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Szkudelski T, Szkudelska K. The relevance of the heme oxygenase system in alleviating diabetes-related hormonal and metabolic disorders. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167552. [PMID: 39490940 DOI: 10.1016/j.bbadis.2024.167552] [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: 09/13/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
Heme oxygenase (HO) is an enzyme that catalyzes heme degradation. HO dysfunction is linked to various pathological conditions, including diabetes. Results of animal studies indicate that HO expression and activity are downregulated in experimentally induced diabetes. This is associated with severe hormonal and metabolic disturbances. However, these pathological changes have been shown to be reversed by therapy with HO activators. In animals with experimentally induced diabetes, HO was upregulated by genetic manipulation or by pharmacological activators such as hemin and cobalt protoporphyrin. Induction of HO alleviated elevated blood glucose levels and improved insulin action, among other effects. This effect resulted from beneficial changes in the main insulin-sensitive tissues, i.e., the skeletal muscle, the liver, and the adipose tissue. The action of HO activators was due to positive alterations in pivotal signaling molecules and regulatory enzymes. Furthermore, diabetes-related oxidative and inflammatory stress was reduced due to HO induction. HO upregulation was effective in various animal models of type 1 and type 2 diabetes. These data suggest the possibility of testing HO activators as a potential tool for alleviating hormonal and metabolic disorders in people with diabetes.
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Affiliation(s)
- Tomasz Szkudelski
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland.
| | - Katarzyna Szkudelska
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Wolynska 35, 60-637 Poznan, Poland.
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Shrestha J, Limbu KR, Chhetri RB, Paudel KR, Hansbro PM, Oh YS, Baek DJ, Ki SH, Park EY. Antioxidant genes in cancer and metabolic diseases: Focusing on Nrf2, Sestrin, and heme oxygenase 1. Int J Biol Sci 2024; 20:4888-4907. [PMID: 39309448 PMCID: PMC11414382 DOI: 10.7150/ijbs.98846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024] Open
Abstract
Reactive oxygen species are involved in the pathogenesis of cancers and metabolic diseases, including diabetes, obesity, and fatty liver disease. Thus, inhibiting the generation of free radicals is a promising strategy to control the onset of metabolic diseases and cancer progression. Various synthetic drugs and natural product-derived compounds that exhibit antioxidant activity have been reported to have a protective effect against a range of metabolic diseases and cancer. This review highlights the development and aggravation of cancer and metabolic diseases due to the imbalance between pro-oxidants and endogenous antioxidant molecules. In addition, we discuss the function of proteins that regulate the production of reactive oxygen species as a strategy to treat metabolic diseases. In particular, we summarize the role of proteins such as nuclear factor-like 2, Sestrin, and heme oxygenase-1, which regulate the expression of various antioxidant genes in metabolic diseases and cancer. We have included recent literature to discuss the latest research on identifying novel signals of antioxidant genes that can control metabolic diseases and cancer.
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Affiliation(s)
- Jitendra Shrestha
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
- Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Khem Raj Limbu
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
| | | | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sci., Sydney, NSW 2007, Australia
| | - Philip M. Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sci., Sydney, NSW 2007, Australia
| | - Yoon Sin Oh
- Department of Food and Nutrition, Eulji University, Seongnam 13135, Republic of Korea
| | - Dong Jae Baek
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Sung-Hwan Ki
- College of Pharmacy, Chosun University, Gwangju 61451, Republic of Korea
| | - Eun-Young Park
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
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Dunaway LS, Loeb SA, Petrillo S, Tolosano E, Isakson BE. Heme metabolism in nonerythroid cells. J Biol Chem 2024; 300:107132. [PMID: 38432636 PMCID: PMC10988061 DOI: 10.1016/j.jbc.2024.107132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/31/2024] [Accepted: 02/23/2024] [Indexed: 03/05/2024] Open
Abstract
Heme is an iron-containing prosthetic group necessary for the function of several proteins termed "hemoproteins." Erythrocytes contain most of the body's heme in the form of hemoglobin and contain high concentrations of free heme. In nonerythroid cells, where cytosolic heme concentrations are 2 to 3 orders of magnitude lower, heme plays an essential and often overlooked role in a variety of cellular processes. Indeed, hemoproteins are found in almost every subcellular compartment and are integral in cellular operations such as oxidative phosphorylation, amino acid metabolism, xenobiotic metabolism, and transcriptional regulation. Growing evidence reveals the participation of heme in dynamic processes such as circadian rhythms, NO signaling, and the modulation of enzyme activity. This dynamic view of heme biology uncovers exciting possibilities as to how hemoproteins may participate in a range of physiologic systems. Here, we discuss how heme is regulated at the level of its synthesis, availability, redox state, transport, and degradation and highlight the implications for cellular function and whole organism physiology.
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Affiliation(s)
- Luke S Dunaway
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Skylar A Loeb
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA; Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Sara Petrillo
- Deptartment Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center "Guido Tarone", University of Torino, Torino, Italy
| | - Emanuela Tolosano
- Deptartment Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center "Guido Tarone", University of Torino, Torino, Italy
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA; Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
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Dayarathne LA, Ko SC, Yim MJ, Lee JM, Kim JY, Oh GW, Kim CH, Kim KW, Lee DS, Je JY. Brown Algae Dictyopteris divaricata Attenuates Adipogenesis by Modulating Adipocyte Differentiation and Promoting Lipolysis through Heme Oxygenase-1 Activation in 3T3-L1 Cells. Mar Drugs 2024; 22:91. [PMID: 38393062 PMCID: PMC10890497 DOI: 10.3390/md22020091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
The present study aims to explore the probable anti-adipogenesis effect of Dictyopteris divaricata (D. divaricata) in 3T3-L1 preadipocytes by regulating heme oxygenase-1 (HO-1). The extract of D. divaricata retarded lipid accretion and decreased triglyceride (TG) content in 3T3-L1 adipocytes but increased free glycerol levels. Treatment with the extract inhibited lipogenesis by inhibiting protein expressions of fatty acid synthase (FAS) and lipoprotein lipase (LPL), whereas lipolysis increased by activating phosphorylation of hormone-sensitive lipase (p-HSL) and AMP-activated protein kinase (p-AMPK). The extract inhibited adipocyte differentiation of 3T3-L1 preadipocytes through down-regulating adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1). This is attributed to the triggering of Wnt/β-catenin signaling. In addition, this study found that treatment with the extract activated HO-1 expression. Pharmacological approaches revealed that treatment with Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, resulted in an increase in lipid accumulation and a decrease in free glycerol levels. Finally, three adipogenic transcription factors, such as PPARγ, C/EBPα, and SREBP1, restored their expression in the presence of ZnPP. Analysis of chemical constituents revealed that the extract of D. divaricata is rich in 1,4-benzenediol, 7-tetradecenal, fucosterol, and n-hexadecanoic acid, which are known to have multiple pharmacological properties.
