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Wen X, Hu J. Targeting STAT3 signaling pathway in the treatment of Alzheimer's disease with compounds from natural products. Int Immunopharmacol 2024; 141:112936. [PMID: 39163684 DOI: 10.1016/j.intimp.2024.112936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/12/2024] [Accepted: 08/12/2024] [Indexed: 08/22/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that is difficult to cure and of global concern. Neuroinflammation is closely associated with the onset and progression of AD, making its treatment increasingly important. Compounds from natural products, with fewer side effects than synthetic drugs, are of high research interest. STAT3, a multifunctional transcription factor, is involved in various cellular processes including inflammation, cell growth, and apoptosis. Its activation and inhibition can have different effects under various pathological conditions. In AD, the STAT3 protein plays a crucial role in promoting neuroinflammation and contributing to disease progression. This occurs primarily through the JAK2-STAT3 signaling pathway, which impacts microglia, astrocytes, and hippocampal neurons. This paper reviews the STAT3 signaling pathway in AD and 25 compounds targeting STAT3 up to 2024. Notably, Rutin, Paeoniflorin, and Geniposide up-regulate STAT3 in hippocampal and cortex neurons, showing neuroprotective effects in various AD models. Other 23 compounds downregulate AD by suppressing neuroinflammation through inhibition of STAT3 activation in microglia and astrocytes. These findings highlight the potential of compounds from natural products in improving AD by targeting STAT3, offering insights into the prevention and management of AD.
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Affiliation(s)
- Xiyue Wen
- Department of Clinical Laboratory, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, China
| | - Jinyue Hu
- Medical Research Center, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, China.
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Harrison SA, Rolph T, Knott M, Dubourg J. FGF21 agonists: An emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond. J Hepatol 2024; 81:562-576. [PMID: 38710230 DOI: 10.1016/j.jhep.2024.04.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/26/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024]
Abstract
The worldwide epidemics of obesity, hypertriglyceridemia, dyslipidaemia, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) represent a major economic burden on healthcare systems. Patients with at-risk MASH, defined as MASH with moderate or significant fibrosis, are at higher risk of comorbidity/mortality, with a significant risk of cardiovascular diseases and/or major adverse liver outcomes. Despite a high unmet medical need, there is only one drug approved for MASH. Several drug candidates have reached the phase III development stage and could lead to several potential conditional drug approvals in the coming years. Within the armamentarium of future treatment options, FGF21 analogues hold an interesting position thanks to their pleiotropic effects in addition to their significant effect on both MASH resolution and fibrosis improvement. In this review, we summarise preclinical and clinical data from FGF21 analogues for MASH and explore additional potential therapeutic indications.
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Affiliation(s)
- Stephen A Harrison
- Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU UK; Pinnacle Clinical Research, San Antonio, Texas, USA
| | - Tim Rolph
- Akero Therapeutics, South San Francisco, California, USA
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Wang L, Fu R, Meng Y, Liang J, Xue W, Hu H, Meng J, Zhang M. pH Sensitive Quercetin Nanoparticles Ameliorate DSS-Induced Colitis in Mice by Colon-Specific Delivery. Mol Nutr Food Res 2024; 68:e2300051. [PMID: 38010348 DOI: 10.1002/mnfr.202300051] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 07/04/2023] [Indexed: 11/29/2023]
Abstract
SCOPE Ulcerative colitis (UC) is a classic inflammatory bowel disease (IBD) that represents a serious threat to human health. As a natural flavonoid with multiple biological activities, quercetin (QCT) suffers from low bioavailability through limitations in chemical stability. Here, the study investigates the regulatory effects of quercetin nanoparticles (QCT NPs) on dextran sulfate sodium (DSS) induced colitis mice. METHODS AND RESULTS Chitosan is modified to obtain N-succinyl chitosan (NSC) with superior water solubility. Nanoparticles composed of sodium alginate (SA) and NSC can encapsulate QCT after cross-linking, forming QCT NPs. In vitro drug release assays demonstrate the pH sensitivity of QCT NPs. Compared with free quercetin, QCT NPs have better therapeutic efficacy in modulating gut microbiota and its metabolites short chain fatty acid (SCFAs) to relieve DSS-induced colitis in mice, thereby alleviating colon inflammatory infiltration, increasing goblet cells density and mucus protein, ameliorating TNF-α, IL-1β, IL-6, IL-10, and Myeloperoxidase (MPO) levels, and recovering intestinal barrier integrity. CONCLUSION pH sensitive QCT nanoparticles can reduce inflammatory reaction, improve gut microbiota, and repair intestinal barrier by targeting colon, thus improving DSS induced colitis in mice, providing reference for the treatment of colitis.
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Affiliation(s)
- Lechen Wang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Rongrong Fu
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Ying Meng
- Department of Rehabilitation Medicine, Shandong Provincial Third Hospital, Shandong University, Jinan, Shandong, 250031, China
| | - Jingjie Liang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Wenqing Xue
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Haitao Hu
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Jing Meng
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
- Tianjin International Joint Academy of Biomedicine, Tianjin, 300457, China
| | - Min Zhang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin, 300457, China
- Tianjin Agricultural University, Tianjin, 300384, China
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Liu X, Tao T, Yao H, Zheng H, Wang F, Gao Y. Mechanism of action of quercetin in rheumatoid arthritis models: meta-analysis and systematic review of animal studies. Inflammopharmacology 2023:10.1007/s10787-023-01196-y. [PMID: 37150762 DOI: 10.1007/s10787-023-01196-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/13/2023] [Indexed: 05/09/2023]
Abstract
Quercetin, a typical flavonoid derived from a common natural plant, has multiple biological activities. Previous research in animal models has demonstrated the effectiveness of quercetin in treating rheumatoid arthritis (RA). The pharmacological effects and probable mechanisms of quercetin were evaluated in this study. Three databases, PubMed, Web of Science, and Embase, were searched for relevant studies from the creation of the databases to November 2022. Methodological quality was assessed using the SYRCLE risk of bias tool. STATA 15.1 was used to perform the statistical analysis. This research included 17 studies involving 251 animals. The results indicated that quercetin was able to reduce arthritis scores, paw swelling, histopathological scores, interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), C-reactive protein (CRP), malondialdehyde (MDA), reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), nuclear factor kappa B (NF-kB) and increase interleukin-10 (IL-10), catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), glutathione (GSH), and heme oxygenase-1 (HO-1). These may be related to quercetin's potential anti-inflammatory, anti-oxidative stress, and osteoprotective properties. However, more high-quality animal studies are needed to assess the effect of quercetin on RA. Additionally, the safety of quercetin requires further confirmation. Given the importance of the active ingredient, dose selection and the improvement of quercetin's bioavailability remain to be explored.
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Affiliation(s)
- Xinru Liu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Tao Tao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Huan Yao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Huilan Zheng
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Fuming Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Yongxiang Gao
- International Education College, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China.
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Lutein Prevents Liver Injury and Intestinal Barrier Dysfunction in Rats Subjected to Chronic Alcohol Intake. Nutrients 2023; 15:nu15051229. [PMID: 36904226 PMCID: PMC10005241 DOI: 10.3390/nu15051229] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
Chronic alcohol intake can affect both liver and intestinal barrier function. The goal of this investigation was to evaluate the function and mechanism of lutein administration on the chronic ethanol-induced liver and intestinal barrier damage in rats. During the 14-week experimental cycle, seventy rats were randomly divided into seven groups, with 10 rats in each group: a normal control group (Co), a control group of lutein interventions (24 mg/kg/day), an ethanol model group (Et, 8-12 mL/kg/day of 56% (v/v) ethanol), three intervention groups with lutein (12, 24 and 48 mg/kg/day) and a positive control group (DG). The results showed that liver index, ALT, AST and TG levels were increased, and SOD and GSH-Px levels were reduced in the Et group. Furthermore, alcohol intake over a long time increased the level of pro-inflammatory cytokines TNF-α and IL-1β, disrupted the intestinal barrier, and stimulated the release of LPS, causing further liver injury. In contrast, lutein interventions prevented alcohol-induced alterations in liver tissue, oxidative stress and inflammation. In addition, the protein expression of Claudin-1 and Occludin in ileal tissues was upregulated by lutein intervention. In conclusion, lutein can improve chronic alcoholic liver injury and intestinal barrier dysfunction in rats.
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Parwani K, Mandal P. Role of advanced glycation end products and insulin resistance in diabetic nephropathy. Arch Physiol Biochem 2023; 129:95-107. [PMID: 32730131 DOI: 10.1080/13813455.2020.1797106] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
Metabolic syndrome (MetS), i.e. a cluster of physiological and biochemical abnormalities can lead to diabetic nephropathy (DN). Insulin resistance, impaired fasting glucose are the main signs and symptoms of MetS. Excess sugar can induce various substantial structural changes like formation of advanced glycation end products (AGEs). AGEs are formed due to reaction of reducing sugars with amino groups of proteins, lipids and nucleic acids. AGEs when bound to the receptor for advanced glycation end products (RAGE) activate increased production of pro-inflammatory markers like interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) along with induction of endoplasmic reticulum (ER) stress. Accumulation of AGEs, enhanced reactive oxygen species (ROS) generation and activation of protein kinase C (PKC), are considered to induce glomerular hypertrophy, podocyte apoptosis, therefore contributing to the development and progression of DN. In this review, we decipher different biochemical and physiological factors that link AGEs and DN.
