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Li O, Zhou Y, Kim D, Xu H, Bao Z, Yang F. Lactococcus petauri LZys1 modulates gut microbiota, diminishes ileal FXR-FGF15 signaling, and regulates hepatic function. Microbiol Spectr 2025:e0171624. [PMID: 40243350 DOI: 10.1128/spectrum.01716-24] [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: 07/10/2024] [Accepted: 03/10/2025] [Indexed: 04/18/2025] Open
Abstract
Recent studies have indicated that Lactococcus petauri LZys1 (L. petauri LZys1), isolated from healthy human feces, exhibits a promising probiotic profile in vitro. However, its impact on the physiological status of the host in vivo remains uncertain. The objective of our study was to investigate the effects and mechanisms of orally administering L. petauri LZys1 on gut microbiota and liver function in mice. We administered L. petauri LZys1 through daily oral gavage to C57BL/6 male mice. Subsequently, we analyzed changes in gut microbiota composition using 16S rRNA sequencing and quantified alterations in hepatic-intestinal bile acid (BA) profile. Serum biochemical parameters were assessed to evaluate liver function. Our findings revealed that L. petauri LZys1 led to an increase in body weight, liver mass, and serum aminotransferase levels. Oral administration altered the gut microbiota composition, resulting in reduced diversity and abundance of intestinal bacteria. Additionally, the profiles of BAs were suppressed across organs, associated with the downregulation of the ileum's farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) signaling pathway. The decrease in circulating FGF15 mediated the downregulation of hepatic fibroblast growth factor receptor 4 (FGFR4)/FXR, disrupting BA metabolism and fatty acid oxidation. Our findings suggest that L. petauri LZys1 may impact liver function by influencing the gut microbiota-mediated ileal FXR-FGF15 axis and inhibiting hepatic bile acid metabolism. IMPORTANCE This work elucidated the impact of L. petauri LZys1 on host gut microbiota metabolism and hepatic physiological metabolism. We observed that L. petauri LZys1 administration induced liver weight gain and biochemical parameters changes, in addition to a altered gut microbiota and suppressed bile acid (BA) profiles. Furthermore, we propose that changes in liver status are related to the enterohepatic farnesoid X receptor-fibroblast growth factor axis, which alters bile acid metabolism and disrupts liver function. The above findings suggest that attention should be paid to the effect of probiotics on liver function.
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Affiliation(s)
- Ouyang Li
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Digestive Endoscopy Center, Huadong Hospital, Fudan University, Shanghai, China
| | - Yingshun Zhou
- Department of Pathogenic Biology, Public Center of Experimental Technology of Pathogen Biology Technology Platform, Southwest Medical University, Luzhou, Sichuan, China
| | - Dayoung Kim
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Gerontology, Huadong Hospital, Fudan University, Shanghai, China
| | - Han Xu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Gerontology, Huadong Hospital, Fudan University, Shanghai, China
| | - Zhijun Bao
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Gerontology, Huadong Hospital, Fudan University, Shanghai, China
| | - Fan Yang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- Department of Gerontology, Huadong Hospital, Fudan University, Shanghai, China
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Pérez Escriva P, Correia Tavares Bernardino C, Letellier E. De-coding the complex role of microbial metabolites in cancer. Cell Rep 2025; 44:115358. [PMID: 40023841 DOI: 10.1016/j.celrep.2025.115358] [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: 08/09/2024] [Revised: 12/11/2024] [Accepted: 02/06/2025] [Indexed: 03/04/2025] Open
Abstract
The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.
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Affiliation(s)
- Pau Pérez Escriva
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Catarina Correia Tavares Bernardino
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisabeth Letellier
- Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
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3
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Belka M, Gostyńska-Stawna A, Stawny M, Krajka-Kuźniak V. Activation of Nrf2 and FXR via Natural Compounds in Liver Inflammatory Disease. Int J Mol Sci 2024; 25:11213. [PMID: 39456994 PMCID: PMC11508530 DOI: 10.3390/ijms252011213] [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: 09/27/2024] [Revised: 10/13/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Liver inflammation is frequently linked to oxidative stress and dysregulation of bile acid and fatty acid metabolism. This review focuses on the farnesoid X receptor (FXR), a critical regulator of bile acid homeostasis, and its interaction with the nuclear factor erythroid 2-related factor 2 (Nrf2), a key modulator of cellular defense against oxidative stress. The review explores the interplay between FXR and Nrf2 in liver inflammatory diseases, highlighting the potential therapeutic effects of natural FXR agonists. Specifically, compounds such as auraptene, cafestol, curcumin, fargesone A, hesperidin, lycopene, oleanolic acid, resveratrol, rutin, ursolic acid, and withaferin A are reviewed for their ability to modulate both the FXR and Nrf2 pathways. This article discusses their potential to alleviate liver inflammation, oxidative stress, and damage in diseases such as metabolic-associated fatty liver disease (MAFLD), cholestatic liver injury, and viral hepatitis. In addition, we address the molecular mechanisms driving liver inflammation, including oxidative stress, immune responses, and bile acid accumulation, while also summarizing relevant experimental models. This review emphasizes the promising therapeutic potential of targeting both the Nrf2 and FXR pathways using natural compounds, paving the way for future treatments for liver diseases. Finally, the limitations of the clinical application were indicated, and further research directions were proposed.
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Affiliation(s)
- Marta Belka
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland;
- Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
| | - Aleksandra Gostyńska-Stawna
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.G.-S.); (M.S.)
| | - Maciej Stawny
- Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.G.-S.); (M.S.)
| | - Violetta Krajka-Kuźniak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland;
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4
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Ning S, Zhang Z, Zhou C, Wang B, Liu Z, Feng B. Cross-talk between macrophages and gut microbiota in inflammatory bowel disease: a dynamic interplay influencing pathogenesis and therapy. Front Med (Lausanne) 2024; 11:1457218. [PMID: 39355844 PMCID: PMC11443506 DOI: 10.3389/fmed.2024.1457218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 08/28/2024] [Indexed: 10/03/2024] Open
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic immune-mediated gastrointestinal disorders. The etiology of IBD is multifactorial, involving genetic susceptibility, environmental factors, and a complex interplay between the gut microbiota and the host's immune system. Intestinal resident macrophages play an important role in the pathogenesis and progress of IBD, as well as in maintaining intestinal homeostasis and facilitating tissue repair. This review delves into the intricate relationship between intestinal macrophages and gut microbiota, highlighting their pivotal roles in IBD pathogenesis. We discuss the impact of macrophage dysregulation and the consequent polarization of different phenotypes on intestinal inflammation. Furthermore, we explore the compositional and functional alterations in gut microbiota associated with IBD, including the emerging significance of fungal and viral components. This review also examines the effects of current therapeutic strategies, such as 5-aminosalicylic acid (5-ASA), antibiotics, steroids, immunomodulators, and biologics, on gut microbiota and macrophage function. We underscore the potential of fecal microbiota transplantation (FMT) and probiotics as innovative approaches to modulate the gut microbiome in IBD. The aim is to provide insights into the development of novel therapies targeting the gut microbiota and macrophages to improve IBD management.
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Affiliation(s)
- Shiyang Ning
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhe Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chuan Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Binbin Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhanju Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Shanghai, China
| | - Baisui Feng
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Navarro León A, Muñoz M, Iglesias N, Blanco-Vázquez C, Balseiro A, Milhano Santos F, Ciordia S, Corrales FJ, Iglesias T, Casais R. Proteomic Serum Profiling of Holstein Friesian Cows with Different Pathological Forms of Bovine Paratuberculosis Reveals Changes in the Acute-Phase Response and Lipid Metabolism. J Proteome Res 2024; 23:2762-2779. [PMID: 37863471 PMCID: PMC11301775 DOI: 10.1021/acs.jproteome.3c00244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 10/22/2023]
Abstract
The lack of sensitive diagnostic methods to detect Mycobacterium avium subsp. paratuberculosis (Map) subclinical infections has hindered the control of paratuberculosis (PTB). The serum proteomic profiles of naturally infected cows presenting focal and diffuse pathological forms of PTB and negative controls (n = 4 per group) were analyzed using TMT-6plex quantitative proteomics. Focal and diffuse are the most frequent pathological forms in subclinical and clinical stages of PTB, respectively. One (focal versus (vs.) control), eight (diffuse vs. control), and four (focal vs. diffuse) differentially abundant (DA) proteins (q-value < 0.05) were identified. Ingenuity pathway analysis of the DA proteins revealed changes in the acute-phase response and lipid metabolism. Six candidate biomarkers were selected for further validation by specific ELISA using serum from animals with focal, multifocal, and diffuse PTB-associated lesions (n = 108) and controls (n = 56). Overall, the trends of the serum expression levels of the selected proteins were consistent with the proteomic results. Alpha-1-acid glycoprotein (ORM1)-based ELISA, insulin-like growth factor-binding protein 2 (IGFBP2)-based ELISA, and the anti-Map ELISA had the best diagnostic performance for detection of animals with focal, multifocal, and diffuse lesions, respectively. Our findings identify potential biomarkers that improve diagnostic sensitivity of PTB and help to elucidate the mechanisms involved in PTB pathogenesis.