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Affiliation(s)
- Lakshi A. Dayarathne
- Department of Food and Nutrition, Pukyong National University, Busan 48513, Republic of Korea;
| | - Seok-Chun Ko
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Mi-Jin Yim
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Jeong Min Lee
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Ji-Yul Kim
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Gun-Woo Oh
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Chul Hwan Kim
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Kyung Woo Kim
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Dae-Sung Lee
- National Marine Biodiversity of Korea (MABIK), Seochun 33662, Republic of Korea; (S.-C.K.); (M.-J.Y.); (J.M.L.); (J.-Y.K.); (G.-W.O.); (C.H.K.); (K.W.K.); (D.-S.L.)
| | - Jae-Young Je
- Major of Human Bioconvergence, Division of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea
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Shen T, Zhong L, Ji G, Chen B, Liao M, Li L, Huang H, Li J, Wei Y, Wu S, Chen Z, Ma W, Dong M, Wu B, Liu T, Chen Q. Associations between metal(loid) exposure with overweight and obesity and abdominal obesity in the general population: A cross-sectional study in China. CHEMOSPHERE 2024; 350:140963. [PMID: 38114022 DOI: 10.1016/j.chemosphere.2023.140963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 11/26/2023] [Accepted: 12/12/2023] [Indexed: 12/21/2023]
Abstract
Previous studies have revealed links between metal(loid)s and health problems; however, the link between metal(loid)s and obesity remains controversial. We evaluated the cross-sectional association between metal(loid) exposure in whole blood and obesity among the general population. Vanadium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), molybdenum (Mo), cadmium (Cd), antimony (Sb), thallium (T1), and lead (Pb) were measured in 3029 subjects in Guangdong Province (China) using ICP-MS. The prevalence of overweight and obesity (OWO) and abdominal obesity (AOB) was calculated according to body mass index (BMI) and waist circumference (WC), respectively. Multivariate analysis showed that elevated blood Cu, Cd, and Pb levels were inversely associated with the risk of OWO, and these associations were confirmed by a linear dose-response relationship. Elevated blood Co concentration was associated with a decreased risk of AOB. A quantile g-computation approach showed a significantly negative mixture-effect of 13 metal(loid)s on OWO (OR: 0.96; 95% CI: 0.92, 0.99). Two metals-Ni and Mo-were inversely associated with the risk of OWO but positively associated with AOB. We cross-grouped the two obesity measurement types and found that the extremes of metal content were present in people with AOB only. In conclusion, blood Cu, Mo, Ni, Cd, and Pb were inversely associated with the risk of OWO. The presence of blood Co may be protective, while Ni and Mo exposure might increase the risk of AOB. The association between metal(loid) exposure and obesity warrants further investigation in longitudinal cohort studies.
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Affiliation(s)
- Tianran Shen
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Liling Zhong
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Guiyuan Ji
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511530, China
| | - Baolan Chen
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Mengfan Liao
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Lvrong Li
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Huiming Huang
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Jiajie Li
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Yuan Wei
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Shan Wu
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China
| | - Zihui Chen
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511530, China
| | - Wenjun Ma
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, 510632, China; China Greater Bay Area Research Center of Environmental Health, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Ming Dong
- Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510399, China
| | - Banghua Wu
- Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510399, China.
| | - Tao Liu
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, 510632, China; China Greater Bay Area Research Center of Environmental Health, School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Qingsong Chen
- Guangdong Pharmaceutical University, Guangzhou, 510310, China; Guangdong Provincial Engineering Research Center of Public Health Detection and Assessment, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, 511400, China.
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Veselov IM, Vinogradova DV, Maltsev AV, Shevtsov PN, Spirkova EA, Bachurin SO, Shevtsova EF. Mitochondria and Oxidative Stress as a Link between Alzheimer's Disease and Diabetes Mellitus. Int J Mol Sci 2023; 24:14450. [PMID: 37833898 PMCID: PMC10572926 DOI: 10.3390/ijms241914450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/15/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer's disease. The pathogenesis of Alzheimer's disease closely intersects with the mechanisms of type 2 diabetes development, and an important risk factor for both pathologies is aging. Common pathological mechanisms include both factors in the development of oxidative stress, neuroinflammation, insulin resistance, and amyloidosis, as well as impaired mitochondrial dysfunctions and increasing cell death. The currently available drugs for the treatment of type 2 diabetes and Alzheimer's disease have limited therapeutic efficacy. It is important to note that drugs used to treat Alzheimer's disease, in particular acetylcholinesterase inhibitors, show a positive therapeutic potential in the treatment of type 2 diabetes, while drugs used in the treatment of type 2 diabetes can also prevent a number of pathologies characteristic for Alzheimer's disease. A promising direction in the search for a strategy for the treatment of type 2 diabetes and Alzheimer's disease may be the creation of complex multi-target drugs that have neuroprotective potential and affect specific common targets for type 2 diabetes and Alzheimer's disease.
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Affiliation(s)
| | | | | | | | | | | | - Elena F. Shevtsova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Chernogolovka 142432, Russia; (I.M.V.); (A.V.M.); (P.N.S.); (E.A.S.); (S.O.B.)
