|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Durmaz S, Kurtoğlu T, Barbarus E, Eliyatkın N, Yılmaz M. TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats. Acta Cir Bras 2020; 35:e202000202. [PMID: 32267288 PMCID: PMC7124089 DOI: 10.1590/s0102-865020200020000002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/06/2020] [Indexed: 02/06/2023] Open
Abstract
Purpose To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury. Methods Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination. Results Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). Conclusions Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.
Collapse
|
|
3
|
NAFLD and Extra-Hepatic Comorbidities: Current Evidence on a Multi-Organ Metabolic Syndrome. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16183415. [PMID: 31540048 PMCID: PMC6765902 DOI: 10.3390/ijerph16183415] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/06/2019] [Accepted: 09/08/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its incidence is definitely increasing. NAFLD is a metabolic disease with extensive multi-organ involvement, whose extra-hepatic manifestations include type 2 diabetes mellitus, cardiovascular disease, obstructive sleep apnea, chronic kidney disease, osteoporosis, and polycystic ovarian syndrome. Recently, further evidence has given attention to pathological correlations not strictly related to metabolic disease, also incorporating in this broad spectrum of systemic involvement hypothyroidism, psoriasis, male sexual dysfunction, periodontitis, and urolithiasis. The most common cause of mortality in NAFLD is represented by cardiovascular disease, followed by liver-related complications. Therefore, clinicians should learn to screen and initiate treatment for these extra-hepatic manifestations, in order to provide appropriate multidisciplinary assessments and rigorous surveillance. This review evaluates the current evidence regarding extra-hepatic associations of NAFLD, focusing on the pathogenic hypothesis and the clinical implications.
Collapse
|
|
4
|
Wahlang B, McClain C, Barve S, Gobejishvili L. Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 2018; 49:105-115. [PMID: 29902522 PMCID: PMC6445381 DOI: 10.1016/j.cellsig.2018.06.005] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023]
Abstract
Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.
Collapse
Affiliation(s)
- Banrida Wahlang
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA
| | - Craig McClain
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA; Robley Rex Louisville VAMC, Louisville, KY, USA
| | - Shirish Barve
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA
| | - Leila Gobejishvili
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA.
| |
Collapse
|
|
5
|
Chao CY, Battat R, Al Khoury A, Restellini S, Sebastiani G, Bessissow T. Co-existence of non-alcoholic fatty liver disease and inflammatory bowel disease: A review article. World J Gastroenterol 2016; 22:7727-7734. [PMID: 27678354 PMCID: PMC5016371 DOI: 10.3748/wjg.v22.i34.7727] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/19/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Emerging data have highlighted the co-existence of non-alcoholic fatty liver disease (NAFLD) and inflammatory bowel disease; both of which are increasingly prevalent disorders with significant complications and impact on future health burden. Cross-section observational studies have shown widely variable prevalence rates of co-existing disease, largely due to differences in disease definition and diagnostic tools utilised in the studies. Age, obesity, insulin resistance and other metabolic conditions are common risks factors in observational studies. However, other studies have also suggested a more dominant role of inflammatory bowel disease related factors such as disease activity, duration, steroid use and prior surgical intervention, in the development of NAFLD. This suggests a potentially more complex pathogenesis and relationship between the two diseases which may be contributed by factors including altered intestinal permeability, gut dysbiosis and chronic inflammatory response. Commonly used immunomodulation agents pose potential hepatic toxicity, however no definitive evidence exist linking them to the development of hepatic steatosis, nor are there any data on the impact of therapy and prognosis in patient with co-existent diseases. Further studies are required to assess the impact and establish appropriate screening and management strategies in order to allow early identification, intervention and improve patient outcomes.
Collapse
|
|
6
|
Zhou Z, Liu YC, Chen XM, Li FQ, Tong XJ, Ding YP, Tang CL. Treatment of experimental non-alcoholic steatohepatitis by targeting α7 nicotinic acetylcholine receptor-mediated inflammatory responses in mice. Mol Med Rep 2015; 12:6925-31. [PMID: 26397391 DOI: 10.3892/mmr.2015.4318] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 06/26/2015] [Indexed: 11/05/2022] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD) is one of the most common types of liver disease, affecting up to 30% of the general population worldwide. Non‑alcoholic steatohepatitis (NASH) is a severe form of NAFLD without any effective therapies available. The present study showed that activation of α7‑nicotinic acetylcholine receptor (α7 nAChR) may be a novel potential strategy for NASH therapy. Treatment with the α7 nAChR agonist nicotine for three weeks obviously attenuated hepatic steatosis in a high-fat diet‑induced mouse model of NASH. Investigation of the underlying mechanism showed that nicotine reduced the secretion of the pro‑inflammatory cytokines tumor necrosis factor α and interleukin 6 in vitro and in vivo. Inflammation is an integral part of NASH and is the most prevalent form of hepatic pathology found in the general population; therefore, the effect of α7 nAChR activation against NASH may be ascribed to its anti‑inflammatory effects. In addition, the present study showed that nicotine‑stimulated α7 nAChR activation led to a significant downregulation of nuclear factor kappa B (NK‑κB) and extracellular signal-regulated kinase (ERK). It therefore appeared that activation of α7 nAChR suppressed the production of pro‑inflammatory cytokines through NK‑κB and ERK pathways. In conclusion, the present study indicated that targeting α7 nAChR may represent a novel treatment strategy for NASH.
Collapse
Affiliation(s)
- Zhou Zhou
- Department of Anesthesiology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Ying-Chao Liu
- Department of Digestive Diseases, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Xiao-Mei Chen
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Fu-Qiang Li
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Xiao-Juan Tong
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Yue-Ping Ding
- Department of Intensive Care Unit, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| | - Cui-Lan Tang
- Department of Infectious Disease, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China
| |
Collapse
|