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Zhang R, Sun J, Wang Y, Yu H, Wang S, Feng X. Ameliorative effect of phenolic compound-pterostilbene on corticosterone-induced hepatic lipid metabolic disorder in broilers. J Nutr Biochem 2025; 137:109822. [PMID: 39645170 DOI: 10.1016/j.jnutbio.2024.109822] [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: 10/28/2024] [Accepted: 12/01/2024] [Indexed: 12/09/2024]
Abstract
The aim of this study was to investigate the ameliorative effects of pterostilbene (PTE), a polyphenolic compound, on stress-induced lipid metabolic disorders in the liver of broiler chickens. Six hundred healthy, 1-day-old Arbor Acres with similar weight were randomly assigned to five groups, each consisting of eight replicates with 15 broilers per replicate. The groups included: a control group (fed a basal diet), and four groups treated with corticosterone (CORT) at varying dietary levels of PTE supplementation: CORT (0 mg/kg PTE), CORT-PT200 (200 mg/kg PTE), CORT-PT400 (400 mg/kg PTE), and CORT-PT600 (600 mg/kg PTE). The results indicated that PTE administration to corticosterone (CORT)-injected broilers significantly improved weight gain, reduced liver index, and lowered the elevation of serum aspartate aminotransferase, gamma-glutamyl transferase, glucose, total cholesterol, triglycerides, and lipoprotein cholesterol concentrations induced by CORT injection (P<.05), but had no significant effect on serum CORT concentration (P>.05). PTE also significantly reduced the increased rate of abdominal fat deposition induced by CORT, decreased the average size of adipocytes, and downregulated the expression of the FAS gene (P<.05). It reversed the increase in liver total cholesterol, triglycerides, lipoprotein cholesterol, and non-esterified fatty acids content induced by CORT (P<.05). PTE had no significant effect on the expression of the glucocorticoid receptor (P>.05), but significantly upregulated the protein expression of Sirt1 and p-AMPK (P<.05), promoted the expression of lipid autophagy genes MAP1LC3B and lipolytic genes LPL, but inhibited the expression of fatty acid synthesis genes SREBP-1c, ACC, and SCD (P<.05). The addition of PTE to the diet alleviated CORT-induced oxidative stress and inflammation by enhancing T-SOD and GSH-Px activities, reducing MDA content, inhibiting p-NF-κB p65 and NLRP3 expression and the release of TNF-α and IL-1β in the serum, and increasing IL-4 content (P<.05). Overall, dietary PTE effectively regulates lipid metabolism and antioxidant status, offering a potential strategy to mitigate stress-induced metabolic disruptions in broilers.
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Affiliation(s)
- Ruoshi Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Jing Sun
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Yingjie Wang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China
| | - Hao Yu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Shenao Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Xingjun Feng
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China.
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2
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Karin M, Kim JY. MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives. Mol Oncol 2025; 19:275-294. [PMID: 38874196 PMCID: PMC11793012 DOI: 10.1002/1878-0261.13685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 04/15/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024] Open
Abstract
Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.
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Affiliation(s)
- Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of MedicineUniversity of California San DiegoLa JollaCAUSA
| | - Ju Youn Kim
- Department of Molecular and Life ScienceHanyang University ERICAAnsanKorea
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Barbhuiya PA, Ahmed A, Dutta PP, Sen S, Pathak MP. Mitigating Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): The Role of Bioactive Phytoconstituents in Indian Culinary Spices. Curr Nutr Rep 2025; 14:20. [PMID: 39841356 DOI: 10.1007/s13668-024-00598-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 01/30/2025]
Abstract
PURPOSE OF REVIEW The term metabolic dysfunction-associated steatotic liver disease (MASLD) refers to a group of progressive steatotic liver conditions that include metabolic dysfunction-associated steatohepatitis (MASH), which has varying degrees of liver fibrosis and may advance to cirrhosis, and independent hepatic steatosis. MASLD has a complex underlying mechanism, with patients exhibiting diverse causes and phases of the disease. India has a pool prevalence of MASLD of 38.6% in adults. In 2023, the term NAFLD has been redefined and changed to MASLD. Currently, there are no drugs approved by the FDA for the treatment of MASLD. This study investigates the potential of bioactive phytoconstituents present in spices as a therapeutic approach for MASLD. Moreover, it offers comprehensive data on several pre-clinical studies of bioactive phytoconstituents derived from spices that primarily focus on treating obesity-associated MASLD. RECENT FINDINGS Spices include a high amount of bioactive chemicals and several research have indicated their diverse pharmacological activities. Bioactive phytoconstituents from common Indian spices like cinnamic acid, eugenol, curcumin, allicin, 6-gingerols, capsaicin, piperine, eucalyptol, trigonelline, and linalool have been reported to exhibit anti-MASLD effects both in-vivo and in-vitro. Bioactive phytoconstituents from different culinary species of India have shown promising potential against MASLD in pre-clinical status. Further clinical studies on a large scale would be beneficial for paving the path to the development of a new drug which is the need of time.
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Affiliation(s)
- Pervej Alom Barbhuiya
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
| | - Ameena Ahmed
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Rahman Institute of Pharmaceutical Sciences and Research, Tepesia, Sonapur, Assam, India, PIN - 782402
| | - Partha Pratim Dutta
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
| | - Saikat Sen
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026.
- Centre for Research On Ethnomedicine, Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India, PIN - 781026.
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4
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Yu J, Chen G, Jin Y, Zhang M, Wu T. Research Progress of Bioactive Peptides in Improving Type II Diabetes. Foods 2025; 14:340. [PMID: 39941934 PMCID: PMC11817365 DOI: 10.3390/foods14030340] [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: 12/02/2024] [Revised: 01/11/2025] [Accepted: 01/16/2025] [Indexed: 02/16/2025] Open
Abstract
Type II diabetes mellitus (T2DM) is a prevalent, long-standing metabolic condition marked by the body's reduced response to insulin and inadequate insulin production, impacting a significant portion of the global population. Research has demonstrated that bioactive peptides play a crucial role in reducing blood sugar levels, enhancing insulin sensitivity, balancing lipid metabolism, and combating inflammation. These peptides also contribute to the enhancement of pancreatic islet function, lowering systemic inflammation by influencing various molecular signaling pathways. This paper provides an overview of recent advancements and potential applications of bioactive peptides in addressing T2DM. It highlights the diverse impacts of bioactive peptides sourced from different origins in combating diabetes. This comprehensive review offers theoretical substantiation and novel insights to support the future clinical utilization and exploration of bioactive peptides for T2DM management.
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Affiliation(s)
- Jiaxin Yu
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of Food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China; (J.Y.); (G.C.); (Y.J.); (M.Z.)
| | - Guoxing Chen
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of Food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China; (J.Y.); (G.C.); (Y.J.); (M.Z.)
| | - Yan Jin
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of Food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China; (J.Y.); (G.C.); (Y.J.); (M.Z.)
| | - Min Zhang
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of Food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China; (J.Y.); (G.C.); (Y.J.); (M.Z.)
| | - Tao Wu
- State Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, College of Food Science and Engineering, Tianjin University of Science & Technology, Tianjin 300457, China; (J.Y.); (G.C.); (Y.J.); (M.Z.)
- School of Ocean and Environment, Tianjin University of Science & Technology, Tianjin 300457, China
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5
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Sha X, Zou X, Liu S, Guan C, Shi W, Gao J, Zhong X, Jiang X. Forkhead box O1 in metabolic dysfunction-associated fatty liver disease: molecular mechanisms and drug research. Front Nutr 2024; 11:1426780. [PMID: 39021599 PMCID: PMC11253077 DOI: 10.3389/fnut.2024.1426780] [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: 05/02/2024] [Accepted: 06/21/2024] [Indexed: 07/20/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.
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Affiliation(s)
| | | | | | | | | | | | - Xiangyu Zhong
- General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xingming Jiang
- General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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6
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Fabunmi OA, Dludla PV, Nkambule BB. High-dose oral contraceptives induce hyperinsulinemia without altering immune activation in diet-induced obesity which persists even following a dietary low-fat diet intervention. J Reprod Immunol 2024; 163:104234. [PMID: 38479054 DOI: 10.1016/j.jri.2024.104234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 02/24/2024] [Accepted: 03/07/2024] [Indexed: 06/03/2024]
Abstract
Combined oral contraceptives (COCs) are known to cause weight gain and alter metabolic and immunological pathways. However, modifications in arterial or venous thrombotic risk profiles of women of reproductive ages on COC remain unclear. The study aimed at assessing the impact of COC on immune activation in diet-induced obesity. We further established whether the dietary intervention of switching from a high-fat diet (HFD) to a low-fat diet (LFD) attenuates immunological responses. Twenty (n=20) five-week-old female Sprague Dawley rats were randomly divided into two diet groups of HFD (n=15) and LFD (n=5) and were monitored for eight weeks. After eight weeks, animals in the HFD group switched diets to LFD and were randomly assigned to receive high-dose COC (HCOC) or low-dose COC (LCOC) for six weeks. Animals on HFD significantly gained weight and had a higher lee index when compared to the LFD group (p < 0.05). Moreover, the triglyceride-glucose index, insulin, and other metabolic parameters also increased in the HFD group compared to the LFD group (p < 0.001). Consistently, the levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), were elevated in the HFD group when compared to the LFD group (p < 0.05). Upon switching from a high-fat to a low-fat diet, insulin levels persistently increased in animals receiving HCOC treatment compared to the LFD and HFD/LFD groups (p < 0.05). Thus, in a rat model of HFD-feeding, short-term HCOC treatment induces long-term metabolic dysregulation, which persists despite dietary intervention. However, further studies are recommended to confirm these findings.
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Affiliation(s)
- Oyesanmi A Fabunmi
- School of Laboratory Medicine and Medical Sciences (SLMMS), College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa; Health-awareness, Exercise and Cardio-immunologic Research Unit (HECIRU), Department of Physiology, College of Medicine, Ekiti State University, Ado-Ekiti 5363, Nigeria.
| | - Phiwayinkosi V Dludla
- Cochrane South Africa, South African Medical Research Council, Tygerberg 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences (SLMMS), College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.
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7
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Meyer M, Schwärzler J, Jukic A, Tilg H. Innate Immunity and MASLD. Biomolecules 2024; 14:476. [PMID: 38672492 PMCID: PMC11048298 DOI: 10.3390/biom14040476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.
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Affiliation(s)
| | | | | | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria; (M.M.); (A.J.)