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Affiliation(s)
- Kirti Parwani
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Gujarat 388421, India
| | - Palash Mandal
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Gujarat 388421, India
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Shi H, Prough RA, McClain CJ, Song M. Different Types of Dietary Fat and Fructose Interactions Result in Distinct Metabolic Phenotypes in Male Mice. J Nutr Biochem 2023; 111:109189. [PMID: 36272691 DOI: 10.1016/j.jnutbio.2022.109189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/19/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022]
Abstract
Fat and fructose are the two major components over-represented in the Western diet. The aim of this study was to determine the combined effects of different types of dietary fat and fructose on the development of nonalcoholic fatty liver disease (NAFLD) in a murine model. Eight-week-old male C57BL/6J mice were fed with high-fat diet enriched with saturated fat (HSF), or omega-6 polyunsaturated fat (n6HUSF), or omega-3 polyunsaturated fat (n3HUSF) with 42% of calories derived from the fat. Fructose supplementation was given via 10% fructose (w/v) in the drinking water ad libitum for 20 weeks. While both HSF and n6HUSF fed mice developed obesity, HSF fed mice exhibited severe hepatic steatosis associated with hepatomegaly and liver injury. Fructose feeding promotes the development of liver fibrosis in HSF fed mice. n6HUSF fed mice were characterized with moderate hepatic steatosis, accompanied with hypertriglyceridemia and hyperlipidemia. Notably, fructose supplementation led to remarkable glucose intolerance in n6HUSF fed mice compared to controls. Hepatic lipidomic analysis revealed that the total saturated fatty acids and total monounsaturated fatty acids were significantly increased by fructose in the free fatty acid pool in HSF fed mice. Moreover, fructose supplementation increased hepatic and plasma cholesterol levels in the HSF fed mice. Our data suggest that excess energy from HSF intake results in fat storage in the liver, likely due to impaired triglyceride secretion; whereas excess energy from n6HUSF diet is stored in the periphery. Both effects are exacerbated by fructose supplementation. n3HUSF is beneficial, even consumed with fructose.
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Affiliation(s)
- Hongxue Shi
- Department of Pharmacology and Toxicology; Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Russell A Prough
- Hepatobiology and Toxicology Center; Department of Biochemistry and Molecular Genetics
| | - Craig J McClain
- Department of Pharmacology and Toxicology; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition; Hepatobiology and Toxicology Center; University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky, USA; Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, USA
| | - Ming Song
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition; Hepatobiology and Toxicology Center.
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Enhanced Immunomodulation, Anti-Apoptosis, and Improved Tear Dynamics of (PEG)-BHD1028, a Novel Adiponectin Receptor Agonist Peptide, for Treating Dry Eye Disease. Pharmaceutics 2022; 15:pharmaceutics15010078. [PMID: 36678707 PMCID: PMC9863990 DOI: 10.3390/pharmaceutics15010078] [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: 11/02/2022] [Revised: 12/14/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
Dry eye disease (DED) is characterized by impaired tear dynamics, leading to complex pathophysiological conditions. (PEG)-BHD1028, a peptide agonist to AdipoRs, was evaluated as a potential therapeutic agent for DED based on the reported physiological function of adiponectin, including anti-inflammation and epithelial protection. Therapeutic effects of (PEG)-BHD1028 were evaluated in experimentally induced EDE with 0.001%, 0.01%, and 0.1% (PEG)-BHD1028 in mice and 0.1%, 0.2%, and 0.4% in rabbits for 10 days. In the rabbit study, 0.05% cyclosporine was also tested as a comparator. The results from the mouse study revealed significant improvement in tear volumes, tear breakup time (TBUT), inflammation, and corneal severity score (CSS) within 10 days at all (PEG)-BHD1028 concentrations. In the rabbit study, the tear volume and TBUT significantly increased in (PEG)-BHD1028 groups compared with vehicle and 0.05% cyclosporine groups. The CSS, apoptosis rate, and corneal thickness of all (PEG)-BHD1028 and 0.05% cyclosporine groups were significantly improved relative to the vehicle group. The immune cell counts of 0.2% and 0.4% (PEG)-BHD1028 treated groups were significantly lower than those of the vehicle group. These results represent the potential of (PEG)-BHD1028 as an effective therapeutic agent for DED.
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Liang Y, Wang L. Carthamus tinctorius L.: A natural neuroprotective source for anti-Alzheimer's disease drugs. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115656. [PMID: 36041691 DOI: 10.1016/j.jep.2022.115656] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 07/24/2022] [Accepted: 08/16/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alzheimer's disease (AD) is a multicausal neurodegenerative disease clinically characterized by generalized dementia. The pathogenic process of AD not only is progressive and complex but also involves multiple factors and mechanisms, including β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. As the first-line treatment for AD, cholinesterase inhibitors can, to a certain extent, relieve AD symptoms and delay AD progression. Nonetheless, the current treatment strategies for AD are far from meeting clinical expectations, and more options for AD treatment should be applied in clinical practice. AIM OF THE REVIEW The aim of this review was to investigate published reports of C. tinctorius L. and its active constituents in AD treatment through a literature review. MATERIALS AND METHODS Information was retrieved from scientific databases including Web of Science, ScienceDirect, Scopus, Google Scholar, Chemical Abstracts Services and books, PubMed, dissertations and technical reports. Keywords used for the search engines were "Honghua" or "Carthamus tinctorius L." or "safflower" in conjunction with "(native weeds OR alien invasive)"AND "Chinese herbal medicine". RESULTS A total of 47 literatures about C. tinctorius L. and its active constituents in AD treatment through signaling pathways, immune cells, and disease-related mediators and systematically elucidates potential mechanisms from the point of anti-Aβ aggregation, suppressing tau protein hyperphosphorylation, increasing cholinergic neurotransmitters levels, inhibiting oxidative stress, anti-neuroinflammation, ameliorating synaptic plasticity, and anti-apoptosis. CONCLUSIONS Chinese herbal medicine (CHM) is a treasure endowed by nature to mankind. Emerging studies have confirmed that CHM and its active constituents play a positive role in AD treatment. Carthamus tinctorius L., the most commonly used CHM, can be used with medicine and food, with the effect of activating blood circulation and eliminating blood stasis. In the paper, we have concluded that the existing therapeutic mechanisms of C. tinctorius L. and summarized the potential mechanisms of C. tinctorius L. and its active constituents in AD treatment through a literature review.
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Affiliation(s)
- Yuanyuan Liang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
| | - Lin Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
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Qu L, Matz AJ, Karlinsey K, Cao Z, Vella AT, Zhou B. Macrophages at the Crossroad of Meta-Inflammation and Inflammaging. Genes (Basel) 2022; 13:2074. [PMID: 36360310 PMCID: PMC9690997 DOI: 10.3390/genes13112074] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/24/2022] [Accepted: 11/07/2022] [Indexed: 08/29/2023] Open
Abstract
Macrophages are central players in systemic inflammation associated with obesity and aging, termed meta-inflammation and inflammaging. Activities of macrophages elicited by the two chronic conditions display shared and distinct patterns mechanistically, resulting in multifaceted actions for their pathogenic roles. Drastically expanded tissue macrophage populations under obesity and aging stress attribute to both enhanced recruitment and local expansion. Importantly, molecular networks governing the multifaceted actions of macrophages are directly altered by environmental cues and subsequently contribute to metabolic reprogramming, resulting in meta-inflammation in obesity or inflammaging in aging. In this review, we will summarize how meta-inflammation and inflammaging affect macrophages and the molecular mechanisms involved in these processes.
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Affiliation(s)
- Lili Qu
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Alyssa J. Matz
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Keaton Karlinsey
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Ziming Cao
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Anthony T. Vella
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
- Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
| | - Beiyan Zhou
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
- Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
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Han F, Kan C, Wu D, Kuang Z, Song H, Luo Y, Zhang L, Hou N, Sun X. Irisin protects against obesity-related chronic kidney disease by regulating perirenal adipose tissue function in obese mice. Lipids Health Dis 2022; 21:115. [PMID: 36335399 PMCID: PMC9636726 DOI: 10.1186/s12944-022-01727-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/19/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. METHODS C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. RESULTS Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor-nitric oxide axis. CONCLUSIONS Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT-kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.
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Affiliation(s)
- Fang Han
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Di Wu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zengguang Kuang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hongwei Song
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Youhong Luo
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Le Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
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12
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Hu S, Zhao M, Li W, Wei P, Liu Q, Chen S, Zeng J, Ma X, Tang J. Preclinical evidence for quercetin against inflammatory bowel disease: a meta-analysis and systematic review. Inflammopharmacology 2022; 30:2035-2050. [PMID: 36227442 DOI: 10.1007/s10787-022-01079-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/08/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic, potentially cancerous disease with limited treatment options. Quercetin may be a novel treatment for IBD. However, its efficacy and safety are unknown. Our goal was to conduct a systematic evaluation to summarize the preclinical effects of quercetin, which may help guide future studies. METHODS The literature was drawn from three English databases (PubMed, Embase, and Web of Science), and the quality of the included literature was assessed using the SYRCLE list (10 items). The meta-analysis was performed using STATA 15.1 software. RESULTS A total of 11 animal studies with 199 animals were involved. The current meta-analysis showed that quercetin could reduce histological score (HS), Disease Activity Index (DAI), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nitric oxide(NO), malondialdehyde (MDA), myeloperoxidase (MPO) activity and increase colon length (CL), weight change degree (WCD), interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase (SOD) activity and catalase (CAT) activity, which may involve anti-inflammatory, anti-oxidative stress, cytoprotective, barrier protection, flora regulation. CONCLUSIONS In conclusion, preclinical evidence suggests that quercetin is an ideal agent for IBD treatment. However, the validity of the findings may be compromised by the low methodological quality and the small number of studies included. There may be some discrepancies between the results of the current analysis and the real situation. More rigorous experimental designs and more comprehensive studies are needed to test the protection of quercetin against IBD.
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Affiliation(s)
- Shuangyuan Hu
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Maoyaun Zhao
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Li
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Pengfei Wei
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qingsong Liu
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuanglan Chen
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China. .,TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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13
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Wang L, He C. Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol 2022; 13:967193. [PMID: 36032081 PMCID: PMC9411667 DOI: 10.3389/fimmu.2022.967193] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 07/27/2022] [Indexed: 12/14/2022] Open
Abstract
Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.
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Affiliation(s)
- Lin Wang
- Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chengqi He
- Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China,Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Chengqi He,
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14
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Luo L, Liu M. Adiponectin: friend or foe in obesity and inflammation. MEDICAL REVIEW (2021) 2022; 2:349-362. [PMID: 37724325 PMCID: PMC10388816 DOI: 10.1515/mr-2022-0002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 09/20/2023]
Abstract
Adiponectin is an adipokine predominantly produced by fat cells, circulates and exerts insulin-sensitizing, cardioprotective and anti-inflammatory effects. Dysregulation of adiponectin and/or adiponectin signaling is implicated in a number of metabolic diseases such as obesity, insulin resistance, diabetes, and cardiovascular diseases. However, while the insulin-sensitizing and cardioprotective effects of adiponectin have been widely appreciated in the field, the obesogenic and anti-inflammatory effects of adiponectin are still of much debate. Understanding the physiological function of adiponectin is critical for adiponectin-based therapeutics for the treatment of metabolic diseases.
