yeping Huang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Yu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Ding
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinyue Li
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Wang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoshan Wu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jie Xu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Wang
- Surgery Centre of Diabetes Mellitus, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Chenxu Tian
- Surgery Centre of Diabetes Mellitus, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Min Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenyan Yan
- Department of Endocrinology, Center for General Practice Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College. Hangzhou, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yingxiang Song
- Department of Endocrinology, Center for General Practice Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College. Hangzhou, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Haijun Huang
- Department of Infectious Diseases, Center for General Practice Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Guangzhong Xu
- Surgery Centre of Diabetes Mellitus, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiao Ye
- Department of Endocrinology, Center for General Practice Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College. Hangzhou, Zhejiang, China
- Key Laboratory for Diagnosis and Treatment of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China
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9
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Schauermann M, Wang R, Pons-Kuehnemann J, Hartmann MF, Remer T, Hua Y, Bereket A, Wasniewska M, Shmoish M, Hochberg Z, Gawlik A, Wudy SA. Targeted quantitative analysis of urinary bile acids by liquid chromatography-tandem mass spectrometry: Method development and application to healthy and obese children. J Steroid Biochem Mol Biol 2025; 249:106712. [PMID: 39988143 DOI: 10.1016/j.jsbmb.2025.106712] [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: 12/30/2024] [Revised: 02/14/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Bile acids (BA) are C24 steroids synthesized from cholesterol in liver. Hardly any data exist on BA in the most accessible human biofluid urine. As bile acids bear great potential as future biomarkers in diagnosis and monitoring of metabolic diseases, we aimed at developing and implementing a new method for the quantification of urinary bile acids using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). A second goal consisted in creating first reference values of urinary bile acids during childhood and to investigate their excretion patterns in obese children and adolescents. Our method required 2 mL of urine and sample preparation consisting of protein precipitation and solid phase extraction. Stable isotopes of BA were included as internal standards (IS). Our method is capable of simultaneously determining 18 BA: the primary BA cholic acid (CA) and chenodeoxycholic acid (CDCA), and the secondary BA deoxycholic acid (DCA) and lithocholic acid (LCA) as well as glycine and taurine conjugates of these four BA. Furthermore, ursodeoxycholic acid (UDCA) and five BA in their sulfated forms (LCA-S, GLCA-S, TLCA-S, GCDCA-S, GDCA-S) were analyzed. After successful validation (intra-day precision 1.02 % - 11.07 %; inter-day precision 0.42-11.47 %.; intra-day accuracy 85.75 % - 108.90 %; inter-day accuracy 86.76 % - 110.99 %; no significant matrix effect; recovery 90.49 % - 113.99 %)., the method was applied to samples of 80 healthy children as well as 237 obese children of various age groups. Sulfated BA showed the highest concentrations, with GCDCA-S (nmol/L, medians, controls vs. obese 588.4 vs. 360.2) being the most abundant among all BA, followed by GLCA-S (353.9 vs. 344.8) and GDCA-S (319,3 vs. 323.9). CA (135.1 vs. 174.6) and GCA (100.2 vs. 92.4) were the two dominant non-sulfated BA. In conclusion, we developed a LC-MS/MS method for the simultaneous determination of 18 urinary bile acids in children and adolescents. We created reference values and investigated obese children. Sulfated bile acids dominated in both study groups. Lower bile acid sulfation and amidation in obese children point to limitations in their hepatic metabolic capacity.
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Affiliation(s)
- M Schauermann
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - R Wang
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - J Pons-Kuehnemann
- Institute of Medical Informatics, Department of Medical Statistics, Justus Liebig University, Giessen, Germany
| | - M F Hartmann
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - T Remer
- DONALD Study Center, Department of Nutritional Epidemiology, Institute of Nutrition and Food Science, University of Bonn, Dortmund, Germany
| | - Y Hua
- DONALD Study Center, Department of Nutritional Epidemiology, Institute of Nutrition and Food Science, University of Bonn, Dortmund, Germany
| | - A Bereket
- Department of Pediatric Endocrinology, Marmara University Faculty of Medicine, Istanbul, Turkey
| | - M Wasniewska
- Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Italy
| | - M Shmoish
- Bioinformatics Knowledge Unit, Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Z Hochberg
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - A Gawlik
- Department of Pediatrics and Pediatric Endocrinology, School of Medicine in Katowice, Medical University of Silesia, Upper Silesia Children's Care Health Center, Katowice, Poland
| | - S A Wudy
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany.
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10
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Ren Z, Ren M, Ling W, Ren D, Liang J, Cai Y, Wang X, Wang S, Duan Y, Ku T, Ning X, Sang N. Cu(OH) 2 nanopesticide induced liver dysfunction in mice by targeting lipoylated tricarboxylic acid cycle proteins via ferredoxin 1. JOURNAL OF HAZARDOUS MATERIALS 2025; 494:138403. [PMID: 40311425 DOI: 10.1016/j.jhazmat.2025.138403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/20/2025] [Accepted: 04/23/2025] [Indexed: 05/03/2025]
Abstract
Copper hydroxide [Cu(OH)2] nanopesticide is an emerging agrochemical known for its ability to mitigate bacterial and fungal damage to host organisms. However, its environmental exposure and potential toxicological effects have garnered significant attention. The liver is regarded as the primary organ for copper storage and utilization within the body. Here, the potential hepatic dyshomeostasis and metabolic dysfunction resulting from exposure to Cu(OH)2 nanopesticide for a month were investigated using the C57BL/6 mouse model. The findings demonstrated that Cu(OH)2 nanopesticide induced damage to the core functions of the mouse liver, evidenced by an impaired tissue microstructure, attenuated biochemical function, as well as disturbed bile acid synthesis and energy metabolism. The regulatory manner of Cu(OH)2 nanopesticide on the lipoylated proteins in the tricarboxylic acid (TCA) cycle by targeting ferredoxin 1 (FDX1) and its associated lipoic acid and iron-sulfur pathways, also shared genetic characteristics with the recently identified cuproptosis mechanism, providing a deeper understanding of the hepatoxic effects induced by this copper nanopesticide. These findings contribute valuable data for evaluating the hepatotoxicity of Cu(OH)2 nanopesticide, and further research into the molecular mechanisms is anticipated to enhance the identification of therapeutic targets for hepatic diseases related to copper metabolism.
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Affiliation(s)
- Zhihua Ren
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Mengyao Ren
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Weibo Ling
- Department of Chemistry, University of California, Riverside, CA 92521, USA
| | - Danqin Ren
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Jiefeng Liang
- Shandong Key Laboratory of Environmental Processes and Health, School of Environmental Science and Engineering, Shandong University, Qingdao 266237, China
| | - Yixue Cai
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Xiao Wang
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Shuo Wang
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Yonghui Duan
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Tingting Ku
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Xia Ning
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China
| | - Nan Sang
- Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Research Center of Environment and Health, College of Environment and Resource, Shanxi University, Taiyuan 030006, China.
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11
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Xue X, He Z, Liu F, Wang Q, Chen Z, Lin L, Chen D, Yuan Y, Huang Z, Wang Y. Taurochenodeoxycholic acid suppresses the progression of glioblastoma via HMGCS1/HMGCR/GPX4 signaling pathway in vitro and in vivo. Cancer Cell Int 2025; 25:160. [PMID: 40264142 PMCID: PMC12016240 DOI: 10.1186/s12935-025-03782-2] [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: 10/24/2024] [Accepted: 04/04/2025] [Indexed: 04/24/2025] Open
Abstract
Glioblastoma multiforme (GBM) is the foremost prevalent and highly aggressive intracranial malignancy, which urgently needs safer and more efficacious therapeutic strategies. Our research aimed to investigate the impact and the underlying mechanism of Taurochenodeoxycholic acid (TCDCA) on GBM. In this study, we explored the suppressive effect of TCDCA in vitro by qualification of proliferation and migration assays and flow cytometry, and subsequently predicted the potential anti-GBM mechanism of TCDCA by mRNA sequencing and the following rescue experiments. An orthotopic GBM model in C57BL/6 mice further demonstrated the anti-GBM mechanism of TCDCA. In vitro experiments verified that TCDCA inhibited the growth and migration of GBM cells and induced cell cycle arrest at the G2/M phase. Subsequent mechanism investigations showed that upregulation of HMGCS1 and HMGCR and downregulation of glutathione peroxidase-4 (GPX4) was observed in GBM cells by TCDCA treatment. Notably, inhibitory effects of proliferation and migration as well as induction of ferroptosis by TCDCA were partially restored by Simvastatin (SIN), a competitive HMGCR inhibitor. Furthermore, TCDCA showed an anti-GBM effect in an orthotopic transplantation model in vivo. TCDCA impedes GBM progression by virtue of this intricately orchestrated molecular cascade, through HMGCS1/HMGCR/GPX4 signaling axis, thus unveiling a novel therapeutic avenue warranting further scrutiny in the treatment landscape of GBM.
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Affiliation(s)
- Xiumin Xue
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Ziwan He
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Furui Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Qian Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Zhichao Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Lin Lin
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Danni Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Yinfeng Yuan
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China
| | - Zhihui Huang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China.
| | - Yongjie Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, China.
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12
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Koh YC, Liu CP, Leung SY, Lin WS, Ho PY, Ho CT, Pan MH. Nobiletin Enhances Skeletal Muscle Mass and Modulates Bile Acid Composition in Diet-Induced Obese Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:9076-9087. [PMID: 40193085 PMCID: PMC12007094 DOI: 10.1021/acs.jafc.5c00255] [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: 01/06/2025] [Revised: 03/11/2025] [Accepted: 03/31/2025] [Indexed: 04/17/2025]
Abstract
Obesity and its associated metabolic disorders─including muscle atrophy─pose significant health challenges, particularly with the increasing prevalence of high-fat diets. This study investigates the effects of nobiletin, a citrus flavonoid, on high-fat-diet-induced obesity-related muscle atrophy and its regulatory role in bile acid metabolism, aiming to determine whether nobiletin supplementation can enhance muscle mass and improve metabolic health in a mouse model. Our findings revealed that nobiletin significantly upregulated CYP7A1 expression in the liver, promoting bile acid synthesis and modulating bile acid composition in the ileum and feces, potentially through microbiota-mediated mechanisms. Furthermore, nobiletin supplementation suppressed muscle atrophy-related proteins, including p-4EBP1, TRIM63, and FBXO32, while promoting the phosphorylation of mTOR/AKT/p70S6K and FOXO3a in skeletal muscle. The FGF15/FGFR4/ERK signaling pathway was notably activated in the skeletal muscle tissues of nobiletin-supplemented mice, suggesting a protective effect against muscle atrophy despite the pathway's inhibition in the liver to promote bile acid synthesis. These results indicate that nobiletin not only mitigates muscle atrophy in the context of obesity but also enhances glucose homeostasis, likely through improved skeletal muscle function. Overall, our study highlights the potential of nobiletin as a therapeutic agent for preventing obesity-related complications, regulating bile acid metabolism, and promoting skeletal muscle health.
