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1
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Hu MX, Li JQ, Zhang HW, Ma YK, Zhao BJ, Xiao L, Liang W, Wang Y, Wang C, Wu CG, Liu TT. 1-benzyl-6-nitro-4-phenyl-4-(methoxycarbonyl)-2(1H)-pyridinone, a novel pirfenidone derivative, alleviate hepatic fibrosis through T cells. Biomed Pharmacother 2025; 184:117907. [PMID: 39978030 DOI: 10.1016/j.biopha.2025.117907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/17/2025] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
Hepatic fibrosis (HF) is a pathological process in many liver diseases, which lack of specific agents. Pirfenidone (PFD) derivatives are potential new drug. The purpose of this study was to investigate the effect and immunological mechanism of PFD derivatives on HF. A total of 11 PFD derivatives were designed, synthesized and screened. 1-benzyl-6-nitro-4-phenyl-4-(methoxycarbonyl)-2(1 H)-pyridinone (code: Compound 5) had optimal effect on inhibiting nitric oxide release, hepatic stellate cells (HSCs) and T cell proliferation, which suggested that Compound 5 showed anti-inflammatory, anti-fibrosis and immunoregulation effects. Compound 5 inhibited the proliferation of HSC-T6 and T cell in dose-dependent manner, the IC50 was 10.19 μM and 17.16 μM, respectively. Compound 5 inhibited the differentiation of CD8+T cells and promoted the differentiation of Tregs in the splenic T lymphocyte of CCl4-induced mouse HF model. Besides, Compound 5 promoted HSC-T6 apoptosis in dose-dependent manner, accompanied by the down-regulation of α-smooth muscle actin (α-SMA) and collagen-I (Col-I). In terms of mechanism, Compound 5 had no significant effect on glucose uptake of T cells. But it inhibited non-esterified fatty acid (NEFA) secretion of T cell by inhibiting the phosphorylation of PI3K-AKT-mTOR signal, which related to the metabolism of T cell. Subsequently, Compound 5 affected α-SMA and Col-I expression of HSC-T6 by T cell modulating in cell co-culture. CONCLUSION: Compound 5 is a promising new drug against HF by the dual role of inhibiting HSCs and modulating T cells lipid metabolism, which affects the immune microenvironment of HF.
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Affiliation(s)
- Meng-Xue Hu
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Jia-Qi Li
- School of Pharmacy, South-Central Minzu University, Wuhan, China
| | - Hong-Wei Zhang
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Yu-Kun Ma
- Department of Pharmacy, the 902nd Hospital of the PLA Joint Logistics Support Force, Bengbu, China
| | - Bao-Jing Zhao
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lei Xiao
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Wei Liang
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China
| | - Yamin Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, the Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Cheng-Gui Wu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.
| | - Ting-Ting Liu
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China.
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Li M, Cui M, Li G, Liu Y, Xu Y, Eftekhar SP, Ala M. The Pathophysiological Associations Between Obesity, NAFLD, and Atherosclerotic Cardiovascular Diseases. Horm Metab Res 2024; 56:683-696. [PMID: 38471571 DOI: 10.1055/a-2266-1503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2024]
Abstract
Obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerotic cardiovascular diseases are common and growing public health concerns. Previous epidemiological studies unfolded the robust correlation between obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is a well-known risk factor for NAFLD, and both of them can markedly increase the odds of atherosclerotic cardiovascular diseases. On the other hand, significant weight loss achieved by lifestyle modification, bariatric surgery, or medications, such as semaglutide, can concomitantly improve NAFLD and atherosclerotic cardiovascular diseases. Therefore, certain pathophysiological links are involved in the development of NAFLD in obesity, and atherosclerotic cardiovascular diseases in obesity and NAFLD. Moreover, recent studies indicated that simultaneously targeting several mechanisms by tirzepatide and retatrutide leads to greater weight loss and markedly improves the complications of metabolic syndrome. These findings remind the importance of a mechanistic viewpoint for breaking the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. In this review article, we mainly focus on shared pathophysiological mechanisms, including insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, and endothelial dysfunction. Most of these pathophysiological alterations are primarily initiated by obesity. The development of NAFLD further exacerbates these molecular and cellular alterations, leading to atherosclerotic cardiovascular disease development or progression as the final manifestation of molecular perturbation. A better insight into these mechanisms makes it feasible to develop new multi-target approaches to simultaneously unhinge the deleterious chain of events linking obesity and NAFLD to atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Meng Li
- Department of Endocrinology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Man Cui
- Department of Endocrinology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guoxia Li