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Affiliation(s)
- Liping Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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15
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Ramos-Ramírez P, Malmhäll C, Tliba O, Rådinger M, Bossios A. Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells. Front Immunol 2021; 12:677550. [PMID: 34084174 PMCID: PMC8167046 DOI: 10.3389/fimmu.2021.677550] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
Background Adiponectin is an important immunomodulatory mediator in inflammatory conditions. While we previously showed that adiponectin receptor 1 (AdipoR1) is expressed in murine regulatory T cells (Tregs), its expression in human Tregs remain unknown. Here, we examined the expression of AdipoR1 in human Tregs and whether its ligand, globular adiponectin (gAd) affects the Treg ability to secrete IL-10 and the role of Type 2 (T2) inflammation in such process. Methods Human Tregs from peripheral blood were analyzed by flow cytometry for AdipoR1, Helios and IL-10 expression. CD4+ T cells enriched from peripheral blood mononuclear cells (PBMCs) were cultured in the presence or the absence of gAd or the chemical adiponectin receptor agonist, AdipoRon, or in a T2 cytokine milieu. Flow cytometry was then used to assess intracellular IL-10, IL-10 secreting cells, FOXP3 and Helios expression, and phosphorylated p38 MAP kinase (MAPK). IL-10 levels in CD4+ T cell supernatants were quantified by ELISA. Results We found that a subset of human Tregs expressed AdipoR1. Importantly, more Helios- cells expressed AdipoR1 than Helios+ cells. Likewise, there was a higher frequency of IL-10+ cells within Helios- AdipoR1+ Tregs compared to Helios+ AdipoR1+ Tregs. In contrast, the IL-10 mean fluorescence intensity (MFI) was higher in Helios+ AdipoR1+ Tregs compared to Helios-AdipoR1+ Tregs. When human CD4+ T cells were treated with gAd or AdipoRon, a significant increase in IL-10 secretion, FOXP3 expression, and p38 MAPK phosphorylation was observed in Helios- AdipoR1+ Tregs. Interestingly, gAd under T2 cytokine milieu significantly increased the intracellular levels of IL-10, mainly in Helios+ AdipoR1+ Tregs, and IL-10 levels in supernatants of CD4+ T cells. Conclusions Collectively, our findings suggest that adiponectin/AdipoR1 axis promotes IL-10 release by Tregs, mainly in Helios- Tregs, and the effect was amplified by T2 inflammation in Helios+ Tregs.
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Affiliation(s)
- Patricia Ramos-Ramírez
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Malmhäll
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Omar Tliba
- Department of Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY, United States
| | - Madeleine Rådinger
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Apostolos Bossios
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Huddinge and Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
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16
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Pasqualotto A, Ayres R, Longo L, Del Duca Lima D, Losch de Oliveira D, Alvares-da-Silva MR, Reverbel da Silveira T, Uribe-Cruz C. Chronic exposure to ethanol alters the expression of miR-155, miR-122 and miR-217 in alcoholic liver disease in an adult zebrafish model. Biomarkers 2021; 26:146-151. [PMID: 33435755 DOI: 10.1080/1354750x.2021.1874051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM The aim of this study was to evaluate the hepatic and circulating expression of miR-155, miR-122 and miR-217 in a model of chronic exposure to ethanol in adult zebrafish. METHODS Wild-type adult zebrafish were divided into two groups (n = 281): an EG (exposed to 0.5% v/v Ethanol in aquarium water) and a CG (without ethanol). After 28 days the animals were euthanized, followed by histopathological analysis, quantification of lipids, triglycerides and inflammatory cytokines in liver tissue. miR-155, miR-122 and miR-217 gene expression was quantified in liver tissue and serum. RESULTS We observed hepatic lesions and increased accumulation of hepatic lipids in the EG. The expression of il-1β was higher in the EG, but there were no differences in il-10 and tnf-α between groups. In the liver, expression of miR-122 and miR-155 was higher in the EG. The circulating expression of miR-155 and miR-217 was significantly higher in the EG. CONCLUSION Chronic exposure to ethanol in zebrafish leads to altered hepatic and circulating expression of miR-155, miR-122 and miR-217. This confirms its potential as a biomarker and therapeutic target.
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Affiliation(s)
- Amanda Pasqualotto
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Raquel Ayres
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Larisse Longo
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Diego Del Duca Lima
- Graduate Program in Biological Sciences-Biochemistry, Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Diogo Losch de Oliveira
- Graduate Program in Biological Sciences-Biochemistry, Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Mário Reis Alvares-da-Silva
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Themis Reverbel da Silveira
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Carolina Uribe-Cruz
- Experimental Hepatology and Gastroenterology Laboratory, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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17
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Shi X, Zhu S, Jin H, Fang J, Xing X, Wang Y, Wang H, Wang C, Niu T, Liu K. The Anti-Inflammatory Effect of KS23, A Novel Peptide Derived From Globular Adiponectin, on Endotoxin-Induced Uveitis in Rats. Front Pharmacol 2021; 11:585446. [PMID: 33510636 PMCID: PMC7835799 DOI: 10.3389/fphar.2020.585446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/24/2020] [Indexed: 12/30/2022] Open
Abstract
Purpose: Adiponectin has been shown to exert potent anti-inflammatory activities in a range of systemic inflammatory diseases. This study aimed to investigate the potential therapeutic effects of KS23, a globular adiponectin-derived peptide, on endotoxin-induced uveitis (EIU) in rats and lipopolysaccharide (LPS)-stimulated mouse macrophage-like RAW 264.7 cells. Methods: EIU was induced in Lewis rats by subcutaneous injection of LPS into a single footpad. KS23 or phosphate-buffered saline (PBS) was administered immediately after LPS induction via intravitreal injection. Twenty-four hours later, clinical and histopathological scores were evaluated, and the aqueous humor (AqH) was collected to determine the infiltrating cells, protein concentration, and levels of inflammatory cytokines. In vitro, cultured RAW 264.7 cells were stimulated with LPS in the presence or absence of KS23, inflammatory cytokine levels in the supernatant, nuclear translocation of nuclear factor kappa B (NF-κB) subunit p65, and the expression of NF-kB signaling pathway components were analyzed. Results: KS23 treatment significantly ameliorated the clinical and histopathological scores of EIU rats and reduced the levels of infiltration cells, protein, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the aqueous humor. Consistently, KS23 decreased the expression of TNF-α and IL-6 in the supernatant of LPS-stimulated RAW 264.7 cells and inhibited the LPS-induced nuclear translocation of NF-κB p65 and the phosphorylation of IKKα/β/IκBα/NF-κB. Conclusion: The in vivo and in vitro results demonstrated the anti-inflammatory effects of the peptide KS23 and suggested that KS23 is a compelling, novel therapeutic candidate for the treatment of ocular inflammation.
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Affiliation(s)
- Xin Shi
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Shaopin Zhu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Huiyi Jin
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Junwei Fang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Xindan Xing
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Yihan Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Hanying Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Chingyi Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Tian Niu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Kun Liu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photo Medicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
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18
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Xu Q, Fan Y, Loor JJ, Liang Y, Lv H, Sun X, Jia H, Xu C. Aloin protects mice from diet-induced non-alcoholic steatohepatitis via activation of Nrf2/HO-1 signaling. Food Funct 2021; 12:696-705. [PMID: 33410857 DOI: 10.1039/d0fo02684k] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Aloin, a naturally occurring anthraquinone glycoside derived from the Aloe species, has antioxidant and anti-inflammatory activities, but its role in non-alcoholic steatohepatitis (NASH) remains unknown. This study was designed to investigate the anti-inflammatory, antioxidant, and anti-apoptotic effects of aloin and the underlying mechanisms during NASH. Wild-type or nuclear erythroid 2-related factor 2 (Nrf2) knock-out (KO) mice were fed a choline-deficient, l-amino acid-defined, high-fat (CDAAH) diet and treated with aloin (10, 20 or 40 mg per kg bw per day) by gavage for twelve weeks. Liver and blood samples were collected to evaluate liver function, protein abundance, and histopathological status. Supplementing aloin at 20 mg kg-1 was optimal for mitigating liver damage during NASH, as evidenced by reduced alanine transaminase and aspartate aminotransferase activity in serum. Supplementation with aloin significantly reduced serum concentration or liver protein abundance of malondialdehyde, tumor necrosis factor alpha, Interleukin (IL)-1β and IL-6. Aloin treatment enhanced hepatic superoxide dismutase activity, glutathione and serum IL-10 levels in mice with NASH. Furthermore, supplementation with aloin inhibited hepatocyte apoptosis caused by Bcl-2 up-regulation and cleaved caspase-3 and Bax down-regulation. Mechanistically, by using Nrf2 KO mice, the protective effects of aloin were associated with enhanced antioxidant, anti-inflammatory and anti-apoptotic activity, all of which were mediated by Nrf2/heme oxygenase-1 (HO-1) signaling activation. Data suggested that aloin activates the Nrf2/HO-1 pathway and has protective potential against liver injury during NASH. Therefore, aloin supplementation might contribute to the prevention and treatment of NASH via activation of the Nrf2/HO-1 pathway.