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Affiliation(s)
- Alejandra
Isabel Navarro León
- Center
for Animal Biotechnology, Servicio Regional
de Investigación y Desarrollo Agroalimentario [SERIDA], 33394 Deva, Asturias, Spain
| | - Marta Muñoz
- Center
for Animal Biotechnology, Servicio Regional
de Investigación y Desarrollo Agroalimentario [SERIDA], 33394 Deva, Asturias, Spain
| | - Natalia Iglesias
- Center
for Animal Biotechnology, Servicio Regional
de Investigación y Desarrollo Agroalimentario [SERIDA], 33394 Deva, Asturias, Spain
| | - Cristina Blanco-Vázquez
- Center
for Animal Biotechnology, Servicio Regional
de Investigación y Desarrollo Agroalimentario [SERIDA], 33394 Deva, Asturias, Spain
| | - Ana Balseiro
- Departamento
de Sanidad Animal, Facultad de Veterinaria, Universidad de León, 24071 León, Spain
| | - Fátima Milhano Santos
- Functional
Proteomics Laboratory, National Center for Biotechnology, Consejo Superior de Investigaciones Científicas [CSIC],
Proteored-ISCIII, 28049 Madrid, Spain
| | - Sergio Ciordia
- Functional
Proteomics Laboratory, National Center for Biotechnology, Consejo Superior de Investigaciones Científicas [CSIC],
Proteored-ISCIII, 28049 Madrid, Spain
| | - Fernando J. Corrales
- Functional
Proteomics Laboratory, National Center for Biotechnology, Consejo Superior de Investigaciones Científicas [CSIC],
Proteored-ISCIII, 28049 Madrid, Spain
| | - Tania Iglesias
- Unidad
de Consultoría Estadística, Servicios Científico-técnicos, Universidad de Oviedo, Campus de Gijón, 33203 Gijón, Asturias, Spain
| | - Rosa Casais
- Center
for Animal Biotechnology, Servicio Regional
de Investigación y Desarrollo Agroalimentario [SERIDA], 33394 Deva, Asturias, Spain
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Miao H, Tang X, Cui Y, Shi J, Xiong X, Wang C, Zhang Y. Obeticholic Acid Inhibit Mitochondria Dysfunction Via Regulating ERK1/2-DRP Pathway to Exert Protective Effect on Lipopolysaccharide-Induced Myocardial Injury. Adv Biol (Weinh) 2024; 8:e2300576. [PMID: 38728002 DOI: 10.1002/adbi.202300576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 04/19/2024] [Indexed: 07/13/2024]
Abstract
Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis-associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre-treated with OCA before LPS treatment, and extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 is used. LPS-induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF-2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochrome C (Cyt-C) diffusion. Moreover, OCA pretreatment inhibited LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway. FXR agonist OCA inhibits LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway to protect mice against LPS-induced myocardial injury.
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Affiliation(s)
- Huijie Miao
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Xiaomeng Tang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Yun Cui
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Jingyi Shi
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Xi Xiong
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Chunxia Wang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Yucai Zhang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
- Clinical Research Unit, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
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Haybar H, Hadi H, Purrahman D, Mahmoudian-Sani MR, Saki N. Emerging roles of HOTAIR lncRNA in the pathogenesis and prognosis of cardiovascular diseases. Biomark Med 2024; 18:203-219. [PMID: 38411079 DOI: 10.2217/bmm-2023-0368] [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] [Indexed: 02/28/2024] Open
Abstract
Highlights HOTAIR, a long noncoding RNA, plays a role in the regulation of proteins involved in the pathogenesis of cardiovascular disease. Furthermore, it has been identified as a biomarker of this type of disease. Several factors and cells contribute to atherosclerosis, a progressive disease. However, the prognosis of HOTAIR in this disease varies depending on the path in which it plays a role. For this condition, there is no single prognosis to consider.
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Affiliation(s)
- Habib Haybar
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hakimeh Hadi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Daryush Purrahman
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Reza Mahmoudian-Sani
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Khan MAH, Nolan B, Stavniichuk A, Merk D, Imig JD. Dual soluble epoxide hydrolase inhibitor - farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis. Front Immunol 2024; 14:1269261. [PMID: 38235144 PMCID: PMC10791967 DOI: 10.3389/fimmu.2023.1269261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 12/12/2023] [Indexed: 01/19/2024] Open
Abstract
Introduction Renal fibrosis associated with inflammation is a critical pathophysiological event in chronic kidney disease (CKD). We have developed DM509 which acts concurrently as a farnesoid X receptor agonist and a soluble epoxide hydrolase inhibitor and investigated DM509 efficacy as an interventional treatment using the unilateral ureteral obstruction (UUO) mouse model. Methods Male mice went through either UUO or sham surgery. Interventional DM509 treatment (10mg/kg/d) was started three days after UUO induction and continued for 7 days. Plasma and kidney tissue were collected at the end of the experimental protocol. Results UUO mice demonstrated marked renal fibrosis with higher kidney hydroxyproline content and collagen positive area. Interventional DM509 treatment reduced hydroxyproline content by 41% and collagen positive area by 65%. Renal inflammation was evident in UUO mice with elevated MCP-1, CD45-positive immune cell positive infiltration, and profibrotic inflammatory gene expression. DM509 treatment reduced renal inflammation in UUO mice. Renal fibrosis in UUO was associated with epithelial-to-mesenchymal transition (EMT) and DM509 treatment reduced EMT. UUO mice also had tubular epithelial barrier injury with increased renal KIM-1, NGAL expression. DM509 reduced tubular injury markers by 25-50% and maintained tubular epithelial integrity in UUO mice. Vascular inflammation was evident in UUO mice with 9 to 20-fold higher ICAM and VCAM gene expression which was reduced by 40-50% with DM509 treatment. Peritubular vascular density was reduced by 35% in UUO mice and DM509 prevented vascular loss. Discussion Interventional treatment with DM509 reduced renal fibrosis and inflammation in UUO mice demonstrating that DM509 is a promising drug that combats renal epithelial and vascular pathological events associated with progression of CKD.
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Affiliation(s)
- Md. Abdul Hye Khan
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Benjamin Nolan
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Anna Stavniichuk
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Daniel Merk
- Department of Pharmacy, Ludwig-Maximilians Universität München, Munich, Germany
| | - John D. Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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Narayanan AK, Surendran S, Balakrishnan D, Gopalakrishnan U, Malick S, Valsan A, Philips CA, Watson CJE. A Short Review on Obeticholic Acid: An Effective Modulator of Farnesoid X Receptor. Curr Rev Clin Exp Pharmacol 2024; 19:225-233. [PMID: 38708917 DOI: 10.2174/0127724328239536230919070001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 07/10/2023] [Accepted: 08/04/2023] [Indexed: 05/07/2024]
Abstract
Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.
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Affiliation(s)
- Anila Kutty Narayanan
- Department of Gastrointestinal Surgery & Solid Organ Transplant, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India
| | - Sudhindran Surendran
- Department of Gastrointestinal Surgery & Solid Organ Transplant, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India
| | - Dinesh Balakrishnan
- Department of Gastrointestinal Surgery & Solid Organ Transplant, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India
| | - Unnikrishnan Gopalakrishnan
- Department of Gastrointestinal Surgery & Solid Organ Transplant, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India
| | - Shweta Malick
- Department of Gastrointestinal Surgery & Solid Organ Transplant, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India
| | - Arun Valsan
- Department of Gastroenterology & Hepatology, Amrita Institute of Medical Sciences & Research Centre, Amrita University, Kochi 682041, Kerala, India
| | - Cyriac Abby Philips
- Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
| | - Christopher John Edward Watson
- University of Cambridge and Honorary Consultant Surgeon, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK
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10
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Nenkov M, Shi Y, Ma Y, Gaßler N, Chen Y. Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy. Int J Mol Sci 2023; 25:6. [PMID: 38203175 PMCID: PMC10778939 DOI: 10.3390/ijms25010006] [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: 11/08/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed.
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Affiliation(s)
- Miljana Nenkov
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Yihui Shi
- California Pacific Medical Center Research Institute, Sutter Bay Hospitals, San Francisco, CA 94107, USA;
| | - Yunxia Ma
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Nikolaus Gaßler
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
| | - Yuan Chen
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
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11
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Bao Z, Wei R, Zheng X, Zhang T, Bi Y, Shen S, Zou P, Zhang J, Yan H, Li MD, Yang Z, Gao H. Landscapes of gut microbiome and bile acid signatures and their interaction in HBV-associated acute-on-chronic liver failure. Front Microbiol 2023; 14:1185993. [PMID: 37275140 PMCID: PMC10233926 DOI: 10.3389/fmicb.2023.1185993] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/17/2023] [Indexed: 06/07/2023] Open
Abstract
Introduction Submassive hepatic necrosis (SMHN, defined as necrosis of 15-90% of the entire liver on explant) is a likely characteristic pathological feature of ACLF in patients with hepatitis B cirrhosis. We aimed to comprehensively explore microbiome and bile acids patterns across enterhepatic circulation and build well-performing machine learning models to predict SMHN status. Methods Based on the presence or absence of SMHN, 17 patients with HBV-related end-stage liver disease who received liver transplantation were eligible for inclusion. Serum, portal venous blood, and stool samples were collected for comparing differences of BA spectra and gut microbiome and their interactions. We adopted the random forest algorithm with recursive feature elimination (RF-RFE) to predict SMHN status. Results By comparing total BA spectrum between SMHN (-) and SMHN (+) patients, significant changes were detected only in fecal (P = 0.015). Compared with the SMHN (+) group, the SMHN (-) group showed that UDCA, 7-KLCA, 3-DHCA, 7-KDCA, ISOLCA and α-MCA in feces, r-MCA, 7-KLCA and 7-KDCA in serum, γ-MCA and 7-KLCA in portal vein were enriched, and TUDCA in feces was depleted. PCoA analysis showed significantly distinct overall microbial composition in two groups (P = 0.026). Co-abundance analysis showed that bacterial species formed strong and broad relationships with BAs. Among them, Parabacteroides distasonis had the highest node degree. We further identified a combinatorial marker panel with a high AUC of 0.92. Discussion Our study demonstrated the changes and interactions of intestinal microbiome and BAs during enterohepatic circulation in ACLF patients with SMHN. In addition, we identified a combinatorial marker panel as non-invasive biomarkers to distinguish the SMHN status with high AUC.