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Affiliation(s)
- Yen-Chun Koh
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Chien-Ping Liu
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Siu-Yi Leung
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Wei-Sheng Lin
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
- Department
of Food Science, National Quemoy University, Quemoy 89250, Taiwan
| | - Pin-Yu Ho
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
| | - Chi-Tang Ho
- Department
of Food Science, Rutgers University, New Brunswick, New Jersey 08901, United States
| | - Min-Hsiung Pan
- Institute
of Food Sciences and Technology, National
Taiwan University, Taipei 10617, Taiwan
- Department
of Medical Research, China Medical University
Hospital, China Medical University, Taichung City 40402, Taiwan
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13
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Xiong S. Gut-Microbiota-Driven Lipid Metabolism: Mechanisms and Applications in Swine Production. Metabolites 2025; 15:248. [PMID: 40278377 PMCID: PMC12029090 DOI: 10.3390/metabo15040248] [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: 03/12/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 04/26/2025] Open
Abstract
Background/Objectives: The gut microbiota plays a pivotal role in host physiology through metabolite production, with lipids serving as essential biomolecules for cellular structure, metabolism, and signaling. This review aims to elucidate the interactions between gut microbiota and lipid metabolism and their implications for enhancing swine production. Methods: We systematically analyzed current literature on microbial lipid metabolism, focusing on mechanistic studies on microbiota-lipid interactions, key regulatory pathways in microbial lipid metabolism, and multi-omics evidence (metagenomic/metabolomic) from swine models. Results: This review outlines the structural and functional roles of lipids in bacterial membranes and examines the influence of gut microbiota on the metabolism of key lipid classes, including cholesterol, bile acids, choline, sphingolipids, and fatty acids. Additionally, we explore the potential applications of microbial lipid metabolism in enhancing swine production performance. Conclusions: Our analysis establishes a scientific framework for microbiota-based strategies to optimize lipid metabolism. The findings highlight potential interventions to improve livestock productivity through targeted manipulation of gut microbial communities.
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Affiliation(s)
- Shuqi Xiong
- National Key Laboratory of Pig Genetic Improvement and Germplasm Innovation, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
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14
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Dzichenka Y, Shapira M, Sachanka A, Cherkesova T, Shchur V, Grbović L, Pavlović K, Vasiljević B, Savić M, Nikolić A, Oklješa A, Ajduković J, Kuzminac I, Yantsevich A, Usanov S, Jovanović-Šanta S. Discovery of the potential of cholesterol-lowering human CYP7 enzymes as biocatalysts for the production of C7 hydroxylated steroids. Biophys Chem 2025; 319:107393. [PMID: 39908942 DOI: 10.1016/j.bpc.2025.107393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/07/2025]
Abstract
Steroidal C7 alcohols and their esters are perspective agents in drug discovery. In addition, hydroxylation at C7 position could allow further modification of steroidal moiety. Such transformation is performed easily by the enzymes. Human steroid 7α-hydroxylases CYP7A1 and CYP7B1 are key enzymes taking part in the biotransformation of cholestanes, androstanes, pregnanes. In the article, we are focusing on the results of in vitro screening of a library of modified steroids toward CYP7 enzymes. A couple of compounds were found to express the affinity for binding to the enzymes, comparable with corresponding values for CYP7 natural ligands. Among them are 17-substituted androstane derivatives with N-containing pyridine ring and enone derivative of lithocholic acid, which bound by human CYP7A1, and D-seco and C16 oxime androstanes, which were identified as novel CYP7B1 ligands. Screening results revealed that both enzymes bind with high affinity a well-known drug abiraterone: in the case of CYP7A1 substrate-like binding mode was detected, with the formation of monohydroxylated product, while in case of CYP7B1 inhibitor-like binding was observed. Since CYP7 enzymes convert some of the studied compounds into their 7-hydroxy derivatives, potential of these enzymes as perspective regio- and stereoselective biocatalysts for obtaining C7 hydroxylated steroids could be assumed.
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Affiliation(s)
- Yaraslau Dzichenka
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus.
| | - Michail Shapira
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Antos Sachanka
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Tatsiana Cherkesova
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Veronika Shchur
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Ljubica Grbović
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Ksenija Pavlović
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Bojana Vasiljević
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia; Institute of Nuclear Sciences Vinča - National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia
| | - Marina Savić
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Andrea Nikolić
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Aleksandar Oklješa
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Jovana Ajduković
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Ivana Kuzminac
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia
| | - Aliaksei Yantsevich
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Sergey Usanov
- Institute of Bioorganic Chemistry NAS of Belarus, Kuprevich str., 5/2, Minsk 220084, Belarus
| | - Suzana Jovanović-Šanta
- University of Novi Sad Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, Novi Sad 21000, Serbia.
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15
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Cao J, Hu W, Chen Y, Ailikaiti A, Zhang Z, Rong L, Yu H, Wang H. Adrenal High-Expressional CYP27A1 Mediates Bile Acid Increase and Functional Impairment in Adult Male Offspring by Prenatal Dexamethasone Exposure. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413299. [PMID: 39950753 PMCID: PMC11984885 DOI: 10.1002/advs.202413299] [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: 10/20/2024] [Revised: 01/16/2025] [Indexed: 04/12/2025]
Abstract
Prenatal dexamethasone exposure (PDE) can impact adrenal corticosteroid synthesis in adult offspring. Furthermore, the adrenal gland can autonomously synthesize bile acids, but local bile acids accumulation has cytotoxic effects. This study found that PDE increased histone 3 lysine 27 acetylation (H3K27ac) levels in the promoter region of cholesterol 27 hydroxylase (CYP27A1) and its expression, as well as total bile acids (TBA) concentrations and enhanced endoplasmic reticulum stress (ERS) and inhibit steroid synthesis in adult male offspring rat adrenal glands. However, it is reversed in females. Tracing back to the prenatal stage and in combination with cellular experiments, it is further revealed that dexamethasone can regulate glucocorticoid receptor (GR)/SET binding protein 1 (SETBP1)/CYP27A1 signal pathway, consequently cause intracellular increase of bile acids. Finally, administration of nilvadipine (CYP27A1 inhibitor) to male offspring for 4 weeks after birth resulted in the reversal of PDE-induced adrenal morphological and functional damage. In conclusion, PDE induces fetal adrenal corticosteroid dysfunction in adult male offspring by upregulating CYP27A1 promoter region H3K27ac levels and expression in the adrenal gland through the GR/SETBP1 signaling pathway. This effect persists beyond birth, leading to bile acids local increase and subsequent enhancement of ERS, ultimately inducing cellular dysfunction in adult adrenal glands.
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Affiliation(s)
- Jiangang Cao
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
- Institute of Clinical Pharmacy ResearchThe Affiliated Nanhua HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan421001China
| | - Wen Hu
- Department of PharmacyZhongnan Hospital of Wuhan UniversityWuhan430071China
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseWuhan430071China
| | - Yawen Chen
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
| | | | - Ziyi Zhang
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
| | - Lingbo Rong
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
| | - Hong Yu
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseWuhan430071China
| | - Hui Wang
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseWuhan430071China
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16
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Li K, Qian W, Zhang F, Zhang W, Lv H, Quan M, Sun W, Liu R, Cao X, Xian Z, Bao S, Jiang H, Du J, Zhang M, Chen Y, Zhang J, Han C, Ai D. Maternal high-fat diet exacerbates atherosclerosis development in offspring through epigenetic memory. NATURE CARDIOVASCULAR RESEARCH 2025; 4:362-379. [PMID: 40087523 DOI: 10.1038/s44161-025-00622-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 02/06/2025] [Indexed: 03/17/2025]
Abstract
Maternal exposure to a Western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis, partly because fetal endothelial cells (ECs) become dysfunctional and inflamed due to risk factors transmitted via maternal-fetal blood exchange. However, the underlying mechanisms remain unclear. Here we show that maternal WD accelerates atherogenesis in adult offspring mice by regulating chromatin dynamics through activator protein-1 (AP-1) in aortic ECs, inducing inflammatory memory at the chromatin level. We found that 27-hydroxycholesterol is involved in memory establishment and also acts as a secondary stimulator, amplifying the expression of inflammatory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mothers with hypercholesterolemia and decreased atherogenesis in offspring mice exposed to maternal WD. Our findings demonstrate that maternal WD exacerbates EC dysfunction and atherosclerosis in adult offspring by inducing AP-1-associated epigenetic memory, which increases chromatin accessibility to inflammatory genes.
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Affiliation(s)
- Kan Li
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
- State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Weiqi Qian
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Fangni Zhang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Wenhui Zhang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Huizhen Lv
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Meixi Quan
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Weiyan Sun
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Ruixin Liu
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Xinyi Cao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Zhong Xian
- Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Suya Bao
- Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Hongfeng Jiang
- Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jie Du
- Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Meng Zhang
- State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yupeng Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China
| | - Jian Zhang
- State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Medicinal Chemistry and Bioinformatics Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cha Han
- Department of Gynecology and Obstetrics, Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China.
| | - Ding Ai
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
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17
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Li X, Walhout AJM, Yilmaz LS. Enhanced flux potential analysis links changes in enzyme expression to metabolic flux. Mol Syst Biol 2025; 21:413-445. [PMID: 39962320 PMCID: PMC11965317 DOI: 10.1038/s44320-025-00090-9] [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: 08/28/2023] [Revised: 01/29/2025] [Accepted: 02/07/2025] [Indexed: 03/28/2025] Open
Abstract
Algorithms that constrain metabolic network models with enzyme levels to predict metabolic activity assume that changes in enzyme levels are indicative of flux variations. However, metabolic flux can also be regulated by other mechanisms such as allostery and mass action. To systematically explore the relationship between fluctuations in enzyme expression and flux, we combine available yeast proteomic and fluxomic data to reveal that flux changes can be best predicted from changes in enzyme levels of pathways, rather than the whole network or only cognate reactions. We implement this principle in an 'enhanced flux potential analysis' (eFPA) algorithm that integrates enzyme expression data with metabolic network architecture to predict relative flux levels of reactions including those regulated by other mechanisms. Applied to human data, eFPA consistently predicts tissue metabolic function using either proteomic or transcriptomic data. Additionally, eFPA efficiently handles data sparsity and noisiness, generating robust flux predictions with single-cell gene expression data. Our approach outperforms alternatives by striking an optimal balance, evaluating enzyme expression at pathway level, rather than either single-reaction or whole-network levels.