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Affiliation(s)
- Qiushi Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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19
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Qiu W, Wu H, Hu Z, Wu X, Tu M, Fang F, Zhu X, Liu Y, Lian J, Valverde P, Van Dyke T, Steffensen B, Dong LQ, Tu Q, Zhou X, Chen J. Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo. Br J Pharmacol 2020; 178:280-297. [PMID: 32986862 DOI: 10.1111/bph.15277] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 08/11/2020] [Accepted: 09/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND PURPOSE Adiponectin (APN) is an adipokine secreted from adipocytes that binds to APN receptors AdipoR1 and AdipoR2 and exerts an anti-inflammatory response through mechanisms not fully understood. There is a need to develop small molecules that activate AdipoR1 and AdipoR2 and to be used to inhibit the inflammatory response in lipopolysaccharide (LPS)-induced endotoxemia and other inflammatory disorders. EXPERIMENTAL APPROACH We designed 10 new structural analogues of an AdipoR agonist, AdipoRon (APR), and assessed their anti-inflammatory properties. Bone marrow-derived macrophages (BMMs) and peritoneal macrophages (PEMs) were isolated from mice. Levels of pro-inflammatory cytokines were measured by reverse transcription and real-time quantitative polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and microarray in LPS-induced endotoxemia mice and diet-induced obesity (DIO) mice in which systemic inflammation prevails. Western blotting, immunohistochemistry (IHC), siRNA interference and immunoprecipitation were used to detect signalling pathways. KEY RESULTS A novel APN receptor agonist named adipo anti-inflammation agonist (AdipoAI) strongly suppresses inflammation in DIO and endotoxemia mice, as well as in cultured macrophages. We also found that AdipoAI attenuated the association of AdipoR1 and APPL1 via myeloid differentiation marker 88 (MyD88) signalling, thus inhibiting activation of nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and c-Maf pathways and limiting the production of pro-inflammatory cytokines in LPS-induced macrophages. CONCLUSION AND IMPLICATIONS AdipoAI is a promising alternative therapeutic approach to APN and APR to suppress inflammation in LPS-induced endotoxemia and other inflammatory disorders via distinct signalling pathways.
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Affiliation(s)
- Wei Qiu
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China.,Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.,Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongle Wu
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China.,Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.,Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhekai Hu
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Xingwen Wu
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Maxwell Tu
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Fuchun Fang
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.,Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaofang Zhu
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Yao Liu
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China.,Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Junxiang Lian
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China.,Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Paloma Valverde
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Thomas Van Dyke
- Clinical and Translational Research, Forsyth Institute, Cambridge, Massachusetts, USA.,Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Bjorn Steffensen
- Department of Periodontology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Lily Q Dong
- Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Qisheng Tu
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA
| | - Xuedong Zhou
- State Key Laboratory of Oral Disease, West China Hospital of Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China.,Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jake Chen
- Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.,Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA
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20
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Abstract
Hepatic fibrosis is a complex mechanism defined by the net deposition of the extracellular matrix (ECM) owing to liver injury caused by multiple etiologies such as viral hepatitis and nonalcoholic fatty liver disease. Many cell types are implicated in liver fibrosis development and progression. In general, liver fibrosis starts with the recruitment of inflammatory immune cells to generate cytokines, growth factors, and other activator molecules. Such chemical mediators drive the hepatic stellate cells (HSCs) to activate the production of the ECM component. The activation of HSC is thus a crucial event in the fibrosis initiation, and a significant contributor to collagen deposition (specifically type I). This review explores the causes and mechanisms of hepatic fibrosis and focuses on the roles of key molecules involved in liver fibro genesis, some of which are potential targets for therapeutics to hamper liver fibro genesis.
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Affiliation(s)
- Reham M Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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21
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Abstract
Significance: Mucosal immunity in the gut has the important task of protecting an organism against potential danger, but at the same time of staying silent in response to harmless antigens present in the intestinal lumen. The delicate balance between immune activation and tolerance is referred to as gut homeostasis. Recent Advances: It has become clear that different types of immune cells and several factors participate in the maintenance of gut homeostasis, having as a final goal the prevention of non-necessary inflammation. Immune cells of the myeloid lineage, such as macrophages located in the lamina propria, represent the most abundant leukocyte population in the intestine and play a critical role in keeping the immune system silent, via the production of the anti-inflammatory cytokine interleukin-10. Critical Issues: Gut macrophages are an important source of the oxidative enzyme heme-oxygenase-1 (HO-1), which has crucial immune-modulatory properties. The protective role of HO-1 in the control of the intestinal inflammation, and its connection with the enteric flora have been demonstrated in experimental settings as well as in human biological samples. Future Directions: Loss of the gut homeostasis gives rise to conditions of acute inflammation that may degenerate into chronic disease, eventually leading to carcinogenesis. Understanding the mechanisms that regulate this enzyme will disclose novel therapeutic approaches that are designed to control chronic inflammation in the intestine.
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Affiliation(s)
- Giulia Marelli
- Humanitas Clinical and Research Center, IRCCS, Milan, Italy
| | - Paola Allavena
- Humanitas Clinical and Research Center, IRCCS, Milan, Italy
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22
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Wan YM, Li ZQ, Zhou Q, Liu C, Wang MJ, Wu HX, Mu YZ, He YF, Zhang Y, Wu XN, Li YH, Xu ZY, Wu HM, Xu Y, Yang JH, Wang XF. Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation. Stem Cell Res Ther 2020; 11:24. [PMID: 31931878 PMCID: PMC6958598 DOI: 10.1186/s13287-019-1547-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/10/2019] [Accepted: 12/29/2019] [Indexed: 12/20/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear. Methods MSCs were isolated from the bone marrow (BM) of 4–6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed. Results MSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone. Conclusions BM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.
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Affiliation(s)
- Yue-Meng Wan
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China.,Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Zhi-Qiang Li
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Qiong Zhou
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Chang Liu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Men-Jie Wang
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Hui-Xin Wu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Yun-Zhen Mu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Yue-Feng He
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Yuan Zhang
- The Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, Yunnan, China
| | - Xi-Nan Wu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China.
| | - Yu-Hua Li
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Zhi-Yuan Xu
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Hua-Mei Wu
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Ying Xu
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Jin-Hui Yang
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Xiao-Fang Wang
- Department of Pathology, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 65010, Yunnan Province, China
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Li H, Di G, Zhang Y, Xue R, Zhang J, Liang J. MicroRNA-155 and microRNA-181a, via HO-1, participate in regulating the immunotoxicity of cadmium in the kidneys of exposed Cyprinus carpio. FISH & SHELLFISH IMMUNOLOGY 2019; 95:473-480. [PMID: 31693945 DOI: 10.1016/j.fsi.2019.11.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/29/2019] [Accepted: 11/02/2019] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) is a nonessential metal that is a contaminant in aquatic ecosystems. Cd can accumulate in aquatic animals, leading to detrimental effects in tissues, and Cd exposure can induce immunotoxicity in fish. MicroRNAs (miRNAs) play critical roles in immune responses, yet the participation of miRNAs in Cd-induced immunotoxicity remains poorly understood. The present study evaluated the effects of Cd exposure on the immune responses and the mRNAs and miRNAs expressions of immune-related genes in Cyprinus carpio (C. carpio). Then, microRNA-155 (miR-155) was overexpressed and microRNA-181a (miR-181a) was knocked down to determine which miRNA plays a key role in the immune response to Cd. The results showed that 0.5 mg/L Cd2+ significantly decreased the activity of alkaline phosphatase (AKP) and acid phosphatase (ACP) in the kidneys of C. carpio. Cd exposure upregulated the mRNA expressions of interleukin (IL)-1β, IL-8, nuclear factor-kappa B (NF-κB), tumour necrosis factor-α (TNF-α), and Toll-like receptor 4(TLR-4) and downregulated those of IL-10 and heme oxygenase-1 (HO-1) in C. carpio kidneys. Cd exposure also led to upregulation of miR-155 and miR-181a expressions. Furthermore, AKP and ACP activity in the kidneys was markedly changed after intraperitoneal injection of C. carpio with miR-155 agomir and miR-181a antagomir. All detected mRNA expressions were significantly decreased after injection of miR-155 agomir, and IL-10, NF-κB, TNF-α, and HO-1 mRNA expressions were markedly increased after injection of miR-181a antagomir. The results of this study demonstrate that Cd exposure can immunocompromise C. carpio by targeting HO-1 through miR-155 and miR-181a. This is the first study to reveal that Cd exposure induces immunotoxicity through miR-155 and miR-181a in the kidneys of C. carpio.
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Affiliation(s)
- Hui Li
- College of Fisheries, Engineering Lab of Henan Province for Aquatic Animal Disease Control, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Henan province, PR China.
| | - Guilan Di
- College of Fisheries, Engineering Lab of Henan Province for Aquatic Animal Disease Control, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Henan province, PR China
| | - Yi Zhang
- College of Fisheries, Engineering Lab of Henan Province for Aquatic Animal Disease Control, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Henan province, PR China
| | - Rongrong Xue
- College of Fisheries, Engineering Lab of Henan Province for Aquatic Animal Disease Control, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Henan province, PR China
| | - Jing Zhang
- College of Fisheries, Engineering Lab of Henan Province for Aquatic Animal Disease Control, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Henan province, PR China
| | - Junping Liang
- College of Fisheries, Engineering Lab of Henan Province for Aquatic Animal Disease Control, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Henan province, PR China.
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Jiang Y, Feng YP, Tang LX, Yan YL, Bai JW. The protective role of NR4A3 in acute myocardial infarction by suppressing inflammatory responses via JAK2-STAT3/NF-κB pathway. Biochem Biophys Res Commun 2019; 517:697-702. [DOI: 10.1016/j.bbrc.2019.07.116] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 07/29/2019] [Indexed: 02/01/2023]
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Levin LM, Völzke H, Lerch MM, Kühn JP, Nauck M, Friedrich N, Zylla S. Associations of circulating chemerin and adiponectin concentrations with hepatic steatosis. Endocr Connect 2019; 8:1097-1107. [PMID: 31265993 PMCID: PMC6652250 DOI: 10.1530/ec-19-0300] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 07/02/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Chemerin and adiponectin are adipokines assumed to be involved in the development of metabolic syndrome-related phenotypes like hepatic steatosis. We aimed to evaluate the associations of circulating chemerin and adiponectin concentrations with liver enzymes, liver fat content, and hepatic steatosis in the general population. METHODS Data of 3951 subjects from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Hepatic steatosis was assumed when either a hyperechogenic liver (assessed via ultrasound) or a magnetic resonance imaging (MRI)-quantified liver fat content >5% was present. Adjusted sex-specific quantile and logistic regression models were applied to analyze the associations of chemerin and adiponectin with liver enzymes, liver fat content and hepatic steatosis. RESULTS The observed associations of chemerin and adiponectin with liver enzymes were very divergent depending on sex, fasting status and the specific enzyme. More consistent results were seen in the analyses of these adipokines in relation to MRI-quantified liver fat content. Here, we observed inverse associations to adiponectin in both sexes as well as a positive (men) or U-shaped (women) association to chemerin. Similarly, the MRI-based definition of hepatic steatosis revealed strongly consistent results: in both sexes, high chemerin concentrations were associated with higher odds of hepatic steatosis, whereas high adiponectin concentrations were associated with lower odds. CONCLUSION Our results suggest a role of these adipokines in the pathogenesis of hepatic steatosis independent of metabolic or inflammatory disorders. However, experimental studies are needed to further clarify the underlying mechanisms and the inter-play between adipokine concentrations and hepatic steatosis.