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8
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Abdelsalam HM. GABA Administration Ameliorates the Toxicity of Doxorubicin on CSF and the Brain of Albino Rats. Ann Neurosci 2024; 31:12-20. [PMID: 38584977 PMCID: PMC10996873 DOI: 10.1177/09727531231161911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 12/03/2022] [Indexed: 04/09/2024] Open
Abstract
Background Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and is a non-proteinogenic amino acid. Doxorubcin (DOX) or adriamycin is one of the most potent chemotherapy drugs for breast cancer. Purpose This study focused on diminishing the brain injury and neurotoxicity of doxorubicin (DOX) by GABA administration. Methods Rats were randomly divided into four groups (8 rats each), which were the control group, DOX group (3 mg/kg for 4 weeks, then 2 mg/kg for 2 weeks), GABA group (2 mg/kg for 21 days), and DOX + GABA group (treated as the second and third groups). Neurotoxicity and brain injury were assessed by determining CSF biomarkers, serum inflammatory markers, and histopathological evaluation of the cerebral cortex. Results DOX treatment significantly increased the levels of all CSF biomarkers (S100B, IL-1β, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), spectrin breakdown products (SBDP145), and C-C motif chemokine ligand 2 (CCL2) and all inflammatory markers (IL-6, TNF-α, and IFN-γ), causing extensive neutrophilic infiltration and great alteration in the cerebral cortex architecture as evidence of neurotoxicity. The oral administration of GABA significantly reduced the levels of all CSF biomarkers and inflammatory markers and restored the normal architecture of the cerebral cortex, with observed ameliorations in neutrophilic infiltration. Conclusion GABA administration can ameliorate neurotoxicity and protect the brain against the negative effects of DOX treatment.
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Burger K, Jung F, Baumann A, Brandt A, Staltner R, Sánchez V, Bergheim I. TNFα is a key trigger of inflammation in diet-induced non-obese MASLD in mice. Redox Biol 2023; 66:102870. [PMID: 37683301 PMCID: PMC10493600 DOI: 10.1016/j.redox.2023.102870] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/28/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
Tumor necrosis factor alpha (TNFα) is thought to be a critical factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we determined the effects of a treatment with the anti-TNFα antibody infliximab and a genetic deletion of TNFα, respectively, in the development of non-obese diet-induced early metabolic dysfunction-associated steatohepatitis (MASH) in mice. The treatment with infliximab improved markers of liver damage in mice with pre-existing early MASH. In TNFα-/- mice, the development of early signs of MASH and insulin resistance was significantly attenuated compared to wild-type animals. While mRNA expression of proinflammatory cytokines like interleukin 1β (Il1b) and interleukin 6 (Il6) were significantly lower in livers of MASH-diet-fed TNFα-/- mice compared to wild-type mice with early MASH, markers of intestinal barrier function were similarly impaired in both MASH-diet-fed groups compared to controls. Our data suggest that TNFα is a key regulator of hepatic inflammation and insulin resistance associated with the development of early non-obese MASH.
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Affiliation(s)
- Katharina Burger
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
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10
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Vachliotis ID, Polyzos SA. The Role of Tumor Necrosis Factor-Alpha in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2023; 12:191-206. [PMID: 37407724 PMCID: PMC10482776 DOI: 10.1007/s13679-023-00519-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2023] [Indexed: 07/07/2023]
Abstract
PURPOSE OF REVIEW To summarize experimental and clinical evidence on the association between tumor necrosis factor-α (TNF-α) and nonalcoholic fatty liver disease (NAFLD) and discuss potential treatment considerations. RECENT FINDINGS Experimental evidence suggests that TNF-α is a cytokine with a critical role in the pathogenesis of NAFLD. Although, the production of TNF-α may be an early event during the course of nonalcoholic fatty liver (NAFL), TNF-α may play a more substantial role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and NAFLD-associated fibrosis. Moreover, TNF-α may potentiate hepatic insulin resistance, thus interconnecting inflammatory with metabolic signals and possibly contributing to the development of NAFLD-related comorbidities, including cardiovascular disease, hepatocellular carcinoma, and extra-hepatic malignancies. In clinical terms, TNF-α is probably associated with the severity of NAFLD; circulating TNF-α gradually increases from controls to patients with NAFL, and then, to patients with NASH. Given this potential association, various therapeutic interventions (obeticholic acid, peroxisome proliferator-activated receptors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, probiotics, synbiotics, rifaximin, vitamin E, pentoxifylline, ursodeoxycholic acid, fibroblast growth factor-21, n-3 polyunsaturated fatty acids, statins, angiotensin receptor blockers) have been evaluated for their effect on TNF-α and NAFLD. Interestingly, anti-TNF biologics have shown favorable metabolic and hepatic effects, which may open a possible therapeutic window for the management of advanced NAFLD. The potential key pathogenic role of TNF-α in NAFLD warrants further investigation and may have important diagnostic and therapeutic implications.
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Affiliation(s)
- Ilias D. Vachliotis
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- Second Department of Internal Medicine, 424 General Military Hospital, Thessaloniki, Greece
| | - Stergios A. Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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11
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Torosian K, Lal E, Kavanaugh A, Loomba R, Ajmera V, Guma M. Psoriatic disease and non-alcoholic fatty liver disease shared pathogenesis review. Semin Arthritis Rheum 2023; 59:152165. [PMID: 36716599 PMCID: PMC9992353 DOI: 10.1016/j.semarthrit.2023.152165] [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: 09/30/2022] [Revised: 12/03/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023]
Abstract
Psoriatic disease (PD) and non-alcoholic fatty liver disease (NAFLD) potentially share disease pathways given the numerous inflammatory pathways involved in both diseases and a higher prevalence of NAFLD in PD patients. Metabolic syndrome and obesity are a key link between the two diseases, but even when controlling for this, associations between both diseases are still seen. Therapeutics that impact metabolic or inflammatory pathways may be impactful in both PD and NAFLD. In this review, we describe common inflammatory pathways contributing to both PD and NAFLD and critically review the potential impact of treatments for and on both diseases.
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Affiliation(s)
- Kelly Torosian
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Esha Lal
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Arthur Kavanaugh
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA; Division of Epidemiology, Department of Family and Preventative Medicine, University of California at San Diego, La Jolla, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA.
| | - Monica Guma
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain; San Diego VA Healthcare Service, San Diego, CA, 92161, USA.
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12
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Xiong P, Zhang F, Liu F, Zhao J, Huang X, Luo D, Guo J. Metaflammation in glucolipid metabolic disorders: Pathogenesis and treatment. Biomed Pharmacother 2023; 161:114545. [PMID: 36948135 DOI: 10.1016/j.biopha.2023.114545] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/11/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
The public health issue of glucolipid metabolic disorders (GLMD) has grown significantly, posing a grave threat to human wellness. Its prevalence is rising yearly and tends to affect younger people. Metaflammation is an important mechanism regulating body metabolism. Through a complicated multi-organ crosstalk network involving numerous signaling pathways such as NLRP3/caspase-1/IL-1, NF-B, p38 MAPK, IL-6/STAT3, and PI3K/AKT, it influences systemic metabolic regulation. Numerous inflammatory mediators are essential for preserving metabolic balance, but more research is needed to determine how they contribute to the co-morbidities of numerous metabolic diseases. Whether controlling the inflammatory response can influence the progression of GLMD determines the therapeutic strategy for such diseases. This review thoroughly examines the role of metaflammation in GLMD and combs the research progress of related therapeutic approaches, including inflammatory factor-targeting drugs, traditional Chinese medicine (TCM), and exercise therapy. Multiple metabolic diseases, including diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and others, respond therapeutically to anti-inflammatory therapy on the whole. Moreover, we emphasize the value and open question of anti-inflammatory-based means for treating GLMD.
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Affiliation(s)
- Pingjie Xiong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Fan Zhang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Fang Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Jiayu Zhao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Xiaoqiang Huang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China.
| | - Duosheng Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China.
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13
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Kucukkurt I, Ince S, Eryavuz A, Demirel HH, Arslan-Acaroz D, Zemheri-Navruz F, Durmus I. The effects of boron-supplemented diets on adipogenesis-related gene expressions, anti-inflammatory, and antioxidative response in high-fat fed rats. J Biochem Mol Toxicol 2023; 37:e23257. [PMID: 36419211 DOI: 10.1002/jbt.23257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 09/27/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022]
Abstract
The fatty liver syndrome caused by nutritional factors is a common cause of hepatic dysfunction globally. This research was designed to study the shielding effect of boron in rats fed a diet having high fat. Overall, 40 Wistar albino male rats were placed into one control and four treatment groups, that is, each having eight rats. Group I was provided with a standard rat diet while group II was only provided a high-fat diet for 60 days. Groups III, IV, and V were provided with 5, 10, and 20 mg/kg/day boron, respectively, by gastric gavage besides a high-fat diet for 60 days. Malondialdehyde was increased significantly in rats' blood and tissue because of high-fat diets. Glutathione was decreased significantly in blood and tissues because of a high-fat diet. Moreover, the activities of superoxide dismutase (SOD) and catalase (CAT) were decreased in the blood and tissues of the high-fat-fed rats. The genes expression for C-reactive protein, interleukin-1β, leptin, and tumor necrosis factor-α were increased while gene expression for peroxisome proliferator-activated receptors was decreased in the liver of rats fed with a high-fat diet. Contrariwise, boron supplementation improves antioxidative response in terms of increased SOD and CAT activities, gene expression regulation, and improved anti-inflammatory activities. In a nutshell, boron has dose-dependent shielding antioxidative and tissue regenerative effects in rats.