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Affiliation(s)
- Zhiwei Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Runan Wei
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoping Zheng
- Department of Infectious Diseases, ShuLan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Ting Zhang
- Department of Infectious Diseases, ShuLan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Yunjiao Bi
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Sijia Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Pengfei Zou
- Department of Infectious Diseases, ShuLan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Junjie Zhang
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Huadong Yan
- Department of Infectious Diseases, ShuLan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Ming D. Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hainv Gao
- Department of Infectious Diseases, ShuLan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
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12
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Cao L, Qin R, Liu J. Farnesoid X receptor protects against lipopolysaccharide-induced endometritis by inhibiting ferroptosis and inflammatory response. Int Immunopharmacol 2023; 118:110080. [PMID: 37001382 DOI: 10.1016/j.intimp.2023.110080] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 03/31/2023]
Abstract
Endometritis is an inflammatory condition that affects the endometrium; it is induced by bacterial infection and often leads to infertility and repeated abortions. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that mediates a variety of inflammatory diseases. In the present study, we determined the protective effects of FXR on lipopolysaccharide (LPS)-induced endometritis in mice and the underlying mechanisms. The results showed that LPS administration reduced the expression of FXR in the uterus, and treatment with the FXR agonist GW4064 and fexaramine significantly alleviated the endometritis induced by LPS. In addition, compared with wild-type (WT) mice, FXR-knockout mice had more severe inflammatory responses in their uteri after LPS treatment. Moreover, ferroptosis was increased during LPS-induced endometritis, as shown by increased levels of malondialdehyde (MDA) and iron, and decreased levels of superoxide dismutase (SOD), glutathione (GSH), GXP4 and SLC7A11. In addition, inhibition of ferroptosis by treatment with ferrostation-1 (Fer-1) and liproxstatin (Lip-1) alleviated LPS-induced endometritis. Additionally, FXR-knockout mice were used to determine the relationship between FXR and ferroptosis. The results showed that knockout of FXR induced ferroptosis, and an FXR agonist inhibited LPS-induced ferroptosis. Finally, the regulatory effects of obeticholic acid (OCA) on FXR/ferroptosis and endometritis were assessed. The results showed that treatment with OCA increased the expression of FXR, decreased the levels of ferroptosis, and inhibited the endometritis induced by LPS. In conclusion, the results showed that activation of FXR can alleviate LPS-induced endometritis by inhibiting ferroptosis, and FXR may be a potential therapeutic target for treating endometritis.
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Affiliation(s)
- Lu Cao
- Department of Obstetrics, China-Japan Union Hospital of Jilin University, Erdao District, 126 Sendai Street, Changchun, Jilin Province 130033, China
| | - Rui Qin
- Department of Gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China
| | - Junbao Liu
- Department of Gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
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13
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George M, Lang M, Gali CC, Babalola JA, Tam-Amersdorfer C, Stracke A, Strobl H, Zimmermann R, Panzenboeck U, Wadsack C. Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells. Cells 2023; 12:cells12081186. [PMID: 37190095 DOI: 10.3390/cells12081186] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/06/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
Oxysterols are oxidized cholesterol derivatives whose systemic levels are found elevated in pregnancy disorders such as gestational diabetes mellitus (GDM). Oxysterols act through various cellular receptors and serve as a key metabolic signal, coordinating inflammation. GDM is a condition of low-grade chronic inflammation accompanied by altered inflammatory profiles in the mother, placenta and fetus. Higher levels of two oxysterols, namely 7-ketocholesterol (7-ketoC) and 7β-hydroxycholesterol (7β-OHC), were observed in fetoplacental endothelial cells (fpEC) and cord blood of GDM offspring. In this study, we tested the effects of 7-ketoC and 7β-OHC on inflammation and investigated the underlying mechanisms involved. Primary fpEC in culture treated with 7-ketoC or 7β-OHC, induced the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling, which resulted in the expression of pro-inflammatory cytokines (IL-6, IL-8) and intercellular cell adhesion molecule-1 (ICAM-1). Liver-X receptor (LXR) activation is known to repress inflammation. Treatment with LXR synthetic agonist T0901317 dampened oxysterol-induced inflammatory responses. Probucol, an inhibitor of LXR target gene ATP-binding cassette transporter A-1 (ABCA-1), antagonized the protective effects of T0901317, suggesting a potential involvement of ABCA-1 in LXR-mediated repression of inflammatory signaling in fpEC. TLR-4 inhibitor Tak-242 attenuated pro-inflammatory signaling induced by oxysterols downstream of the TLR-4 inflammatory signaling cascade. Taken together, our findings suggest that 7-ketoC and 7β-OHC contribute to placental inflammation through the activation of TLR-4. Pharmacologic activation of LXR in fpEC decelerates its shift to a pro-inflammatory phenotype in the presence of oxysterols.
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Affiliation(s)
- Meekha George
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria
| | - Magdalena Lang
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, Austria
| | | | | | - Carmen Tam-Amersdorfer
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, Austria
| | - Anika Stracke
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, Austria
| | - Herbert Strobl
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, Austria
| | - Robert Zimmermann
- Institute for Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Ute Panzenboeck
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, Austria
| | - Christian Wadsack
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria
- BioTech-Med, 8010 Graz, Austria
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14
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Repurposing FDA-approved drugs as FXR agonists: a structure based in silico pharmacological study. Biosci Rep 2023; 43:231090. [PMID: 35348180 PMCID: PMC9977715 DOI: 10.1042/bsr20212791] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/10/2022] [Accepted: 03/28/2022] [Indexed: 11/17/2022] Open
Abstract
Farnesoid X receptor (FXR) modulates the expression of genes involved in lipid and carbohydrate homeostasis and inflammatory processes. This nuclear receptor is likely a tumor suppressor in several cancers, but its molecular mechanism of suppression is still under study. Several studies reported that FXR agonism increases the survival of colorectal, biliary tract, and liver cancer patients. In addition, FXR expression was shown to be down-regulated in many diseases such as obesity, irritable bowel syndrome, glomerular inflammation, diabetes, proteinuria, and ulcerative colitis. Therefore, development of novel FXR agonists may have significant potential in the prevention and treatment of these diseases. In this scenario, computer-aided drug design procedures can be resourcefully applied for the rapid identification of promising drug candidates. In the present study, we applied the molecular docking method in conjunction with molecular dynamics (MD) simulations to find out potential agonists for FXR based on structural similarity with the drug that is currently used as FXR agonist, obeticholic acid. Our results showed that alvimopan and montelukast could be used as potent FXR activators and outperform the binding affinity of obeticholic acid by forming stable conformation with the protein in silico. However, further investigational studies and validations of the selected drugs are essential to figure out their suitability for preclinical and clinical trials.
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15
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Jin HL, Liu XJ, Feng XY, Zhu WT, Feng SL, Cao LP, Yuan ZW. Quercetin 7-rhamnoside protects against alpha-naphthylisothiocyanate (ANIT)-induced in cholestatic hepatitis rats by improving biliary excretion and inhibiting inflammatory responses. Front Pharmacol 2023; 13:1116257. [PMID: 36699093 PMCID: PMC9868710 DOI: 10.3389/fphar.2022.1116257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Objective: To explore the pharmacological effects and molecular mechanism of quercetin 7-rhamnoside (Q7R) in the treatment of cholestatic hepatitis induced by alpha-naphthylisothiocyanate (ANIT). Methods: ANIT-induced cholestatic hepatitis rat model was used to investigate the hepatoprotective effects of three different doses of Q7R (1.25 mg/kg; 2.5 mg/kg; 5 mg/kg). Serum biochemical indices were detected using commercial kits. H&E and masson staining were used to observe hepatic tissue damage and collagen deposition in hepatocytes. The metabolism of bile acid-related substances was detected via HPLC-MS/MS by 5-(diisopropylamino) amylamine (DIAAA) derivative method. Hepatocyte injury, cholestasis, and inflammation were detected at the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, respectively. Results: Q7R can decrease the level of CYP7A1, and increase FXR, CYP27A1 so then improving abnormal bile acid secretion. Furthermore, Q7R can also ameliorating inflammation by reduce TNF-α, IL-1β, PTGS1, PTGS2, NCOA2, NF-κB level. Therefore, Q7R had an effective therapeutic effect on ANIT-induced cholestatic hepatitis, improving abnormal bile acid secretion, and inhibiting inflammatory responses. Conclusion: The results demonstrated that Q7R treat cholestatic hepatitis by regulating bile acid secretion and alleviating inflammation.
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Affiliation(s)
- Hong-Liu Jin
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Xiao-Jia Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Ying Feng
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Wen-Ting Zhu
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Sen-Ling Feng
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China
| | - Li-Ping Cao
- Department of Pharmacy, Shenzhen Bao’an Traditional Chinese Medicine Hospital Group, Guangzhou University of Chinese Medicine, Shenzhen, China,*Correspondence: Li-Ping Cao, ; Zhong-Wen Yuan,
| | - Zhong-Wen Yuan
- Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China,Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangzhou Medical University, Guangzhou, China,*Correspondence: Li-Ping Cao, ; Zhong-Wen Yuan,
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16
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Xu J, Yao X, Li X, Xie S, Chi S, Zhang S, Cao J, Tan B. Farnesoid X receptor regulates PI 3K/AKT/mTOR signaling pathway, lipid metabolism, and immune response in hybrid grouper. FISH PHYSIOLOGY AND BIOCHEMISTRY 2022; 48:1521-1538. [PMID: 36210393 DOI: 10.1007/s10695-022-01130-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 09/28/2022] [Indexed: 05/13/2023]
Abstract
Some diseases related to lipid metabolism increase yearly in cultured fish, and the farnesoid X receptor (FXR) is a nuclear protein that plays a key role in inflammatory responses and lipid metabolism. However, the roles of FXR in hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂) remain poorly understood. The main objective of this study was to explore the roles of hepatic FXR in triggering the immune response and the potential functions of FXR in regulating the lipid metabolism. In the present study, the full-length sequence of fxr from hybrid grouper was cloned and characterized for the first time. Upon the Vibrio parahaemolyticus stimulation, the transcriptional level of fxr was rapidly elevated in the head kidney tissue in the early stage of infection. In vivo and vitro, activation of FXR by obeticholic acid (OA) significantly increased the concentrations and mRNA levels of hepatic inflammatory cytokines. These effects were inversed when FXR was inhibited by guggulsterone (GU). Moreover, the activation of FXR to suppress the PI3K/AKT/mTOR signaling pathway improves hepatic lipid metabolism and reduces hepatic lipid accumulation in vivo and vitro. In addition, the inhibition of FXR activated the PI3K/AKT/mTOR pathway, decreased the lipolysis and increased the lipogenesis, and subsequently increased the lipid accumulation in fish. These results revealed the positive roles of FXR in triggering immune responses and improving lipid metabolism and accumulation in hybrid grouper.