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Affiliation(s)
- Lena-Maria Levin
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
- DZD (German Center for Diabetes Research), Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Jens-Peter Kühn
- Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
- Institute and Policlinic for Radiology and Interventional Radiology, University Hospital, Carl-Gustav-Carus University Dresden, Dresden, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
| | - Nele Friedrich
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
| | - Stephanie Zylla
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Greifswald, Germany
- Correspondence should be addressed to S Zylla:
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Gu X, Luo X, Wang Y, He Z, Li X, Wu K, Zhang Y, Yang Y, Ji J, Luo X. Ascorbic acid attenuates cell stress by activating the fibroblast growth factor 21/fibroblast growth factor receptor 2/adiponectin pathway in HepG2 cells. Mol Med Rep 2019; 20:2450-2458. [PMID: 31322211 DOI: 10.3892/mmr.2019.10457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 05/29/2019] [Indexed: 11/05/2022] Open
Abstract
Increasing prevalence of obesity‑induced non‑alcoholic fatty liver disease (NAFLD) and non‑alcoholic steatohepatitis (NASH) has been reported. Ascorbic acid (AA), also known as vitamin C, an excellent antioxidant, has been shown to exert beneficial effects on NAFLD; however, the underlying mechanisms are yet to be fully elucidated. In the present study, the role of AA on cell stress in tumor necrosis factor α (TNFα)‑treated HepG2 cells was investigated. Our findings revealed that exposure to AA effectively ameliorated TNFα‑induced cell stresses, including hypoxia, inflammation and endoplasmic reticulum (ER) stress by reducing the expression of Hif1α and its target genes (glucose transporter 1), pro‑inflammatory genes (monocyte chemoattractant 1) and ER stress‑related genes (glucose‑regulated protein, 78 kDa). AA also decreased the protein level of HIF1α. Additionally, AA significantly increased the secretion of total adiponectin and high molecular weight (HMW) adiponectin. Mechanistically, AA was determined to increase the expression of fibroblast growth factor 21 (FGF21) and its receptor, fibroblast growth factor receptor 2 (FGFR2). Knockdown of FGFR2 not only decreased the levels of total adiponectin and HMW adiponectin, but almost abolished the beneficial effects of AA in ameliorating cell stress. Collectively, the findings of our study demonstrated that AA may attenuate hepatocyte stress induced by TNFα via activation of the FGF21/FGFR2/adiponectin pathway. This could a novel mechanism of action of AA, and its potential for the treatment of NAFLD/NASH.
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Affiliation(s)
- Xinqian Gu
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiao Luo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yanxin Wang
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zhangya He
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaomin Li
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Kunjin Wu
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yifan Zhang
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yafeng Yang
- Department of Clinical Nutrition, Xian Yang Central Hospital, Xianyang, Shaanxi 712000, P.R. China
| | - Jing Ji
- Department of Obstetrics, Northwest Women and Children Hospital, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaoqin Luo
- Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Qiao Y, Li X, Zhang X, Xiao F, Zhu Y, Fang Z, Sun J. Hepatocellular iNOS protects liver from NASH through Nrf2-dependent activation of HO-1. Biochem Biophys Res Commun 2019; 514:372-378. [PMID: 31043271 DOI: 10.1016/j.bbrc.2019.04.144] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 04/19/2019] [Indexed: 12/20/2022]
Abstract
Multiple molecular events are involved in non-alcoholic steatohepatitis (NASH). There is no consensus on the role of inducible nitric oxide synthase (iNOS) in the progression of NASH. The present study therefore investigated the role of iNOS in NASH pathogenesis using bone marrow-transplanted iNOS chimeric mice under high-fat diet (HFD) conditions. The chimeric mice were fed a HFD for 16 wk, and primary hepatocytes were stimulated with oleic acid (OA). The molecular mechanisms underlying the role of iNOS in NASH were investigated. Marked hepatic steatosis and injury observed in the HFD mice and OA-stimulated hepatocytes were reduced by hepatocyte-derived iNOS. Mechanistically, iNOS upregulated heme oxygenase 1 (HO-1) by augmenting nuclear factor erythroid 2-related factor 2 (Nrf-2) binding to the HO-1 gene promoter. In conclusion, hepatocyte-derived iNOS may play a protective role against the progression of NASH by upregulating HO-1 through Nrf-2. Upregulation of hepatocellular iNOS may represent a potentially new therapeutic paradigm to combat NASH.
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Affiliation(s)
- Yingli Qiao
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China
| | - Xuehua Li
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Xueli Zhang
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Fei Xiao
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China
| | - Yu Zhu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China; Medical College of Shandong University, Jinan, Shandong, 250021, China; The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
| | - Jie Sun
- Department of Endocrinology, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, China.
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Choi WM, Kim MH, Jeong WI. Functions of hepatic non-parenchymal cells in alcoholic liver disease. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Mohan R, Jose S, Sukumaran S, S A, S S, John G, I M K. Curcumin‐galactomannosides mitigate alcohol‐induced liver damage by inhibiting oxidative stress, hepatic inflammation, and enhance bioavailability on TLR4/MMP events compared to curcumin. J Biochem Mol Toxicol 2019; 33:e22315. [DOI: 10.1002/jbt.22315] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 12/05/2018] [Accepted: 01/09/2019] [Indexed: 01/09/2023]
Affiliation(s)
- Ratheesh Mohan
- Department of BiochemistrySt. Thomas College Kottayam Kerala India
| | - Svenia Jose
- Department of BiochemistrySt. Thomas College Kottayam Kerala India
| | - Sandya Sukumaran
- Department of Inorganic and Physical ChemistryIndian Institute of Science Bangalore Karnataka India
| | - Asha S
- Department of BiochemistrySt. Thomas College Kottayam Kerala India
| | - Sheethal S
- Department of BiochemistrySt. Thomas College Kottayam Kerala India
| | - Grace John
- Department of BiochemistrySt. Thomas College Kottayam Kerala India
| | - Krishnakumar I M
- R&D Centre, Akay Flavours & Aromatics Pvt Ltd Cochin Kerala India
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Rajan S, Panzade G, Srivastava A, Shankar K, Pandey R, Kumar D, Gupta S, Gupta A, Varshney S, Beg M, Mishra RK, Shankar R, Gaikwad A. miR-876-3p regulates glucose homeostasis and insulin sensitivity by targeting adiponectin. J Endocrinol 2018; 239:1–17. [PMID: 30307150 DOI: 10.1530/joe-17-0387] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
miRNA has been known to regulate diverse cellular and molecular functions. In the earlier study, we have reported that adipocytes differentiated from human mesenchymal stem cells (hMSC) on 72-h chronic insulin (CI) treatment exhibit insulin resistance (IR). Present study has further explored above model to investigate the role of early expressed miRNAs within human adipocytes to modulate differential adipokine expression as observed during IR. Our results highlight that miR-876-3p regulate glucose homeostasis and its dysregulation leads to IR. We found that miR-876-3p level is a critical determinant of adiponectin expression by virtue of its target within adiponectin 3′UTR. Regulatory effect of miR-876-3p impacts crosstalk between adiponectin and insulin signaling. Rosiglitazone treatment in CI-induced IR adipocytes drastically reduced miR-876-3p expression and increased adiponectin level. In line with this, lentiviral-mediated inhibition of miR-876-3p expression ameliorated CI and high-fat diet (HFD)-induced IR in adipocytes differentiated from hMSC and C57BL/6 mice, respectively. Our findings thus suggest that modulating miR-876-3p expression could provide novel opportunities for therapeutic intervention of obesity-associated metabolic syndrome.
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Affiliation(s)
- Sujith Rajan
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
| | - Ganesh Panzade
- Studio of Computational Biology and Bioinformatics, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, India
- Academy of Scientific and Innovative Research, CSIR-IHBT, Palampur, India
| | - Ankita Srivastava
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
| | - Kripa Shankar
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rajesh Pandey
- CSIR Ayurgenomics Unit-TRISUTRA, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Durgesh Kumar
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
| | - Sanchita Gupta
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
| | - Abhishek Gupta
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
| | - Salil Varshney
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
| | - Muheeb Beg
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
| | | | - Ravi Shankar
- Studio of Computational Biology and Bioinformatics, Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, India
- Academy of Scientific and Innovative Research, CSIR-IHBT, Palampur, India
| | - Anil Gaikwad
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
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Park PH. Autophagy induction: a critical event for the modulation of cell death/survival and inflammatory responses by adipokines. Arch Pharm Res 2018; 41:1062-1073. [DOI: 10.1007/s12272-018-1082-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022]
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Gamberi T, Magherini F, Modesti A, Fiaschi T. Adiponectin Signaling Pathways in Liver Diseases. Biomedicines 2018; 6:biomedicines6020052. [PMID: 29735928 PMCID: PMC6027295 DOI: 10.3390/biomedicines6020052] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/26/2018] [Accepted: 05/02/2018] [Indexed: 02/07/2023] Open
Abstract
In the liver, adiponectin regulates both glucose and lipid metabolism and exerts an insulin-sensitizing effect. The binding of adiponectin with its specific receptors induces the activation of a proper signaling cascade that becomes altered in liver pathologies. This review describes the different signaling pathways in healthy and diseased hepatocytes, also highlighting the beneficial role of adiponectin in autophagy activation and hepatic regeneration.