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Juin SK, Ouseph R, Gondim DD, Jala VR, Sen U. Diabetic Nephropathy and Gaseous Modulators. Antioxidants (Basel) 2023; 12:antiox12051088. [PMID: 37237955 DOI: 10.3390/antiox12051088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic nephropathy (DN) remains the leading cause of vascular morbidity and mortality in diabetes patients. Despite the progress in understanding the diabetic disease process and advanced management of nephropathy, a number of patients still progress to end-stage renal disease (ESRD). The underlying mechanism still needs to be clarified. Gaseous signaling molecules, so-called gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), have been shown to play an essential role in the development, progression, and ramification of DN depending on their availability and physiological actions. Although the studies on gasotransmitter regulations of DN are still emerging, the evidence revealed an aberrant level of gasotransmitters in patients with diabetes. In studies, different gasotransmitter donors have been implicated in ameliorating diabetic renal dysfunction. In this perspective, we summarized an overview of the recent advances in the physiological relevance of the gaseous molecules and their multifaceted interaction with other potential factors, such as extracellular matrix (ECM), in the severity modulation of DN. Moreover, the perspective of the present review highlights the possible therapeutic interventions of gasotransmitters in ameliorating this dreaded disease.
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Affiliation(s)
- Subir Kumar Juin
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Rosemary Ouseph
- Division of Nephrology & Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Dibson Dibe Gondim
- Department of Pathology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Venkatakrishna Rao Jala
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Zhai H, Ni L, Wu X. The roles of heme oxygenase-1 in renal disease. FRONTIERS IN NEPHROLOGY 2023; 3:1156346. [PMID: 37675385 PMCID: PMC10479750 DOI: 10.3389/fneph.2023.1156346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/17/2023] [Indexed: 09/08/2023]
Abstract
Heme oxygenase (HO), a heat shock protein containing hemoglobin, is an important enzyme in heme catabolism. It is involved in cell homeostasis and has anti-inflammatory, antioxidant, anti-apoptosis, immunomodulation, and other functions. It is expressed at a modest level in most normal tissues. When the body suffers from ischemia hypoxia, injury, toxins, and other nociceptive stimuli, the expression increases, which can transform the oxidative microenvironment into an antioxidant environment to promote tissue recovery from damage. In recent years, research has continued to verify its value in a variety of human bodily systems. It is also regarded as a key target for the treatment of numerous disorders. With the advancement of studies, its significance in renal disease has gained increasing attention. It is thought to have a significant protective function in preventing acute kidney injury and delaying the progression of chronic renal diseases. Its protective mechanisms include anti-inflammatory, antioxidant, cell cycle regulation, apoptosis inhibition, hemodynamic regulation, and other aspects, which have been demonstrated in diverse animal models. Furthermore, as a protective factor, its potential therapeutic efficacy in renal disease has recently become a hot area of research. Although a large number of preclinical trials have confirmed its therapeutic potential in reducing kidney injury, due to the problems and side effects of HO-1 induction therapy, its efficacy and safety in clinical application need to be further explored. In this review, we summarize the current state of research on the mechanism, location, and treatment of HO and its relationship with various renal diseases.
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Affiliation(s)
- Hongfu Zhai
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lihua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiaoyan Wu
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of General Practice, Zhongnan Hospital of Wuhan University, Wuhan, China
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Mohan S, Barel LA, Benrahla DE, Do B, Mao Q, Kitagishi H, Rivard M, Motterlini R, Foresti R. Development of carbon monoxide-releasing molecules conjugated to polysaccharides (glyco-CORMs) for delivering CO during obesity. Pharmacol Res 2023; 191:106770. [PMID: 37068532 DOI: 10.1016/j.phrs.2023.106770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 04/19/2023]
Abstract
Metal carbonyls have been developed as carbon monoxide-releasing molecules (CO-RMs) to deliver CO for therapeutic purposes. The manganese-based CORM-401 has been recently reported to exert beneficial effects in obese animals by reducing body weight gain, improving glucose metabolism and reprogramming adipose tissue towards a healthy phenotype. Here, we report on the synthesis and characterization of glyco-CORMs, obtained by grafting manganese carbonyls on dextrans (70 and 40kDa), based on the fact that polysaccharides facilitate the targeting of drugs to adipose tissue. We found that glyco-CORMs efficiently deliver CO to cells in vitro with higher CO accumulation in adipocytes compared to other cell types. Oral administration of two selected glyco-CORMs (5b and 6b) resulted in CO accumulation in various organs, including adipose tissue. In addition, glyco-CORM 6b administered for eight weeks elicited anti-obesity and positive metabolic effects in mice fed a high fat diet. Our study highlights the feasibility of creating carriers with multiple functionalized CO-RMs.
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Affiliation(s)
- Shruti Mohan
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France.
| | | | | | - Bernard Do
- Materials and Health, University Paris-Saclay, 91400 Orsay, France; Department of Pharmacy, Henri Mondor Hospital, AP-HP, 94000 Créteil, France.
| | - Qiyue Mao
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan.
| | - Hiroaki Kitagishi
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan.
| | - Michael Rivard
- ICMPE (UMR 7182), CNRS, UPEC, University Paris Est, F-94320 Thiais, France.
| | | | - Roberta Foresti
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France.