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Affiliation(s)
- Ismail Kucukkurt
- Department of Biochemistry, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Turkey
| | - Sinan Ince
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Turkey
| | - Abdullah Eryavuz
- Department of Physiology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Turkey
| | - Hasan H Demirel
- Bayat Vocational School, Afyon Kocatepe University, Afyonkarahisar, Turkey
| | | | - Fahriye Zemheri-Navruz
- Department of Molecular Biology and Genetics, Faculty of Science, Bartın University, Bartın, Turkey
| | - Ibrahim Durmus
- Suhut Vocational School, Afyon Kocatepe University, Afyonkarahisar, Turkey
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Finney AC, Das S, Kumar D, McKinney MP, Cai B, Yurdagul A, Rom O. The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease. Front Cardiovasc Med 2023; 10:1116861. [PMID: 37200978 PMCID: PMC10185914 DOI: 10.3389/fcvm.2023.1116861] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/23/2023] [Indexed: 05/20/2023] Open
Abstract
Therapeutic approaches that lower circulating low-density lipoprotein (LDL)-cholesterol significantly reduced the burden of cardiovascular disease over the last decades. However, the persistent rise in the obesity epidemic is beginning to reverse this decline. Alongside obesity, the incidence of nonalcoholic fatty liver disease (NAFLD) has substantially increased in the last three decades. Currently, approximately one third of world population is affected by NAFLD. Notably, the presence of NAFLD and particularly its more severe form, nonalcoholic steatohepatitis (NASH), serves as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), thus, raising interest in the relationship between these two diseases. Importantly, ASCVD is the major cause of death in patients with NASH independent of traditional risk factors. Nevertheless, the pathophysiology linking NAFLD/NASH with ASCVD remains poorly understood. While dyslipidemia is a common risk factor underlying both diseases, therapies that lower circulating LDL-cholesterol are largely ineffective against NASH. While there are no approved pharmacological therapies for NASH, some of the most advanced drug candidates exacerbate atherogenic dyslipidemia, raising concerns regarding their adverse cardiovascular consequences. In this review, we address current gaps in our understanding of the mechanisms linking NAFLD/NASH and ASCVD, explore strategies to simultaneously model these diseases, evaluate emerging biomarkers that may be useful to diagnose the presence of both diseases, and discuss investigational approaches and ongoing clinical trials that potentially target both diseases.
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Affiliation(s)
- Alexandra C. Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Sandeep Das
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Dhananjay Kumar
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - M. Peyton McKinney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Bishuang Cai
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, United States
| | - Arif Yurdagul
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
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15
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Ionescu VA, Gheorghe G, Varlas VN, Stanescu AMA, Diaconu CC. Hepatobiliary Impairments in Patients with Inflammatory Bowel Diseases: The Current Approach. GASTROENTEROLOGY INSIGHTS 2022; 14:13-26. [DOI: 10.3390/gastroent14010002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Inflammatory bowel disease (IBD) refers to chronic conditions with a low mortality but high disability. The multisystemic nature of these diseases can explain the appearance of some extraintestinal manifestations, including liver damage. Abnormal liver biochemical tests can be identified in approximately one third of patients with IBD and chronic liver disease in 5% of them. Among the liver diseases associated with IBD are primary sclerosing cholangitis, cholelithiasis, fatty liver disease, hepatic amyloidosis, granulomatous hepatitis, drug-induced liver injury, venous thromboembolism, primary biliary cholangitis, IgG4-related cholangiopathy, autoimmune hepatitis, liver abscesses or the reactivation of viral hepatitis. The most common disease is primary sclerosing cholangitis, a condition diagnosed especially in patients with ulcerative colitis. The progress registered in recent years in the therapeutic management of IBD has not eliminated the risk of drug-induced liver disease. Additionally, the immunosuppression encountered in these patients increases the risk of opportunistic infections, including the reactivation of viral hepatitis. Currently, one of the concerns consists of establishing an efficiency and safety profile of the use of direct-acting antiviral agents (DAA) among patients with hepatitis C and IBD. Early diagnosis and optimal treatment of liver complications can improve the prognoses of these patients.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Valentin Nicolae Varlas
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
| | | | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
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16
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Huang C, Wei X, Luo Q, Xia Y, Pan T, He J, Jahangir A, Jia L, Liu W, Zou Y, Li L, Guo H, Geng Y, Chen Z. Loss of TRIM67 Attenuates the Progress of Obesity-Induced Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23137475. [PMID: 35806477 PMCID: PMC9267895 DOI: 10.3390/ijms23137475] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/01/2022] [Accepted: 07/02/2022] [Indexed: 02/01/2023] Open
Abstract
Obesity is considered as a major cause for the development and progress of non-alcoholic fatty liver disease (NAFLD), which is one of the most prevalent chronic liver diseases worldwide. However, molecular mechanisms that implicate in obesity-driven pathophysiology of NAFLD are not well defined. Here, we report a tripartite motif (TRIM) protein family member—TRIM67—that is hardly expressed in liver but is inducible on obese conditions. Enhanced expression of TRIM67 activates hepatic inflammation to disturb lipid metabolic homeostasis and promote the progress of NAFLD induced by obesity, while the deficiency in TRIM67 is protective against these pathophysiological processes. Finally, we show that the important transcription coactivator PGC-1α implicates in the response of hepatic TRIM67 to obesity.
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Affiliation(s)
- Chao Huang
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
- Correspondence: (C.H.); (Z.C.)
| | - Xiaoli Wei
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Qihui Luo
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Yu Xia
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Ting Pan
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Junbo He
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Asad Jahangir
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Lanlan Jia
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Wentao Liu
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Yuanfeng Zou
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Lixia Li
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Hongrui Guo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Yi Geng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
| | - Zhengli Chen
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (X.W.); (Q.L.); (Y.X.); (T.P.); (J.H.); (A.J.); (L.J.); (W.L.)
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.Z.); (L.L.); (H.G.); (Y.G.)
- Correspondence: (C.H.); (Z.C.)
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Papaefthymiou A, Potamianos S, Goulas A, Doulberis M, Kountouras J, Polyzos SA. Inflammatory Bowel Disease-associated Fatty Liver Disease: the Potential Effect of Biologic Agents. J Crohns Colitis 2022; 16:852-862. [PMID: 34972203 DOI: 10.1093/ecco-jcc/jjab212] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/02/2021] [Accepted: 11/19/2021] [Indexed: 01/16/2023]
Abstract
Inflammatory bowel diseases [IBD] exhibit intestinal and systemic manifestations. Nonalcoholic fatty liver disease [NAFLD] is a common co-existing condition, possibly contributing to the cardio-metabolic burden and overall morbidity. Εmerging therapeutic choices of biologic agents have modified the clinical course of IBD; however, their impact on IBD-associated NAFLD has not been extensively evaluated. The prevalence of NAFLD varies among IBD patients, but it appears higher than in the general population in the majority of quality studies. In terms of pathogenetic and risk factors of NAFLD, they may vary with IBD activity. Dysbiosis, mucosal damage, and cytokine release have been implicated in the pathogenesis during the relapses, whereas metabolic risk factors seem to play a dominant role during the remissions of IBD. Considering biologics, although quality data are scarce, agents suppressing tumour necrosis factor may offer potential benefits in IBD-associated NAFLD, whereas anti-integrins do not appear to confer any therapeutic advantage. In conclusion, IBD-associated NAFLD possibly follows two different patterns, one manifested during the relapses and one during the remissions of IBD. Some, but not all, biologics may benefit NAFLD in patients with IBD. Further mechanistic and prospective cohort studies are warranted to illuminate the effects of various biologics on NAFLD.
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Affiliation(s)
- Apostolis Papaefthymiou
- Department of Gastroenterology, University Hospital of Larisa, Larisa, Thessaly, Greece.,First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Spyros Potamianos
- Department of Gastroenterology, University Hospital of Larisa, Larisa, Thessaly, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Michael Doulberis
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece.,Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland
| | - Jannis Kountouras
- Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
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18
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Veltkamp C, Lan S, Korompoki E, Weiss KH, Schmidt H, Seitz HK. Hepatic Steatosis and Fibrosis in Chronic Inflammatory Bowel Disease. J Clin Med 2022; 11:jcm11092623. [PMID: 35566749 PMCID: PMC9105667 DOI: 10.3390/jcm11092623] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 02/04/2023] Open
Abstract
Background and Purpose: Chronic inflammatory bowel diseases (IBD) frequently affect extraintestinal organs including the liver. Since limited evidence suggests the presence of liver disease in IBD patients, we studied the frequency of hepatic steatosis and fibrosis in these patients and characterized disease-related factors. Methods: In this retrospective, cross-sectional, hospital-based, single-center study, consecutive patients with Crohn’s disease (CD) and ulcerative colitis (UC) were included who had undergone routine abdominal ultrasound including transhepatic elastography. Hepatic steatosis was diagnosed by hyperechogenicity on B-mode ultrasound and by measuring controlled attenuation parameter (CAP). Hepatic fibrosis was assumed if transhepatic elastography yielded a stiffness > 7 kPa. Results: 132 patients (60% CD) with a median disease duration of 10 years were included. Steatosis assessed by B-mode ultrasound and CAP correlated well. Of the IBD patients, 30.3% had non-alcoholic fatty liver (NAFL). Factors associated with NAFL were age, BMI, duration of disease, as well as serum activities of aspartate-aminotransferase (AST) and gamma-glutamyl-transpeptidase (GGT). In multivariate analysis, only disease duration was independently associated with hepatic steatosis. Hepatic fibrosis was found in 10 (8%) of all IBD patients, predominantly in patients with CD (10/11). Conclusions: Pure hepatic steatosis is common in both CD and UC, whereas hepatic fibrosis occurs predominantly in CD patients. Association of disease duration with NAFLD suggests a contribution of IBD-related pathogenetic factors. Longitudinal studies are needed to better understand the impact of IBD on hepatic disorders.
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Affiliation(s)
- Claudia Veltkamp
- Department of Gastroenterology, Hepatology and Transplantation Medicine, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
- Correspondence: ; Tel.: +49-201723-0
| | - Shuai Lan
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
| | - Eleni Korompoki
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 157 72 Athens, Greece;
| | - Karl-Heinz Weiss
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
| | - Hartmut Schmidt
- Department of Gastroenterology, Hepatology and Transplantation Medicine, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;
| | - Helmut K. Seitz
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
- Centre of Liver- and Alcohol Diseases, Ethianum Clinic, 69115 Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, 69117 Heidelberg, Germany
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19
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Zhang H, Gao X, Chen P, Wang H. Protective Effects of Tiaoganquzhi Decoction in Treating inflammatory Injury of Nonalcoholic Fatty liver Disease by Promoting CGI-58 and Inhibiting Expression of NLRP3 Inflammasome. Front Pharmacol 2022; 13:851267. [PMID: 35586044 PMCID: PMC9108379 DOI: 10.3389/fphar.2022.851267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/08/2022] [Indexed: 12/14/2022] Open
Abstract
Tiaoganquzhi Decoction (TGQZD) is a traditional Chinese herbal formulation demonstrated to be a clinically effective treatment for nonalcoholic fatty liver disease (NAFLD), although details concerning its clinical mechanism are poor. This study aimed to explore the mechanism of TGQZD on improvement of inflammatory damage and dyslipidemia caused by NAFLD through the CGI-58/ROS/NLRP3 inflammasome pathway. In our research, the in vivo protective effects of TGQZD on HFD-induced liver injury in rats and in vitro using lipopolysaccharide (LPS)+palmitate (PA)-stimulated HepG-2 cells model. Histological changes were evaluated by hematoxylin-eosin and Oil Red O staining. Inflammatory cytokines and protein expression were analyzed by ELISA, Real time PCR and western blotting. Liver function, blood lipids, free fatty acids (FFA), and reactive oxygen species (ROS) were determined by biochemical detection. Our results indicated that TGQZD exhibited anti-inflammatory activity, reduced the severity of NAFLD and ameliorated the pathological changes. Further, TGQZD improved liver function and lipid metabolism in NAFLD rats. TGQZD lowered serum aspartate aminotransferase, alanine aminotransferase, triglyceride, and total cholesterol levels. TGQZD suppressed the formulation of FFA and ROS. It also reduced the expression and release of the inflammatory cytokine interleukin-1β by promoting CGI-58 expression and inhibiting the expression of FFA, TNF-α, and the NLRP3 inflammasome induced by ROS. TGQZD exhibited anti-inflammatory effects via the CGI-58, ROS and NLRP3 inflammasome pathway in vivo and in vitro, respectively. Our findings demonstrated that TGQZD is a useful and effective therapeutic agent for treating NAFLD via promotion of CGI-58 to inhibit the expression of ROS-induced NLRP3 inflammasome.