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Affiliation(s)
- Jia Xu
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China
| | - Xinzhou Yao
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China
| | - Xiaoyue Li
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China
| | - Shiwei Xie
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China.
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China.
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China.
- Guangdong Provincial Key Lab of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Zhanjiang, China.
| | - Shuyan Chi
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Junming Cao
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524088, China.
- Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Center of Guangdong Province, Zhanjiang, China.
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, China.
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17
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Fiaschini N, Mancuso M, Tanori M, Colantoni E, Vitali R, Diretto G, Lorenzo Rebenaque L, Stronati L, Negroni A. Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier. Int J Mol Sci 2022; 23:ijms232214254. [PMID: 36430732 PMCID: PMC9697805 DOI: 10.3390/ijms232214254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/21/2022] Open
Abstract
A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharide-binding protein (LBP) and S100β protein (S100β) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100β were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation.
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Affiliation(s)
- Noemi Fiaschini
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Mariateresa Mancuso
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Mirella Tanori
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Eleonora Colantoni
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Roberta Vitali
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Gianfranco Diretto
- Biotechnology Laboratory, Division of Biotechnologies and Agroindustry, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Laura Lorenzo Rebenaque
- Departamento Producción y Sanidad Animal, Salud Pública Veterinaria y Ciencia y Tecnología de los Alimentos, Universidad CEU-Cardenal Herrera, CEU Universities, Alfara del Patriarca, 46115 Valencia, Spain
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy
| | - Anna Negroni
- Biomedical Technologies Laboratory, Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
- Correspondence:
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18
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Huo X, Li D, Wu F, Li S, Qiao Y, Wang C, Wang Y, Zhou C, Sun L, Luan Z, Yan Q, Wang J, Zhang Y, Zhao T, An Y, Zhang B, Tian X, Yu Z, Ma X. Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists. Gut 2022; 71:2205-2217. [PMID: 35173042 DOI: 10.1136/gutjnl-2021-325413] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 01/25/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice. DESIGN Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo. RESULTS The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1-F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice. CONCLUSION This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.
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Affiliation(s)
- Xiaokui Huo
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dawei Li
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fan Wu
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shenghui Li
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yanling Qiao
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Chao Wang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Yan Wang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
| | | | - Liqun Sun
- Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Zhilin Luan
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Qiulong Yan
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Jiayue Wang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yu Zhang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ting Zhao
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yue An
- Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Baojing Zhang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xiangge Tian
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China.,Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhenlong Yu
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xiaochi Ma
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, Dalian Medical University, Dalian, China .,Second Affiliated Hospital of Dalian Medical University, Dalian, China
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19
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Murray A, Banota T, Guo GL, Smith LC, Meshanni JA, Lee J, Kong B, Abramova EV, Goedken M, Gow AJ, Laskin JD, Laskin DL. Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure. Toxicol Appl Pharmacol 2022; 454:116208. [PMID: 35998709 PMCID: PMC9960619 DOI: 10.1016/j.taap.2022.116208] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/14/2022] [Accepted: 08/17/2022] [Indexed: 02/04/2023]
Abstract
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR-/- mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR-/- mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR-/- mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.
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Affiliation(s)
- Alexa Murray
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Tanvi Banota
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Ley Cody Smith
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Jaclynn A Meshanni
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Jordan Lee
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Elena V Abramova
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Michael Goedken
- Research Pathology Services, Rutgers University, Piscataway, NJ 08854, USA
| | - Andrew J Gow
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
| | - Jeffrey D Laskin
- Department of Environmental and Occupational Health and Justice, School of Public Health, Rutgers University, Piscataway, NJ 08854, USA
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
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20
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 184] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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21
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Xia Y, Xu X, Guo Y, Lin C, Xu X, Zhang F, Fan M, Qi T, Li C, Hu G, Peng L, Wang S, Zhang L, Hai C, Liu R, Yan W, Tao L. Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200431. [PMID: 35780502 PMCID: PMC9404394 DOI: 10.1002/advs.202200431] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 05/14/2022] [Indexed: 06/15/2023]
Abstract
Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI.
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Affiliation(s)
- Yunlong Xia
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Xinyue Xu
- State Key Laboratory of Military StomatologyNational Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced ManufactureDepartment of PeriodontologySchool of StomatologyFourth Military Medical UniversityXi'anShaanxi710032China
| | - Yongzhen Guo
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Chen Lin
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
- CardiologyGeneral Hospital of Eastern Theater Command of Chinese PLANanjing210002China
| | - Xiaoming Xu
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Fuyang Zhang
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Miaomiao Fan
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Tingting Qi
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Congye Li
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Guangyu Hu
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Lu Peng
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Shan Wang
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Ling Zhang
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Chunxu Hai
- Department of ToxicologyShanxi Provincial Key Lab of Free Radical Biology and MedicineMinistry of Education Key Lab of Hazard Assessment and Control in Special Operational EnvironmentSchool of Public HealthFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Rui Liu
- Department of ToxicologyShanxi Provincial Key Lab of Free Radical Biology and MedicineMinistry of Education Key Lab of Hazard Assessment and Control in Special Operational EnvironmentSchool of Public HealthFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Wenjun Yan
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
| | - Ling Tao
- CardiologyXijing HospitalFourth Military Medical UniversityXi'an710032China
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22
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Shao G, Liu Y, Lu L, Zhang G, Zhou W, Wu T, Wang L, Xu H, Ji G. The Pathogenesis of HCC Driven by NASH and the Preventive and Therapeutic Effects of Natural Products. Front Pharmacol 2022; 13:944088. [PMID: 35873545 PMCID: PMC9301043 DOI: 10.3389/fphar.2022.944088] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a clinical syndrome with pathological changes that are similar to those of alcoholic hepatitis without a history of excessive alcohol consumption. It is a specific form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatocyte inflammation based on hepatocellular steatosis. Further exacerbation of NASH can lead to cirrhosis, which may then progress to hepatocellular carcinoma (HCC). There is a lack of specific and effective treatments for NASH and NASH-driven HCC, and the mechanisms of the progression of NASH to HCC are unclear. Therefore, there is a need to understand the pathogenesis and progression of these diseases to identify new therapeutic approaches. Currently, an increasing number of studies are focusing on the utility of natural products in NASH, which is likely to be a promising prospect for NASH. This paper reviews the possible mechanisms of the pathogenesis and progression of NASH and NASH-derived HCC, as well as the potential therapeutic role of natural products in NASH and NASH-derived HCC.
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Affiliation(s)
- Gaoxuan Shao
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangtao Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Biomedical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Wang
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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23
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Wen Y, Zhang G, Wu X. The role of the farnesoid X receptor in quadruple anti-tuberculosis drug-induced liver injury. Toxicology 2022; 476:153256. [PMID: 35835356 DOI: 10.1016/j.tox.2022.153256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 01/07/2023]
Abstract
Anti-tuberculosis drugs-induced liver injury may be associated with the hepatic farnesoid X receptor (FXR). However, the relationship between isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) coadministration-induced liver injury and FXR has not been clarified. The purpose of this study was to clarify the role of FXR in HRZE-induced liver injury. To measure indices of liver injury, blood samples were collected from clinical tuberculosis patients who had taken HRZE for approximately two months; in these patients serum total bile acids were increased, while other hepatic biochemical indexes showed no significant changes. When Wistar rats were orally administered isoniazid (30 or 60 mg/kg) + rifampicin (45 or 90 mg/kg) + pyrazinamide (150 or 300 mg/kg) + ethambutol (75 or 150 mg/kg) in combination for 15 days, the expression and function of FXR was up-regulated, and hepatic bile acids were decreased. However, following 30 days of HRZE treatment the expression and function of FXR was down-regulated and bile acids accumulated in the liver, suggestive of hepatotoxicity. Treatment of HepaRG cells with HRZE lead to time- and dose- dependent cytotoxicity, with the expression of FXR up-regulated in early stage, but down-regulated with prolonged HRZE treatment, consistent with the results of animal experiments. In summary, HRZE may upregulate FXR with short-term administration, but more prolonged treatment appears to suppress FXR function, resulting in hepatic bile acid accumulation.
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Affiliation(s)
- Yuanjie Wen
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China; Engineering Research Centre of Prevention and Control for Clinical Medication Risk, Gansu Province, China
| | - Guoqiang Zhang
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China; Engineering Research Centre of Prevention and Control for Clinical Medication Risk, Gansu Province, China
| | - Xin'an Wu
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou 730000, China; Engineering Research Centre of Prevention and Control for Clinical Medication Risk, Gansu Province, China.
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24
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Lin QX, Huang WW, Shen W, Deng XS, Tang ZY, Chen ZH, Zhao W, Fan HY. Intrahepatic Cholestasis of Pregnancy Increases Inflammatory Susceptibility in Neonatal Offspring by Modulating Gut Microbiota. Front Immunol 2022; 13:889646. [PMID: 35769469 PMCID: PMC9234109 DOI: 10.3389/fimmu.2022.889646] [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: 03/04/2022] [Accepted: 05/05/2022] [Indexed: 11/13/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterized by increased bile acid levels in maternal serum. Studies have shown that cholestatic pregnancy can result in long-term metabolic disturbances in the offspring. However, how ICP shapes the offspring’s immunity and predisposition to inflammatory disorders at an early stage is unknown. In this study, we investigated the effect of maternal cholestasis on neonatal offspring metabolism and immune function. We compared 71 neonates with ICP mothers and 63 neonates with healthy mothers and found that the incidence of jaundice and infection was significantly higher in ICP offspring. Maternal serum total bile acid level was associated with blood cell counts in full-term ICP offspring. In animal experiments, a compensatory activation of hepatic and ileal farnesoid X receptor (FXR) and altered gut microbiota in the first week were found in ICP offspring. We also investigated lipopolysaccharide (LPS)-induced inflammatory responses in neonatal rats and found that ICP offspring were more susceptible to inflammation. To understand the correlation between congenital abnormal FXR activation and tissue immunity dysregulation, we assessed the effects of the FXR agonist GW4064 and FXR antagonist E/Z-GS in ICP offspring after LPS exposure. The expression of several pro-inflammatory cytokines significantly decreased after treatment with E/Z-GS but increased after treatment with GW4064. Treatment with the probiotic Lactobacillus rhamnosus LRX01 that inhibits FXR expression in the ileum reduced susceptibility to LPS exposure in ICP offspring. The current study indicated that cholestatic pregnancy may increase the susceptibility of the offspring to inflammation by altering bile acid metabolism and gut microbiota at an early stage. We suggest that supplementation with Lactobacillus rhamnosus LRX01, which inhibits FXR expression in the ileum, may improve intestinal immunity in ICP offspring.