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10
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Therapeutic or lifelong training effects on pancreatic morphological and functional parameters in an animal model of aging and obesity. Exp Gerontol 2023; 175:112144. [PMID: 36907475 DOI: 10.1016/j.exger.2023.112144] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023]
Abstract
AIMS Obesity, aging, and physical training are factors influencing pancreatic functional and morphological parameters. Aiming to clarify the impact of the interaction of these factors, we analyzed the effect of therapeutic or lifelong physical training on body adiposity and pancreatic functional and morphological parameters of aged and obese rats. METHODS 24 male Wistar rats were (initial age = 4 months and final age = 14 months) randomly divided into three aged and obese experimental groups (n = 8/group): untrained, therapeutic trained, and lifelong trained. Body adiposity, plasmatic concentration and pancreatic immunostaining of insulin, markers of tissue inflammation, lipid peroxidation, activity and immunostaining of antioxidant enzymes, and parameters of pancreatic morphology were evaluated. RESULTS Lifelong physical training improved the body adiposity, plasmatic insulin concentration, and macrophage immunostaining in the pancreas. The animals submitted to therapeutic and lifelong training showed an increase in the density of the pancreatic islets; lower insulin, Nuclear Factor Kappa B (NF-κB), and Transforming Growth Factor beta (TGF-β) immunostaining in the pancreatic parenchyma, as well as lower pancreatic tissue lipid peroxidation, lower fibrosis area, increased catalase and glutathione peroxidase (GPx) activity and increased heme oxygenase-1 (HO-1) immunostaining, with the greatest effect in the lifelong training group. CONCLUSION Lifelong training promoted greater beneficial effects on the pancreatic functional and morphological parameters of aged and obese animals compared to therapeutic exercise.
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11
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Chen YK, Wu PY, Huang JC, Chen SC, Chang JM. Sex difference in the associations among liver function parameters with incident diabetes mellitus in a large Taiwanese population follow-up study. Front Public Health 2023; 10:1081374. [PMID: 36684957 PMCID: PMC9845575 DOI: 10.3389/fpubh.2022.1081374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/12/2022] [Indexed: 01/06/2023] Open
Abstract
Background The prevalence of diabetes mellitus (DM) in Taiwan between 2017 and 2020 was 11.05%, which is higher than the global prevalence (10.5%). Previous studies have shown that patients with DM have higher liver enzyme levels than those without DM. However, it is unclear whether there are sex differences in the association between incident DM and liver function. Therefore, the aim of this longitudinal study was to investigate this issue in a large Taiwanese cohort. Methods We identified 27,026 participants from the Taiwan Biobank, and excluded those with baseline DM (n = 2,637), and those without follow-up data on DM, serum fasting glucose or glycosylated hemoglobin A1c (n = 43). The remaining 24,346 participants (male: 8,334; female: 16,012; mean age 50.5 ± 10.4 years) were enrolled and followed for a median of 4 years. Results Of the enrolled participants, 1,109 (4.6%) had incident DM and 23,237 (95.4%) did not. Multivariable analysis showed that high levels of glutamic-oxaloacetic transaminase (AST) (p < 0.001), glutamic-pyruvic transaminase (ALT) (p < 0.001), albumin (p = 0.003), α-fetoprotein (p = 0.019), and gamma-glutamyl transpeptidase (GGT) (p = 0.001) were significantly associated with incident DM in the male participants. In comparison, high levels of AST (p = 0.010), ALT (p < 0.001), albumin (p = 0.001) and GGT (p < 0.001), and low total bilirubin (p = 0.001) were significantly associated with incident DM in the female participants. There were significant interactions between total bilirubin and sex (p = 0.031), and GGT and sex (p = 0.011) on incident DM. Conclusion In conclusion, liver function parameters were significantly associated with incident DM. Further, there were differences in the associations between the male and female participants.
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Affiliation(s)
- Yi-Kong Chen
- Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Yu Wu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jiun-Chi Huang
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jer-Ming Chang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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12
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Krukowska K, Magierowski M. Carbon monoxide (CO)/heme oxygenase (HO)-1 in gastrointestinal tumors pathophysiology and pharmacology - possible anti- and pro-cancer activities. Biochem Pharmacol 2022; 201:115058. [PMID: 35490732 DOI: 10.1016/j.bcp.2022.115058] [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: 02/18/2022] [Revised: 04/20/2022] [Accepted: 04/20/2022] [Indexed: 11/02/2022]
Abstract
Gastrointestinal (GI) tract cancers pose a significant pharmacological challenge for researchers in terms of the discovery of molecular agents and the development of targeted therapies. Although many ongoing clinical trials have brought new perspectives, there is still a lack of successful long-term treatment. Several novel pharmacological and molecular agents are being studied in the prevention and treatment of GI cancers. On the other hand, pharmacological tools designed to release an endogenous gaseous mediator, carbon monoxide (CO), were shown to prevent the gastric mucosa against various types of injuries and exert therapeutic properties in the treatment of GI pathologies. In this review, we summarized the current evidence on the role of CO and heme oxygenase 1 (HO-1) as a CO producing enzyme in the pathophysiology of GI tumors. We focused on a beneficial role of HO-1 and CO in biological systems and common pathological conditions. We further discussed the complex and ambiguous function of the HO-1/CO pathway in cancer cells with a special emphasis on molecular and cellular pro-cancerous and anti-cancer mechanisms. We also focused on the role that HO-1/CO plays in GI cancers, especially within upper parts such as esophagus or stomach.
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Affiliation(s)
- Kinga Krukowska
- Cellular Engineering and Isotope Diagnostics Laboratory, Department of Physiology, Jagiellonian University Medical College, Poland
| | - Marcin Magierowski
- Cellular Engineering and Isotope Diagnostics Laboratory, Department of Physiology, Jagiellonian University Medical College, Poland.