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Affiliation(s)
- Huicun Zhang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- Beijing Institute of Chinese Medicine, Beijing, China
- *Correspondence: Huicun Zhang,
| | - Xiang Gao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | | | - Hongbing Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- Beijing Hospital of Traditional Chinese Medicine Yanqing Hospital, Beijing, China
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20
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Explore the Mechanism of Astragalus mongholicus Bunge against Nonalcoholic Fatty Liver Disease Based on Network Pharmacology and Experimental Verification. Gastroenterol Res Pract 2022; 2022:4745042. [PMID: 35422858 PMCID: PMC9005278 DOI: 10.1155/2022/4745042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
Objective Astragalus mongholicus Bunge [Fabaceae] (AMB), a traditional Chinese medicine (TCM), has been widely used to treat liver diseases in the clinic. However, the efficacy and mechanism of AMB in the treatment of nonalcoholic fatty liver disease (NAFLD) remain unclear. The purpose of this study was to systematically investigate the active components and mechanisms of AMB against NAFLD based on network pharmacology, molecular docking, and experimental verification. Methods First, the bioactive components and relevant targets of AMB were screened from the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database, and NAFLD-related targets were obtained from the GeneCards database. Then, the AMB-NAFLD protein target interaction network was built by the STRING database. GO and KEGG pathway enrichment analyses were performed using the DAVID database. The component targets were visualized using Cytoscape software. Finally, molecular docking and experiments were used to verify the results of network pharmacological prediction. Results Network pharmacology predicted that quercetin may be the main active component in AMB, and the TNF and MAPK signaling pathways may be the key targets of AMB against NAFLD. Molecular docking validation results demonstrated that quercetin, as the main active component of AMB, had the highest binding affinity with TNF. Furthermore, quercetin played a distinct role in alleviating NAFLD through in vitro experiments. Quercetin upregulated the phosphorylation levels of AMPK and inhibited the expression of p-MAPK and TNF-α. In addition, we further discovered that quercetin could increase ACC phosphorylation and CPT1α expression in PA-induced HepG2 cells. Conclusions Our results indicated that quercetin, as the main active component in AMB, exerts an anti-NAFLD effect by regulating the AMPK/MAPK/TNF-α and AMPK/ACC/CPT1α signaling pathways to inhibit inflammation and alleviate lipid accumulation.
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21
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Gaspar R, Branco CC, Macedo G. Liver manifestations and complications in inflammatory bowel disease: A review. World J Hepatol 2021; 13:1956-1967. [PMID: 35070000 PMCID: PMC8727205 DOI: 10.4254/wjh.v13.i12.1956] [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: 02/25/2021] [Revised: 05/27/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary manifestations are common in inflammatory bowel disease (IBD), with 30% of patients presenting abnormal liver tests and 5% developing chronic liver disease. They range from asymptomatic elevated liver tests to life-threatening disease and usually follow an independent course from IBD. The pathogenesis of liver manifestations or complications and IBD can be closely related by sharing a common auto-immune background (in primary sclerosing cholangitis, IgG4-related cholangitis, and autoimmune hepatitis), intestinal inflammation (in portal vein thrombosis and granulomatous hepatitis), metabolic impairment (in non-alcoholic fatty liver disease or cholelithiasis), or drug toxicity (in drug induced liver injury or hepatitis B virus infection reactivation). Their evaluation should prompt a full diagnostic workup to identify and readily treat all complications, improving management and outcome.
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Affiliation(s)
- Rui Gaspar
- Department of Gastroenterology and Hepatology, Centro Hospitalar de São João, Porto 4200, Portugal
| | - Catarina Castelo Branco
- Internal Medicine Department, Centro Hospitalar e Universitário do Porto, Porto 4200, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar de São João, Porto 4200, Portugal
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22
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Perez-Carreras M, Casis-Herce B, Rivera R, Fernandez I, Martinez-Montiel P, Villena V. Non-alcoholic fatty liver disease in patients with intestinal, pulmonary or skin diseases: Inflammatory cross-talk that needs a multidisciplinary approach. World J Gastroenterol 2021; 27:7113-7124. [PMID: 34887631 PMCID: PMC8613653 DOI: 10.3748/wjg.v27.i41.7113] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/04/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common cause of liver disease. Its prevalence is increasing in parallel with the obesity and type 2 diabetes mellitus (DM2) epidemics in developed countries. Several recent studies have suggested that NAFLD may be the hepatic manifestation of a systemic inflammatory metabolic disease that also affects other organs, such as intestine, lungs, skin and vascular endothelium. It appears that local and systemic proinflammatory/anti-inflammatory cytokine imbalance, together with insulin resistance and changes in the intestinal microbiota, are pathogenic mechanisms shared by NAFLD and other comorbidities. NAFLD is more common in patients with extrahepatic diseases such as inflammatory bowel disease (IBD), obstructive syndrome apnea (OSA) and psoriasis than in the general population. Furthermore, there is evidence that this association has a negative impact on the severity of liver lesions. Specific risk characteristics for NAFLD have been identified in populations with IBD (i.e. age, obesity, DM2, previous bowel surgery, IBD evolution time, methotrexate treatment), OSA (i.e. obesity, DM2, OSA severity, increased transaminases) and psoriasis (i.e. age, metabolic factors, severe psoriasis, arthropathy, elevated transaminases, methotrexate treatment). These specific phenotypes might be used by gastroenterologists, pneumologists and dermatologists to create screening algorithms for NAFLD. Such algorithms should include non-invasive markers of fibrosis used in NAFLD to select subjects for referral to the hepatologist. Prospective, controlled studies in NAFLD patients with extrahepatic comorbidities are required to demonstrate a causal relationship and also that appropriate multidisciplinary management improves these patients’ prognosis and survival.
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Affiliation(s)
- Mercedes Perez-Carreras
- Gastroenterology and Hepatology Unit, 12 de Octubre Universitary Hospital, Madrid 28041, Spain
- Faculty of Medicine, Complutense University, Madrid 28040, Spain
| | - Begoña Casis-Herce
- Gastroenterology and Hepatology Unit, 12 de Octubre Universitary Hospital, Madrid 28041, Spain
- Faculty of Medicine, Complutense University, Madrid 28040, Spain
| | - Raquel Rivera
- Faculty of Medicine, Complutense University, Madrid 28040, Spain
- Dermatology Department, 12 de Octubre Universitary Hospital, Madrid 28041, Spain
| | - Inmaculada Fernandez
- Gastroenterology and Hepatology Unit, 12 de Octubre Universitary Hospital, Madrid 28041, Spain
- Faculty of Medicine, Complutense University, Madrid 28040, Spain
| | - Pilar Martinez-Montiel
- Gastroenterology and Hepatology Unit, 12 de Octubre Universitary Hospital, Madrid 28041, Spain
- Faculty of Medicine, Complutense University, Madrid 28040, Spain
| | - Victoria Villena
- Faculty of Medicine, Complutense University, Madrid 28040, Spain
- Pneumology Service, 12 de Octubre Universitary Hospital, Madrid 28041, Spain
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23
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Manka P, Sydor S, Wase N, Best J, Brandenburg M, Hellbeck A, Schänzer J, Vilchez-Vargas R, Link A, Figge A, Jähnert A, von Arnim U, Coombes JD, Cubero FJ, Kahraman A, Kim MS, Kälsch J, Kinner S, Faber KN, Moshage H, Gerken G, Syn WK, Friedman SL, Canbay A, Bechmann LP. Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status. Liver Int 2021; 41:2646-2658. [PMID: 34219348 DOI: 10.1111/liv.15003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/04/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. METHODS This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. RESULTS Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. CONCLUSIONS Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.
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Affiliation(s)
- Paul Manka
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Svenja Sydor
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Nishikant Wase
- Biomolecular Analysis Facility, University of Virginia, School of Medicine, Charlottesville, VA, USA
| | - Jan Best
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Malte Brandenburg
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Annika Hellbeck
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Julia Schänzer
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Ramiro Vilchez-Vargas
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke-University Hospital Magdeburg, Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke-University Hospital Magdeburg, Magdeburg, Germany
| | - Anja Figge
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Andreas Jähnert
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Ulrike von Arnim
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke-University Hospital Magdeburg, Magdeburg, Germany
| | - Jason D Coombes
- Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Francisco-Javier Cubero
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain.,12 de Octubre Health Research Institute (imas 12), Madrid, Spain
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Moon-Sung Kim
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany
| | - Julia Kälsch
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Sonja Kinner
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany
| | - Klaas-Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.,Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.,Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, Vizcaya, Spain
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Lars P Bechmann
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
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24
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Lu S, Wang Y, Liu J. TNF-α signaling in non-alcoholic steatohepatitis and targeted therapies. J Genet Genomics 2021; 49:269-278. [PMID: 34757037 DOI: 10.1016/j.jgg.2021.09.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/07/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), is featured by significantly elevated levels of various pro-inflammatory cytokines. Among numerous pro-inflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α) plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression was regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in future.