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Affiliation(s)
- Qiong-xi Lin
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Wan-wen Huang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Wei Shen
- Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-shi Deng
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zi-yu Tang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Zhen-hui Chen
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Wei Zhao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Hong-ying Fan
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China
- *Correspondence: Hong-ying Fan,
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25
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Mooranian A, Jones M, Walker D, Ionescu C, Wagle S, Kovačević B, Chester J, Foster T, Johnston E, Mikov M, Al-Salami H. 'In vitro' assessments of microencapsulated viable cells as a result of primary bile acid-encapsulated formulation for inflammatory disorders. SCRIPTA MEDICA 2022. [DOI: 10.5937/scriptamed53-36574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background / Aim: Metformin is widely used in type 2 diabetes and exhibits many positive biological effects on pancreatic b-cells and muscle cells, such as supporting insulin release by b-cells and glucose uptake by muscle cells and reducing oxidative stress, particularly due to diabetes-associated hyperglycaemia. Interestingly, for type 1 diabetes, transplantation of healthy b-cells has been proposed as a novel way to replace insulin therapy. Recently, bile acid-formulations containing transplantable b-cells showed best stability. Hence, this study aimed to explore the effects of metformin-bile acid formulations in b-cell encapsulation and on the biological activities of b-cells and muscle-cells. Methods: Two sets of biological effects were examined, using metformin-bile acid formulations, on encapsulated b-cells and on muscle cells exposed to the formulations. Results: Various encapsulated b-cell formulations' cell viability, insulin levels, cellular oxidative stress, cellular inflammatory profile and bioenergetics at the normoand hyperglycaemic states showed differing results based upon the metformin concentration and the inclusion or absence of bile acid. Similar effects were observed with muscle cells. Low ratios of metformin and bile acids showed best biological effects, suggesting a formulation dependent result. The formulations' positive effects were more profound at the hyperglycaemic state suggesting efficient cell protective effects. Conclusion: Overall, metformin had positive impacts on the cells in a concentration-dependent manner, with the addition of chenodeoxycholic acid further improving results.
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26
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Cao X, Ren S, Cai C, Ni Q, Li X, Meng Y, Meng Z, Shi Y, Chen H, Jiang R, Wu P, Ye Y. Dietary pectin caused great changes in bile acid profiles of Pelteobagrus fulvidraco. FISH PHYSIOLOGY AND BIOCHEMISTRY 2021; 47:2015-2025. [PMID: 34709495 DOI: 10.1007/s10695-021-01028-2] [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: 05/18/2021] [Accepted: 10/13/2021] [Indexed: 06/13/2023]
Abstract
To reveal the impact of dietary fiber (DF) on the bile acid (BA) profiles of fish, yellow catfish (Pelteobagrus fulvidraco) were fed a diet containing 300 g kg-1 dextrin (CON diet, control) or pectin (a type of soluble DF, PEC diet) for 7 days, and then the BA profiles were analyzed by UHPLC-MS/MS. A total of 26 individuals of BAs were detected in the fish body, with 8, 10, 14, and 22 individuals of BAs detected in the liver, serum, bile, and hindgut digesta, respectively. The conjugated BAs (CBAs) of fish were dominated by taurine CBAs (TCBAs). The concentrations of free BAs (FBAs) and the value of FBAs/CBAs in the bile of fish fed the PEC diet were nearly 5 and 7 times higher, respectively than those in fish fed the CON diet. The value of glycine CBAs/TCBAs in the liver, serum and bile of fish fed the PEC diet was significantly lower, and in the hindgut digesta was higher than that of fish fed the CON diet (P < 0.05). These results suggested that dietary pectin greatly changed the BA profiles of Pelteobagrus fulvidraco, attributed to inhibition of reabsorption of BAs. Therefore, attention should be paid to the impact on BA homeostasis when replacing fishmeal with DF-rich plant ingredients in the fish diet.
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Affiliation(s)
- Xiamin Cao
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China.
| | - Shengjie Ren
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Chunfang Cai
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China.
| | - Qin Ni
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Xinyue Li
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Yunhe Meng
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Zijing Meng
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Ye Shi
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Huangen Chen
- Jiangsu Fisheries Technology Promotion Center, Nanjing, 210036, People's Republic of China
| | - Rong Jiang
- Wuxi Sanzhi Biotech Co., Ltd, Wuxi, 214101, People's Republic of China
| | - Ping Wu
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Yuantu Ye
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
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27
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Anderson KM, Gayer CP. The Pathophysiology of Farnesoid X Receptor (FXR) in the GI Tract: Inflammation, Barrier Function and Innate Immunity. Cells 2021; 10:cells10113206. [PMID: 34831429 PMCID: PMC8624027 DOI: 10.3390/cells10113206] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
Abstract
The Farnesoid-X Receptor, FXR, is a nuclear bile acid receptor. Its originally described function is in bile acid synthesis and regulation within the liver. More recently, however, FXR has been increasingly appreciated for its breadth of function and expression across multiple organ systems, including the intestine. While FXR’s role within the liver continues to be investigated, increasing literature indicates that FXR has important roles in responding to inflammation, maintaining intestinal epithelial barrier function, and regulating immunity within the gastrointestinal (GI) tract. Given the complicated and multi-factorial nature of intestinal barrier dysfunction, it is not surprising that FXR’s role appears equally complicated and not without conflicting data in different model systems. Recent work has suggested translational applications of FXR modulation in GI pathology; however, a better understanding of FXR physiology is necessary for these treatments to gain widespread use in human disease. This review aims to discuss current scientific work on the role of FXR within the GI tract, specifically in its role in intestinal inflammation, barrier function, and immune response, while also exploring areas of controversy.
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Affiliation(s)
- Kemp M. Anderson
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Christopher P. Gayer
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
- Correspondence: ; Tel.: +1-323-361-4974
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28
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Zhao W, Zhang X, Rong J. SUMOylation as a Therapeutic Target for Myocardial Infarction. Front Cardiovasc Med 2021; 8:701583. [PMID: 34395563 PMCID: PMC8355363 DOI: 10.3389/fcvm.2021.701583] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/01/2021] [Indexed: 12/23/2022] Open
Abstract
Myocardial infarction is a prevalent and life-threatening cardiovascular disease. The main goal of existing interventional therapies is to restore coronary reperfusion while few are designed to ameliorate the pathology of heart diseases via targeting the post-translational modifications of those critical proteins. Small ubiquitin-like modifier (SUMO) proteins are recently discovered to form a new type of protein post-translational modifications (PTM), known as SUMOylation. SUMOylation and deSUMOylation are dynamically balanced in the maintenance of various biological processes including cell division, DNA repair, epigenetic transcriptional regulation, and cellular metabolism. Importantly, SUMOylation plays a critical role in the regulation of cardiac functions and the pathology of cardiovascular diseases, especially in heart failure and myocardial infarction. This review summarizes the current understanding on the effects of SUMOylation and SUMOylated proteins in the pathophysiology of myocardial infarction and identifies the potential treatments against myocardial injury via targeting SUMO. Ultimately, this review recommends SUMOylation as a key therapeutic target for treating cardiovascular diseases.
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Affiliation(s)
- Wei Zhao
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, University of Hong Kong, Hong Kong, China.,Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiuying Zhang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, University of Hong Kong, Hong Kong, China
| | - Jianhui Rong
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, University of Hong Kong, Hong Kong, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
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Francis M, Guo G, Kong B, Abramova EV, Cervelli JA, Gow AJ, Laskin JD, Laskin DL. Regulation of Lung Macrophage Activation and Oxidative Stress Following Ozone Exposure by Farnesoid X Receptor. Toxicol Sci 2021; 177:441-453. [PMID: 32984886 PMCID: PMC7548292 DOI: 10.1093/toxsci/kfaa111] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80+CD11c+CD11b+Ly6CHi) and anti-inflammatory (F4/80+CD11c+CD11b+Ly6CLo) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR-/- mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77. This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α, Il-1β, Ccr2, Ccl2, Cx3cr1, and Cx3cl1 were also increased in lungs of FXR-/- relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα, Apoe, Vldlr, Abcg1, and Abca1 were downregulated, irrespective of ozone exposure. In FXR-/- mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR-/- mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants.
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Affiliation(s)
- Mary Francis
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Grace Guo
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Bo Kong
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Elena V Abramova
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Jessica A Cervelli
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Andrew J Gow
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
| | - Jeffrey D Laskin
- Department of Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, New Jersey 08854
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
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30
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Fang X, Zhang S, Wang Z, Zhou J, Qi C, Song J. Cigarette smoke extract combined with LPS down-regulates the expression of MRP2 in chronic pulmonary inflammation may be related to FXR. Mol Immunol 2021; 137:174-186. [PMID: 34273652 DOI: 10.1016/j.molimm.2021.06.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/13/2021] [Accepted: 06/25/2021] [Indexed: 01/19/2023]
Abstract
The transporter multidrug resistance protein 2 (MRP2) plays an important role in chronic pulmonary inflammation by transporting cigarette smoke and other related inflammatory mediators. However, it is not completely clear whether pulmonary inflammation caused by cigarette smoke extract (CSE) and lipopolysaccharide (LPS) is related to MRP2 and its signal factors. In this study, CSE combined with LPS was used to establish an inflammation model in vivo and in vitro. We found that compared with the control group, after CSE combined with LPS treatment, the expression of MRP2 in rat lung tissue in vivo and human alveolar cell line in vitro was down-regulated, while the expression of inflammatory factors was up-regulated. Through silencing and overexpression of FXR, it was found that silent FXR could down-regulate MRP2 and up-regulate the expression of inflammatory factors. On the contrary, overexpression of FXR could up-regulate MRP2 and down-regulate the expression of inflammatory factors. Our results show that CSE combined with LPS can down-regulate the expression of MRP2 under inflammatory conditions, and the down-regulation of MRP2 expression may be achieved partly through the FXR signal pathway.