- Department of Endocrinology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yueqiu Liu
- Clinical Specialty of Integrated Chinese and Western Medicine, The First Clinical School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunsheng Xu
- Department of Endocrinology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | | | - Moein Ala
- Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran
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Cheng MK, Guo YY, Kang XN, Zhang L, Wang D, Ren HH, Yuan G. Advances in cardiovascular-related biomarkers to predict diabetic peripheral neuropathy. World J Diabetes 2023; 14:1226-1233. [PMID: 37664477 PMCID: PMC10473952 DOI: 10.4239/wjd.v14.i8.1226] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/24/2023] [Accepted: 07/07/2023] [Indexed: 08/11/2023] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus. One of the most common types is distal symmetric poly-neuropathy, which begins as bilateral symmetry pain and hyperesthesia and gradually progresses into hypoesthesia with nerve fibre disorder and is frequently accompanied by depression and anxiety. Notably, more than half of patients with DPN can be asymptomatic, which tends to delay early detection. Furthermore, the study of adverse outcomes showed that DPN is a prominent risk factor for foot ulceration, gangrene and nontraumatic amputation, which decreases quality of life. Thus, it is essential to develop convenient diagnostic biomarkers with high sensitivity for screening and early intervention. It has been reported that there may be common pathways for microvascular and macrovascular complications of diabetes. The pathogenesis of both disorders involves vascular endothelial dys-function. Emerging evidence indicates that traditional and novel cardiovascular-related biomarkers have the potential to characterize patients by subclinical disease status and improve risk prediction. Additionally, beyond traditional cardiovascular-related biomarkers, novel cardiovascular-related biomarkers have been linked to diabetes and its complications. In this review, we evaluate the association between major traditional and nontraditional car-diovascular-related biomarkers of DPN, such as cardiac troponin T, B-type natriuretic peptide, C-reactive protein, myeloperoxidase, and homocysteine, and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN.
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Affiliation(s)
- Meng-Ke Cheng
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Yao-Yao Guo
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Xiao-Nan Kang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Lu Zhang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Dan Wang
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Hui-Hui Ren
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
| | - Gang Yuan
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, Hubei Province, China
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Sonkawade SD, Xu S, Kim M, Nepali S, Karambizi VG, Sexton S, Turowski SG, Li K, Spernyak JA, Lovell JF, George A, Suwal S, Sharma UC, Pokharel S. Phospholipid Encapsulation of an Anti-Fibrotic Endopeptide to Enhance Cellular Uptake and Myocardial Retention. Cells 2023; 12:1589. [PMID: 37371059 PMCID: PMC10296995 DOI: 10.3390/cells12121589] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/24/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Cardioprotective effects of N-acetyl-ser-asp-lys-pro (Ac-SDKP) have been reported in preclinical models of myocardial remodeling. However, the rapid degradation of this endogenous peptide in vivo limits its clinical use. METHOD To prolong its bioavailability, Ac-SDKP was encapsulated by phosphocholine lipid bilayers (liposomes) similar to mammalian cell membranes. The physical properties of the liposome structures were assessed by dynamic light scattering and scanning electron microscopy. The uptake of Ac-SDKP by RAW 264.7 macrophages and human and murine primary cardiac fibroblasts was confirmed by fluorescence microscopy and flow cytometry. Spectrum computerized tomography and competitive enzyme-linked immunoassays were performed to measure the ex vivo cardiac biodistribution of Ac-SDKP. The biological effects of this novel synthetic compound were examined in cultured macrophages and cardiac fibroblasts and in a murine model of acute myocardial infarction induced by permanent coronary artery ligation. RESULTS A liposome formulation resulted in the greater uptake of Ac-SDKP than the naked peptide by cultured RAW 264.7 macrophages and cardiac fibroblasts. Liposome-delivered Ac-SDKP decreased fibroinflammatory genes in cultured cardiac fibroblasts co-treated with TGF-β1 and macrophages stimulated with LPS. Serial tissue and serum immunoassays showed the high bioavailability of Ac-SDKP in mouse myocardium and in circulation. Liposome-delivered Ac-SDKP improved cardiac function and reduced myocardial fibroinflammatory responses in mice with acute myocardial infarction. CONCLUSION Encapsulation of Ac-SDKP in a cell membrane-like phospholipid bilayer enhances its plasma and tissue bioavailability and offers cardioprotection against ischemic myocardial injury. Future clinical trials can use this novel approach to test small protective endogenous peptides in myocardial remodeling.