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Affiliation(s)
- Xuhang Li
- Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Albertha J M Walhout
- Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| | - L Safak Yilmaz
- Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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18
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Yuan Y, Xue T, Ren M, Liu Y, Song Z, Xiong Z, Qin F. Design and application of graphene oxide-based molecularly imprinted covalent organic framework for simultaneous and precise recognition of bile acid metabolites. Mikrochim Acta 2025; 192:271. [PMID: 40163176 DOI: 10.1007/s00604-025-07120-1] [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: 01/13/2025] [Accepted: 03/17/2025] [Indexed: 04/02/2025]
Abstract
In this study a bile acid (BA)-imprinted covalent organic framework (COF) was constructed via Schiff base reactions, which integrated the advantages of both inherent structural stability of COF and exceptional selectivity of molecular imprinting technology. Besides, it was found that the addition of graphene oxide (GO) effectively increased the dispersibility of nanoparticles, ultimately resulting in a GO-based molecularly imprinted COF (GO@MICOF). The GO@MICOF was identified with the characteristics of excellent mass transfer performance (20.09 mg g-1), specific surface area (152.35 m2 g-1), selectivity (IFs = 2.4), and regeneration ability (n ≥ 10). By coupling the GO@MICOF-based pretreatment method with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis, sensitive and accurate validation results (LOQs, 0.01-2.5 µmol L-1; extraction efficiency, 81.1-118.9%) were obtained. Notably, the application of the proposed pretreatment techniques to metabolomics analysis holds great significance for the precision of metabolomics results. Sixteen BA metabolites were successfully quantified in rat liver and fecal samples, and some potential biomarkers and related metabolic pathways associated with postmenopausal osteoporosis had been identified. Therefore, the integrated analysis strategy has significant advantages in purifying complex biological samples and has great application prospects in targeted metabolomics research.
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Affiliation(s)
- Yue Yuan
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China
| | - Tianyi Xue
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China
| | - Mengxin Ren
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China
| | - Yanzhu Liu
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China
| | - Zhexue Song
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China
| | - Zhili Xiong
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China.
| | - Feng Qin
- School of Pharmacy, Shenyang Pharmaceutical University, New Tech Development Zone, No. 26 Huatuo Street, High &Liaoning Province, 117004, Benxi, China.
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19
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Braun BC, Hryciuk MM, Meneghini D. Transcriptome analysis of corpora lutea in domestic cats (Felis catus) reveals strong differences in gene expression of various hormones, hormone receptors and regulators across different developmental stages. BMC Genomics 2025; 26:325. [PMID: 40165054 PMCID: PMC11959938 DOI: 10.1186/s12864-025-11510-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/20/2025] [Indexed: 04/02/2025] Open
Abstract
In the domestic cat (Felis catus), the corpus luteum (CL) is the main source of progestogen during pregnancy. Here, we studied gene expression changes in different life cycle stages of the CL of pseudopregnant cats to identify potential regulatory factors. Results revealed no support for different regression substages, which were previously defined on the basis of morphological examination analysis and intraluteal hormone content, as only a very low number of differentially expressed genes and no subclusters in PCA plot were detected. By comparing the regression stage with the developmental/maintenance stage, we detected a total of 6174 differentially expressed genes in the sample set, of which 2882 were upregulated and 3292 were downregulated. The large changes in the expression levels of some genes indicate that the endocrine function of the CL may not be restricted to progesterone (P4) secretion. The findings suggest that domestic cat CLs could also be a source of adipokines such as adiponectin or APELA. The expression of these genes is highly variable and reversed between stages. The life cycle and activity of CLs seem to be regulated by different factors, as genes encoding for the hormone receptors LHCGR and PAQR5 were more highly expressed in the development/maintenance stage, in contrast to this encoding for LEPR, which is higher expressed in regression stage. For regression stage, we identified different potential ways to modulate the cholesterol level and/or P4 concentration. Furthermore, we found differences from previous studies in other species for many genes that were studied in more detail, as well as when analysing functions and pathways. Our findings support the hypothesis that different stages of the CL life cycle in domestic cats can be characterized by changes in gene regulation and that CL life cycles are partly differentially regulated between species.
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Affiliation(s)
- Beate C Braun
- Department of Reproduction Biology, Leibniz Institute for Zoo and Wildlife Research, 10315, Berlin, Germany.
| | - Michał M Hryciuk
- Department of Reproduction Biology, Leibniz Institute for Zoo and Wildlife Research, 10315, Berlin, Germany
| | - Dorina Meneghini
- Department for Evolutionary Genetics, Leibniz Institute for Zoo and Wildlife Research, 10315, Berlin, Germany
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20
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Bao Y, Macelline SP, Selle PH, Chrystal PV, Wang M, Liu SY, Cao A, Toghyani M. Dietary bile acid supplementation influences protein digestibility and alters plasma amino acid profiles in broiler chickens fed conventional and reduced-protein diets. Poult Sci 2025; 104:105107. [PMID: 40187008 PMCID: PMC12002919 DOI: 10.1016/j.psj.2025.105107] [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: 01/19/2025] [Revised: 03/25/2025] [Accepted: 03/29/2025] [Indexed: 04/07/2025] Open
Abstract
Reduced crude protein (CP) diets based on wheat have been shown to lower body weight (BW), increase feed conversion ratio (FCR), and elevate fat-pad deposition in broiler chickens. Bile acids facilitate lipid digestion and nutrient absorption by emulsifying fats and promoting micelle formation in the intestine. Therefore, it was hypnotized that supplementing reduced CP diets with bile acids may enhance fat utilization, improve energy efficiency, and mitigate the negative effects of low-CP diets on broiler performance and nutrient digestibility. Four dietary treatments were arranged in a 2 × 2 factorial layout, with two CP levels (standard and a 30 g/kg CP reduction), with or without 0.2 g/kg bile acids. A total of 840 off-sex male Ross 308 chicks were randomly assigned into 24 floor pens, with six replicates of 35 birds per treatment. From 0 to 42 days post-hatch, there was no interaction between dietary CP and bile acids supplementation for BW, feed intake (FI), FCR, abdominal fat pad, and nutrient digestibility (P > 0.05). As a main effect, reducing dietary CP decreased BW, FI, fat digestibility, and increased FCR and abdominal fat pad (P < 0.01). The reduced CP diet resulted in lower plasma concentrations of valine, isoleucine, arginine, histidine, phenylalanine, leucine, and tryptophan, while increasing lysine, methionine, and threonine concentrations (P < 0.01). Bile acids supplementation enhanced dry matter and protein digestibility (P < 0.05). Bile acids also showed a tendency to increase plasma methionine concentrations (P = 0.055). A significant interaction effect was observed for overall mortality, with bile acids supplementation reducing mortality in birds fed reduced CP diets (P < 0.01). These findings suggest that in reduced CP diets, the current ideal AA profile may be deficient in arginine and histidine, potentially contributing to increased fat pad weight. Elevated wheat-derived non-starch polysaccharide concentrations might lower fat digestibility in reduced CP diets. Supplementation of bile acids in these diets could mitigate endogenous taurine losses and improve overall health in broiler chickens.
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Affiliation(s)
- Yumin Bao
- Redox Pty Ltd, Minto, NSW 2566, Australia
| | - Shemil P Macelline
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia; Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia
| | - Peter H Selle
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia
| | - Peter V Chrystal
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia; Aviagen, Auckland, New Zealand
| | - Mengzhu Wang
- Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia
| | - Sonia Y Liu
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia; Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia
| | | | - Mehdi Toghyani
- Poultry Research Foundation, The University of Sydney, Camden NSW 2570, Australia.
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21
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Ferrari A, Tontonoz P. Nonvesicular cholesterol transport in physiology. J Clin Invest 2025; 135:e188127. [PMID: 40091839 PMCID: PMC11910210 DOI: 10.1172/jci188127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.
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22
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Xu J, Xue Q, Xiong A, Chen Y, Wang X, Yan X, Ruan D, Zhang Y, Wang Z, Ding L, Yang L. Chlorogenic acid attenuates pyrrolizidine alkaloid-induced liver injury through modulation of the SIRT1/FXR signaling pathway. Chin Med 2025; 20:34. [PMID: 40069808 PMCID: PMC11899315 DOI: 10.1186/s13020-025-01077-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Pyrrolizidine alkaloids (PAs), recognized globally for their hepatotoxic properties, significantly contribute to liver damage through an imbalance in bile acid homeostasis. Addressing this imbalance is crucial for therapeutic interventions in PA-related liver injuries. Chlorogenic acid (Cga), a phenolic compound derived from medicinal plants, has demonstrated hepato-protective effects across a spectrum of liver disorders. The specific influence and underlying mechanisms by which Cga mitigates PA-induced liver damage have not been clearly defined. MATERIALS AND METHODS To explore the protective effects of Cga against acute PA toxicity, a murine model was established. The influence of Cga on bile acid metabolism was confirmed through a variety of molecular biology techniques. These included RNA sequencing, western blotting, and immunoprecipitation, along with quantitative analyses of bile acid concentrations. RESULTS Our findings indicate that Cga enhances sirtuin 1 (SIRT1) activation and increases farnesoid X receptor (FXR) signaling, which are crucial for maintaining bile acid balance in PA-induced hepatic injury. When mice subjected to PA-induced hepatic injury were treated with SIRT1 inhibitors alongside Cga, the hepatoprotective effects of Cga were significantly reduced. In Fxr-KO mice, the ability of Cga to mitigate liver damage induced by PAs was substantially reduced, which underscores the role of the SIRT1/FXR signaling axis in mediating the protective effects of Cga. CONCLUSION Our research suggests that Cga can serve as an effective treatment for PA-mediated hepatotoxicity. It appears that influencing the SIRT1/FXR signaling pathway might provide an innovative pharmacological approach to address liver damage caused by PAs.