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13
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Marasinghe CK, Je JY. Heme oxygenase-1 induction by gallic acid-g-chitosan is an important event in modulating adipocyte differentiation. J Food Biochem 2022; 46:e14179. [PMID: 35393708 DOI: 10.1111/jfbc.14179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 11/29/2022]
Abstract
Obesity, one of the common worldwide chronic health diseases co-relates with adipogenesis. Adipogenesis is a complex biological action of the emergence of mature adipocytes from the differentiation of pre-adipocytes and the disfunction of this process leads to the development of metabolic issues in obesity. Recently, much attention has been paid to utilizing natural compounds to discover their biological activities. This study focused on investigating the probable anti-adipogenic effects of gallic acid-g-chitosan (GAC) and plain chitosan (PC) through regulating the heme oxygenase-1 (HO-1)/Nrf2 pathway on mesenchymal stem cells. Gallic acid is grafted onto the PC backbone to improve its specific physical and biological properties. GAC showed promising anti-adipogenic effects by enhancing HO-1 expression and lipolysis and as well as suppressing lipid accumulation, reactive oxygen species, and pro-inflammatory cytokines production, transcription factor expression compared to the PC treatment. On the contrary, zinc protoporphyrin ІX (ZnPP), a HO-1 inhibitor reversed these effects of GAC on adipogenesis. Taken all together, this study revealed that grafting GA onto the chitosan improved potential anti-adipogenic activity by induction of the HO-1/Nrf2 pathway on mesenchymal stem cells (MSCs). PRACTICAL APPLICATIONS: GAC is a well-known copolymer with versatile bioactivities such as antimicrobial, antioxidant, and anti-diabetic activity. However, the anti-adipogenic effect of GAC has not been explored in MSCs. This study demonstrated that GAC inhibited adipocyte differentiation in MSCs through HO-1 activation. These findings suggest that GAC can be applied practically from different perspectives. GAC can be applied in the pharmacological industry to the development of anti-obesity drugs, medicinal perspectives for the treatment of obesity and obesity-related diseases, and in the food industry as a functional food to promote health and decrease the risk of diseases.
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Affiliation(s)
- Chathuri K Marasinghe
- Department of Food and Life Science, Pukyong National University, Busan, Republic of Korea
| | - Jae-Young Je
- Major of Human Bioconvergence, Division of Smart Healthcare, Pukyong National University, Busan, Republic of Korea
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14
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Yang X, Yi X, Zhang F, Li F, Lang L, Ling M, Lai X, Chen L, Quan L, Fu Y, Feng S, Shu G, Wang L, Zhu X, Gao P, Jiang Q, Wang S. Cytochrome P450 epoxygenase-derived EPA and DHA oxylipins 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid promote BAT thermogenesis and WAT browning through the GPR120-AMPKα signaling pathway. Food Funct 2022; 13:1232-1245. [PMID: 35019933 DOI: 10.1039/d1fo02608a] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The mechanisms whereby fish oil rich in EPA and DHA promotes BAT thermogenesis and WAT browning are not fully understood. Thus, this study aimed to investigate the effects of cytochrome P450 (CYP) epoxygenase-derived EPA and DHA oxylipins 17,18-EpETE and 19,20-EpDPE on BAT thermogenesis and WAT browning and explore the underlying mechanism. Stromal vascular cells (SVCs) were subjected to 17,18-EpETE or 19,20-EpDPE treatment and mice were treated with the CYP epoxygenase inhibitor, the thermogenic marker genes were detected and the involvement of GPR120 and AMPKα were assessed. The in vitro results indicated that 17,18-EpETE and 19,20-EpDPE induced brown and beige adipocyte thermogenesis, with increased expression of thermogenic marker gene UCP1 in differentiated SVCs. Meanwhile, the expression of GPR120 and phosphorylation of AMPKα were increased in response to these two oxylipins. However, the inhibition of GPR120 and AMPKα inhibited the promotion of adipocyte thermogenesis. In addition, in the presence of CYP epoxygenase inhibitor MS-PPOH, EPA and DHA had no effect on increasing UCP1 expression in differentiated SVCs. Consistent with the in vitro results, the in vivo findings demonstrated that fish oil had no body fat-lowering effects and no effects on enhancing energy metabolism, iBAT thermogenesis and iWAT browning in mice fed HFD after intraperitoneal injection of CYP epoxygenase inhibitor SKF-525A. Moreover, fish oil had no effect on the elevation of GPR120 expression and activation of AMPKα in iBAT and iWAT in mice fed HFD after intraperitoneal injection of SKF-525A. In summary, our results showed that CYP epoxygenase-derived EPA and DHA oxylipins 17,18-EpETE and 19,20-EpDPE promoted BAT thermogenesis and WAT browning through the GPR120-AMPKα signaling pathway, which might contribute to the thermogenic and anti-obesity effects of fish oil.
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Affiliation(s)
- Xiaohua Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Xin Yi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Fenglin Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Fan Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Limin Lang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Mingfa Ling
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Xumin Lai
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Lin Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Lulu Quan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Yiming Fu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Shengchun Feng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Xiaotong Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, P. R. China. .,National Engineering Research Center for Breeding Swine Industry and UBT Lipid Suite Functional Fatty Acids Research Center, South China Agricultural University, Guangzhou 510642, P. R. China
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15
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Cimini FA, Barchetta I, Zuliani I, Pagnotta S, Bertoccini L, Dule S, Zampieri M, Reale A, Baroni MG, Cavallo MG, Barone E. Biliverdin reductase-A protein levels are reduced in type 2 diabetes and are associated with poor glycometabolic control. Life Sci 2021; 284:119913. [PMID: 34453944 DOI: 10.1016/j.lfs.2021.119913] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/09/2021] [Accepted: 08/09/2021] [Indexed: 12/14/2022]
Abstract
AIM Biliverdin reductase-A (BVR-A) other than its canonical role in the degradation pathway of heme as partner of heme oxygenase-1 (HO1), has recently drawn attention as a protein with pleiotropic functions involved in insulin-glucose homeostasis. However, whether BVR-A expression is altered in type 2 diabetes (T2D) has never been evaluated. MAIN METHODS BVR-A protein levels were evaluated in T2D (n = 44) and non-T2D (n = 29) subjects, who underwent complete clinical workup and routine biochemistry. In parallel, levels HO1, whose expression is regulated by BVR-A as well as levels of tumor necrosis factor α (TNFα), which is a known repressor for BVR-A with pro-inflammatory properties, were also assessed. KEY FINDINGS BVR-A levels were significantly lower in T2D subjects than in non-T2D subjects. Reduced BVR-A levels were associated with greater body mass, systolic blood pressure, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), triglycerides, transaminases and TNFα, and with lower high-density lipoprotein (HDL) levels. Lower BVR-A levels are associated with reduced HO1 protein levels and the multivariate analysis showed that BVR-A represented the main determinant of HO1 levels in T2D after adjustment. In addition, reduced BVR-A levels were able to predict the presence of T2D with AUROC = 0.69. for potential confounders. SIGNIFICANCE Our results demonstrate for the first time that BVR-A protein levels are reduced in T2D individuals, and that this alteration strictly correlates with poor glycometabolic control and a pro-inflammatory state. Hence, these observations reinforce the hypothesis that reduced BVR-A protein levels may represent a key event in the dysregulation of intracellular pathways finally leading to metabolic disorders.