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Affiliation(s)
- Xin Fang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Shuyi Zhang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Zihao Wang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jian Zhou
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Chuanzong Qi
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jue Song
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.
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31
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Miura K, Oshima T, Ito C, Horikawa T, Yamada M, Tomita T, Fukui H, Miwa H. Vitamin D receptor is overexpressed in the duodenum of patients with irritable bowel syndrome. J Gastroenterol Hepatol 2021; 36:951-958. [PMID: 32839988 DOI: 10.1111/jgh.15225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/21/2020] [Accepted: 08/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, and bile acids are thought to be associated with the pathogenesis of IBS. Bile acid receptors are expressed on intestinal epithelial cells. However, no study has assessed bile acid receptor proteins in IBS. Therefore, we examined the intestinal mucosal expression of bile acid receptors in patients with IBS. METHODS Intestinal biopsies were performed in patients with IBS and controls. Mast cells, vitamin D receptor (VDR), and somatostatin were stained with specific antibodies. Levels of VDR, farnesoid X receptor (FXR), takeda-G-protein-receptor-5 (TGR5), claudins, and transient-receptor-potential-cation-channel-subfamily-V-member 6 (TRPV6) were assessed by western blotting. RESULTS 3Mast cell counts in the second part of the duodenum were significantly higher in patients with IBS than in controls. VDR protein levels were significantly elevated in the duodenum and terminal ileum of patients with IBS compared with controls, although this difference was not seen in the cecum or rectum. FXR and TGR5 protein levels did not differ in any part of the intestine. VDR-positive cryptal epithelia in IBS were distributed not only at basal crypt but also along the upper part of the basal crypt epithelial cells. In contrast, the pattern of gut somatostatin-positive cells, claudins, and TRPV6 levels did not differ. CONCLUSIONS The number of mast cells in the duodenum was significantly increased, and the protein expression levels of VDR, but not those of FXR or TGR5, were elevated in the duodenal epithelial crypt in patients with IBS.
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Affiliation(s)
- Ko Miura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Chiyomi Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoki Horikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mayumi Yamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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Alatshan A, Benkő S. Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function. Front Immunol 2021; 12:630569. [PMID: 33717162 PMCID: PMC7952630 DOI: 10.3389/fimmu.2021.630569] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.
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Affiliation(s)
- Ahmad Alatshan
- Departments of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cellular and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szilvia Benkő
- Departments of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cellular and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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33
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Tiwari D, Gupta P. Nuclear Receptors in Asthma: Empowering Classical Molecules Against a Contemporary Ailment. Front Immunol 2021; 11:594433. [PMID: 33574813 PMCID: PMC7870687 DOI: 10.3389/fimmu.2020.594433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023] Open
Abstract
The escalation in living standards and adoption of 'Western lifestyle' has an allied effect on the increased allergy and asthma burden in both developed and developing countries. Current scientific reports bespeak an association between allergic diseases and metabolic dysfunction; hinting toward the critical requirement of organized lifestyle and dietary habits. The ubiquitous nuclear receptors (NRs) translate metabolic stimuli into gene regulatory signals, integrating diet inflences to overall developmental and physiological processes. As a consequence of such promising attributes, nuclear receptors have historically been at the cutting edge of pharmacy world. This review discusses the recent findings that feature the cardinal importance of nuclear receptors and how they can be instrumental in modulating current asthma pharmacology. Further, it highlights a possible future employment of therapy involving dietary supplements and synthetic ligands that would engage NRs and aid in eliminating both asthma and linked comorbidities. Therefore, uncovering new and evolving roles through analysis of genomic changes would represent a feasible approach in both prevention and alleviation of asthma.
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Affiliation(s)
| | - Pawan Gupta
- Department of Molecular Biology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
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34
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Zhang R, Ma WQ, Fu MJ, Li J, Hu CH, Chen Y, Zhou MM, Gao ZJ, He YL. Overview of bile acid signaling in the cardiovascular system. World J Clin Cases 2021; 9:308-320. [PMID: 33521099 PMCID: PMC7812903 DOI: 10.12998/wjcc.v9.i2.308] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.
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Affiliation(s)
- Rou Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Wen-Qi Ma
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Meng-Jun Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chun-Hua Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Mi-Mi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhi-Jie Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Ying-Li He
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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35
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Kumari A, Pal Pathak D, Asthana S. Bile acids mediated potential functional interaction between FXR and FATP5 in the regulation of Lipid Metabolism. Int J Biol Sci 2020; 16:2308-2322. [PMID: 32760200 PMCID: PMC7378638 DOI: 10.7150/ijbs.44774] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
Perturbation in lipid homeostasis is one of the major bottlenecks in metabolic diseases, especially Non-alcoholic Fatty Liver Disease (NAFLD), which has emerged as a leading global cause of chronic liver disease. The bile acids (BAs) and their derivatives exert a variety of metabolic effects through complex and intertwined pathways, thus becoming the attractive target for metabolic syndrome treatment. To modulate the lipid homeostasis, the role of BAs, turn out to be paramount as it is essential for the absorption, transport of dietary lipids, regulation of metabolic enzymes and transporters that are essential for lipid modulation, flux, and excretion. The synthesis and transport of BAs (conjugated and unconjugated) is chiefly controlled by nuclear receptors and the uptake of long-chain fatty acids (LCFA) and BA conjugation via transporters. Among them, from in-vivo studies, farnesoid X receptor (FXR) and liver-specific fatty acid transport protein 5 (FATP5) have shown convincing evidence for their key roles in lipid homeostasis and reversal of fatty liver disease substantially. BAs have a wider range of biological effects as they are identified as modulators for FXR and FATP5 both and therefore hold a significant promise for altering the lipid content in the treatment of a metabolic disorder. BAs also have received noteworthy interest in drug delivery research due to its peculiar physicochemical properties and biocompatibility. Here, we are highlighting the connecting possibility of BAs as an agonist for FXR and antagonist for FATP5, paving an avenue to target them for designing synthetic small molecules for lipid homeostasis.
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Affiliation(s)
- Anita Kumari
- Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India.,Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India
| | - Dharam Pal Pathak
- Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), New Delhi, India.,Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India
| | - Shailendra Asthana
- Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India
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36
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Lucchinetti E, Lou PH, Wawrzyniak P, Wawrzyniak M, Scharl M, Holtzhauer GA, Krämer SD, Hersberger M, Rogler G, Zaugg M. Novel Strategies to Prevent Total Parenteral Nutrition-Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes. Mol Nutr Food Res 2020; 65:e1901270. [PMID: 32359213 DOI: 10.1002/mnfr.201901270] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/09/2020] [Indexed: 12/15/2022]
Abstract
Total parenteral nutrition (TPN) is a life-saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN-associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut-originating incretins as well as the potentially toxicity of phytosterols and pro-inflammatory fatty acids mainly released from soybean oil-based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti-inflammatory n-3 to pro-inflammatory n-6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN-associated adverse effects.
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Affiliation(s)
- Eliana Lucchinetti
- Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada
| | - Phing-How Lou
- Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada
| | - Paulina Wawrzyniak
- Division of Clinical Chemistry and Biochemistry, Children's Hospital Zurich, Zurich, 8032, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Gregory A Holtzhauer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Stefanie D Krämer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Martin Hersberger
- Division of Clinical Chemistry and Biochemistry, Children's Hospital Zurich, Zurich, 8032, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Michael Zaugg
- Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada.,Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada
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Verna EC, Schluger A, Brown RS. Opioid epidemic and liver disease. JHEP Rep 2019; 1:240-255. [PMID: 32039374 PMCID: PMC7001546 DOI: 10.1016/j.jhepr.2019.06.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/27/2019] [Accepted: 06/29/2019] [Indexed: 12/12/2022] Open
Abstract
Opioid use in the United States and in many parts of the world has reached epidemic proportions. This has led to excess mortality as well as significant changes in the epidemiology of liver disease. Herein, we review the impact of the opioid epidemic on liver disease, focusing on the multifaceted impact this epidemic has had on liver disease and liver transplantation. In particular, the opioid crisis has led to a significant shift in incident hepatitis C virus infection to younger populations and to women, leading to changes in screening recommendations. Less well characterized are the potential direct and indirect hepatotoxic effects of opioids, as well as the changes in the incidence of hepatitis B virus infection and alcohol abuse that are likely rising in this population as well. Finally, the opioid epidemic has led to a significant rise in the proportion of organ donors who died due to overdose. These donors have led to an overall increase in donor numbers, but also to new considerations about the better use of donors with perceived or actual risk of disease transmission, especially hepatitis C. Clearly, additional efforts are needed to combat the opioid epidemic. Moreover, better understanding of the epidemiology and underlying pathophysiology will help to identify and treat liver disease in this high-risk population.
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Affiliation(s)
- Elizabeth C. Verna
- Center for Liver Disease and Transplantation, Columbia University Vagelos College of Physicians and Surgeons, New York, NY
| | - Aaron Schluger
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY
| | - Robert S. Brown
- Center for Liver Disease and Transplantation, Columbia University Vagelos College of Physicians and Surgeons, New York, NY
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY
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Milosevic I, Vujovic A, Barac A, Djelic M, Korac M, Radovanovic Spurnic A, Gmizic I, Stevanovic O, Djordjevic V, Lekic N, Russo E, Amedei A. Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature. Int J Mol Sci 2019; 20:395. [PMID: 30658519 PMCID: PMC6358912 DOI: 10.3390/ijms20020395] [Citation(s) in RCA: 330] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 01/13/2019] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
The rapid scientific interest in gut microbiota (GM) has coincided with a global increase in the prevalence of infectious and non-infectivous liver diseases. GM, which is also called "the new virtual metabolic organ", makes axis with a number of extraintestinal organs, such as kidneys, brain, cardiovascular, and the bone system. The gut-liver axis has attracted greater attention in recent years. GM communication is bi-directional and involves endocrine and immunological mechanisms. In this way, gut-dysbiosis and composition of "ancient" microbiota could be linked to pathogenesis of numerous chronic liver diseases such as chronic hepatitis B (CHB), chronic hepatitis C (CHC), alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), development of liver cirrhosis, and hepatocellular carcinoma (HCC). In this paper, we discuss the current evidence supporting a GM role in the management of different chronic liver diseases and potential new therapeutic GM targets, like fecal transplantation, antibiotics, probiotics, prebiotics, and symbiotics. We conclude that population-level shifts in GM could play a regulatory role in the gut-liver axis and, consequently, etiopathogenesis of chronic liver diseases. This could have a positive impact on future therapeutic strategies.