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Affiliation(s)
- Jie Xu
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Pharmacy, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Qiongwen Xue
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Aizhen Xiong
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yilin Chen
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xing Yan
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Deqing Ruan
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yumeng Zhang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Gu M, Jiang H, Ma F, Li S, Guo Y, Zhu L, Shi C, Na R, Wang Y, Zhang W. Multi-Omics Analysis Revealed the Molecular Mechanisms Affecting Average Daily Gain in Cattle. Int J Mol Sci 2025; 26:2343. [PMID: 40076961 PMCID: PMC11900032 DOI: 10.3390/ijms26052343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/25/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
The average daily gain (ADG) is a critical index for evaluating growth rates in cattle and is closely linked to the economic benefits of the cattle industry. Heredity is one of the factors affecting the daily gain of cattle. However, the molecular mechanisms regulating ADG remain incompletely understood. This study aimed to systematically unravel the molecular mechanisms underlying the divergence in ADG between high average daily gain (HADG) and low average daily gain (LADG) Angus cattle through integrated multi-omics analyses (microbiome, metabolome, and transcriptome), hypothesizing that the gut microbiota-host gene-metabolism axis is a key regulatory network driving ADG divergence. Thirty Angus cattle were classified according to their HADG and LADG. Fecal and serum samples were collected for 16S, fecal metabolome, and blood transcriptome analysis. The results showed that compared with the LADG group, the abundance of Firmicutes increased in the HADG group, while the abundance of Bacteroidetes and Proteobacteria decreased. Metabolomics and transcriptomic analysis revealed that KEGG pathways associated with differentially expressed genes (DEGs) and differentially abundant metabolites (DAMs) were enriched in bile acid metabolism. Spearman correlation analysis showed that Oscillospira was positively correlated with ZBTB20 and negatively correlated with RADIL. ZBTB20 was negatively correlated with dgA-11_gut_group. This study analyzed the regulatory mechanism of average daily gain of beef cattle from genetic, metabolic, and microbial levels, providing a theoretical basis for analyzing the mechanism of differential daily gain of beef cattle, and has important significance for improving the production performance of beef cattle. The multi-omics network provides biomarker foundations for machine learning-based ADG prediction models, offering potential applications in precision breeding. While these biomarkers show promise for precision breeding, their causal roles require further validation. The conclusions are derived from a single breed (Angus) and gender (castrated males). Future studies should include females and diverse breeds to assess generalizability.
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Affiliation(s)
- Mingjuan Gu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Hongyu Jiang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Fengying Ma
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Shuai Li
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Yaqiang Guo
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Lin Zhu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Caixia Shi
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Risu Na
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Yu Wang
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010010, China
| | - Wenguang Zhang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
- College of Life Science, Inner Mongolia Agricultural University, Hohhot 010010, China
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24
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Li Z, Deng L, Cheng M, Ye X, Yang N, Fan Z, Sun L. Emerging role of bile acids in colorectal liver metastasis: From molecular mechanism to clinical significance (Review). Int J Oncol 2025; 66:24. [PMID: 39981904 PMCID: PMC11844338 DOI: 10.3892/ijo.2025.5730] [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: 10/25/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Liver metastasis is the leading cause of colorectal cancer (CRC)‑related mortality. Microbiota dysbiosis serves a role in the pathogenesis of colorectal liver metastases. Bile acids (BAs), cholesterol metabolites synthesized by intestinal bacteria, contribute to the metastatic cascade of CRC, encompassing colorectal invasion, migration, angiogenesis, anoikis resistance and the establishment of a hepatic pre‑metastatic niche. BAs impact inflammation and modulate the immune landscape within the tumor microenvironment by activating signaling pathways, which are used by tumor cells to facilitate metastasis. Given the widespread distribution of BA‑activated receptors in both tumor and immune cells, strategies aimed at restoring BA homeostasis and blocking metastasis‑associated signaling are of importance in cancer therapy. The present study summarizes the specific role of BAs in each step of colorectal liver metastasis, elucidating the association between BA and CRC progression to highlight the potential of BAs as predictive biomarkers for colorectal liver metastasis and their therapeutic potential in developing novel treatment strategies.
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Affiliation(s)
- Zhaoyu Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Lingjun Deng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Mengting Cheng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Xiandong Ye
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Nanyan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
| | - Li Sun
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
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25
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Ozbey AC, Meneses-Lorente G, Simmons B, McCallum S, Annaert P, Parrott N, Umehara K. Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics. Clin Pharmacokinet 2025; 64:437-451. [PMID: 39934586 DOI: 10.1007/s40262-024-01468-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2024] [Indexed: 02/13/2025]
Abstract
BACKGROUND AND OBJECTIVES This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically. METHOD After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp®. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined. RESULTS Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUCinf) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (Cmax) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted Cmax within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The Cmax and AUCinf were overestimated in HI patients and the trend to reduction of Cmax with minimal change in AUCinf with increasing severity of HI was not well captured. Decreasing Simcyp® default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5. CONCLUSION Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels. TRIAL REGISTRATION NCT number: NCT04226833.
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Affiliation(s)
- Agustos C Ozbey
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
- Drug Delivery and Disposition Lab, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Georgina Meneses-Lorente
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Brian Simmons
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Sam McCallum
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Pieter Annaert
- Drug Delivery and Disposition Lab, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
- BioNotus GCV, Niel, Belgium
| | - Neil Parrott
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
| | - Kenichi Umehara
- Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland
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26
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Meloun A, León B. Beyond CCR7: dendritic cell migration in type 2 inflammation. Front Immunol 2025; 16:1558228. [PMID: 40093008 PMCID: PMC11906670 DOI: 10.3389/fimmu.2025.1558228] [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] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Conventional dendritic cells (cDCs) are crucial antigen-presenting cells that initiate and regulate T cell responses, thereby shaping immunity against pathogens, innocuous antigens, tumors, and self-antigens. The migration of cDCs from peripheral tissues to draining lymph nodes (dLNs) is essential for their function in immune surveillance. This migration allows cDCs to convey the conditions of peripheral tissues to antigen-specific T cells in the dLNs, facilitating effective immune responses. Migration is primarily mediated by chemokine receptor CCR7, which is upregulated in response to homeostatic and inflammatory cues, guiding cDCs to dLNs. However, during type 2 immune responses, such as those triggered by parasites or allergens, a paradox arises-cDCs exhibit robust migration to dLNs despite low CCR7 expression. This review discusses how type 2 inflammation relies on additional signaling pathways, including those induced by membrane-derived bioactive lipid mediators like eicosanoids, sphingolipids, and oxysterols, which cooperate with CCR7 to enhance cDC migration and T helper 2 (Th2) differentiation. We explore the potential regulatory mechanisms of cDC migration in type 2 immunity, offering insights into the differential control of cDC trafficking in diverse immune contexts and its impact on immune responses.
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Affiliation(s)
- Audrey Meloun
- Innate Cells and Th2 Immunity Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Beatriz León
- Innate Cells and Th2 Immunity Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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27
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Wang Y, Bendre SV, Krauklis SA, Steelman AJ, Nelson ER. Role of Protein Regulators of Cholesterol Homeostasis in Immune Modulation and Cancer Pathophysiology. Endocrinology 2025; 166:bqaf031. [PMID: 39951497 PMCID: PMC11878532 DOI: 10.1210/endocr/bqaf031] [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: 10/28/2024] [Revised: 01/30/2025] [Accepted: 02/12/2025] [Indexed: 02/16/2025]
Abstract
Cholesterol metabolism and homeostasis have emerged as important factors governing various aspects of cancer biology. Clinical associations between circulating cholesterol and poor prognosis or use of cholesterol-lowering medication and improved prognosis have been noted for several different solid tumors. Mechanistically, cholesterol has many different direct and indirect effects on cancer cells themselves but is also critically involved in shaping the function of other cells of the tumor microenvironment, especially immune cells. There are 2 major feedback loops regulating cholesterol homeostasis. Here we highlight the major proteins involved in the so-called oxysterol-bile acid feedback loop and discuss how each has been implicated in cancer biology. We focus on roles within the immune system with implications for cancer. Given that many of these proteins are enzymes or nuclear receptors, both of which are amenable to small molecule intervention, we posit that this axis may represent a promising area for therapeutic intervention.
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Affiliation(s)
- Yu Wang
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Shruti V Bendre
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Steven A Krauklis
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Andrew J Steelman
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Urbana, IL 61801, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology- Anticancer Discovery from Pets to People (ERN) and Regenerative Biology & Tissue Engineering (AJS), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology- Anticancer Discovery from Pets to People (ERN) and Regenerative Biology & Tissue Engineering (AJS), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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28
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Caratis F, Karaszewski B, Klejbor I, Furihata T, Rutkowska A. Differential expression and modulation of EBI2 and 7α,25-OHC synthesizing (CH25H, CYP7B1) and degrading (HSD3B7) enzymes in mouse and human brain vascular cells. PLoS One 2025; 20:e0318822. [PMID: 39999050 PMCID: PMC11856462 DOI: 10.1371/journal.pone.0318822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
The endogenous ligand for the EBI2 receptor, oxysterol 7α,25OHC, crucial for immune responses, is finely regulated by CH25H, CYP7B1 and HSD3B7 enzymes. Lymphoid stromal cells and follicular dendritic cells within T cell follicles maintain a gradient of 7α,25OHC, with stromal cells increasing and dendritic cells decreasing its concentration. This gradient is pivotal for proper B cell positioning in lymphoid tissue. In the animal model of multiple sclerosis, the experimental autoimmune encephalomyelitis, the levels of 7α,25OHC rapidly increase in the central nervous system driving the migration of EBI2 expressing immune cells through the blood-brain barrier (BBB). To explore if blood vessel cells in the brain express these enzymes, we examined normal mouse brain microvessels and studied changes in their expression during inflammation. Ebi2 was abundantly expressed in endothelial cells, pericytes/smooth muscle cells, and astrocytic endfeet. Ch25h, Cyp7b1, and Hsd3b7 were variably detected in each cell type, suggesting their active involvement in oxysterol 7α,25OHC synthesis and gradient maintenance under normal conditions. Significant species-specific differences emerged in EBI2 and the enzyme levels between mouse and human BBB-forming cells. Under acute inflammatory conditions, Ebi2 and synthesizing enzyme modulation occurred in the brain, with the magnitude and direction of change based on the enzyme. Lastly, in an in vitro astrocyte migration model, CYP7B1 inhibitor clotrimazole, as well as EBI2 antagonist, NIBR189, inhibited lipopolysaccharide-induced cell migration indicating the involvement of EBI2 and its ligand in brain cell migration under inflammatory conditions.