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Affiliation(s)
| | - Ilaria Barchetta
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Ilaria Zuliani
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy
| | - Sara Pagnotta
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy
| | - Laura Bertoccini
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Sara Dule
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Michele Zampieri
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Anna Reale
- Department of Experimental Medicine, Sapienza University of Rome, Italy
| | - Marco Giorgio Baroni
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences (MeSVA), University of L'Aquila, Italy; Neuroendocrinology and Metabolic Diseases, IRCCS Neuromed, Pozzilli, Is, Italy
| | | | - Eugenio Barone
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.
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16
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Paeschke S, Winter K, Bechmann I, Klöting N, Blüher M, Baum P, Kosacka J, Nowicki M. Leptin Receptor-Deficient db/db Mice Show Significant Heterogeneity in Response to High Non-heme Iron Diet. Front Nutr 2021; 8:741249. [PMID: 34646852 PMCID: PMC8503537 DOI: 10.3389/fnut.2021.741249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/30/2021] [Indexed: 12/22/2022] Open
Abstract
Recent studies have shown an association between iron homeostasis, obesity and diabetes. In this work, we investigated the differences in the metabolic status and inflammation in liver, pancreas and visceral adipose tissue of leptin receptor-deficient db/db mice dependent on high iron concentration diet. 3-month-old male BKS-Leprdb/db/JOrlRj (db/db) mice were divided into two groups, which were fed with different diets containing high iron (29 g/kg, n = 57) or standard iron (0.178 g/kg; n = 42) concentrations for 4 months. As anticipated, standard iron-fed db/db mice developed obesity and diabetes. However, high iron-fed mice exhibited a wide heterogeneity. By dividing into two subgroups at the diabetes level, non-diabetic subgroup 1 (<13.5 mmol/l, n = 30) significantly differed from diabetic subgroup two (>13.5 mmol/l, n = 27). Blood glucose concentration, HbA1c value, inflammation markers interleukin six and tumor necrosis factor α and heme oxygenase one in visceral adipose tissue were reduced in subgroup one compared to subgroup two. In contrast, body weight, C-peptide, serum insulin and serum iron concentrations, pancreatic islet and signal ratio as well as cholesterol, LDL and HDL levels were enhanced in subgroup one. While these significant differences require further studies and explanation, our results might also explain the often-contradictory results of the metabolic studies with db/db mice.
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Affiliation(s)
- Sabine Paeschke
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Karsten Winter
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Ingo Bechmann
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Nora Klöting
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum Munchen at the University of Leipzig, Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum Munchen at the University of Leipzig, Leipzig, Germany.,Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Petra Baum
- Department of Neurology, University of Leipzig, Leipzig, Germany
| | - Joanna Kosacka
- Department of Medicine, University of Leipzig, Leipzig, Germany.,Applied Molecular Hepatology Lab, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany
| | - Marcin Nowicki
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
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17
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Li Y, Ma K, Han Z, Chi M, Sai X, Zhu P, Ding Z, Song L, Liu C. Immunomodulatory Effects of Heme Oxygenase-1 in Kidney Disease. Front Med (Lausanne) 2021; 8:708453. [PMID: 34504854 PMCID: PMC8421649 DOI: 10.3389/fmed.2021.708453] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/31/2021] [Indexed: 01/23/2023] Open
Abstract
Kidney disease is a general term for heterogeneous damage that affects the function and the structure of the kidneys. The rising incidence of kidney diseases represents a considerable burden on the healthcare system, so the development of new drugs and the identification of novel therapeutic targets are urgently needed. The pathophysiology of kidney diseases is complex and involves multiple processes, including inflammation, autophagy, cell-cycle progression, and oxidative stress. Heme oxygenase-1 (HO-1), an enzyme involved in the process of heme degradation, has attracted widespread attention in recent years due to its cytoprotective properties. As an enzyme with known anti-oxidative functions, HO-1 plays an indispensable role in the regulation of oxidative stress and is involved in the pathogenesis of several kidney diseases. Moreover, current studies have revealed that HO-1 can affect cell proliferation, cell maturation, and other metabolic processes, thereby altering the function of immune cells. Many strategies, such as the administration of HO-1-overexpressing macrophages, use of phytochemicals, and carbon monoxide-based therapies, have been developed to target HO-1 in a variety of nephropathological animal models, indicating that HO-1 is a promising protein for the treatment of kidney diseases. Here, we briefly review the effects of HO-1 induction on specific immune cell populations with the aim of exploring the potential therapeutic roles of HO-1 and designing HO-1-based therapeutic strategies for the treatment of kidney diseases.
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Affiliation(s)
- Yunlong Li
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kuai Ma
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Zhongyu Han
- School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingxuan Chi
- School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiyalatu Sai
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhaolun Ding
- Department of Emergency Surgery, Shannxi Provincial People's Hospital, Xi'an, China
| | - Linjiang Song
- School of Medical and Life Sciences, Reproductive and Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chi Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
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18
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McClung JA, Levy L, Garcia V, Stec DE, Peterson SJ, Abraham NG. Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications. Pharmacol Ther 2021; 231:107975. [PMID: 34499923 DOI: 10.1016/j.pharmthera.2021.107975] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/08/2021] [Accepted: 07/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity-mediated metabolic syndrome remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves the heme oxygenase (HO) system, specifically its inducible form, HO-1. This review collects and updates much of the current knowledge relevant to pharmacology and clinical medicine concerning HO-1 in metabolic diseases and its effect on lipid metabolism. HO-1 has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin and leptin sensitivity. Recent reports indicate that HO-1 with its antioxidants via the effect of bilirubin increases formation of biologically active lipid metabolites such as epoxyeicosatrienoic acid (EET), omega-3 and other polyunsaturated fatty acids (PUFAs). Similarly, HO-1and bilirubin are potential therapeutic targets in the treatment of fat-induced liver diseases. HO-1-mediated upregulation of EET is capable not only of reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, a hallmark of the metabolic syndrome. This process involves browning of white fat tissue (i.e. formation of healthy adipocytes) and reduced lipotoxicity, which otherwise will be toxic to the heart. More importantly, this review examines the activity of EET in biological systems and a series of pathways that explain its mechanism of action and discusses how these might be exploited for potential therapeutic use. We also discuss the link between cardiac ectopic fat deposition and cardiac function in humans, which is similar to that described in obese mice and is regulated by HO-1-EET-PGC1α signaling, a potent negative regulator of the inflammatory adipokine NOV.