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Affiliation(s)
- Ivana Milosevic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Ankica Vujovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Aleksandra Barac
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Marina Djelic
- Faculty of Medicine, Universisty of Belgrade; Institute of Medical Physiology "Rihard Burijan", 11000 Belgrade, Serbia.
| | - Milos Korac
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Aleksandra Radovanovic Spurnic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Ivana Gmizic
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Olja Stevanovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Hospital for Infectious and Tropical Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Vladimir Djordjevic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Clinic for Digestive Surgery, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Nebojsa Lekic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- Clinic for Digestive Surgery, Clinical Center of Serbia, 11000 Belgrade, Serbia.
| | - Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
- Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), 50134 Florence, Italy.
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Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases. Int J Mol Sci 2018; 19:ijms19113630. [PMID: 30453651 PMCID: PMC6274770 DOI: 10.3390/ijms19113630] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 02/06/2023] Open
Abstract
Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.
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40
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Chang S, Kim YH, Kim YJ, Kim YW, Moon S, Lee YY, Jung JS, Kim Y, Jung HE, Kim TJ, Cheong TC, Moon HJ, Cho JA, Kim HR, Han D, Na Y, Seok SH, Cho NH, Lee HC, Nam EH, Cho H, Choi M, Minato N, Seong SY. Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice. Front Immunol 2018; 9:1984. [PMID: 30279688 PMCID: PMC6153344 DOI: 10.3389/fimmu.2018.01984] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 08/13/2018] [Indexed: 01/01/2023] Open
Abstract
Bile acids (BAs) control metabolism and inflammation by interacting with several receptors. Here, we report that intravenous infusion of taurodeoxycholate (TDCA) decreases serum pro-inflammatory cytokines, normalizes hypotension, protects against renal injury, and prolongs mouse survival during sepsis. TDCA increases the number of granulocytic myeloid-derived suppressor cells (MDSCLT) distinctive from MDSCs obtained without TDCA treatment (MDSCL) in the spleen of septic mice. FACS-sorted MDSCLT cells suppress T-cell proliferation and confer protection against sepsis when adoptively transferred better than MDSCL. Proteogenomic analysis indicated that TDCA controls chromatin silencing, alternative splicing, and translation of the immune proteome of MDSCLT, which increases the expression of anti-inflammatory molecules such as oncostatin, lactoferrin and CD244. TDCA also decreases the expression of pro-inflammatory molecules such as neutrophil elastase. These findings suggest that TDCA globally edits the proteome to increase the number of MDSCLT cells and affect their immune-regulatory functions to resolve systemic inflammation during sepsis.
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Affiliation(s)
- Sooghee Chang
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
| | - Youn-Hee Kim
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Young-Joo Kim
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Young-Woo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Sungyoon Moon
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Yong Yook Lee
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Jin Sun Jung
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Youngsoo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Hi-Eun Jung
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Tae-Joo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Taek-Chin Cheong
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye-Jung Moon
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
| | - Jung-Ah Cho
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Hang-Rae Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea
| | - Dohyun Han
- Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Yirang Na
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Seung-Hyeok Seok
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Nam-Hyuk Cho
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Hai-Chon Lee
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Eun-Hee Nam
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
| | - Hyosuk Cho
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Nagahiro Minato
- Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seung-Yong Seong
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Wide River Institute of Immunology, Seoul National University, Seoul, South Korea
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Gao Y, Zhao Y, Yuan A, Xu L, Huang X, Su Y, Gao L, Ji Q, Pu J, He B. Effects of farnesoid-X-receptor SUMOylation mutation on myocardial ischemia/reperfusion injury in mice. Exp Cell Res 2018; 371:301-310. [PMID: 30098335 DOI: 10.1016/j.yexcr.2018.07.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 06/29/2018] [Accepted: 07/03/2018] [Indexed: 12/19/2022]
Abstract
Myocardial ischemia/reperfusion (MI/R) injury induces excessive cellular apoptosis and contributes significantly to final infarct size. We previously demonstrated that a nuclear receptor, Farnesoid X receptor (FXR), plays a crucial role in mediating myocardial apoptosis. The FXR functions are regulated by post translational modifications (PTM). However, whether the proapoptotic effect of FXR in MI/R injury is regulated by PTM remains unclear. Here, we aimed to study the effect of SUMOylation, a PTM involved in the pathogenesis of MI/R injury per se, on the proapoptotic effect of FXR in MI/R injury. We observed that FXR could be SUMOylated in heart tissues, and FXR SUMOylation levels were downregulated in ischemia reperfused myocardium. By overexpression of SUMOylation-defective FXR mutant, it was demonstrated that decreased SUMOylation augmented the detrimental effect of FXR, via activation of mitochondrial apoptosis pathway and autophagy dysfunction in MI/R injury. Further mechanistic studies suggested that decreased SUMOylation levels increased the transcription activity of FXR, and the subsequently upregulated FXR target gene SHP mediated the proapoptotic effects of FXR. Taken together, we provided the first evidence that the cardiac effects of FXR could be regulated by SUMOylation, and that manipulating FXR SUMOylation levels may hold therapeutic promise for constraining MI/R injury.
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Affiliation(s)
- Yi Gao
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yichao Zhao
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ancai Yuan
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Longwei Xu
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xian Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, China
| | - Yuanyuan Su
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Lingchen Gao
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qingqi Ji
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jun Pu
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Ben He
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
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Du J, Xiang X, Li Y, Ji R, Xu H, Mai K, Ai Q. Molecular cloning and characterization of farnesoid X receptor from large yellow croaker ( Larimichthys crocea ) and the effect of dietary CDCA on the expression of inflammatory genes in intestine and spleen. Comp Biochem Physiol B Biochem Mol Biol 2018; 216:10-17. [DOI: 10.1016/j.cbpb.2017.09.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 09/22/2017] [Accepted: 09/28/2017] [Indexed: 12/25/2022]
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Rock KD, Horman B, Phillips AL, McRitchie SL, Watson S, Deese-Spruill J, Jima D, Sumner S, Stapleton HM, Patisaul HB. EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain. Endocr Connect 2018; 7:305-324. [PMID: 29351906 PMCID: PMC5817967 DOI: 10.1530/ec-17-0373] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 01/19/2018] [Indexed: 12/13/2022]
Abstract
Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, composed of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity has raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300 or 1000 µg/day) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.
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Affiliation(s)
- Kylie D Rock
- Department of Biological SciencesNorth Carolina State University, Raleigh, North Carolina, USA
| | - Brian Horman
- Department of Biological SciencesNorth Carolina State University, Raleigh, North Carolina, USA
| | - Allison L Phillips
- Nicholas School of the EnvironmentDuke University, Durham, North Carolina, USA
| | - Susan L McRitchie
- NIH Eastern Regional Comprehensive Metabolomics Res. CoreUniv. of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Scott Watson
- NIH Eastern Regional Comprehensive Metabolomics Res. CoreUniv. of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jocelin Deese-Spruill
- NIH Eastern Regional Comprehensive Metabolomics Res. CoreUniv. of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Dereje Jima
- Center for Human Health and the EnvironmentNorth Carolina State University, Raleigh, North Carolina, USA
- Bioinformatics Research CenterNorth Carolina State University, Raleigh, North Carolina, USA
| | - Susan Sumner
- NIH Eastern Regional Comprehensive Metabolomics Res. CoreUniv. of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Center for Human Health and the EnvironmentNorth Carolina State University, Raleigh, North Carolina, USA
| | - Heather M Stapleton
- Nicholas School of the EnvironmentDuke University, Durham, North Carolina, USA
| | - Heather B Patisaul
- Department of Biological SciencesNorth Carolina State University, Raleigh, North Carolina, USA
- Center for Human Health and the EnvironmentNorth Carolina State University, Raleigh, North Carolina, USA
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Comeglio P, Morelli A, Adorini L, Maggi M, Vignozzi L. Beneficial effects of bile acid receptor agonists in pulmonary disease models. Expert Opin Investig Drugs 2017; 26:1215-1228. [PMID: 28949776 DOI: 10.1080/13543784.2017.1385760] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions. Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.
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Affiliation(s)
- Paolo Comeglio
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| | - Annamaria Morelli
- b Department of Experimental and Clinical Medicine , University of Florence , Florence , Italy
| | | | - Mario Maggi
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| | - Linda Vignozzi
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
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Chronic microaspiration of bile acids induces lung fibrosis through multiple mechanisms in rats. Clin Sci (Lond) 2017; 131:951-963. [PMID: 28341659 DOI: 10.1042/cs20160926] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 03/19/2017] [Accepted: 03/23/2017] [Indexed: 12/22/2022]
Abstract
Gastroesophageal reflux (GER) and microaspiration of duodenogastric refluxate have been recognized as a risk factor for pulmonary fibrosis. Recent evidence suggests that bile acid microaspiration may contribute to the development of lung fibrosis. However, the molecular evidence is scarce and the underlying mechanisms remain to be elucidated. We have recently demonstrated that bile acids induce activation of alveolar epithelial cells (AECs) and lung fibroblasts in vitro In the present study, a rat model of bile acid microaspiration was established by weekly intratracheal instillation of three major bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). Repeated microaspiration of CDCA, DCA, and LCA caused fibrotic changes, including alveolar wall thickening and extensive collagen deposition, in rat lungs. Bile acid microaspiration also induced alveolar epithelial-mesenchymal transition (EMT), as indicated by up-regulation of mesenchymal markers α-smooth muscle actin (α-SMA) and vimentin, as well as down-regulaton of epithelial markers E-cadherin and cytokeratin in alveolar epithelium of rat lungs. The expression of fibrogenic mediators, including transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and periostin, was significantly elevated in rat lungs exposed to microaspiration of bile acids. Furthermore, microaspiration of bile acids also induced p-Smad3 and farnesoid X receptor (FXR) expression in rat lungs. Our findings suggest that microaspiration of bile acids could promote the development of pulmonary fibrosis in vivo, possibly via stimulating fibrogenic mediator expression and activating TGF-β1/Smad3 signaling and FXR.