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Affiliation(s)
- Fionä Caratis
- Department of Anatomy and Neurobiology, Medical University of Gdansk, Gdansk, Poland
| | - Bartosz Karaszewski
- Department of Adult Neurology, Medical University of Gdansk & University Clinical Center, Gdansk, Poland
- Brain Diseases Centre, Medical University of Gdansk, Gdansk, Poland
| | - Ilona Klejbor
- Department of Anatomy, Collegium Medicum, Jan Kochanowski University in Kielce, Kielce, Poland
| | - Tomomi Furihata
- Laboratory of Clinical Pharmacy and Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Aleksandra Rutkowska
- Department of Anatomy and Neurobiology, Medical University of Gdansk, Gdansk, Poland
- Brain Diseases Centre, Medical University of Gdansk, Gdansk, Poland
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29
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Tang Y, Zhang Y, Chen C, Cao Y, Wang Q, Tang C. Gut microbiota: A new window for the prevention and treatment of neuropsychiatric disease. J Cent Nerv Syst Dis 2025; 17:11795735251322450. [PMID: 39989718 PMCID: PMC11846125 DOI: 10.1177/11795735251322450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/11/2024] [Accepted: 01/27/2025] [Indexed: 02/25/2025] Open
Abstract
Under normal physiological conditions, gut microbiota and host mutually coexist. They play key roles in maintaining intestinal barrier integrity, absorption, and metabolism, as well as promoting the development of the central nervous system (CNS) and emotional regulation. The dysregulation of gut microbiota homeostasis has attracted significant research interest, specifically in its impact on neurological and psychiatric disorders. Recent studies have highlighted the important role of the gut- brain axis in conditions including Alzheimer's Disease (AD), Parkinson's Disease (PD), and depression. This review aims to elucidate the regulatory mechanisms by which gut microbiota affect the progression of CNS disorders via the gut-brain axis. Additionally, we discuss the current research landscape, identify gaps, and propose future directions for microbial interventions against these diseases. Finally, we provide a theoretical reference for clinical treatment strategies and drug development for AD, PD, and depression.
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Affiliation(s)
- Yali Tang
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yizhu Zhang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Chen Chen
- Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Ying Cao
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, People’s Republic of China
| | - Qiaona Wang
- School of Ecology and Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing, People’s Republic of China
| | - Chuanfeng Tang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
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30
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Soma H, Yoshida R, Ishizuka S. Quantitative analysis of sterol balance in a mouse model of hepatic lipid accumulation induced by cholesterol and cholic acid supplementation. Biosci Biotechnol Biochem 2025; 89:438-445. [PMID: 39656874 DOI: 10.1093/bbb/zbae183] [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: 09/25/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024]
Abstract
The cholesterol balance and bile acid metabolism in a mouse model of hepatic lipid accumulation induced by a diet supplemented with cholesterol and cholic acid (CA) were quantitatively evaluated. The mice were fed diets supplemented with different levels of cholesterol (0, 3, or 6 g/kg of diet) and CA (0.5 g/kg of diet) for 6 weeks. Cholesterol supplementation doubled the hepatic triglyceride concentration, regardless of the supplementation level, without inflammation or gallstone formation. Both cholesterol supplementations enhanced fecal excretion of muricholic acid. Additionally, the higher cholesterol supplementation led to an increase in fecal cholesterol excretion, accompanied by elevated expression of hepatic cholesterol exporters and a reduction in fecal bile acid excretion. In this mouse study, supplementation with 3 g cholesterol/kg diet and 0.5 g CA/kg diet was sufficient to induce hepatic lipid accumulation.
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Affiliation(s)
- Hinata Soma
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Ryo Yoshida
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Satoshi Ishizuka
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
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31
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Lu Y, Du J, Peng S, Wang Y, Xiao Y. Therapeutic potential of isoallolithocholic acid in methicillin-resistant Staphylococcus Aureus peritoneal infection. J Antibiot (Tokyo) 2025; 78:166-180. [PMID: 39690242 DOI: 10.1038/s41429-024-00800-9] [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: 09/17/2024] [Revised: 11/17/2024] [Accepted: 12/04/2024] [Indexed: 12/19/2024]
Abstract
A significant increase in multidrug-resistant Methicillin-resistant Staphylococcus aureus (MRSA) infections has made it crucial to explore new antimicrobial drugs and strategies. Emerging evidence suggests that the bile acid metabolite isoallolithocholic acid (isoallo-LCA) may contribute to reducing the risk of infection among centenarians. However, its precise role remains somewhat ambiguous and necessitates further investigation. This study aims to investigate the roles of isoallo-LCA in MRSA-associated peritoneal infection. The effects of isoallo-LCA on peritoneal infection are examined in a MRSA-induced peritoneal infected model. Antibacterial activity, biofilm formation assay, and bacterial membrane permeability experiments are conducted to explore the mechanisms involved. Our findings demonstrate that isoallo-LCA effectively suppresses the replication of MRSA with minimal adverse effects on mammalian cells. Furthermore, isoallo-LCA significantly inhibits the formation of bacterial biofilms and eradicates existing bacterial biofilms of MRSA. Administration of isoallo-LCA reduces MRSA colonization in peritoneal organs and alleviates peritonitis-related inflammation and damage in a MRSA-infected peritonitis mice. Mechanistically, isoallo-LCA exhibits potent bactericidal activity against MRSA by disrupting the integrity and permeability of bacterial cells. In addition, isoallo-LCA also enhances the macrophage phagocytosis. In conclusion, our results suggest that isoallo-LCA could be an effective treatment for infections caused by MRSA.
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Affiliation(s)
- Ying Lu
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Jun Du
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Shicheng Peng
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
- Shanghai Institute of Pediatric Research, Shanghai, China
| | - Ying Wang
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
- Shanghai Institute of Pediatric Research, Shanghai, China.
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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32
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Lin Q, Zhang J, Qi J, Tong J, Chen S, Zhang S, Liu X, Lou H, Lv J, Lin R, Xie J, Jin Y, Wang Y, Ying L, Wu J, Niu J. Hepatocyte-Derived FGF1 Alleviates Isoniazid and Rifampicin-Induced Liver Injury by Regulating HNF4α-Mediated Bile Acids Synthesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408688. [PMID: 39731358 PMCID: PMC11831436 DOI: 10.1002/advs.202408688] [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: 07/27/2024] [Revised: 12/09/2024] [Indexed: 12/29/2024]
Abstract
Isoniazid and rifampicin co-therapy are the main causes of anti-tuberculosis drug-induced liver injury (ATB-DILI) and acute liver failure, seriously threatening human health. However, its pathophysiology is not fully elucidated. Growing evidences have shown that fibroblast growth factors (FGFs) play a critical role in diverse aspects of liver pathophysiology. The aim of this study is to investigate the role of FGFs in the pathogenesis of isoniazid (INH) and rifampicin (RIF)-induced liver injury. Through systematic screening, this study finds that hepatic FGF1 expression is significantly downregulated in both mouse model and human patients challenged with INH and RIF. Hepatocyte-specific Fgf1 deficiency exacerbates INH and RIF-induced liver injury resulted from elevated bile acids (BAs) synthases and aberrant BAs accumulation. Conversely, pharmacological administration of the non-mitogenic FGF1 analog - FGF1ΔHBS significantly alleviated INH and RIF-induced liver injury via restoring BAs homeostasis. Mechanically, FGF1 repressed hepatocyte nuclear factor 4α (Hnf4α) transcription via activating FGF receptor 4 (FGFR4)-ERK1/2 signaling pathway, thus reducing BAs synthase. The findings demonstrate hepatic FGF1 functions as a negative regulator of BAs biosynthesis to protect against INH and RIF-induced liver injury via normalizing hepatic BAs homeostasis, providing novel mechanistic insights into the pathogenesis of ATB-DILI and potential therapeutic strategies for treatment of ATB-DILI.
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Affiliation(s)
- Qian Lin
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jiaren Zhang
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jie Qi
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jialin Tong
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Shenghuan Chen
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Sudan Zhang
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Xingru Liu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Huatong Lou
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jiaxuan Lv
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Ruoyu Lin
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Junjun Xie
- Department of PharmacySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310016China
| | - Yi Jin
- Department of PathologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325035China
| | - Yang Wang
- School of Basic Medical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Lei Ying
- School of Basic Medical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jiamin Wu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
| | - Jianlou Niu
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouZhejiang325035China
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33
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Cai X, Cai X, Xie Q, Xiao X, Li T, Zhou T, Sun H. NLRP3 inflammasome and gut microbiota-brain axis: a new perspective on white matter injury after intracerebral hemorrhage. Neural Regen Res 2025; 21:01300535-990000000-00684. [PMID: 39885662 PMCID: PMC12094575 DOI: 10.4103/nrr.nrr-d-24-00917] [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: 10/08/2024] [Revised: 10/09/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025] Open
Abstract
ABSTRACT Intracerebral hemorrhage is the most dangerous subtype of stroke, characterized by high mortality and morbidity rates, and frequently leads to significant secondary white matter injury. In recent decades, studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota-brain axis. This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury. The NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in this context. This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome. These mechanisms include metabolic pathways (involving short-chain fatty acids, lipopolysaccharides, lactic acid, bile acids, trimethylamine-N-oxide, and tryptophan), neural pathways (such as the vagus nerve and sympathetic nerve), and immune pathways (involving microglia and T cells). We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage. The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood-brain barrier, inducing neuroinflammation, and interfering with nerve regeneration. Finally, we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury. Our review highlights the critical role of the gut microbiota-brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage, paving the way for exploring potential therapeutic approaches.
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Affiliation(s)
- Xiaoxi Cai
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xinhong Cai
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Quanhua Xie
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xueqi Xiao
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Tong Li
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Tian Zhou
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong–Hong Kong–Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Haitao Sun
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong–Hong Kong–Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, Guangdong Province, China
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Atkins JS, Keevil BG, Taylor AE, Ludwig C, Hawley JM. Development and validation of a novel 7α-hydroxy-4-cholesten-3-one (C4) liquid chromatography tandem mass spectrometry method and its utility to assess pre-analytical stability. Clin Chem Lab Med 2025; 63:154-163. [PMID: 39097844 DOI: 10.1515/cclm-2024-0275] [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: 02/29/2024] [Accepted: 07/12/2024] [Indexed: 08/05/2024]
Abstract
OBJECTIVES 7α-Hydroxy-4-cholesten-3-one (C4) is the common intermediary of both primary bile acids. C4 is recommended by the British Society of Gastroenterology for the investigation of bile acid diarrhoea (BAD) in patients with chronic diarrhoea. This project aimed to develop and validate an assay to quantitate C4 in serum and assess the stability of C4 in unseparated blood. METHODS Accuracy was underpinned by calibrating to quantitative nuclear magnetic resonance analysis. C4 was analysed in a 96-well plate format with a deuterated C4 internal standard and liquid-liquid extraction. Validation followed the 2018 Food and Drug Administration guidelines. To assess C4 stability, healthy volunteers (n=12) donated 8 fasted samples each. Samples were incubated at 20 °C for up to 72 h and retrieved, centrifuged, aliquoted and frozen for storage at different time points prior to C4 analysis. RESULTS The C4 method demonstrated excellent analytical performance and passed all validation criteria. The method was found to be accurate, precise, free from matrix effects and interference. After 72 h of delayed sample separation, C4 concentration gradually declined by up to 14 % from baseline. However, the change was not significant for up to 12 h. CONCLUSIONS We present a robust method of analysing serum C4, offering a convenient alternative to 75SeHCAT for BAD investigation. C4 was found to decline in unseparated blood over time; however, after 12 h the mean change was <5 % from baseline. Our results suggest C4 is suitable for collection from both primary and secondary care prior to gastroenterology referral.