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Affiliation(s)
- Swati D. Sonkawade
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14260, USA; (S.D.S.)
- Laboratory Medicine, Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Shirley Xu
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14260, USA; (S.D.S.)
- Laboratory Medicine, Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Minhyung Kim
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Sarmila Nepali
- Laboratory Medicine, Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Victoire-Grace Karambizi
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14260, USA; (S.D.S.)
- Laboratory Medicine, Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Sandra Sexton
- Laboratory Animal Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Steven G. Turowski
- Translational Imaging Shared Resources, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Kunpeng Li
- Department of Physiology and Biophysics, Case Western Reserve School of Medicine, Cleveland, OH 44106, USA
| | - Joseph A. Spernyak
- Translational Imaging Shared Resources, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Jonathan F. Lovell
- Department of Biomedical Engineering, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14260, USA
| | - Anthony George
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
| | - Sujit Suwal
- Department of Chemistry, Buffalo State University, Buffalo, NY 14222, USA
| | - Umesh C. Sharma
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14260, USA; (S.D.S.)
| | - Saraswati Pokharel
- Laboratory Medicine, Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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A Wrong Fate Decision in Adipose Stem Cells upon Obesity. Cells 2023; 12:cells12040662. [PMID: 36831329 PMCID: PMC9954614 DOI: 10.3390/cells12040662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Progress has been made in identifying stem cell aging as a pathological manifestation of a variety of diseases, including obesity. Adipose stem cells (ASCs) play a core role in adipocyte turnover, which maintains tissue homeostasis. Given aberrant lineage determination as a feature of stem cell aging, failure in adipogenesis is a culprit of adipose hypertrophy, resulting in adiposopathy and related complications. In this review, we elucidate how ASC fails in entering adipogenic lineage, with a specific focus on extracellular signaling pathways, epigenetic drift, metabolic reprogramming, and mechanical stretch. Nonetheless, such detrimental alternations can be reversed by guiding ASCs towards adipogenesis. Considering the pathological role of ASC aging in obesity, targeting adipogenesis as an anti-obesity treatment will be a key area of future research, and a strategy to rejuvenate tissue stem cell will be capable of alleviating metabolic syndrome.
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Ivanova GT. Reactivity of Mesenteric Arteries in the Development of Metabolic Syndrome in Rats Fed on a High-Fat Diet. J EVOL BIOCHEM PHYS+ 2023. [DOI: 10.1134/s0022093023010131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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Jiang Y, Zhao T, Zhou X, Xiang Y, Gutierrez‐Castrellon P, Ma X. Inflammatory pathways in COVID-19: Mechanism and therapeutic interventions. MedComm (Beijing) 2022; 3:e154. [PMID: 35923762 PMCID: PMC9340488 DOI: 10.1002/mco2.154] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID-19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS-CoV-2 is important in providing otential therapeutic targets and treatment strategies against COVID-19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID-19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID-19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID-19.