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Affiliation(s)
- John A McClung
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America
| | - Lior Levy
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America
| | - Victor Garcia
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, United States of America.
| | - Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, United States of America; New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States of America
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America; Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America.
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19
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Žiberna L, Jenko-Pražnikar Z, Petelin A. Serum Bilirubin Levels in Overweight and Obese Individuals: The Importance of Anti-Inflammatory and Antioxidant Responses. Antioxidants (Basel) 2021; 10:antiox10091352. [PMID: 34572984 PMCID: PMC8472302 DOI: 10.3390/antiox10091352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 12/14/2022] Open
Abstract
Obesity is a chronic condition involving low-grade inflammation and increased oxidative stress; thus, obese and overweight people have lower values of serum bilirubin. Essentially, bilirubin is a potent endogenous antioxidant molecule with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties. This review paper presents the interplay between obesity-related pathological processes and bilirubin, with a focus on adipose tissue and adipokines. We discuss potential strategies to mildly increase serum bilirubin levels in obese patients as an adjunctive therapeutic approach.
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Affiliation(s)
- Lovro Žiberna
- Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | | | - Ana Petelin
- Faculty of Health Sciences, University of Primorska, SI-6310 Izola, Slovenia;
- Correspondence: ; Tel.: +386-5-66-2469
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20
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Fakih TM, Kurniawan F, Yusuf M, Mudasir M, Tjahjono DH. Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ. Molecules 2021; 26:3251. [PMID: 34071361 PMCID: PMC8198987 DOI: 10.3390/molecules26113251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/15/2021] [Accepted: 05/26/2021] [Indexed: 11/17/2022] Open
Abstract
Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.
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Affiliation(s)
- Taufik Muhammad Fakih
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40135, Indonesia; (T.M.F.); (F.K.)
- Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Jalan Rangga Gading 8, Bandung 40116, Indonesia
| | - Fransiska Kurniawan
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40135, Indonesia; (T.M.F.); (F.K.)
| | - Muhammad Yusuf
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jalan Raya Bandung Sumedang Km 21, Sumedang 45363, Indonesia;
| | - Mudasir Mudasir
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara BLS 21, Yogyakarta 55281, Indonesia;
| | - Daryono Hadi Tjahjono
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40135, Indonesia; (T.M.F.); (F.K.)
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21
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Grunenwald A, Roumenina LT, Frimat M. Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases. Int J Mol Sci 2021; 22:2009. [PMID: 33670516 PMCID: PMC7923026 DOI: 10.3390/ijms22042009] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022] Open
Abstract
The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney's filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1's functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1's role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.
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Affiliation(s)
- Anne Grunenwald
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France; (A.G.); (L.T.R.)
| | - Lubka T. Roumenina
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France; (A.G.); (L.T.R.)
| | - Marie Frimat
- U1167-RID-AGE, Institut Pasteur de Lille, Inserm, Univ. Lille, F-59000 Lille, France
- Nephrology Department, CHU Lille, Univ. Lille, F-59000 Lille, France
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22
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Wang Z, Zeng M, Wang Z, Qin F, Chen J, He Z. Dietary Luteolin: A Narrative Review Focusing on Its Pharmacokinetic Properties and Effects on Glycolipid Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:1441-1454. [PMID: 33522240 DOI: 10.1021/acs.jafc.0c08085] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Luteolin, a flavone subclass of flavonoids, is commonly found in food plants and has multiple biological activities. Recently, evidence is growing with regard to the potential of luteolin intake to beneficially affect glycolipid metabolism disorders (GLMDs), particularly insulin resistance, diabetes, and obesity. The aim of this contribution is to provide an overview of recent advances in identifying and understanding the pharmacokinetic properties (absorption, metabolism, and bioavailability) of luteolin, its regulatory effects on glycolipid metabolism, and the underlying mechanisms of action of luteolin in the brain, liver, adipose tissues, and other tissues/organs. Collectively, luteolin or its principal metabolites may contribute to counteracting GLMDs, especially for human obesity and diabetes.