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Affiliation(s)
- Jonathan S Atkins
- Department of Clinical Biochemistry, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Wythenshawe, UK
| | - Brian G Keevil
- Department of Clinical Biochemistry, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Wythenshawe, UK
| | - Angela E Taylor
- Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, UK
| | - Christian Ludwig
- Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, UK
| | - James M Hawley
- Department of Clinical Biochemistry, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Wythenshawe, UK
- Medical Research Council, Laboratory of Medical Sciences, London, UK
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Bintee B, Banerjee R, Hegde M, Vishwa R, Alqahtani MS, Abbas M, Alqahtani A, Rangan L, Sethi G, Kunnumakkara AB. Exploring bile acid transporters as key players in cancer development and treatment: Evidence from preclinical and clinical studies. Cancer Lett 2025; 609:217324. [PMID: 39571783 DOI: 10.1016/j.canlet.2024.217324] [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: 07/11/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 12/01/2024]
Abstract
Bile acid transporters (BATs) are integral membrane proteins belonging to various families, such as solute carriers, organic anion transporters, and ATP-binding cassette families. These transporters play a crucial role in bile acid transportation within the portal and systemic circulations, with expression observed in tissues, including the liver, kidney, and small intestine. Bile acids serve as signaling molecules facilitating the absorption and reabsorption of fats and lipids. Dysregulation of bile acid concentration has been implicated in tumorigenesis, yet the role of BATs in this process remains underexplored. Emerging evidence suggests that BATs may modulate various stages of cancer progression, including initiation, development, proliferation, metastasis, and tumor microenvironment regulation. Targeting BATs using siRNAs, miRNAs, and small compound inhibitors in preclinical models and their polymorphisms are well-studied for transporters like BSEP, MDR1, MRP2, OATP1A2, etc., and have shed light on their involvement in tumorigenesis, particularly in cancers such as those affecting the liver and gastrointestinal tract. While BATs' role in diseases like Alagille syndrome, biliary atresia, and cirrhosis have been extensively studied, their implications in cancer warrant further investigation. This review highlights the expression and function of BATs in cancer development and emphasizes the potential of targeting these transporters as a novel therapeutic strategy for various malignancies.
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Affiliation(s)
- Bintee Bintee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ruchira Banerjee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India; Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Athba Alqahtani
- Research Centre, King Fahad Medical City, P.O. Box: 59046, Riyadh, 11525, Saudi Arabia
| | - Latha Rangan
- Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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Ghannadzadeh Kermani Pour R, Kamali Zounouzi S, Farshbafnadi M, Rezaei N. The interplay between gut microbiota composition and dementia. Rev Neurosci 2025:revneuro-2024-0113. [PMID: 39829047 DOI: 10.1515/revneuro-2024-0113] [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: 08/20/2024] [Accepted: 01/03/2025] [Indexed: 01/22/2025]
Abstract
Recently, researchers have been interested in the potential connection between gut microbiota composition and various neuropsychological disorders. Dementia significantly affects the socioeconomics of families. Gut microbiota is considered as a probable factor in its pathogenesis. Multiple bacterial metabolites such as short-chain fatty acids, lipopolysaccharides, and various neurotransmitters that are responsible for the incidence and progression of dementia can be produced by gut microbiota. Various bacterial species such as Bifidobacterium breve, Akkermansia muciniphila, Streptococcus thermophilus, Escherichia coli, Blautia hydrogenotrophica, etc. are implicated in the pathogenesis of dementia. Gut microbiota can be a great target for imitating or inhibiting their metabolites as an adjunctive therapy based on their role in its pathogenesis. Therefore, some diets can prevent or decelerate dementia by altering the gut microbiota composition. Moreover, probiotics can modulate gut microbiota composition by increasing beneficial bacteria and reducing detrimental species. These therapeutic modalities are considered novel methods that are probably safe and effective. They can enhance the efficacy of traditional medications and improve cognitive function.
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Affiliation(s)
| | - Sara Kamali Zounouzi
- School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
| | - Melina Farshbafnadi
- School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
| | - Nima Rezaei
- Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Department of Immunology, School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
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Li S, An J, Zhang T, Chen G, Zhang Z, Guo Z, Dai Z, Cheng X, Cheng S, Xiong X, Wang N, Jiang G, Xu B, Lei H. Integration of network pharmacology, UHPLC-Q exactive orbitrap HRMS technique and metabolomics to elucidate the active ingredients and mechanisms of compound danshen pills in treating hypercholesterolemic rats. JOURNAL OF ETHNOPHARMACOLOGY 2025; 336:118759. [PMID: 39209003 DOI: 10.1016/j.jep.2024.118759] [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: 06/22/2024] [Revised: 08/18/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hypercholesterolemia (HLC) was a key risk factor for cardiovascular disease (CVD) characterized by elevated cholesterol levels, particularly LDL. While traditional Chinese medicine preparations Compound Danshen Pills(CDP) has been clinically used for hypercholesterolemia and coronary heart disease, its specific therapeutic effect on HLC remains understudied, necessitating further investigation into its mechanisms. AIM OF THE STUDY The aim of this study was to explore the potential of CDP in treating HLC and elucidate its underlying mechanisms and active components. MATERIALS AND METHODS A hypercholesterolemic lipemia rat model induced by a high-fat diet was employed. Network pharmacology combined with UHPLC-Q exactive orbitrap HRMS technique was used to predict the active components, targets and mechanisms of CDP for HLC. Histological analysis and serum biochemical assays were used to assess the therapeutic effect of CDP and its main active ingredient Sa B on hypercholesterolemic lipemia rat model. Immunofluorescence assays and western blotting were used to verify the mechanism of CDP and Sa B in the treatment of HLC. Metabolomics approach was used to demonstrate that CDP and Sa B affected the metabolic profile of HLC. RESULTS Our findings demonstrated that both CDP and its main active ingredient Sa B significantly ameliorated hypercholesterolemic lipemic lesions, reducing levels of TC, LDL, AST, ALT, and ALP. Histological analysis revealed a decrease in lipid droplet accumulation and collagen fiber deposition in the liver, as well as reduced collagen fiber deposition in the aorta. Network pharmacology predicted potential targets such as PPARα and CYP27A1. Immunofluorescence assays and western blotting confirmed that CDP and Sa B upregulated the expression of Adipor1, PPARα and CYP27A1. Metabolomics analyses further indicated improvements in ABC transporters metabolic pathways, with differential metabolites such as riboflavin, taurine, and choline showed regression in levels after CDP treatment and riboflavin, L-Threonine, Thiamine, L-Leucine, and Adenosine showed improved expression after Sa B treatment. CONCLUSION CDP and Sa B have been shown to alleviate high-fat diet-induced hypercholesterolemia by activating the PPAR pathway and improving hepatic lipid metabolism. Our study demonstrated, for the first time, the complex mechanism of CDP, Sa B in the treatment of hypercholesterolemia at the protein and metabolic levels and provided a new reference that could elucidate the pharmacological effects of traditional Chinese medicine on hypercholesterolemia from multiple perspectives.
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Affiliation(s)
- Shanlan Li
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Jin An
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Tong Zhang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Guangyun Chen
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Zixuan Zhang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Zhuoqian Guo
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Ziqi Dai
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Xuehao Cheng
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China
| | - Sijin Cheng
- School of Nursing, Beijing University of Chinese Medicine, Beijing, 102488, China
| | | | - Nan Wang
- Aimin Pharmaceutical Group, Henan, 463500, China
| | | | - Bing Xu
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China.
| | - Haimin Lei
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102400, China.
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Zhang J, Xu S, Yue L, Lei H, Zhai X. A Collection of Novel Antitumor Agents That Regulate Lipid Metabolism in the Tumor Microenvironment. J Med Chem 2025; 68:49-80. [PMID: 39726379 DOI: 10.1021/acs.jmedchem.4c02809] [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: 12/28/2024]
Abstract
Lipid metabolism disorder is the cause of one of the most significant metabolic changes in tumors. In the process of tumor occurrence and development, tumor cells choose a continuous metabolic adaptation to accommodate the changing environment to the maximum extent possible. In a variety of tumors, the uptake, production, and storage of lipids are generally upregulated. Tumor cells take advantage of lipid metabolism to access basic energy, biofilm components, and signal molecules of the tumor microenvironment required for proliferation, survival, invasion, and metastasis. This Perspective briefly uncovers the main metabolic processes and key factors involved in lipid metabolism reprogramming, mainly related to lipid uptake, de novo synthesis and storage of fatty acids, oxidation of fatty acids, cholesterol synthesis, and related regulatory factors. From a medicinal chemistry perspective, agents against related key targets are reviewed, expecting to pave the way for promising antitumor drugs with prospects for application through lipid metabolism reprogramming.
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Affiliation(s)
- Jiahao Zhang
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
| | - Sha Xu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
| | - Lingfeng Yue
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
| | - Hongrui Lei
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
| | - Xin Zhai
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China
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Song L, Hou Y, Xu D, Dai X, Luo J, Liu Y, Huang Z, Yang M, Chen J, Hu Y, Chen C, Tang Y, Rao Z, Ma J, Zheng M, Shi K, Cai C, Lu M, Tang R, Ma X, Xie C, Luo Y, Li X, Huang Z. Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress. Cell Metab 2025; 37:104-120.e9. [PMID: 39393353 DOI: 10.1016/j.cmet.2024.09.008] [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: 03/11/2024] [Revised: 07/31/2024] [Accepted: 09/12/2024] [Indexed: 10/13/2024]
Abstract
Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.
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Affiliation(s)
- Lintao Song
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yushu Hou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Da Xu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xijia Dai
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianya Luo
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhuobing Huang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Miaomiao Yang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jie Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yue Hu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuchu Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yuli Tang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhiheng Rao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianjia Ma
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minghua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chao Cai
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Mingqin Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yongde Luo
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Zhifeng Huang
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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Kastrinou-Lampou V, Rodríguez-Pérez R, Poller B, Huth F, Schadt HS, Kullak-Ublick GA, Arand M, Camenisch G. Drug-induced cholestasis (DIC) predictions based on in vitro inhibition of major bile acid clearance mechanisms. Arch Toxicol 2025; 99:377-391. [PMID: 39542928 DOI: 10.1007/s00204-024-03895-z] [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: 09/28/2023] [Accepted: 10/17/2024] [Indexed: 11/17/2024]
Abstract
Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (p-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision-recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.