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Affiliation(s)
- Sijia Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yibing Wang
- School of Kinesiology, Shanghai University of Sports, Shanghai 200438, China.
| | - Junli Liu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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25
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Lambrecht J, Tacke F. Controversies and Opportunities in the Use of Inflammatory Markers for Diagnosis or Risk Prediction in Fatty Liver Disease. Front Immunol 2021; 11:634409. [PMID: 33633748 PMCID: PMC7900147 DOI: 10.3389/fimmu.2020.634409] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
In the Western society, non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat in the liver, represents the most common cause of chronic liver disease. If left untreated, approximately 15%-20% of patients with NAFLD will progress to non-alcoholic steatohepatitis (NASH), in which lobular inflammation, hepatocyte ballooning and fibrogenesis further contribute to a distorted liver architecture and function. NASH initiation has significant effects on liver-related mortality, as even the presence of early stage fibrosis increases the chances of adverse patient outcome. Therefore, adequate diagnostic tools for NASH are needed, to ensure that relevant therapeutic actions can be taken as soon as necessary. To date, the diagnostic gold standard remains the invasive liver biopsy, which is associated with several drawbacks such as high financial costs, procedural risks, and inter/intra-observer variability in histology analysis. As liver inflammation is a major hallmark of disease progression, inflammation-related circulating markers may represent an interesting source of non-invasive biomarkers for NAFLD/NASH. Examples for such markers include cytokines, chemokines or shed receptors from immune cells, circulating exosomes related to inflammation, and changing proportions of peripheral blood mononuclear cell (PBMC) subtypes. This review aims at documenting and critically discussing the utility of such novel inflammatory markers for NAFLD/NASH-diagnosis, patient stratification and risk prediction.
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Affiliation(s)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
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26
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Yuan Y, Naito H, Kitamori K, Hashimoto S, Asano T, Nakajima T. The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension. PLoS One 2020; 15:e0243846. [PMID: 33315911 PMCID: PMC7735612 DOI: 10.1371/journal.pone.0243846] [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: 07/16/2020] [Accepted: 11/28/2020] [Indexed: 11/18/2022] Open
Abstract
Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
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Affiliation(s)
- Yuan Yuan
- College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan
| | - Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Kazuya Kitamori
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Sayuki Hashimoto
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Tomomi Asano
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan
| | - Tamie Nakajima
- College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan
- * E-mail:
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27
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Abdelhamid YA, Elyamany MF, Al-Shorbagy MY, Badary OA. Effects of TNF-α antagonist infliximab on fructose-induced metabolic syndrome in rats. Hum Exp Toxicol 2020; 40:801-811. [PMID: 33118400 DOI: 10.1177/0960327120969960] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Public health issues have been raised regarding fructose toxicity and its serious metabolic disorders. Deleterious effects of high fructose intake on insulin sensitivity, body weight, lipid homeostasis have been identified. The new millennium has witnessed the emergence of a modern epidemic, the metabolic syndrome (MS), in approximately 25% of the world's adult population. The current study aimed to investigate the effect of the TNF-α antagonist infliximab on fructose-induced MS in rats. Rats were administered fructose (10%) in drinking water for 12 weeks to induce the experimental MS model. infliximab (5 mg/kg) was injected once weekly intraperitoneally starting on the 13th week for 4 weeks. Increase in body weight, blood glucose level, serum triglycerides (TGs), adiponectin level and blood pressure were present in MS rats. They also prompted increases in serum of leptin, TNF-α, and malondialdehyde (MDA) levels. Treatment with infliximab did not affect body weight, hyperglycemia or hypertension, but decreased serum TGs and increased serum HDL-c levels. Infliximab also decreased adiponectin levels. Surprisingly, infliximab increased MDA above its value in the MS group. These results reflect the fact that infliximab affects the manifestations of MS in rats. Though infliximab reduced TGs, increased HDL-c levels, reversed adiponectin resistance occurred by fructose, the drug failed to combat MS-mediated hyperglycemia, hypertension, and elevated MDA above the insult.
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Affiliation(s)
| | - Mohammed F Elyamany
- Pharmacology & Toxicology Department, 110154Faculty of Pharmacy, Cairo University, Giza, Egypt
| | - Muhammad Y Al-Shorbagy
- Pharmacology & Toxicology Department, 110154Faculty of Pharmacy, Cairo University, Giza, Egypt.,Pharmacology & Toxicology Department, School of Pharmacy, Newgiza University, Egypt
| | - Osama A Badary
- Clinical Pharmacy Department, Faculty of Pharmacy, British University in Egypt, Cairo, Egypt
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28
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Potential anti-inflammatory effect of dapagliflozin in HCHF diet- induced fatty liver degeneration through inhibition of TNF-α, IL-1β, and IL-18 in rat liver. Int Immunopharmacol 2020; 86:106730. [DOI: 10.1016/j.intimp.2020.106730] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/01/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
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29
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Tang KT, Dufour JF, Chen PH, Hernaez R, Hutfless S. Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort. BMJ Open Gastroenterol 2020; 7:e000349. [PMID: 32377366 PMCID: PMC7199652 DOI: 10.1136/bmjgast-2019-000349] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/23/2019] [Accepted: 12/06/2019] [Indexed: 12/16/2022] Open
Abstract
Objective Elevated tumour necrosis factor (TNF)-α has been implicated in the progression of liver fibrosis and pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aim to investigate the impact of anti-TNF-α agents on the development of cirrhosis and NAFLD. Design This retrospective cohort study used a US claims database between 1 January 2010 and 31 December 2016. We identified adult patients with ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis. Anti-TNF-α agents of interest included adalimumab, certolizumab, etanercept, golimumab and infliximab. The primary composite outcome was the development of new-onset cirrhosis, NAFLD or non-alcoholic steatohepatitis (NASH). The secondary outcomes were the development of (1) cirrhosis and (2) NAFLD or NASH. Propensity score for anti-TNF-α agent use was generated by logistic regression. Cox proportional hazard models adjusting for the propensity score were used with regard to time-varying anti-TNF-α agent exposure. Results This study included 226 555 incident patients with immune-related diseases. During the median 1.5 years follow-up, there was an increased hazard with anti-TNF-α agent use in regard to liver outcomes (composite outcome HR: 1.47, 95% CI 1.27 to 1.70; cirrhosis HR 1.47, 95% CI 0.96 to 2.23; NAFLD or NASH HR 1.53, 95% CI 1.32 to 1.77). The composite outcome hazard was increased for each immune-related disease (HR 1.25–1.90). Conclusion In the short term, we did not observe a beneficial effect of anti-TNF-α agent use for development of cirrhosis, NAFLD or NASH in patients with immune-related diseases.
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Affiliation(s)
- Kuo-Tung Tang
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.,Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Jean-François Dufour
- Department of Visceral Surgery and Medicine, Inselspital University Hospital Bern, Bern, Switzerland.,Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Po-Hung Chen
- Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ruben Hernaez
- Section of Gastroenterology, Michael E DeBakey VA Medical Center, Houston, Texas, USA.,Center for Innovations in Quality, Effectiveness and Safety, Michael E DeBakey VA Medical Center, Houston, Texas, USA
| | - Susan Hutfless
- Division of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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30
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Mohamad HE, Asker ME, Keshawy MM, Abdel Aal SM, Mahmoud YK. Infliximab ameliorates tumor necrosis factor-alpha exacerbated renal insulin resistance induced in rats by regulating insulin signaling pathway. Eur J Pharmacol 2020; 872:172959. [PMID: 32004528 DOI: 10.1016/j.ejphar.2020.172959] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/24/2020] [Accepted: 01/24/2020] [Indexed: 12/17/2022]
Abstract
Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1β and 6 (Il-1β, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.
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Affiliation(s)
- Hoda E Mohamad
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Mervat E Asker
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Mohammed M Keshawy
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Ismailia, 41522, Suez Canal University, Egypt
| | - Sara M Abdel Aal
- Department of Histology& Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Yasmin K Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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31
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Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance. Mol Cell Biochem 2020; 466:45-54. [PMID: 31933108 DOI: 10.1007/s11010-020-03686-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 01/04/2020] [Indexed: 01/25/2023]
Abstract
Insulin resistance (IR) has emerged as one of the main risk factors for renal fibrosis (RF) that represents a common stage in almost all chronic kidney disease. The present study aims to investigate the inhibitory effect of empagliflozin (EMPA "a sodium-glucose co-transporter 2 inhibitor") and infliximab [IFX "a tumor necrosis factor-α (TNF-α) antibody"] on RF in rats with induced IR. IR was induced by adding 10% fructose in drinking water for 20 weeks. Thereafter, fructose-induced IR rats were concurrently treated with EMPA (30 mg/kg), IFX (1 dose 5 mg/kg), or EMPA + IFX for 4 weeks, in addition to IR control group (received 10% fructose in water) and normal control (NC) group. Rats with IR displayed hyperglycemia, deterioration in kidney functions, glomerulosclerosis, and collagen fiber deposition in renal tissues as compared to NC. This was associated with downregulation of the renal sirtuin 1 (Sirt 1) expression along with higher renal tissue TNF-α and transforming growth factor-β1 (TGF-β1) levels. Both EMPA and IFX significantly modulated the aforementioned fibrotic cytokines, upregulated the renal Sirt 1 expression, and attenuated RF compared to IR control group. Of note, IFX effect was superior to that of EMPA. However, the combination of EMPA and IFX alleviated RF to a greater extent surpassing the monotherapy. This may be attributed to the further upregulation of renal Sirt 1 in addition to the downregulation of fibrotic cytokines. These findings suggest that the combination of EMPA and IFX offers additional benefits and may represent a promising therapeutic option for RF.