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Horvatits T, Drolz A, Roedl K, Rutter K, Ferlitsch A, Fauler G, Trauner M, Fuhrmann V. Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis. Liver Int 2017; 37:224-231. [PMID: 27416294 DOI: 10.1111/liv.13201] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Accepted: 07/04/2016] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Retention of bile acids (BAs) plays a central role in hepatic damage and disturbed BA signalling in liver disease. However, there is lack of data regarding the association of BAs with clinical complications, acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Thus, we aimed to evaluate the impact of circulating serum BAs for complications in patients with cirrhosis. METHODS One hundred and forty-three patients with cirrhosis were included in this prospective cohort-type observational study. Total serum BAs and individual BA composition were assessed in all patients on admission via high-performance liquid chromatography. Clinical complications with respect to AD, ACLF and 1-year transplant-free survival were recorded. RESULTS Total BAs and individual serum BAs were significantly higher in patients with bacterial infection, AD and ACLF (P<.001) and correlated significantly with model of end-stage liver disease (MELD) and hepatic venous pressure gradient (P<.001). Total BAs predicted new onset of AD or ACLF during follow-up (OR 1.025, 95% CI: 1.012-1.038, P<.001). Best cut-off predicting new onset of AD/ACLF and survival during course of time was total BAs ≥36.9 μmol/L. CONCLUSIONS Serum total and individual BAs are associated with AD and ACLF in patients with cirrhosis. Assessment of total BAs could serve as additional marker for risk stratification in cirrhotic patients with respect to new onset of AD and ACLF.
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Affiliation(s)
- Thomas Horvatits
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Drolz
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kevin Roedl
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karoline Rutter
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Arnulf Ferlitsch
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Günter Fauler
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Valentin Fuhrmann
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Park R, Ji JD. The Role of Bile Acid Receptors in Chronic Inflammatory Diseases. JOURNAL OF RHEUMATIC DISEASES 2017. [DOI: 10.4078/jrd.2017.24.5.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Robin Park
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jong Dae Ji
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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48
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van Niekerk G, Hattingh SM, Engelbrecht AM. Enhanced Therapeutic Efficacy in Cancer Patients by Short-term Fasting: The Autophagy Connection. Front Oncol 2016; 6:242. [PMID: 27896219 PMCID: PMC5107564 DOI: 10.3389/fonc.2016.00242] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 10/31/2016] [Indexed: 12/26/2022] Open
Abstract
Preclinical studies suggest that fasting prior to chemotherapy may be an effective strategy to protect patients against the adverse effects of chemo-toxicity. Fasting may also sensitize cancer cells to chemotherapy. It is further suggested that fasting may similarly augment the efficacy of oncolytic viral therapy. The primary mechanism mediating these beneficial effects is thought to relate to the fact that fasting results in a decrease of circulating growth factors. In turn, such fasting cues would prompt normal cells to redirect energy toward cell maintenance and repair processes, rather than growth and proliferation. However, fasting is also known to upregulate autophagy, an evolutionarily conserved catabolic process that is upregulated in response to various cell stressors. Here, we review a number of mechanisms by which fasting-induced autophagy may have an impact on both chemo-tolerance and chemo-sensitization. First, fasting may exert a protective effect by mobilizing autophagic components prior to chemo-induction. In turn, the autophagic apparatus can be repurposed for removing cellular components damaged by chemotherapy. Autophagy also plays a key role in epitope expression as well as in modulating inflammation. Chemo-sensitization resulting from fasting may in fact be an effect of enhanced immune surveillance as a result of better autophagy-dependent epitope processing. Finally, autophagy is involved in host defense against viruses, and aspects of the autophagic process are also often targets for viral subversion. Consequently, altering autophagic flux by fasting may alter viral infectivity. These observations suggest that fasting-induced autophagy may have an impact on therapeutic efficacy in various oncological contexts.
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Affiliation(s)
- Gustav van Niekerk
- Department of Physiological Sciences, Stellenbosch University , Stellenbosch , South Africa
| | - Suzèl M Hattingh
- Department of Biomedical Sciences, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University , Tygerberg , South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University , Stellenbosch , South Africa
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Banerjee S, Sindberg G, Wang F, Meng J, Sharma U, Zhang L, Dauer P, Chen C, Dalluge J, Johnson T, Roy S. Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 2016; 9:1418-1428. [PMID: 26906406 PMCID: PMC4996771 DOI: 10.1038/mi.2016.9] [Citation(s) in RCA: 208] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 12/30/2015] [Indexed: 02/04/2023]
Abstract
Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces bacterial translocation across the gut barrier. The enteric microbiome has been shown to have a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of Gram-positive pathogenic and reduction in bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine-induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management.
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Affiliation(s)
- Santanu Banerjee
- Department of Surgery, 515 Delaware St SE, Moos 11-204, University
of Minnesota, MN 55455, USA
| | - Gregory Sindberg
- Department of Veterinary Medicine, 515 Delaware St SE, Moos 11-204,
University of Minnesota, MN 55455, USA
| | - Fuyuan Wang
- Department of Veterinary Medicine, 515 Delaware St SE, Moos 11-204,
University of Minnesota, MN 55455, USA
| | - Jingjing Meng
- Department of Surgery, 515 Delaware St SE, Moos 11-204, University
of Minnesota, MN 55455, USA
| | - Umakant Sharma
- Department of Surgery, 515 Delaware St SE, Moos 11-204, University
of Minnesota, MN 55455, USA
| | - Li Zhang
- Department of Pharmacology, 515 Delaware St SE, Moos 11-204,
University of Minnesota, MN 55455, USA
| | - Patricia Dauer
- Department of Pharmacology, 515 Delaware St SE, Moos 11-204,
University of Minnesota, MN 55455, USA
| | - Chi Chen
- Department of Food Science and Nutrition, 515 Delaware St SE, Moos
11-204, University of Minnesota, MN 55455, USA
| | - Joseph Dalluge
- Department of Chemistry, 515 Delaware St SE, Moos 11-204, University
of Minnesota, MN 55455, USA
| | - Timothy Johnson
- Department of Veterinary Medicine, 515 Delaware St SE, Moos 11-204,
University of Minnesota, MN 55455, USA
| | - Sabita Roy
- Department of Surgery, 515 Delaware St SE, Moos 11-204, University
of Minnesota, MN 55455, USA,Department of Pharmacology, 515 Delaware St SE, Moos 11-204,
University of Minnesota, MN 55455, USA,To whom correspondence should be addressed. Prof. Sabita
Roy, Director, Division of Infection, Inflammation and Vascular Biology,
Department of Surgery and Pharmacology Telephone Number: 612-624-4615, Fax
Number 612 626-4900,
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50
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Gu M, Zhao P, Huang J, Zhao Y, Wang Y, Li Y, Li Y, Fan S, Ma YM, Tong Q, Yang L, Ji G, Huang C. Silymarin Ameliorates Metabolic Dysfunction Associated with Diet-Induced Obesity via Activation of Farnesyl X Receptor. Front Pharmacol 2016; 7:345. [PMID: 27733832 PMCID: PMC5039206 DOI: 10.3389/fphar.2016.00345] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 09/14/2016] [Indexed: 12/17/2022] Open
Abstract
Background and purpose: Silymarin, a standardized extract of the milk thistle seeds, has been widely used to treat chronic hepatitis, cirrhosis, and other types of toxic liver damage. Despite increasing studies on the action of silymarin and its major active constituent, silybin in their therapeutic properties against insulin resistance, diabetes and hyperlipidaemia in vitro and in vivo, the mechanism underlying silymarin action remains unclear. Experimental approach: C57BL/6 mice were fed high-fat diet (HFD) for 3 months to induce obesity, insulin resistance, hyperlipidaemia, and fatty liver. These mice were then continuously treated with HFD alone or mixed with silymarin at 40 mg/100 g for additional 6 weeks. Biochemical analysis was used to test the serum lipid and bile acid profiles. Farnesyl X receptor (FXR) and nuclear factor kappa B (NF-κB) transactivities were analyzed in liver using a gene reporter assay based on quantitative RT-PCR. Key results: Silymarin treatment ameliorated insulin resistance, dyslipidaemia and inflammation, and reconstituted the bile acid pool in liver of diet-induced obesity. Associated with this, silybin and silymarin enhanced FXR transactivity. Consistently, in HepG2 cells, silybin inhibited NF-κB signaling, which was enhanced by FXR activation. Conclusion and implications: Our results suggest that silybin is an effective component of silymarin for treating metabolic syndrome by stimulating FXR signaling.
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Affiliation(s)
- Ming Gu
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Ping Zhao
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Jinwen Huang
- School of Chemical and Environmental Engineering, Shanghai Institute of TechnologyShanghai, China
| | - Yuanyuan Zhao
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Yahui Wang
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Yin Li
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Yifei Li
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Shengjie Fan
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
- Brown Foundation Institute of Molecular Medicine and Program in Neuroscience, Graduate School of Biological Sciences, University of Texas McGovern Medical SchoolHouston, TX, USA
| | - Yue-Ming Ma
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Qingchun Tong
- Brown Foundation Institute of Molecular Medicine and Program in Neuroscience, Graduate School of Biological Sciences, University of Texas McGovern Medical SchoolHouston, TX, USA
| | - Li Yang
- Research Centre for Traditional Chinese Medicine of Complexity Systems, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese MedicineShanghai, China
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