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Affiliation(s)
- Vlasia Kastrinou-Lampou
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Birk Poller
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Felix Huth
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Heiko S Schadt
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, CMO and Patient Safety, Global Drug Development, Novartis, Basel, Switzerland
| | - Michael Arand
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Gian Camenisch
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland.
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41
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Aydin Ö, Wahlström A, de Jonge PA, Meijnikman AS, Sjöland W, Olsson L, Henricsson M, de Goffau MC, Oonk S, Bruin SC, Acherman YIZ, Marschall HU, Gerdes VEA, Nieuwdorp M, Bäckhed F, Groen AK. An integrated analysis of bile acid metabolism in humans with severe obesity. Hepatology 2025; 81:19-31. [PMID: 39010331 DOI: 10.1097/hep.0000000000000938] [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: 02/12/2024] [Accepted: 03/26/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND AND AIMS Bile acids (BA) are vital regulators of metabolism. BAs are AQ6 secreted in the small intestine, reabsorbed, and transported back to the liver, where they can modulate metabolic functions. There is a paucity of data regarding the portal BA composition in humans. This study aimed to address this knowledge gap by investigating portal BA composition and the relation with peripheral and fecal BA dynamics in conjunction with the gut microbiome. APPROACH AND RESULTS Thirty-three individuals from the BARIA cohort were included. Portal plasma, peripheral plasma, and feces were collected. BA and C4 levels were measured employing mass spectrometry. FGF19 was measured using ELISA. Gut microbiota composition was determined through metagenomics analysis on stool samples. Considerable diversity in the portal BA composition was observed. The majority (n = 26) of individuals had a 9-fold higher portal than peripheral BA concentration. In contrast, 8 individuals showed lower portal BA concentration compared with peripheral and had higher levels of unconjugated and secondary BA in this compartment, suggesting more distal origin. The altered portal BA profile was associated with altered gut microbiota composition. In particular, taxa within Bacteroides were reduced in abundance in the feces of these individuals. CONCLUSIONS Characterization of the portal BA composition in relation to peripheral and fecal BA increased insight into the dynamics of BA metabolism in individuals with obesity. Peripheral BA composition was much more diverse due to microbial metabolism. About 24% of the portal samples was surprisingly low in total BA; the underlying mechanism requires further exploration.
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Affiliation(s)
- Ömrüm Aydin
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Annika Wahlström
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Patrick A de Jonge
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Abraham S Meijnikman
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Wilhelm Sjöland
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lisa Olsson
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Marcus Henricsson
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Marcus C de Goffau
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Stijn Oonk
- Department of Scientific Research, Data Science, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Sjoerd C Bruin
- Department of Bariatric Surgery, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Yair I Z Acherman
- Department of Bariatric Surgery, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Hanns-Ulrich Marschall
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Victor E A Gerdes
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Bariatric Surgery, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
- Department of Internal Medicine, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Max Nieuwdorp
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Fredrik Bäckhed
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Albert K Groen
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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42
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Hazra S, Chakraborthy G. Effects of Diabetes and Hyperlipidemia in Physiological Conditions - A Review. Curr Diabetes Rev 2025; 21:24-34. [PMID: 38409688 DOI: 10.2174/0115733998289406240214093815] [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: 12/01/2023] [Revised: 01/19/2024] [Accepted: 01/25/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND Diabetes mellitus (DM) is an autoimmune manifestation defined by persistent hyperglycemia and alterations in protein, fatty substances, and carbohydrate metabolism as an effect of problems with the secretion of insulin action or both. Manifestations include thirst, blurred eyesight, weight loss, and ketoacidosis, which can majorly lead to coma. There are different types of diabetes according to class or by cellular level. They are interrelated with hyperlipidemia as they are involved in the metabolism and regulation of physiological factors. Most parameters are seen at cellular or humoral levels, yet the underlying concern remains the same. OBJECTIVE To create a systematic correlation between the disease and locate the exact mechanism and receptors responsible for it. So, this article covers a proper way to resolve the conditions and their manifestation through literacy and diagrammatic. CONCLUSION Hence, this will be an insight for many scholars to understand the exact mechanism involved in the process.
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Affiliation(s)
- Sayan Hazra
- Department of Pharmacology, Parul Institute of Pharmacy and Research, Parul University, Vadodara, Gujarat, 391760, India
| | - Gunosindhu Chakraborthy
- Parul Institute of Pharmacy and Research, Parul University, Vadodara, Gujarat, 391760, India
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43
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Green M, Trivedi MH, Foster JA. Microbes and mood: innovative biomarker approaches in depression. Trends Mol Med 2025; 31:50-63. [PMID: 39353744 DOI: 10.1016/j.molmed.2024.09.002] [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: 05/14/2024] [Revised: 08/18/2024] [Accepted: 09/09/2024] [Indexed: 10/04/2024]
Abstract
Although the field of psychiatry has made gains in biomarker discovery, our ability to change long-term outcomes remains inadequate. Matching individuals to the best treatment for them is a persistent clinical challenge. Moreover, the development of novel treatments has been hampered in part due to a limited understanding of the biological mechanisms underlying individual differences that contribute to clinical heterogeneity. The gut microbiome has become an area of intensive research in conditions ranging from metabolic disorders to cancer. Innovation in these spaces has led to translational breakthroughs, offering novel microbiome-informed approaches that may improve patient outcomes. In this review we examine how translational microbiome research is poised to advance biomarker discovery in mental health, with a focus on depression.
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Affiliation(s)
- Miranda Green
- Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, ON, Canada
| | - Madhukar H Trivedi
- Center for Depression Research and Clinical Care, Department of Psychiatry and Peter O'Donnell Jr Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jane A Foster
- Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, ON, Canada; Center for Depression Research and Clinical Care, Department of Psychiatry and Peter O'Donnell Jr Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
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44
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K M M, Ghosh P, Nagappan K, Palaniswamy DS, Begum R, Islam MR, Tagde P, Shaikh NK, Farahim F, Mondal TK. From Gut Microbiomes to Infectious Pathogens: Neurological Disease Game Changers. Mol Neurobiol 2025; 62:1184-1204. [PMID: 38967904 DOI: 10.1007/s12035-024-04323-0] [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: 04/02/2024] [Accepted: 06/19/2024] [Indexed: 07/06/2024]
Abstract
Gut microbiota and infectious diseases affect neurological disorders, brain development, and function. Compounds generated in the gastrointestinal system by gut microbiota and infectious pathogens may mediate gut-brain interactions, which may circulate throughout the body and spread to numerous organs, including the brain. Studies shown that gut bacteria and disease-causing organisms may pass molecular signals to the brain, affecting neurological function, neurodevelopment, and neurodegenerative diseases. This article discusses microorganism-producing metabolites with neuromodulator activity, signaling routes from microbial flora to the brain, and the potential direct effects of gut bacteria and infectious pathogens on brain cells. The review also considered the neurological aspects of infectious diseases. The infectious diseases affecting neurological functions and the disease modifications have been discussed thoroughly. Recent discoveries and unique insights in this perspective need further validation. Research on the complex molecular interactions between gut bacteria, infectious pathogens, and the CNS provides valuable insights into the pathogenesis of neurodegenerative, behavioral, and psychiatric illnesses. This study may provide insights into advanced drug discovery processes for neurological disorders by considering the influence of microbial communities inside the human body.
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Affiliation(s)
- Muhasina K M
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India.
| | - Puja Ghosh
- Department of Pharmacognosy, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | - Krishnaveni Nagappan
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ooty, Tamil Nadu, 643001, India
| | | | - Rahima Begum
- Department of Microbiology, Gono Bishwabidyalay, Dhaka, Bangladesh
| | - Md Rabiul Islam
- Tennessee State University Chemistry department 3500 John A Merritt Blvd, Nashville, TN, 37209, USA
| | - Priti Tagde
- PRISAL(Pharmaceutical Royal International Society), Branch Office Bhopal, Bhopal, Madhya Pradesh, 462042, India
| | - Nusrat K Shaikh
- Department of Quality Assurance, Smt. N. M, Padalia Pharmacy College, Navapura, Ahmedabad, 382 210, Gujarat, India
| | - Farha Farahim
- Department of Nursing, King Khalid University, Abha, 61413, Kingdom of Saudi Arabia
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45
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Roumain M, Muccioli GG. Development and application of an LC-MS/MS method for the combined quantification of oxysterols and bile acids. J Lipid Res 2025; 66:100697. [PMID: 39557296 PMCID: PMC11761337 DOI: 10.1016/j.jlr.2024.100697] [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: 04/10/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/20/2024] Open
Abstract
Oxysterols and bile acids are interconnected bioactive lipids playing pivotal roles in diverse physiological and pathological processes. For this reason, they are increasingly studied together for their implications in various diseases. However, due to analytical challenges inherent to the nature of these analytes, very few methods have been developed for the simultaneous analysis of these lipids. We here report the development of a sensitive LC-MS/MS method for the combined quantification of 18 oxysterols, 11 unconjugated, 15 conjugated bile acids, and 1 bile acid precursor, using 8 isotope-labeled internal standards, addressing the need for a more comprehensive analysis of these interesting lipid families. During the method development, we investigated different extraction protocols, set up a purification step, and achieved chromatographic separation for these lipids, overcoming challenges such as the large number of analytes, isomers, and wide range of polarity across the analytes. Finally, the method was successfully applied to the analysis of preclinical and clinical samples, quantifying 12 oxysterols and 14 bile acids in human plasma, 10 oxysterols and 18 bile acids in mouse plasma from the vena cava, and 10 oxysterols and 20 bile acids in mouse plasma from the portal vein within a single chromatographic run.
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Affiliation(s)
- Martin Roumain
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
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46
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Darmanto AG, Yen TL, Jan JS, Linh TTD, Taliyan R, Yang CH, Sheu JR. Beyond metabolic messengers: Bile acids and TGR5 as pharmacotherapeutic intervention for psychiatric disorders. Pharmacol Res 2025; 211:107564. [PMID: 39733841 DOI: 10.1016/j.phrs.2024.107564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Psychiatric disorders pose a significant global health challenge, exacerbated by the COVID-19 pandemic and insufficiently addressed by the current treatments. This review explores the emerging role of bile acids and the TGR5 receptor in the pathophysiology of psychiatric conditions, emphasizing their signaling within the gut-brain axis. We detail the synthesis and systemic functions of bile acids, their transformation by gut microbiota, and their impact across various neuropsychiatric disorders, including major depressive disorder, general anxiety disorder, schizophrenia, autism spectrum disorder, and bipolar disorder. The review highlights how dysbiosis and altered bile acid metabolism contribute to the development and exacerbation of these neuropsychiatric disorders through mechanisms involving inflammation, oxidative stress, and neurotransmitter dysregulation. Importantly, we detail both pharmacological and non-pharmacological interventions that modulate TGR5 signaling, offering potential breakthroughs in treatment strategies. These include dietary adjustments to enhance beneficial bile acids production and the use of specific TGR5 agonists that have shown promise in preclinical and clinical settings for their regulatory effects on critical pathways such as cAMP-PKA, NRF2-mediated antioxidant responses, and neuroinflammation. By integrating findings from the dynamics of gut microbiota, bile acids metabolism, and TGR5 receptor related signaling events, this review underscores cutting-edge therapeutic approaches poised to revolutionize the management and treatment of psychiatric disorders.