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Jin M, Pan T, Tocher DR, Betancor MB, Monroig Ó, Shen Y, Zhu T, Sun P, Jiao L, Zhou Q. Dietary choline supplementation attenuated high-fat diet-induced inflammation through regulation of lipid metabolism and suppression of NFκB activation in juvenile black seabream ( Acanthopagrus schlegelii). J Nutr Sci 2019; 8:e38. [PMID: 32042405 PMCID: PMC6984006 DOI: 10.1017/jns.2019.34] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/10/2019] [Accepted: 10/11/2019] [Indexed: 12/18/2022] Open
Abstract
The present study aimed to investigate whether dietary choline can regulate lipid metabolism and suppress NFκB activation and, consequently, attenuate inflammation induced by a high-fat diet in black sea bream (Acanthopagrus schlegelii). An 8-week feeding trial was conducted on fish with an initial weight of 8·16 ± 0·01 g. Five diets were formulated: control, low-fat diet (11 %); HFD, high-fat diet (17 %); and HFD supplemented with graded levels of choline (3, 6 or 12 g/kg) termed HFD + C1, HFD + C2 and HFD + C3, respectively. Dietary choline decreased lipid content in whole body and tissues. Highest TAG and cholesterol concentrations in serum and liver were recorded in fish fed the HFD. Similarly, compared with fish fed the HFD, dietary choline reduced vacuolar fat drops and ameliorated HFD-induced pathological changes in liver. Expression of genes of lipolysis pathways were up-regulated, and genes of lipogenesis down-regulated, by dietary choline compared with fish fed the HFD. Expression of nfκb and pro-inflammatory cytokines in liver and intestine was suppressed by choline supplementation, whereas expression of anti-inflammatory cytokines was promoted in fish fed choline-supplemented diets. In fish that received lipopolysaccharide to stimulate inflammatory responses, the expression of nfκb and pro-inflammatory cytokines in liver, intestine and kidney were all down-regulated by dietary choline compared with the HFD. Overall, the present study indicated that dietary choline had a lipid-lowering effect, which could protect the liver by regulating intrahepatic lipid metabolism, reducing lipid droplet accumulation and suppressing NFκB activation, consequently attenuating HFD-induced inflammation in A. schlegelii.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Choline
- HFD + C1, HFD + choline (3 g/kg)
- HFD + C2, HFD + choline (6 g/kg)
- HFD + C3, HFD + choline (12 g/kg)
- HFD, high-fat diet
- High-fat diets
- Inflammation
- LPS, lipopolysaccharide
- Lipid metabolism
- NFκB
- accα, acetyl-CoA carboxylase α
- cpt1a, carnitine palmitoyltransferase 1a
- fas, fatty acid synthase
- hsl, hormone-sensitive lipase
- qPCR, quantitative PCR
- srebp-1, sterol regulatory element-binding protein-1
- tgfβ-1, transforming growth factor β-1
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Affiliation(s)
- Min Jin
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
| | - Tingting Pan
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
| | - Douglas R. Tocher
- Faculty of Natural Sciences, Institute of Aquaculture, University of Stirling, StirlingFK9 4LA, UK
| | - Mónica B. Betancor
- Faculty of Natural Sciences, Institute of Aquaculture, University of Stirling, StirlingFK9 4LA, UK
| | - Óscar Monroig
- Instituto de Acuicultura Torre de la Sal, Consejo Superior de Investigaciones Científicas (IATS-CSIC), 12595 Ribera de Cabanes, Castellón, Spain
| | - Yuedong Shen
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
| | - Tingting Zhu
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
| | - Peng Sun
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
| | - Lefei Jiao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
| | - Qicun Zhou
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo315211, People's Republic of China
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Habib R, Wahdan SA, Gad AM, Azab SS. Infliximab abrogates cadmium-induced testicular damage and spermiotoxicity via enhancement of steroidogenesis and suppression of inflammation and apoptosis mediators. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 182:109398. [PMID: 31276887 DOI: 10.1016/j.ecoenv.2019.109398] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/22/2019] [Accepted: 06/27/2019] [Indexed: 02/08/2023]
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Likhitsup A, Dundulis J, Ansari S, Patibandla S, Hutton C, Kennedy K, Helzberg JH, Chhabra R. High prevalence of non-alcoholic fatty liver disease in patients with inflammatory bowel disease receiving anti-tumor necrosis factor therapy. Ann Gastroenterol 2019; 32:463-468. [PMID: 31474792 PMCID: PMC6686093 DOI: 10.20524/aog.2019.0405] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is common in patients with inflammatory bowel disease (IBD). This study evaluated the prevalence of NAFLD and the associated risk factors among IBD patients who received anti-tumor necrosis factor (TNF) therapy. Methods: Adult IBD patients receiving anti-TNF therapy (infliximab, adalimumab, certolizumab, golimumab) were enrolled. Hepatic steatosis was assessed by abdominal ultrasound. Patients with a history of excessive alcohol or recent steroid use were excluded. Univariate and multivariate analysis were performed. Results: Eighty patients, 55% male, mean age 42±15 years, were enrolled. The sonographic prevalence of NAFLD was 54% (43/80), significantly higher than the general prevalence in the US adult population (30%) (P<0.0001). NAFLD patients had a significantly higher proportion of males, as well as greater body weight and body mass index, compared to non-NAFLD. The Crohns disease activity index (CDAI) was significantly higher among patients with NAFLD. Multivariate analysis demonstrated that a higher CDAI was independently associated with NAFLD, with an odds ratio of 1.6 (95% confidence interval 1.05-2.44; P=0.03). Conclusions: The presence of IBD is strongly associated with NAFLD. We identified a high prevalence of NAFLD among IBD patients receiving anti-TNF. CDAI was independently associated with hepatic steatosis. Further studies are still needed to evaluate the pathophysiology of NAFLD development and disease progression among IBD populations.
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Affiliation(s)
- Alisa Likhitsup
- University of Missouri Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, Sruthi Patibandla, John H. Helzberg, Rajiv Chhabra).,Saint Luke's Hospital of Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, John H. Helzberg, Rajiv Chhabra)
| | - Jason Dundulis
- University of Missouri Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, Sruthi Patibandla, John H. Helzberg, Rajiv Chhabra).,Saint Luke's Hospital of Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, John H. Helzberg, Rajiv Chhabra)
| | - Shaya Ansari
- University of Missouri Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, Sruthi Patibandla, John H. Helzberg, Rajiv Chhabra).,Saint Luke's Hospital of Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, John H. Helzberg, Rajiv Chhabra)
| | - Sruthi Patibandla
- University of Missouri Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, Sruthi Patibandla, John H. Helzberg, Rajiv Chhabra)
| | - Colleen Hutton
- Mid-America Heart Institute St. Luke's Health System (Colleen Hutton, Kevin Kennedy), Kansas City, MO, USA
| | - Kevin Kennedy
- Mid-America Heart Institute St. Luke's Health System (Colleen Hutton, Kevin Kennedy), Kansas City, MO, USA
| | - John H Helzberg
- University of Missouri Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, Sruthi Patibandla, John H. Helzberg, Rajiv Chhabra).,Saint Luke's Hospital of Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, John H. Helzberg, Rajiv Chhabra)
| | - Rajiv Chhabra
- University of Missouri Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, Sruthi Patibandla, John H. Helzberg, Rajiv Chhabra).,Saint Luke's Hospital of Kansas City (Alisa Likhitsup, Jason Dundulis, Shaya Ansari, John H. Helzberg, Rajiv Chhabra)
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Heikal MM, Shaaban AA, Elkashef WF, Ibrahim TM. Effect of febuxostat on biochemical parameters of hyperlipidemia induced by a high-fat diet in rabbits. Can J Physiol Pharmacol 2019; 97:611-622. [DOI: 10.1139/cjpp-2018-0731] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Febuxostat, a highly potent xanthine oxidase inhibitor with an antioxidant effect, inhibits elevated xanthine oxidase, leading to reduction of reactive oxygen species and oxidative stress, the main causes of vascular inflammation in hyperlipidemia. The aim of this study was to test the potential antioxidant and anti-inflammatory effects of febuxostat and (or) stopping a high-fat diet on the biochemical parameters in rabbits with hyperlipidemia induced by a high-fat diet. Male New Zealand rabbits were distributed into 3 groups: a normal control group fed standard chow for 12 weeks and 2 other groups fed a high-fat diet with 1% cholesterol for 8 weeks, and then shifted to standard chow for 4 weeks. During the last 4 weeks, one high-fat diet group received 0.5% carboxymethyl cellulose, whereas the other group was treated with febuxostat (2 mg/kg per day p.o.). Febuxostat significantly lowered low-density lipoprotein cholesterol (“bad” cholesterol) compared to the untreated group (high-fat diet group). Febuxostat also displayed a potent anti-inflammatory and antioxidant activity by decreasing serum levels of lipid peroxidation index, proinflammatory cytokines, and enhancing antioxidant enzyme activity. Stopping the hyperlipidemic diet in the high-fat diet group did not show improvement. These findings indicate the antioxidant and anti-inflammatory effects of febuxostat that may be common mechanisms of the anti-hyperlipidemic effect of this drug. Stopping a hyperlipidemic diet without treatment is not sufficient once injury has occurred.
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Affiliation(s)
- Mohammed M. Heikal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ahmed A. Shaaban
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Faculty of Pharmacy, Aqaba University of Technology, Jordan
| | - Wagdi F. Elkashef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Tarek M. Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Seo KI, Kang SB. [Hepatobiliary Manifestation of Inflammatory Bowel Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 73:248-259. [PMID: 31132831 DOI: 10.4166/kjg.2019.73.5.248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/05/2019] [Accepted: 05/12/2019] [Indexed: 12/13/2022]
Abstract
The hepatobiliary system is one of the most common sites of extraintestinal manifestation in patients with inflammatory bowel disease (IBD). The progression of IBD can lead to a primary hepatobiliary manifestation and can occur secondary to multiple drugs or accompanying viral infections. Primary sclerosing cholangitis is the representative hepatobiliary manifestation of IBD, particularly in ulcerative colitis. Although most agents used in the treatment of IBD are potentially hepatotoxic, the risk of serious hepatitis or liver failure is low. The prevalence of HBV and HCV in IBD is similar to the general population, but the clinical concern is HBV reactivation associated with immunosuppressive therapy. Patients undergoing cytotoxic chemotherapy or immunosuppressive therapy with a moderate to high risk of HBV reactivation require prophylactic antiviral therapy. On the other hand, HCV has little risk of reactivation. Patients with IBD are more likely to have nonalcoholic fatty liver disease than the general population and tend to occur at younger ages. IBD and cholelithiasis are closely related, especially in Crohn's disease.
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Affiliation(s)
- Kwang Il Seo
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Sang-Bum Kang
- Division of Gastroenterology, Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea
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Abstract
Hepatobiliary disorders are commonly encountered in patients with inflammatory bowel disease (IBD). Although primary sclerosing cholangitis is the stereotypical hepatobiliary disorder associated with IBD, other diseases, including autoimmune hepatitis and nonalcoholic fatty liver disease, also are encountered in this population. Several agents used for treatment of IBD may cause drug-induced liver injury, although severe hepatotoxicity occurs infrequently. Furthermore, reactivation of hepatitis B virus infection may occur in patients with IBD treated with systemic corticosteroids and biologic agents.