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Affiliation(s)
- Yujie Jiang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Tingmei Zhao
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Xueyan Zhou
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Yu Xiang
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
| | - Pedro Gutierrez‐Castrellon
- Center for Translational Research on Health Science Hospital General Dr. Manuel Gea GonzalezMinistry of HealthMexico CityMexico
| | - Xuelei Ma
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
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Yi H, Liu C, Shi J, Wang S, Zhang H, He Y, Tao J, Li S, Zhang R. EGCG Alleviates Obesity-Induced Myocardial Fibrosis in Rats by Enhancing Expression of SCN5A. Front Cardiovasc Med 2022; 9:869279. [PMID: 35571212 PMCID: PMC9098820 DOI: 10.3389/fcvm.2022.869279] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/07/2022] [Indexed: 11/18/2022] Open
Abstract
Object Obesity is an increase in body weight beyond the limitation of skeletal and physical requirement, as the result of an excessive accumulation of fat in the body. Obesity could increase the risk of myocardial fibrosis. (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant substance in green tea and has been reported to have multiple pharmacological activities. However, there is not enough evidence to show that EGCG has a therapeutic effect on obesity-induced myocardial fibrosis. This study aims to investigate whether EGCG is a potential drug for obesity-induced myocardial fibrosis. Methods Obesity-induced myocardial fibrosis rat model was established by HFD feeding for 36 weeks. EGCG was intragastrically administered at 160 mg/kg/d for the last 4 weeks. The pathological changes of myocardial fibrosis were evaluated by tissue pathological staining and collagen quantification. Furthermore, total RNA was extracted from the heart for RNA-seq to identify the changes in the transcript profile, and the relevant hub genes were verified by quantitative real-time PCR and western blot. Results EGCG significantly relieved HFD diet-induced obesity and alleviated the pathology of myocardial fibrosis. Biochemical analysis showed that EGCG could relieve the burden of lipid metabolism and injury to the myocardium and transcript profile analysis showed that EGCG could alleviate obesity-induced myocardial fibrosis by increasing the level of Scn5a in the heart. Furthermore, quantitative real-time PCR and western blot analysis for SCN5A also confirmed this finding. Conclusion Taken together, these results suggest that EGCG could protect against the obesity-induced myocardial fibrosis. EGCG plays an anti-myocardial fibrosis role by regulating the expression of SCN5A in the heart.
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Affiliation(s)
- Haoan Yi
- Department of Cell Biology and Medical Genetics, School of Basic Medicine, Kunming Medical University, Kunming, China
| | - Cong Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
- Department of Orthopedics, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jing Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Kunming Medical University, Kunming, China
| | - Shuo Wang
- Department of Pharmacology, School of Basic Medicine, Kunming Medical University, Kunming, China
| | - Haoxin Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yongshu He
- Department of Cell Biology and Medical Genetics, School of Basic Medicine, Kunming Medical University, Kunming, China
| | - Jianping Tao
- Department of Anesthesiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shude Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Kunming Medical University, Kunming, China
- Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China
- *Correspondence: Shude Li
| | - Renfa Zhang
- Department of Physical Education, Kunming Medical University, Kunming, China
- Renfa Zhang
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Gutiérrez-Cuevas J, Galicia-Moreno M, Monroy-Ramírez HC, Sandoval-Rodriguez A, García-Bañuelos J, Santos A, Armendariz-Borunda J. The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors. Antioxidants (Basel) 2022; 11:235. [PMID: 35204118 PMCID: PMC8868420 DOI: 10.3390/antiox11020235] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/18/2022] [Accepted: 01/18/2022] [Indexed: 02/05/2023] Open
Abstract
The raising prevalence of obesity is associated with an increased risk for cardiovascular diseases (CVDs), particularly coronary artery disease (CAD), and heart failure, including atrial fibrillation, ventricular arrhythmias and sudden death. Obesity contributes directly to incident cardiovascular risk factors, including hyperglycemia or diabetes, dyslipidemia, and hypertension, which are involved in atherosclerosis, including structural and functional cardiac alterations, which lead to cardiac dysfunction. CVDs are the main cause of morbidity and mortality worldwide. In obesity, visceral and epicardial adipose tissue generate inflammatory cytokines and reactive oxygen species (ROS), which induce oxidative stress and contribute to the pathogenesis of CVDs. Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by Nfe2l2 gene) protects against oxidative stress and electrophilic stress. NRF2 participates in the regulation of cell inflammatory responses and lipid metabolism, including the expression of over 1000 genes in the cell under normal and stressed environments. NRF2 is downregulated in diabetes, hypertension, and inflammation. Nfe2l2 knockout mice develop structural and functional cardiac alterations, and NRF2 deficiency in macrophages increases atherosclerosis. Given the endothelial and cardiac protective effects of NRF2 in experimental models, its activation using pharmacological or natural products is a promising therapeutic approach for obesity and CVDs. This review provides a comprehensive summary of the current knowledge on the role of NRF2 in obesity-associated cardiovascular risk factors.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara 44340, JAL, Mexico; (M.G.-M.); (H.C.M.-R.); (A.S.-R.); (J.G.-B.)