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Affiliation(s)
- Arief Gunawan Darmanto
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; School of Medicine, Universitas Ciputra, Surabaya 60219, Indonesia
| | - Ting-Lin Yen
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Department of Medical Research, Cathay General Hospital, Taipei 22174, Taiwan, ROC
| | - Jing-Shiun Jan
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC
| | - Tran Thanh Duy Linh
- Family Medicine Training Center, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Viet Nam
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Chih-Hao Yang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Joen-Rong Sheu
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan, ROC; Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
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47
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Pollard MD, Meyer WK, Puckett EE. Convergent relaxation of molecular constraint in herbivores reveals the changing role of liver and kidney functions across mammalian diets. Genome Res 2024; 34:2176-2189. [PMID: 39578099 PMCID: PMC11694762 DOI: 10.1101/gr.278930.124] [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: 01/01/2024] [Accepted: 10/16/2024] [Indexed: 11/24/2024]
Abstract
Mammalia comprises a great diversity of diet types and associated adaptations. An understanding of the genomic mechanisms underlying these adaptations may offer insights for improving human health. Comparative genomic studies of diet that employ taxonomically restricted analyses or simplified diet classifications may suffer reduced power to detect molecular convergence associated with diet evolution. Here, we use a quantitative carnivory score-indicative of the amount of animal protein in the diet-for 80 mammalian species to detect significant correlations between the relative evolutionary rates of genes and changes in diet. We have identified six genes-ACADSB, CLDN16, CPB1, PNLIP, SLC13A2, and SLC14A2-that experienced significant changes in evolutionary constraint alongside changes in carnivory score, becoming less constrained in lineages evolving more herbivorous diets. We further consider the biological functions associated with diet evolution and observe that pathways related to amino acid and lipid metabolism, biological oxidation, and small molecule transport experienced reduced purifying selection as lineages became more herbivorous. Liver and kidney functions show similar patterns of constraint with dietary change. Our results indicate that these functions are important for the consumption of animal matter and become less important with the evolution of increasing herbivory. So, genes expressed in these tissues experience a relaxation of evolutionary constraint in more herbivorous lineages.
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Affiliation(s)
- Matthew D Pollard
- Department of Biological Sciences, University of Memphis, Memphis, Tennessee 38152, USA;
- Center for Biodiversity Research, University of Memphis, Memphis, Tennessee 38152, USA
| | - Wynn K Meyer
- Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015, USA
| | - Emily E Puckett
- Department of Biological Sciences, University of Memphis, Memphis, Tennessee 38152, USA
- Center for Biodiversity Research, University of Memphis, Memphis, Tennessee 38152, USA
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48
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Qu Q, Chen Y, Wang Y, Long S, Wang W, Yang HY, Li M, Tian X, Wei X, Liu YH, Xu S, Zhang C, Zhu M, Lam SM, Wu J, Yun C, Chen J, Xue S, Zhang B, Zheng ZZ, Piao HL, Jiang C, Guo H, Shui G, Deng X, Zhang CS, Lin SC. Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature 2024:10.1038/s41586-024-08329-5. [PMID: 39695227 DOI: 10.1038/s41586-024-08329-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 10/31/2024] [Indexed: 12/20/2024]
Abstract
Calorie restriction (CR) is a dietary intervention used to promote health and longevity1,2. CR causes various metabolic changes in both the production and the circulation of metabolites1; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, we identify that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner.
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Affiliation(s)
- Qi Qu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Yan Chen
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Yu Wang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Shating Long
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Weiche Wang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Heng-Ye Yang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Mengqi Li
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Xiao Tian
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Xiaoyan Wei
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Yan-Hui Liu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Shengrong Xu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Cixiong Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Mingxia Zhu
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | | | - Jianfeng Wu
- Laboratory Animal Research Centre, Xiamen University, Fujian, China
| | - Chuyu Yun
- State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, China
| | - Junjie Chen
- Analysis and Measurement Centre, School of Pharmaceutical Sciences, Xiamen University, Fujian, China
| | - Shengye Xue
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Baoding Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Zhong-Zheng Zheng
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Hai-Long Piao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Liaoning, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, Department of Immunology, School of Basic Medical Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University, Beijing, China
| | - Hao Guo
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
- Xiang'an Hospital of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Guanghou Shui
- Institute of Genetics and Development Biology, Chinese Academy of Sciences, Beijing, China
| | - Xianming Deng
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China
| | - Chen-Song Zhang
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
| | - Sheng-Cai Lin
- State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
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49
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Zhao Z, Xing N, Sun G. Identification of 7-HOCA as a Potential Biomarker in Glioblastoma: Evidence from Genome-Wide Association Study and Clinical Validation. Int J Gen Med 2024; 17:6185-6197. [PMID: 39691836 PMCID: PMC11651077 DOI: 10.2147/ijgm.s493488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/27/2024] [Indexed: 12/19/2024] Open
Abstract
Purpose Glioblastoma (GBM) is associated with metabolic disturbances, yet the relationships between metabolites with GBM have not been comprehensively explored. This study aims to fill this gap by integrating Mendelian randomization (MR) analysis with clinical validation. Patients and Methods Summary data from genome-wide association study (GWAS) of cerebrospinal fluid (CSF) metabolites, plasma metabolites, and GBM were obtained separately. A total of 338 CSF metabolites and 1400 plasma metabolites were utilized as exposures. Concurrently, GBM was designated as the outcome. A two-sample bidirectional MR study was conducted to investigate the potential association. The inverse variance weighted (IVW) analyses were conducted as causal estimates, accompanied by a series of sensitivity analyses to evaluate the robustness of the results. Additionally, metabolite levels in clinical plasma and CSF samples were quantified using liquid chromatography-mass spectrometry to validate the findings. Results MR analysis identified eight CSF metabolites and six plasma metabolites that were closely associated with GBM. Among these, elevated levels of 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) in both CSF and plasma were found to promote GBM. In terms of clinical validation, compared to the control group, 7-HOCA levels were significantly higher in both the CSF and plasma of GBM group. Conclusion This study provides a comprehensive analysis of the metabolic factors contributing to GBM. The identification of specific metabolites, particularly 7-HOCA, that have vital roles in GBM pathogenesis suggests new biomarkers and therapeutic targets, offering potential pathways for improved diagnosis and treatment of GBM.
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Affiliation(s)
- Zhenxiang Zhao
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Na Xing
- Department of Endocrinology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Guozhu Sun
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
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Lu C, Gao Z, Zhang S, Du K, Xu D, Dong W, Zhang Y, Lei X. The bile acid metabolome in umbilical cord blood and meconium of healthy newborns: distinct characteristics and implications. PeerJ 2024; 12:e18506. [PMID: 39686994 PMCID: PMC11648689 DOI: 10.7717/peerj.18506] [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: 06/12/2024] [Accepted: 10/21/2024] [Indexed: 12/18/2024] Open
Abstract
Objective To characterize the bile acid metabolomic profiles of umbilical cord blood and meconium in healthy newborns. Methods Fifteen healthy newborns, which born in the Obstetrics Department of the Affiliated Hospital of Southwest Medical University between July 1 and August 31, 2023, were selected as study subjects. Umbilical cord blood and meconium samples were collected, and bile acid metabolomics were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry. Results The ratio of primary to secondary bile acids in cord blood was significantly higher than in meconium [2.64 (2.49, 5.70) vs. 0.99 (0.37, 1.58), Z = -3.80, P < 0.05]. The ratio of unconjugated to conjugated bile acids was notably higher in cord blood than in meconium [0.14 (0.07, 0.18) vs. 0.01 (0.01, 0.04), Z = -3.88, P < 0.05]. The ratio of cholic acid to chenodeoxycholic acid in conjugated primary bile acids was significantly lower in cord blood than in meconium [0.59 (0.19, 0.75) vs. 2.21 (1.34, 3.04), Z = -4.21, P < 0.05], but the ratio of cholic acid to chenodeoxycholic acid in secondary bile acids was significantly higher in cord blood than in meconium [0.42 (0.21, 0.63) vs. 0.03 (0.01, 0.05), Z = -4.54, P < 0.05]. Only three primary bile acids (taurochenodeoxycholic acid, glycochenodeoxycholic acid, and glycochenodeoxycholic acid 3-glucoside in umbilical cord blood) were correlated with their downstream metabolites in meconium (with hyodesoxycholic acid (r = -0.66, P = 0.01), tauro-ω-muricholic acid (r = 0.52, P = 0.048) and ursodeoxycholic acid-7S (r = -0.53, P = 0.04), respectively). In meconium, most of primary bile acids were correlated with their downstream metabolites (P all < 0.05): cholic acid was positively correlated with 3-dehydrocholic acid, taurocholic acid was positively correlated with taurodeoxycholic acid and 3-dehydrocholic acid, glycocholic acid was positively correlated with 3-dehydrocholic acid, chenodeoxycholic acid was positively correlated with glycoursodeoxycholic acid, taurolithocholic acid, and 7-keto lithocholic acid and negatively correlated with isolithocholic acid. Taurochenodeoxycholic acid was positively correlated with taurohyodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, taurolithocholic acid, tauro-ω-muricholic acid, and glycohyodeoxycholic acid, while glycochenodeoxycholic acid was positively correlated with tauroursodeoxycholic acid, glycoursodeoxycholic acid, taurolithocholic acid, and glycohyodeoxycholic acid, and negatively correlated with isolithocholic acid. Conclusion The bile acid metabolites in umbilical cord blood and meconium differ significantly, and the downstream bile acid metabolites in meconium are predominantly correlated with their upstream bile acids in meconium, but not those bile acids in umbilical cord blood. These findings contribute to a better understanding of bile acid metabolism in utero and lay the foundation for future research in this topic.
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Affiliation(s)
- Chunxia Lu
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhiyong Gao
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Siqi Zhang
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Ke Du
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Die Xu
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Wenbin Dong
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yujiao Zhang
- Department of Obstetrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Xiaoping Lei
- Division of Neonatology, Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Sichuan Clinical Research Center for Birth Defects, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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