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Affiliation(s)
- Mahmoud Mahfouz
- Department of Internal Medicine, Mount Sinai Medical Center, 4300 Alton Road, Suite 301, Miami Beach, FL 33140, USA
| | - Paul Martin
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, 1120 Northwest 14 Street #1115, Miami, FL 33136, USA.
| | - Andres F Carrion
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, 1120 Northwest 14 Street #1115, Miami, FL 33136, USA
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38
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Liver dysfunction in anti-melanoma differentiation-associated gene 5 antibody-positive patients with dermatomyositis. Rheumatol Int 2019; 39:901-909. [PMID: 30790016 DOI: 10.1007/s00296-019-04255-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 02/14/2019] [Indexed: 12/18/2022]
Abstract
The objective was to investigate the clinical and histological features of liver dysfunction in patients with polymyositis (PM) or dermatomyositis (DM).A total of 115 patients (38 with PM and 77 with DM), who were admitted to our hospital between 2001 and 2012, were retrospectively reviewed. Liver dysfunction was defined as an alanine transaminase (ALT) level ≥ 60 U/l and a disproportionate ALT elevation relative to the creatine kinase level. The histological findings from liver biopsies were also assessed.The frequencies of liver dysfunction were 3% and 17% in the patients with PM and DM, respectively. Liver dysfunction was not observed in the patients who had malignancies. Among the patients with DM with no malignancies (n = 50), 20% had liver dysfunction, and all of the patients with liver dysfunction were positive for the anti-melanoma differentiation-associated gene 5 (MDA5) antibody. Compared with those in the patients who did not have liver dysfunction, the ALT, alkaline phosphatase, γ-glutamyl transferase, and KL-6 levels were significantly elevated in the patients who had liver dysfunction. Six patients, comprising four with DM and two with PM, underwent liver biopsies, and the common histological findings associated with DM were steatosis, hepatocyte ballooning, increases in the pigmented macrophage numbers, and glycogenated nuclei. Hemophagocytosis was detected in two of three patients with DM who underwent liver biopsies and bone marrow aspirations. In conclusion, Liver dysfunction might be an extramuscular manifestation in patients with DM who are anti-MDA5 antibody-positive. Steatosis and hepatocyte ballooning could be common histological features.
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Horst AK, Najjar SM, Wagener C, Tiegs G. CEACAM1 in Liver Injury, Metabolic and Immune Regulation. Int J Mol Sci 2018; 19:ijms19103110. [PMID: 30314283 PMCID: PMC6213298 DOI: 10.3390/ijms19103110] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/02/2018] [Accepted: 10/04/2018] [Indexed: 02/06/2023] Open
Abstract
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that is expressed on epithelial, endothelial and immune cells. CEACAM1 is a differentiation antigen involved in the maintenance of epithelial polarity that is induced during hepatocyte differentiation and liver regeneration. CEACAM1 regulates insulin sensitivity by promoting hepatic insulin clearance, and controls liver tolerance and mucosal immunity. Obese insulin-resistant humans with non-alcoholic fatty liver disease manifest loss of hepatic CEACAM1. In mice, deletion or functional inactivation of CEACAM1 impairs insulin clearance and compromises metabolic homeostasis which initiates the development of obesity and hepatic steatosis and fibrosis with other features of non-alcoholic steatohepatitis, and adipogenesis in white adipose depot. This is followed by inflammation and endothelial and cardiovascular dysfunctions. In obstructive and inflammatory liver diseases, soluble CEACAM1 is shed into human bile where it can serve as an indicator of liver disease. On immune cells, CEACAM1 acts as an immune checkpoint regulator, and deletion of Ceacam1 gene in mice causes exacerbation of inflammation and hyperactivation of myeloid cells and lymphocytes. Hence, hepatic CEACAM1 resides at the central hub of immune and metabolic homeostasis in both humans and mice. This review focuses on the regulatory role of CEACAM1 in liver and biliary tract architecture in health and disease, and on its metabolic role and function as an immune checkpoint regulator of hepatic inflammation.
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Affiliation(s)
- Andrea Kristina Horst
- Institute of Experimental Immunology and Hepatology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany.
| | - Sonia M Najjar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Irvine Hall, 1 Ohio University, Athens, OH 45701-2979, USA.
- The Diabetes Institute, Heritage College of Osteopathic Medicine, Irvine Hall, 1 Ohio University, Athens, OH 45701-2979, USA.
| | - Christoph Wagener
- University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany.
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany.
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Colon Epithelial MicroRNA Network in Fatty Liver. Can J Gastroenterol Hepatol 2018; 2018:8246103. [PMID: 30345259 PMCID: PMC6174781 DOI: 10.1155/2018/8246103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 08/15/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Intestinal barrier alterations are associated with fatty liver (FL) and metabolic syndrome (MetS), but microRNA (miR) signaling pathways in MetS-FL pathogenesis remain unclear. This study investigates an epithelial-focused miR network in colorectal cell models based on the previously reported MetS-FL miR trio of hsa-miR-142-3p, hsa-miR-18b, and hsa-miR-890. METHODS Each miR mimic construct of MetS-FL miR trio was transfected into human colorectal cells, CRL-1790 or Caco-2. Global miRNome changes posttransfection were profiled (nCounter® Human v3 miRNA, NanoString Technologies). Changes in barrier (transepithelial electrical resistance, TEER) and epithelial cell junction structure (Occludin and Zona Occludens-1/ZO-1 immunofluorescence staining-confocal microscopy) were examined pre- and posttransfection in Caco-2 cell monolayers. A signaling network was constructed from the MetS-FL miR trio, MetS-FL miR-induced colorectal miRNome changes, ZO-1, and Occludin. RESULTS Transfection of CRL-1790 cells with each MetS-FL miR mimic led to global changes in the cellular miRNome profile, with 288 miRs being altered in expression by more than twofold. Eleven miRs with known cytoskeletal and metabolic roles were commonly altered in expression by all three miR mimics. Transfection of Caco-2 cell monolayers with each MetS-FL miR mimic induced barrier-associated TEER variations and led to structural modifications of ZO-1 and Occludin within epithelial cell junctions. Pathway analysis incorporating the MetS-FL miR trio, eleven common target miRs, ZO-1, and Occludin revealed a signaling network centered on TNF and AKT2, which highlights injury, inflammation, and hyperplasia. CONCLUSIONS Colon-specific changes in epithelial barriers, cell junction structure, and a miRNome signaling network are described from functional studies of a MetS-FL miR trio signature.
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Hepatoprotective Effects of MHY3200 on High-Fat, Diet-Induced, Non-Alcoholic Fatty Liver Disease in Rats. Molecules 2018; 23:molecules23082057. [PMID: 30115876 PMCID: PMC6222757 DOI: 10.3390/molecules23082057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/03/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023] Open
Abstract
This study investigated the effects of 2-(4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-2,2-difluoroacetic acid (MHY3200) on high-fat diet (HFD)-induced hepatic lipid accumulation and inflammation. The measurement of peroxisome proliferator-activated receptor (PPAR)α activity by using a luciferase assay indicated that MHY3200 was more potent than a known PPARα agonist, WY14643, in AC2F cells. Six-month-old male SD rats were fed chow or HFD for 1 month, and after, with or without added MHY3200 (1 or 2 mg/kg/day) for 4 weeks. The oral administration of MHY3200 caused a significant decrease in serum triglyceride (TG), glucose, alanine aminotransferase, and insulin, as well as a slight decrease in the level of free fatty acid and aspartate transaminase. No weight gain was detected when compared with HFD rats, and hepatic TG content was also attenuated by the administration of MHY3200. Furthermore, phosphorylation of the ER stress marker, inositol-requiring kinase 1 and its downstream gene, c-Jun N-terminal kinase, in addition to serine phosphorylation of insulin receptor substrate 1 were suppressed by MHY3200. Consistent with these results, MHY3200 administration reduced the levels of activation of protein-1, cyclooxygenase-2, and inducible nitric oxide synthase. Our results suggested that MHY3200 ameliorated HFD-induced hepatic lipid accumulation and inflammation, and improved insulin resistance through PPARα activation.
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Effects of inflammatory bowel disease treatment on the risk of nonalcoholic fatty liver disease: a meta-analysis. Eur J Gastroenterol Hepatol 2018; 30:854-860. [PMID: 29697458 DOI: 10.1097/meg.0000000000001144] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Epidemiological studies have demonstrated an association between inflammatory bowel disease (IBD) and an increased risk for the development of nonalcoholic fatty liver disease (NAFLD). However, the risk of NAFLD in IBD patients who receive different medical treatments including glucocorticoids, immunomodulators, and tumor necrosis factor-α inhibitors remains unclear. We aimed to assess whether the use of certain IBD medications is associated with the development of NAFLD. MATERIALS AND METHODS A systematic review was carried out in Medline, Embase, and Cochrane databases from inception through October 2017 to identify studies that assessed the association between the use of IBD medications and the risk of developing NAFLD. Effect estimates from the individual study were derived and combined using random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS Seven observational studies with a total of 1610 patients were enrolled. There was no significant association between the use of IBD medications and the incidence of NAFLD. The pooled odds ratios of NAFLD in patients who use biological agents, immunomodulators, methotrexate, and steroids were 0.85 [95% confidence interval (CI): 0.49-1.46], 1.19 (95% CI: 0.70-2.01), 3.62 (95% CI: 0.48-27.39), and 1.24 (95% CI: 0.85-1.82), respectively. Egger's regression asymmetry test was performed and showed no publication bias. CONCLUSION Our study demonstrates no significant association between medications used in the treatment of IBD and the risk of developing NAFLD. The findings of our study suggest a complex, multifactorial relationship between IBD and the development of NAFLD beyond the scope of current pharmacological intervention.