| | - Marina Galicia-Moreno
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara 44340, JAL, Mexico; (M.G.-M.); (H.C.M.-R.); (A.S.-R.); (J.G.-B.)
| | - Hugo Christian Monroy-Ramírez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara 44340, JAL, Mexico; (M.G.-M.); (H.C.M.-R.); (A.S.-R.); (J.G.-B.)
| | - Ana Sandoval-Rodriguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara 44340, JAL, Mexico; (M.G.-M.); (H.C.M.-R.); (A.S.-R.); (J.G.-B.)
| | - Jesús García-Bañuelos
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara 44340, JAL, Mexico; (M.G.-M.); (H.C.M.-R.); (A.S.-R.); (J.G.-B.)
| | - Arturo Santos
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Campus Guadalajara, Zapopan 45201, JAL, Mexico;
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara 44340, JAL, Mexico; (M.G.-M.); (H.C.M.-R.); (A.S.-R.); (J.G.-B.)
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Campus Guadalajara, Zapopan 45201, JAL, Mexico;
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Rao S, Yang X, Ohshiro K, Zaidi S, Wang Z, Shetty K, Xiang X, Hassan I, Mohammad T, Latham PS, Nguyen BN, Wong L, Yu H, Al-Abed Y, Mishra B, Vacca M, Guenigault G, Allison MED, Vidal-Puig A, Benhammou JN, Alvarez M, Pajukanta P, Pisegna JR, Mishra L. β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Sci Transl Med 2021; 13:eabk2267. [PMID: 34910547 PMCID: PMC8941321 DOI: 10.1126/scitranslmed.abk2267] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.
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Affiliation(s)
- Shuyun Rao
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Sobia Zaidi
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Zhanhuai Wang
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Kirti Shetty
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, 21201, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Patricia S. Latham
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
- Department of Pathology, The George Washington University, DC, 20037, USA
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
| | - Linda Wong
- Cancer Biology department, University of Hawaii Cancer Center, HI, 96813, USA
- Dept of Surgery, University of Hawaii John A. Burns School of Medicine, HI, 96813, USA
| | - Herbert Yu
- Epidemiology Program, University of Hawaii Cancer Center, HI, 96813, USA
| | - Yousef Al-Abed
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
| | - Bibhuti Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Department of Neurology, Northwell Health, Manhasset, NY, 11030, USA
| | - Michele Vacca
- TVP Lab, Metabolic Research Laboratories, WT/MRC Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
| | | | - Michael ED Allison
- Liver Unit, Cambridge Biomedical Research Centre, Cambridge University Hospitals, CB2 0QQ, United Kingdom
| | - Antonio Vidal-Puig
- TVP Lab, Metabolic Research Laboratories, WT/MRC Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
- Welcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom
- Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei Area, Nanjing, 210000, China
| | - Jihane N Benhammou
- Vatche and Tamar Manoukian Division of Digestive Diseases and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, 90095, USA
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Joseph R. Pisegna
- Department of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, CA, 90095, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, & Cold Spring Harbor Laboratory, Department of Medicine, Divisions of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY, 11030, USA
- Center for Translational Medicine, Department of Surgery, The George Washington University, DC, 20037, USA
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Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol 2021; 18:809-823. [PMID: 34127848 DOI: 10.1038/s41569-021-00569-6] [Citation(s) in RCA: 495] [Impact Index Per Article: 123.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2021] [Indexed: 12/22/2022]
Abstract
Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.