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Affiliation(s)
- Tania Gamberi
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
| | - Francesca Magherini
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
| | - Alessandra Modesti
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
| | - Tania Fiaschi
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
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Yousefian M, Nemati R, Daryabor G, Gholijani N, Nikseresht A, Borhani-Haghighi A, Kamali-Sarvestani E. Gender-Specific Association of Leptin and Adiponectin Genes With Multiple Sclerosis. Am J Med Sci 2018; 356:159-167. [PMID: 30219158 DOI: 10.1016/j.amjms.2018.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 03/01/2018] [Accepted: 03/02/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND Adipocytokines such as leptin (LEP) and adiponectin (ADIPOQ) represent a link between metabolism, nutritional status and immune responses. The present study aimed to determine the possible association between single nucleotide polymorphisms of LEP and ADIPOQ genes with multiple sclerosis (MS). MATERIALS AND METHODS Single nucleotide polymorphisms in LEP (rs2167270 or 19G > A and rs7799039 or -2,548G > A) and ADIPOQ (rs1501299 or +276G > T and rs266729 or -11,377C > G) were genotyped in 305 patients and 255 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. Sera levels of leptin and adiponectin were measured using enzyme-linked immunosorbent assay. RESULTS The frequencies of low leptin producer rs2167270GG genotype and rs2167270G allele were significantly lower in patients with MS compared to those of controls (for GG genotype: 39.7% and 49.8%, respectively; P = 0.01; for G allele: 63.3% and 68.8%, respectively; P = 0.05). Both polymorphisms in ADIPOQ did not show any significant association with disease susceptibility, though after gender categorization the frequency of high adiponectin producer rs1501299TT genotype and rs1501299T allele were significantly higher in male controls compared to male patients (TT genotype: P = 0.006; T allele: P = 0.006). Additionally, rs1501299TT genotype in ADIPOQ was associated with susceptibility to primary progressive multiple sclerosis (PP-MS) (P = 0.02). Moreover, while the sera levels of leptin were only different between male patients and controls (P = 0.05), adiponectin levels were significantly higher in total and female healthy controls (P < 0.001, P = 0.002, respectively). CONCLUSIONS Our findings provide evidence to support the hypothesis that functional ADIPOQ and LEP gene polymorphisms are associated with susceptibility to MS and its clinical forms.
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Affiliation(s)
- Marziyeh Yousefian
- Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Nemati
- Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholamreza Daryabor
- Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Naser Gholijani
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Nikseresht
- Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Afshin Borhani-Haghighi
- Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Eskandar Kamali-Sarvestani
- Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Elfeky M, Yoneshiro T, Okamatsu-Ogura Y, Kimura K. Adiponectin suppression of late inflammatory mediator, HMGB1-induced cytokine expression in RAW264 macrophage cells. J Biochem 2018; 163:143-153. [PMID: 29048484 DOI: 10.1093/jb/mvx069] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 09/02/2017] [Indexed: 12/27/2022] Open
Abstract
High-mobility group protein B1 (HMGB1) is a late inflammatory mediator released from inflammatory cells when stimulated, resulting in exaggerating septic symptoms. We recently demonstrated that full-length adiponectin, a potent anti-inflammatory adipokine, inhibits lipopolysaccharide-induced HMGB1 release. However, the effects of adiponectin on HMGB1-induced exaggerating signals currently remain unknown. This study aimed to investigate the effects of adiponectin on the pro-inflammatory function of HMGB1 in RAW264 macrophage cells. The treatment of RAW264 cells with HMGB1 significantly up-regulated the mRNA expression of tumour necrosis factor-α, interleukin-1β and C-X-C motif chemokine 10. HMGB1-induced cytokine expression was markedly suppressed by a toll-like receptor 4 (TLR4) antagonist and slightly suppressed by an antagonist of the receptor for advanced glycation end products. A prior treatment with full-length or globular adiponectin dose-dependently suppressed all types of HMGB1-induced cytokine expression, and this suppression was abolished by compound C, an AMPK inhibitor, but not by the haem oxygenase (HO)-1 inhibitor, zinc protoporphyrin IX. Both forms of adiponectin also reduced the mRNA expression of TLR4. These results suggest that full-length and globular adiponectin suppress HMGB1-induced cytokine expression through an AMPK-mediated HO-1-independent pathway.
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Affiliation(s)
- Mohamed Elfeky
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan.,Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Edfina, Rosetta-Line, Rashid, Behera Governate 22758, Egypt
| | - Takeshi Yoneshiro
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan
| | - Yuko Okamatsu-Ogura
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan
| | - Kazuhiro Kimura
- Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi9, Kita-ku, Sapporo 060-0818, Japan
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Tilija Pun N, Park PH. Adiponectin inhibits inflammatory cytokines production by Beclin-1 phosphorylation and B-cell lymphoma 2 mRNA destabilization: role for autophagy induction. Br J Pharmacol 2018; 175:1066-1084. [PMID: 29333604 DOI: 10.1111/bph.14144] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 11/24/2017] [Accepted: 12/19/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Adiponectin potently suppresses inflammatory mediator production. Autophagy is known to play a critical role in the modulation of inflammatory responses by adiponectin. However, the underlying mechanisms are not clearly understood. Interaction between Beclin-1 and B-cell lymphoma 2 (Bcl-2) is a critical event in autophagy induction. We examined the effects of globular adiponectin (gAcrp) on the Beclin-1/Bcl-2 association and its underlying mechanisms. EXPERIMENTAL APPROACH The effect of gAcrp on the interaction between Beclin-1 and Bcl-2 was examined by immunoprecipitation followed by Western blotting. To elucidate the underlying mechanisms, we determined the effects of gAcrp on Beclin-1 phosphorylation and Bcl-2 mRNA stability, and investigated their role in the suppression of inflammatory mediators using pharmacological inhibitors and transient target gene knockdown. KEY RESULTS Globular adiponectin disrupted the association between Beclin-1 and Bcl-2 and increased Beclin-1 phosphorylation at Thr119 , critical residue for binding with Bcl-2, via a death-associated protein kinase-1 (DAPK1)-dependent mechanism. Moreover, gAcrp reduced Bcl-2 expression via Bcl-2 mRNA destabilization, without significantly affecting Bcl-2 promoter activity and protein degradation, which was mediated by tristetraprolin (TTP) induction. Finally, DAPK1 and TTP were shown to play key roles in gAcrp-induced autophagosome formation and suppression of LPS-stimulated TNF-α and IL-1β expression. CONCLUSION AND IMPLICATIONS Beclin-1 phosphorylation and Bcl-2 mRNA destabilization mediated by DAPK1 and TTP are crucial events leading to autophagy and the suppression of inflammatory cytokine production by gAcrp. These results provide novel mechanisms underlying adiponectin's modulation of inflammatory responses. DAPK and TTP are potential therapeutic targets for the management of inflammation.
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Affiliation(s)
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Korea
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The macrophage heme-heme oxygenase-1 system and its role in inflammation. Biochem Pharmacol 2018; 153:159-167. [PMID: 29452096 DOI: 10.1016/j.bcp.2018.02.010] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 02/12/2018] [Indexed: 02/07/2023]
Abstract
Heme oxygenase (HO)-1, the inducible isoform of the heme-degrading enzyme HO, plays a critical role in inflammation and iron homeostasis. Regulatory functions of HO-1 are mediated via the catalytic breakdown of heme, which is an iron-containing tetrapyrrole complex with potential pro-oxidant and pro-inflammatory effects. In addition, the HO reaction produces the antioxidant and anti-inflammatory compounds carbon monoxide (CO) and biliverdin, subsequently converted into bilirubin, along with iron, which is reutilized for erythropoiesis. HO-1 is up-regulated by a plethora of stimuli and injuries in most cell types and tissues and provides salutary effects by restoring physiological homeostasis. Notably, HO-1 exhibits critical immuno-modulatory functions in macrophages, which are a major cell population of the mononuclear phagocyte system. Macrophages play key roles as sentinels and regulators of the immune system and HO-1 in these cells appears to be of critical importance for driving resolution of inflammatory responses. In this review, the complex functions and regulatory mechanisms of HO-1 in macrophages will be high-lighted. A particular focus will be the intricate interactions of HO-1 with its substrate heme, which play a contradictory role in distinct physiological and pathophysiological settings. The therapeutic potential of targeted modulation of the macrophage heme-HO-1 system will be discussed in the context of inflammatory disorders.
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Liu S, Tian L, Chai G, Wen B, Wang B. Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation. Food Funct 2018; 9:4184-4193. [PMID: 29993075 DOI: 10.1039/c8fo00650d] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Quercetin can ameliorate alcohol-induced acute liver injury via inducing heme oxygenase-1 and inhibiting NLRP3 inflammasome activation.
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Affiliation(s)
- Shu Liu
- Department of Geriatrics
- The First Affiliated Hospital of China Medical University
- China
| | - Lei Tian
- Department of Gastroenterology
- The First Affiliated Hospital of Jinzhou Medical University
- China
| | - Guangrui Chai
- Department of Ophthalmology
- Shengjing Hospital of China Medical University
- China
| | - Bo Wen
- Department of Geriatrics
- The First Affiliated Hospital of China Medical University
- China
| | - Bingyuan Wang
- Department of Geriatrics
- The First Affiliated Hospital of China Medical University
- China
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Lu Y, Cederbaum AI. Cytochrome P450s and Alcoholic Liver Disease. Curr Pharm Des 2018; 24:1502-1517. [PMID: 29637855 PMCID: PMC6053342 DOI: 10.2174/1381612824666180410091511] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/30/2018] [Accepted: 04/06/2018] [Indexed: 12/19/2022]
Abstract
Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.