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Lopetuso LR, Mocci G, Marzo M, D'Aversa F, Rapaccini GL, Guidi L, Armuzzi A, Gasbarrini A, Papa A. Harmful Effects and Potential Benefits of Anti-Tumor Necrosis Factor (TNF)-α on the Liver. Int J Mol Sci 2018; 19:E2199. [PMID: 30060508 PMCID: PMC6121684 DOI: 10.3390/ijms19082199] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 02/08/2023] Open
Abstract
Anti-tumor necrosis factor (TNF)-α agents represent an effective treatment for chronic inflammatory diseases. However, some concerns about their potentially undesirable effects on liver function have been reported. On the other hand, evidence of their therapeutic effects on certain liver diseases is accumulating. Many data showed the safety of anti-TNF-α in patients with chronic hepatitis B and C and in liver transplanted patients even if a strict follow-up and prophylaxis are recommended in well-defined subgroups. On the other side, anti-TNF-α-induced liver injury is not a rare event. However, it is often reversible after anti-TNF-α withdrawal. Anti-TNF-α agents have been tested in advanced stages of severe alcoholic hepatitis and non-alcoholic fatty liver disease. Limited data on the efficacy of anti-TNF-α in patients with autoimmune hepatitis and primary biliary cholangitis are also available. In this review, we explored the hepatic safety concerns in patients receiving anti-TNF-α agents with and without pre-existent hepatic diseases. In addition, the available evidence on their potential benefits in the treatment of specific hepatic diseases is discussed.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Giammarco Mocci
- Gastroenterology Unit, Brotzu Hospital, 09121 Cagliari, Italy.
| | - Manuela Marzo
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Francesca D'Aversa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Gian Lodovico Rapaccini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Luisa Guidi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Alessandro Armuzzi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Alfredo Papa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
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Abd El-Aziz R, Naguib M, Rashed LA. Spleen size in patients with metabolic syndrome and its relation to metabolic and inflammatory parameters. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2018. [DOI: 10.4103/ejim.ejim_86_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Rodrigues PM, Rodrigues CMP, Castro RE. Modulation of liver steatosis by miR-21/PPAR α. Cell Death Discov 2018; 4:9. [PMID: 30062058 PMCID: PMC6060160 DOI: 10.1038/s41420-018-0076-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 06/09/2018] [Accepted: 06/12/2018] [Indexed: 12/28/2022] Open
Affiliation(s)
- Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Karin M. New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance. PRECISION CLINICAL MEDICINE 2018; 1:21-28. [PMID: 30687560 PMCID: PMC6333043 DOI: 10.1093/pcmedi/pby005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/21/2018] [Accepted: 05/07/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths
worldwide. HCC initiates as a consequence of chronic liver damage and inflammation caused
by hepatitis B and C virus infections, excessive alcohol consumption, or non-alcoholic
fatty liver disease (NAFLD). Until recently, no effective treatments for advanced HCC were
available and the 5-year survival rate had remained below 8% for many years. New insights
into the mechanisms that drive the development of NAFLD-related HCC indicate that loss of
T-cell-mediated immunosurveillance plays a cardinal role in tumor growth and malignant
progression, in addition to previously identified inflammation-driven compensatory
proliferation. Recently completed groundbreaking clinical studies have shown that
treatments that restore antitumor immunity represent a highly effective therapeutic option
for approximately 20% of advanced HCC patients. Understanding the causes of
inflammation-driven immunosuppression and immune system dysfunction in the 80% of patients
who fail to reignite antitumor immunity despite treatment with checkpoint inhibitors
should lead to further and even more dramatic improvements in HCC immunotherapy.
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Affiliation(s)
- Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, Department of Pharmacology, 9500 Gilman Drive, La Jolla, CA, USA
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Fousekis FS, Theopistos VI, Katsanos KH, Tsianos EV, Christodoulou DK. Hepatobiliary Manifestations and Complications in Inflammatory Bowel Disease: A Review. Gastroenterology Res 2018; 11:83-94. [PMID: 29707074 PMCID: PMC5916631 DOI: 10.14740/gr990w] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Liver and biliary track diseases are common extraintestinal manifestations of inflammatory bowel disease (IBD), reported both in Crohn’s disease and ulcerative colitis, and may occur at any time during the natural course of the disease. Their etiology is mainly related to pathophysiological changes induced by IBD, and secondary, due to drugs used in IBD. Fatty liver is considered as the most frequent hepatobiliary manifestation in IBD, while primary sclerosing cholangitis (PSC) is the most correlated hepatobiliary disorder and is more prevalent in patients with ulcerative colitis. PSC can cause serious complications from the liver, biliary tree, and gallbladder and can lead to liver failure. Less frequently, IBD-associated hepatobiliary manifestations include cholelithiasis, granulomatous hepatitis, portal vein thrombosis, IgG4-related cholangiopathy, pyogenic liver abscess, hepatic amyloidosis and primary biliary cirrhosis. Most of the drugs used for IBD treatment may cause liver toxicity. Methotrexate and thiopurines carry the higher risk for hepatotoxicity, and in many cases, dose adjustment may normalize the liver biochemical tests. Reactivation of hepatitis B and C virus during immunosuppressive use, especially during use of biological agents, is a major concern, and adequate screening, vaccination and prophylactic treatment is warranted.
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Affiliation(s)
- Fotios S Fousekis
- Department of Gastroenterology and Hepatology, Medical School of Ioannina, Greece
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Guo Y, Li JX, Mao TY, Zhao WH, Liu LJ, Wang YL. Targeting Sirt1 in a rat model of high-fat diet-induced non-alcoholic fatty liver disease: Comparison of Gegen Qinlian decoction and resveratrol. Exp Ther Med 2017; 14:4279-4287. [PMID: 29104641 PMCID: PMC5658732 DOI: 10.3892/etm.2017.5076] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 06/29/2017] [Indexed: 12/19/2022] Open
Abstract
The present study aimed to explore the mechanism of action of Gegen Qinlian decoction (GGQLD) in experimental non-alcoholic fatty liver disease (NAFLD). A total of 30 rats were randomly divided into five groups: The chow, model, high- and low-dose GGQLD (GGQLD-H and GGQLD-L, respectively) and resveratrol (Resl) groups, and were treated with saline, GGQLD and Resl when a model of high-fat diet (HFD)-induced NAFLD was established. Blood lipid and liver enzymes were detected following treatment for 8 weeks and liver tissue pathology was observed using Oil Red O and haematoxylin and eosin staining. Furthermore, the liver protein and mRNA expression of sirtuin (Sirt)1, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) were measured using western blotting and reverse transcription-quantitative polymerase chain reaction. Compared with the chow group, the model group demonstrated significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P<0.01). GGQLD doses and Resl attenuated the elevated serum ALT and AST levels. GGQLD-H and Resl significantly increased the serum high-density lipoprotein cholesterol level compared with that in the model group (P<0.01), while GGQLD-L and Resl significantly decreased serum low-density lipoprotein cholesterol levels (P<0.01). The GGQLDs and Resl groups revealed an evident improvement in Sirt1 protein and mRNA expression. Although GGQLD and Resl significantly decreased NF-κB gene expression compared with the model group (P<0.01), the effect on NF-κB protein expression was not significant. Furthermore, the PGC-1α gene and protein expression in the HFD rat group slightly decreased compared to the levels in the chow group, but the decrease was insignificant. However, an evident increase in PGC-1α mRNA expression was observed in the GGQLD-H group compared with the model group (P<0.01). Histological staining revealed that GGQLD and Resl decreased the lipid droplets in hepatocytes and normalized steatosis in rats fed with a HFD. The results indicated that GGQLD treatment may be a potent strategy for managing NAFLD by managing lipid metabolism and inflammatory and histological abnormalities by triggering the Sirt1 pathway.
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Affiliation(s)
- Yi Guo
- Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China.,Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Jun-Xiang Li
- Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China
| | - Tang-You Mao
- Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China.,Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Wei-Han Zhao
- Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China.,Graduate School, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Li-Juan Liu
- Department of Gastroenterology of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Yun-Liang Wang
- Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, P.R. China
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Yinchen Linggui Zhugan Decoction Ameliorates Nonalcoholic Fatty Liver Disease in Rats by Regulating the Nrf2/ARE Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:6178358. [PMID: 28932253 PMCID: PMC5592414 DOI: 10.1155/2017/6178358] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 07/11/2017] [Accepted: 07/30/2017] [Indexed: 12/13/2022]
Abstract
Yinchen Linggui Zhugan Decoction (YCLGZGD) is the combination of Linggui Zhugan (LGZGD) and Yinchenhao (YCHD) decoctions, two famous traditional Chinese medicine prescriptions. In previous studies, we found that Yinchen Linggui Zhugan Decoction (YCLGZGD) could regulate lipid metabolism disorder and attenuate inflammation in pathological process of nonalcoholic fatty liver disease (NAFLD). However, the exact underlying mechanism remains unknown. The aim of this study was to explore the effect of Yinchen Linggui Zhugan Decoction on experimental NAFLD and its mechanism in rats with high-fat diet (HFD) which was established by 8-week administration of HFD. YCLGZGD, LGZGD, and YCHD were administered daily for 4 weeks, after which the rats were euthanized. The level of blood lipid, liver enzymes, H&E, and Oil Red O staining were determined to evaluate NAFLD severity. Western blotting and real-time polymerase chain reaction were, respectively, used to determine hepatic protein and gene expression of Keap1, Nrf2, NQO1, and HO-1. Oral YCLGZGD ameliorated HFD-induced NAFLD. Furthermore, YCLGZGD increased the protein and gene expression of Nrf2, NQO1, and HO-1 without changing Keap1. Overall, these results suggest that YCLGZGD ameliorates HFD-induced NAFLD in rats by upregulating the Nrf2/ARE signaling pathway.
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Hamada D, Maynard R, Schott E, Drinkwater CJ, Ketz JP, Kates SL, Jonason JH, Hilton MJ, Zuscik MJ, Mooney RA. Suppressive Effects of Insulin on Tumor Necrosis Factor-Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus. Arthritis Rheumatol 2017; 68:1392-402. [PMID: 26713606 PMCID: PMC4882234 DOI: 10.1002/art.39561] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 12/17/2015] [Indexed: 12/24/2022]
Abstract
Objective Obesity is a state of chronic inflammation that is associated with insulin resistance and type 2 diabetes mellitus (DM), as well as an increased risk of osteoarthritis (OA). This study was undertaken to define the links between obesity‐associated inflammation, insulin resistance, and OA, by testing the hypotheses that 1) tumor necrosis factor (TNF) is critical in mediating these pathologic changes in OA, and 2) insulin has direct effects on the synovial joint that are compromised by insulin resistance. Methods The effects of TNF and insulin on catabolic gene expression were determined in fibroblast‐like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high‐fat (HF) diet–fed obese mice with type 2 DM and TNF‐knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM. Results Insulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose‐dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of MMP1, MMP13, and ADAMTS4 by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by >50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF‐knockout mice, increases in osteophyte formation and synovial hyperplasia associated with the HF diet were blunted. The synovium from OA patients with type 2 DM contained markedly more macrophages and showed elevated TNF levels as compared to the synovium from OA patients without diabetes. Moreover, insulin‐dependent phosphorylation of IRs and Akt was blunted in cultures of OA FLS from patients with type 2 DM. Conclusion TNF appears to be involved in mediating the advanced progression of OA seen in type 2 DM. While insulin plays a protective, antiinflammatory role in the synovium, insulin resistance in patients with type 2 DM may impair this protective effect and promote the progression of OA.
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Affiliation(s)
- Daisuke Hamada
- University of Rochester Medical Center, Rochester, New York
| | - Robert Maynard
- University of Rochester Medical Center, Rochester, New York
| | - Eric Schott
- University of Rochester Medical Center, Rochester, New York
| | | | - John P Ketz
- University of Rochester Medical Center, Rochester, New York
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