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Affiliation(s)
- David Montaigne
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Laura Butruille
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
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Gutiérrez-Cuevas J, Santos A, Armendariz-Borunda J. Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases. Int J Mol Sci 2021; 22:11629. [PMID: 34769060 PMCID: PMC8583943 DOI: 10.3390/ijms222111629] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Obesity is now a worldwide epidemic ensuing an increase in comorbidities' prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico;
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico;
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Pirfenidone modifies hepatic miRNAs expression in a model of MAFLD/NASH. Sci Rep 2021; 11:11709. [PMID: 34083664 PMCID: PMC8175718 DOI: 10.1038/s41598-021-91187-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/24/2021] [Indexed: 12/18/2022] Open
Abstract
miRNAs are involved in the development of metabolic associated fatty liver disease (MAFLD) and nonalcoholic steatohepatitis (NASH). We aimed to evaluate modifications by prolonged-release pirfenidone (PR-PFD) on key hepatic miRNAs expression in a MAFLD/NASH model. First, male C57BL/6J mice were randomly assigned into groups and fed with conventional diet (CVD) or high fat and carbohydrate diet (HFD) for 16 weeks. At the end of the eighth week, HFD mice were divided in two and only one half was treated with 300 mg/kg/day of PR-PFD mixed with food. Hepatic expression of miRNAs and target genes that participate in inflammation and lipid metabolism was determined by qRT-PCR and transcriptome by microarrays. Increased hepatic expression of miR-21a-5p, miR-34a-5p, miR-122-5p and miR-103-3p in MAFLD/NASH animals was reduced with PR-PFD. Transcriptome analysis showed that 52 genes involved in lipid and collagen biosynthesis and inflammatory response were downregulated in PR-PFD group. The expression of Il1b, Tnfa, Il6, Tgfb1, Col1a1, and Srebf1 were decreased in PR-PFD treated animals. MAFLD/NASH animals compared to CVD group showed modifications in gene metabolic pathways implicated in lipid metabolic process, inflammatory response and insulin resistance; PR-PFD reversed these modifications.
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Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection: a theoretical perspective. Pharmacol Rep 2021; 73:712-727. [PMID: 33880743 PMCID: PMC8057922 DOI: 10.1007/s43440-021-00255-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/14/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. Drug Suggestion Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. Conclusion The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.
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Gutiérrez-Cuevas J, Sandoval-Rodriguez A, Meza-Rios A, Monroy-Ramírez HC, Galicia-Moreno M, García-Bañuelos J, Santos A, Armendariz-Borunda J. Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge. Cells 2021; 10:629. [PMID: 33809061 PMCID: PMC8000147 DOI: 10.3390/cells10030629] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023] Open
Abstract
Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Ana Sandoval-Rodriguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Campus Guadalajara, Zapopan, School of Medicine and Health Sciences, Jalisco 45201, Mexico; (A.M.-R.); (A.S.)
| | - Hugo Christian Monroy-Ramírez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Marina Galicia-Moreno
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Jesús García-Bañuelos
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Arturo Santos
- Tecnologico de Monterrey, Campus Guadalajara, Zapopan, School of Medicine and Health Sciences, Jalisco 45201, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
- Tecnologico de Monterrey, Campus Guadalajara, Zapopan, School of Medicine and Health Sciences, Jalisco 45201, Mexico; (A.M.-R.); (A.S.)
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Galicia-Moreno M, Lucano-Landeros S, Monroy-Ramirez HC, Silva-Gomez J, Gutierrez-Cuevas J, Santos A, Armendariz-Borunda J. Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects. Antioxidants (Basel) 2020; 9:980. [PMID: 33066023 PMCID: PMC7601324 DOI: 10.3390/antiox9100980] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/10/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023] Open
Abstract
Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined.
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Affiliation(s)
- Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Silvia Lucano-Landeros
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Jorge Silva-Gomez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Jorge Gutierrez-Cuevas
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45201, Jalisco, Mexico;
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.G.-M.); (S.L.-L.); (H.C.M.-R.); (J.S.-G.); (J.G.-C.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45201, Jalisco, Mexico;
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