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Affiliation(s)
- Yongke Lu
- Department of Health Sciences, College of Public Health, East Tennessee State University
- Center of Excellence for Inflammation, Infectious Disease and Immunity, East Tennessee State University
| | - Arthur I. Cederbaum
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai
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Alzahrani B, Iseli T, Ramezani-Moghadam M, Ho V, Wankell M, Sun EJ, Qiao L, George J, Hebbard LW. The role of AdipoR1 and AdipoR2 in liver fibrosis. Biochim Biophys Acta Mol Basis Dis 2017; 1864:700-708. [PMID: 29237572 DOI: 10.1016/j.bbadis.2017.12.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 12/05/2017] [Accepted: 12/08/2017] [Indexed: 12/17/2022]
Abstract
Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock-out mice in the carbon tetrachloride (CCl4) model of liver fibrosis. In addition, we knocked down receptor function in primary hepatic stellate cells (HSCs) in vitro. Following the development of fibrosis, AdipoR1 and AdipoR2 KO mice had no quantitative difference in fibrosis by Sirius red staining. However, AdipoR2 KO mice had an enhanced fibrotic signature with increased Col1-α1, TGFß-1, TIMP-1, IL-10, MMP-2 and MMP-9. Knockdown of AdipoR1 or AdipoR2 in HSCs followed by APN treatment demonstrated that AdipoR1 and AdipoR2 did not affect proliferation or TIMP-1 gene expression, while AdipoR2 modulated Col1-α1 and α-SMA gene expression, HSC migration, and AMPK activity. These finding suggest that AdipoR2 is the major APN receptor on HSCs responsible for mediating its anti-fibrotic effects.
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Affiliation(s)
- Badr Alzahrani
- The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Tristan Iseli
- The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Mehdi Ramezani-Moghadam
- The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Vikki Ho
- The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, Centre for Comparative Genomics, The Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, Townsville, QLD, 4811, Australia
| | - Eun Jin Sun
- Department of Molecular and Cell Biology, Centre for Comparative Genomics, The Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, Townsville, QLD, 4811, Australia
| | - Liang Qiao
- The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Jacob George
- The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
| | - Lionel W Hebbard
- Department of Molecular and Cell Biology, Centre for Comparative Genomics, The Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, Townsville, QLD, 4811, Australia; The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia.
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Gong Z, Tas E, Yakar S, Muzumdar R. Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. Mol Cell Endocrinol 2017; 455:115-130. [PMID: 28017785 DOI: 10.1016/j.mce.2016.12.022] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 09/23/2016] [Accepted: 12/16/2016] [Indexed: 02/06/2023]
Abstract
Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.
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Affiliation(s)
- Zhenwei Gong
- Department of Pediatrics, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Emir Tas
- Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, USA
| | - Radhika Muzumdar
- Department of Pediatrics, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, 3500 Terrace Street, 5362 Biomedical Sciences Tower, Pittsburgh, PA 15261, USA.
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Heil LBB, Silva PL, Pelosi P, Rocco PRM. Immunomodulatory effects of anesthetics in obese patients. World J Crit Care Med 2017; 6:140-152. [PMID: 28828299 PMCID: PMC5547428 DOI: 10.5492/wjccm.v6.i3.140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 04/27/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Anesthesia and surgery have an impact on inflammatory responses, which influences perioperative homeostasis. Inhalational and intravenous anesthesia can alter immune-system homeostasis through multiple processes that include activation of immune cells (such as monocytes, neutrophils, and specific tissue macrophages) with release of pro- or anti-inflammatory interleukins, upregulation of cell adhesion molecules, and overproduction of oxidative radicals. The response depends on the timing of anesthesia, anesthetic agents used, and mechanisms involved in the development of inflammation or immunosuppression. Obese patients are at increased risk for chronic diseases and may have the metabolic syndrome, which features insulin resistance and chronic low-grade inflammation. Evidence has shown that obesity has adverse impacts on surgical outcome, and that immune cells play an important role in this process. Understanding the effects of anesthetics on immune-system cells in obese patients is important to support proper selection of anesthetic agents, which may affect postoperative outcomes. This review article aims to integrate current knowledge regarding the effects of commonly used anesthetic agents on the lungs and immune response with the underlying immunology of obesity. Additionally, it identifies knowledge gaps for future research to guide optimal selection of anesthetic agents for obese patients from an immunomodulatory standpoint.
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Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions. Int J Mol Sci 2017; 18:ijms18081649. [PMID: 28758929 PMCID: PMC5578039 DOI: 10.3390/ijms18081649] [Citation(s) in RCA: 154] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 07/18/2017] [Accepted: 07/26/2017] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.
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Kema VH, Khan I, Jamal R, Vishwakarma SK, Lakki Reddy C, Parwani K, Patel F, Patel D, Khan AA, Mandal P. Protective Effects of Diallyl Sulfide Against Ethanol-Induced Injury in Rat Adipose Tissue and Primary Human Adipocytes. Alcohol Clin Exp Res 2017; 41:1078-1092. [PMID: 28414868 DOI: 10.1111/acer.13398] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 04/06/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Alcohol consumption is the fourth leading cause of death and disability worldwide. Several cellular pathways contribute to alcohol-mediated tissue injury. Adipose tissue apart from functioning as an endocrine organ secretes several hormones and cytokines known as adipokines that are known to play a significant role in alcohol-induced tissue damage. This study was designed to test the efficacy of diallyl sulfide (DAS) in regulating the alcohol-induced outcomes on adipose tissue. METHODS Male Wistar rats were fed with 36% Lieber-DeCarli liquid diet containing ethanol (EtOH) for 4 weeks. Control rats were pair-fed with isocaloric diet containing maltodextrin instead of EtOH. During the last week of feeding protocol, the EtOH-fed rat group was given 200 mg/kg body weight of DAS through diet. We also studied DAS effect on isolated human primary adipocytes. Viability of human primary adipocytes on DAS treatment was assessed by MTT assay. Malondialdehyde (MDA), a marker of oxidative stress, was measured by HPLC and the thiobarbituric acid method. Expression of inflammatory genes and lipogenic genes was studied by qRT-PCR and Western blotting. Serum inflammatory gene expression was studied by ELISA. RESULTS Our study results showed that DAS could alleviate EtOH-induced expression levels of proinflammatory and endoplasmic reticulum (ER) stress genes and improve adipose tissue mass and adipocyte morphology in male Wistar rats fed Lieber-DeCarli diet containing 6% EtOH. Further, we showed that DAS reduced the expression of lipogenic genes and improved lipid accumulation and adipocyte mass in human primary adipocytes treated with EtOH. Subsequently, we also showed that oxidative stress, as measured by the changes in MDA levels, was reduced in both male Wistar rats and human primary adipocytes treated with EtOH plus DAS. CONCLUSIONS Our study results prove that DAS is effective in ameliorating EtOH-induced damage to adipose tissue as evidenced by the reduction brought about by DAS in oxidative stress, ER stress, and proinflammatory gene expression levels. DAS treatment also regulated lipogenic gene expression levels, thereby reducing free fatty acid release. In conclusion, this study has clinical implications with respect to alcohol-induced adipose tissue injury among alcohol users.
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Affiliation(s)
| | - Imran Khan
- Department of Biological Sciences , BITS Pilani, Hyderabad, India
| | - Reshma Jamal
- Department of Biological Sciences , BITS Pilani, Hyderabad, India
| | - Sandeep Kumar Vishwakarma
- Central Laboratory for Stem Cell Research & Translational Medicine , CLRD, Deccan College of Medical Sciences, Hyderabad, India
| | - Chandrakala Lakki Reddy
- Central Laboratory for Stem Cell Research & Translational Medicine , CLRD, Deccan College of Medical Sciences, Hyderabad, India
| | - Kirti Parwani
- Department of Biological Sciences , P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
| | - Farhin Patel
- Department of Biological Sciences , P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
| | - Dhara Patel
- Department of Biological Sciences , P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
| | - Aleem A Khan
- Central Laboratory for Stem Cell Research & Translational Medicine , CLRD, Deccan College of Medical Sciences, Hyderabad, India
| | - Palash Mandal
- Department of Biological Sciences , BITS Pilani, Hyderabad, India
- Department of Biological Sciences , P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
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Sharma AX, Holland WL. Adiponectin and its Hydrolase-Activated Receptors. JOURNAL OF NATURE AND SCIENCE 2017; 3:e396. [PMID: 28758149 PMCID: PMC5531184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The relevance of adiponectin to insulin sensitivity has been elucidated over the last two decades. As a promoter of ceramide degradation, it works through its cognate receptors, AdipoR1 and AdipoR2, to alter bioactive sphingolipid species. Adiponectin diminishes the accumulation of ceramide, a lipid metabolite which can play a causal role in obesity-induced insulin resistance. Concurrently, adiponectin stimulates the production of sphingosine-1-phosphate (S1P), a cyto-protective molecule that accentuates adiponectin's positive metabolic effects. This review focuses on recent work that solidifies knowledge of the adiponectin signaling pathway, gives new insight into some notable characteristics of adiponectin's receptors, and most importantly, affirms adiponectin receptor agonism as a viable therapeutic tool to combat elevated ceramide levels and improve insulin sensitivity in obese patients with type II diabetes.
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Affiliation(s)
| | - William L. Holland
- Corresponding Author: William L. Holland. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-8549, USA. Tel: 214-648-2566; Fax: 214-648-8720.
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Gonzalez-Lopez L, Fajardo-Robledo NS, Miriam Saldaña-Cruz A, Moreno-Sandoval IV, Bonilla-Lara D, Zavaleta-Muñiz S, Nava-Zavala AH, Hernandez-Cuervo P, Rocha-Muñoz A, Rodriguez-Jimenez NA, Vazquez-Villegas ML, Muñoz-Valle JF, Salazar-Paramo M, Cardona-Muñoz EG, Gamez-Nava JI. Association of adipokines, interleukin-6, and tumor necrosis factor-α concentrations with clinical characteristics and presence of spinal syndesmophytes in patients with ankylosing spondylitis: A cross-sectional study. J Int Med Res 2017; 45:1024-1035. [PMID: 28534699 PMCID: PMC5536407 DOI: 10.1177/0300060517708693] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Objective To identify correlations of the serum leptin, adiponectin, interleukin-6 (IL-6), and
tumor necrosis factor-α (TNF-α) concentrations with the clinical characteristics,
presence of spinal syndesmophytes, and body composition in patients with ankylosing
spondylitis (AS). Methods Forty-eight patients with AS were compared with 41 sex- and age-matched controls.
Assessment included clinical characteristics and the presence of spinal syndesmophytes.
The serum leptin, adiponectin, TNF-α, and IL-6 concentrations were determined. Body
composition was evaluated using dual-energy X-ray absorptiometry. Results Patients with AS and controls had similar fat mass and lean mass. Patients with AS had
higher serum TNF-α and leptin concentrations than controls (52.3 vs. 1.5 pg/mL and 17.2
vs. 9.0 µg/mL, respectively). The IL-6 and adiponectin concentrations were not
significantly different between the two groups. Patients with syndesmophytes had higher
leptin concentrations than those without syndesmophytes (22.1 vs. 10.9 µg/mL); this
difference remained after adjustment for the body mass index. Conclusion Elevated leptin concentrations are associated with spinal radiographic damage in
patients with AS and can serve as a biomarker. Future studies should evaluate whether
leptin might be a potential target for treatments to avoid structural damage.
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Affiliation(s)
- Laura Gonzalez-Lopez
- 1 Departamento de Medicina Interna/Reumatología, Hospital General Regional 110 del Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jal., México.,2 Doctorado en Farmacología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México
| | - Nicte S Fajardo-Robledo
- 3 Laboratorio de Investigación y Desarrollo Farmacéutico, Centro Universitario de Ciencias Exactas e Ingeniería, Universidad de Guadalajara, Guadalajara, Jal., México
| | - A Miriam Saldaña-Cruz
- 4 División de Ciencias de la Salud, Departamento de Ciencias Biomédicas, Centro Universitario de Tonalá (CUTonalá), Universidad de Guadalajara, 48525 Tonalá, Jal., México
| | - Inocente V Moreno-Sandoval
- 1 Departamento de Medicina Interna/Reumatología, Hospital General Regional 110 del Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jal., México
| | - David Bonilla-Lara
- 1 Departamento de Medicina Interna/Reumatología, Hospital General Regional 110 del Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jal., México.,2 Doctorado en Farmacología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México
| | - Soraya Zavaleta-Muñiz
- 5 División de Estudios de Posgrado, Facultad de Ciencias de la Salud, Universidad Juárez del Estado de Durango, Gómez Palacio, 35050 Durango, México
| | - Arnulfo Hernan Nava-Zavala
- 6 Unidad de Investigación Biomédica 02, UIEC, UMAE, HE CMNO, IMSS, Guadalajara, Jal., México.,7 Programa Internacional de Medicina, Universidad Autónoma de Guadalajara, Guadalajara, Jal., México
| | | | - Alberto Rocha-Muñoz
- 8 División de Ciencias de la Salud, Departamento de Ciencias de la Salud-enfermedad como proceso individual, Centro Universitario de Tonalá (CUTonalá), Universidad de Guadalajara, 48525 Tonalá, Jal., México
| | - Norma Alejandra Rodriguez-Jimenez
- 1 Departamento de Medicina Interna/Reumatología, Hospital General Regional 110 del Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jal., México.,9 Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México
| | - Maria L Vazquez-Villegas
- 10 Departamento en Salud Pública, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México.,11 Departamento de Epidemiología, Unidad Médica Familiar 4, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jal., México
| | - J Francisco Muñoz-Valle
- 12 Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jal., México
| | - Mario Salazar-Paramo
- 9 Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México.,13 División de Investigación en Salud, UMAE, HE CMNO, IMSS, Guadalajara, Jal., México
| | - Ernesto G Cardona-Muñoz
- 9 Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México
| | - Jorge I Gamez-Nava
- 2 Doctorado en Farmacología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal., México.,6 Unidad de Investigación Biomédica 02, UIEC, UMAE, HE CMNO, IMSS, Guadalajara, Jal., México
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Rehman K, Akash MSH. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? J Biomed Sci 2016; 23:87. [PMID: 27912756 PMCID: PMC5135788 DOI: 10.1186/s12929-016-0303-y] [Citation(s) in RCA: 375] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/24/2016] [Indexed: 02/06/2023] Open
Abstract
Background Insulin resistance (IR) is one of the major hallmark for pathogenesis and etiology of type 2 diabetes mellitus (T2DM). IR is directly interlinked with various inflammatory responses which play crucial role in the development of IR. Inflammatory responses play a crucial role in the pathogenesis and development of IR which is one of the main causative factor for the etiology of T2DM. Methods A comprehensive online English literature was searched using various electronic search databases. Different search terms for pathogenesis of IR, role of various inflammatory responses were used and an advanced search was conducted by combining all the search fields in abstracts, keywords, and titles. Results We summarized the data from the searched articles and found that inflammatory responses activate the production of various pro-inflammatory mediators notably cytokines, chemokines and adipocytokines through the involvement of various transcriptional mediated molecular pathways, oxidative and metabolic stress. Overnutrition is one of the major causative factor that contributes to induce the state of low-grade inflammation due to which accumulation of elevated levels of glucose and/or lipids in blood stream occur that leads to the activation of various transcriptional mediated molecular and metabolic pathways. This results in the induction of various pro-inflammatory mediators that are decisively involved to provoke the pathogenesis of tissue-specific IR by interfering with insulin signaling pathways. Once IR is developed, it increases oxidative stress in β-cells of pancreatic islets and peripheral tissues which impairs insulin secretion, and insulin sensitivity in β-cells of pancreatic islets and peripheral tissues, respectively. Moreover, we also summarized the data regarding various treatment strategies of inflammatory responses-induced IR. Conclusions In this article, we have briefly described that how pro-inflammatory mediators, oxidative stress, transcriptional mediated molecular and metabolic pathways are involved in the pathogenesis of tissues-specific IR. Moreover, based on recent investigations, we have also described that to counterfeit these inflammatory responses is one of the best treatment strategy to prevent the pathogenesis of IR through ameliorating the incidences of inflammatory responses.
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Affiliation(s)
- Kanwal Rehman
- Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
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Hou N, Liu Y, Han F, Wang D, Hou X, Hou S, Sun X. Irisin improves perivascular adipose tissue dysfunction via regulation of the heme oxygenase-1/adiponectin axis in diet-induced obese mice. J Mol Cell Cardiol 2016; 99:188-196. [PMID: 27638193 DOI: 10.1016/j.yjmcc.2016.09.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 07/27/2016] [Accepted: 09/11/2016] [Indexed: 02/07/2023]
Abstract
AIMS To determine whether irisin could improve perivascular adipose tissue (PVAT) dysfunction via regulation of the heme oxygenase-1 (HO-1)/adiponectin axis in obesity. MATERIALS AND METHODS C57BL/6 mice were given chow or a high-fat diet (HFD) with or without treatment with irisin. The concentration-dependent responses of the thoracic aorta with or without PVAT (PVAT+ or PVAT-) to phenylephrine were studied in an organ bath. Protein levels of HO-1 and adiponectin were determined by western blot. UCP-1, Cidea, and TNF-α gene expression in PVAT were analyzed by real-time PCR. RESULTS Treatment of obese mice with irisin improved glucose and lipid metabolism, reduced plasma levels of TNF-α and malondialdehyde, and increased plasma adiponectin levels (P<0.01). The anti-contractile effects of PVAT were attenuated in HFD mice and this attenuation was restored in HFD mice treated with irisin (P<0.05). Incubation of aortas (PVAT+) with the HO-1 inhibitor and adiponectin receptor blocking peptide in irisin-treated HFD mice abolished the beneficial effects of irisin on PVAT function. The same results were also observed in HFD mice treated with irisin ex vivo. Treatment of HFD mice with irisin significantly enhanced protein levels of HO-1 and adiponectin, and reduced superoxide production and TNF-α expression in PVAT. Irisin treatment enhanced brown adipocyte markers UCP-1 and Cidea expression in PVAT from HFD mice. CONCLUSION Irisin improved the anti-contractile properties of PVAT from the thoracic aorta in diet-induced obese mice. The mechanism for protective effects of irisin appeared to be related to upregulation of the HO-1/adiponectin axis in PVAT and browning of PVAT.
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Affiliation(s)
- Ningning Hou
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yihui Liu
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Di Wang
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaoshuang Hou
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Shuting Hou
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China.
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Grander C, Grabherr F, Moschen AR, Tilg H. Non-Alcoholic Fatty Liver Disease: Cause or Effect of Metabolic Syndrome. Visc Med 2016; 32:329-334. [PMID: 27921044 DOI: 10.1159/000448940] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease throughout the world. Pathophysiological insights into this disease have recently illustrated that various factors such as insulin resistance, innate immunity, metabolic inflammation, and the microbiota are of relevance. NAFLD, metabolic syndrome (MS), and type 2 diabetes (T2D) share many pathophysiological aspects, and inflammatory processes in the adipose tissue, gut, and liver have evolved to be of exceptional importance. Most of NAFLD patients are obese and encounter a high risk of developing MS and T2D. NAFLD, however, is also highly common in subjects with MS and T2D. Furthermore, reflecting its nature of a multisystem disease, NAFLD is associated with a high prevalence and incidence of cardiovascular and chronic kidney disease. These facts require screening strategies for MS/T2D in NAFLD patients and vice versa. Thus, the question of cause or effect cannot be answered as MS and NAFLD share many pathomechanisms, and at the time of either diagnosis both frequently coexist. This is also reflected by a global prevalence rate of 25% for both NAFLD and MS. For this reason, it is crucial that physicians are aware of the 'unholy liaison' between MS, T2D, and NAFLD.
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Affiliation(s)
- Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Alexander R Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
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50
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Shih SC, Ho TC, Chen SL, Tsao YP. Pigment Epithelium Derived Factor Peptide Protects Murine Hepatocytes from Carbon Tetrachloride-Induced Injury. PLoS One 2016; 11:e0157647. [PMID: 27384427 PMCID: PMC4934881 DOI: 10.1371/journal.pone.0157647] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 06/02/2016] [Indexed: 12/31/2022] Open
Abstract
Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl4). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl4, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl4-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl4 caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl4 injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl4 injury. This protective effect may stem from strengthening the counter oxidative stress capacity and induction of hepatoprotective factors.
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Affiliation(s)
- Shou-Chuan Shih
- Mackay Medical College, New Taipei City, Taiwan
- Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
- * E-mail: (SCS); (YPT)
| | - Tsung-Chuan Ho
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
| | - Show-Li Chen
- Department of Microbiology, School of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yeou-Ping Tsao
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan
- * E-mail: (SCS); (YPT)
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