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Affiliation(s)
- Zhenyu Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
- International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Maomao Zeng
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
- International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Zhaojun Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
- International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Fang Qin
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
- International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Jie Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
- International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
| | - Zhiyong He
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
- International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu 214122, People's Republic of China
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23
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Xie ZJ, Novograd J, Itzkowitz Y, Sher A, Buchen YD, Sodhi K, Abraham NG, Shapiro JI. The Pivotal Role of Adipocyte-Na K peptide in Reversing Systemic Inflammation in Obesity and COVID-19 in the Development of Heart Failure. Antioxidants (Basel) 2020; 9:E1129. [PMID: 33202598 PMCID: PMC7697697 DOI: 10.3390/antiox9111129] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 01/10/2023] Open
Abstract
This review summarizes data from several laboratories that have demonstrated a role of the Na/K-ATPase, specifically its α1 subunit, in the generation of reactive oxygen species (ROS) via the negative regulator of Src. Together with Src and other signaling proteins, the Na/K-ATPase forms an oxidant amplification loop (NKAL), amplifies ROS, and participates in cytokines storm in obesity. The development of a peptide fragment of the α1 subunit, NaKtide, has been shown to negatively regulate Src. Several groups showed that the systemic administration of the cell permeable modification of NaKtide (pNaKtide) or its selective delivery to fat tissue-adipocyte specific expression of NaKtide-ameliorate the systemic elevation of inflammatory cytokines seen in chronic obesity. Severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), the RNA Coronavirus responsible for the COVID-19 global pandemic, invades cells via the angiotensin converting enzyme 2 (ACE-2) receptor (ACE2R) that is appended in inflamed fat tissue and exacerbates the formation of the cytokines storm. Both obesity and heart and renal failure are well known risks for adverse outcomes in patients infected with COVID-19. White adipocytes express ACE-2 receptors in high concentration, especially in obese patients. Once the virus invades the white adipocyte cell, it creates a COVID19-porphyrin complex which degrades and produces free porphyrin and iron and increases ROS. The increased formation of ROS and activation of the NKAL results in a further potentiated formation of ROS production, and ultimately, adipocyte generation of more inflammatory mediators, leading to systemic cytokines storm and heart failure. Moreover, chronic obesity also results in the reduction of antioxidant genes such as heme oxygenase-1 (HO-1), increasing adipocyte susceptibility to ROS and cytokines. It is the systemic inflammation and cytokine storm which is responsible for many of the adverse outcomes seen with COVID-19 infections in obese subjects, leading to heart failure and death. This review will also describe the potential antioxidant drugs and role of NaKtide and their demonstrated antioxidant effect used as a major strategy for improving obesity and epicardial fat mediated heart failure in the context of the COVID pandemic.
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Affiliation(s)
- Zi-jian Xie
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (Z.-j.X.); (K.S.)
| | - Joel Novograd
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA; (J.N.); (Y.I.); (A.S.); (Y.D.B.)
| | - Yaakov Itzkowitz
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA; (J.N.); (Y.I.); (A.S.); (Y.D.B.)
| | - Ariel Sher
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA; (J.N.); (Y.I.); (A.S.); (Y.D.B.)
| | - Yosef D. Buchen
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA; (J.N.); (Y.I.); (A.S.); (Y.D.B.)
| | - Komal Sodhi
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (Z.-j.X.); (K.S.)
| | - Nader G. Abraham
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (Z.-j.X.); (K.S.)
- Department of Medicine, New York Medical College, Valhalla, NY 10595, USA; (J.N.); (Y.I.); (A.S.); (Y.D.B.)
| | - Joseph I. Shapiro
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; (Z.-j.X.); (K.S.)
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24
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Carr JF, Garcia D, Scaffa A, Peterson AL, Ghio AJ, Dennery PA. Heme Oxygenase-1 Supports Mitochondrial Energy Production and Electron Transport Chain Activity in Cultured Lung Epithelial Cells. Int J Mol Sci 2020; 21:ijms21186941. [PMID: 32971746 PMCID: PMC7554745 DOI: 10.3390/ijms21186941] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/17/2020] [Accepted: 09/20/2020] [Indexed: 12/13/2022] Open
Abstract
Heme oxygenase-1 is induced by many cellular stressors and catalyzes the breakdown of heme to generate carbon monoxide and bilirubin, which confer cytoprotection. The role of HO-1 likely extends beyond the simple production of antioxidants, for example HO-1 activity has also been implicated in metabolism, but this function remains unclear. Here we used an HO-1 knockout lung cell line to further define the contribution of HO-1 to cellular metabolism. We found that knockout cells exhibit reduced growth and mitochondrial respiration, measured by oxygen consumption rate. Specifically, we found that HO-1 contributed to electron transport chain activity and utilization of certain mitochondrial fuels. Loss of HO-1 had no effect on intracellular non-heme iron concentration or on proteins whose levels and activities depend on available iron. We show that HO-1 supports essential functions of mitochondria, which highlights the protective effects of HO-1 in diverse pathologies and tissue types. Our results suggest that regulation of heme may be an equally significant role of HO-1.
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Affiliation(s)
- Jennifer F. Carr
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02906, USA; (J.F.C.); (A.L.P.)
| | - David Garcia
- Department of Chemistry, Brown University, Providence, RI 02906, USA;
| | - Alejandro Scaffa
- Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02906, USA;
| | - Abigail L. Peterson
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02906, USA; (J.F.C.); (A.L.P.)
| | - Andrew J. Ghio
- National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC 27599, USA;
| | - Phyllis A. Dennery
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02906, USA; (J.F.C.); (A.L.P.)
- Department of Pediatrics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
- Hasbro Children’s Hospital, Providence, RI 02903, USA
- Correspondence: ; Tel.: +1-401-444-5648
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Furuhata R, Kabe Y, Kanai A, Sugiura Y, Tsugawa H, Sugiyama E, Hirai M, Yamamoto T, Koike I, Yoshikawa N, Tanaka H, Koseki M, Nakae J, Matsumoto M, Nakamura M, Suematsu M. Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes. Commun Biol 2020; 3:479. [PMID: 32887925 PMCID: PMC7473863 DOI: 10.1038/s42003-020-01202-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/03/2020] [Indexed: 12/26/2022] Open
Abstract
Progesterone receptor membrane associated component 1 (PGRMC1) exhibits haem-dependent dimerization on cell membrane and binds to EGF receptor and cytochromes P450 to regulate cancer proliferation and chemoresistance. However, its physiological functions remain unknown. Herein, we demonstrate that PGRMC1 is required for adipogenesis, and its expression is significantly enhanced by insulin or thiazolidine, an agonist for PPARγ. The haem-dimerized PGRMC1 interacts with low-density lipoprotein receptors (VLDL-R and LDL-R) or GLUT4 to regulate their translocation to the plasma membrane, facilitating lipid uptake and accumulation, and de-novo fatty acid synthesis in adipocytes. These events are cancelled by CO through interfering with PGRMC1 dimerization. PGRMC1 expression in mouse adipose tissues is enhanced during obesity induced by a high fat diet. Furthermore, adipose tissue-specific PGRMC1 knockout in mice dramatically suppressed high-fat-diet induced adipocyte hypertrophy. Our results indicate a pivotal role of PGRMC1 in developing obesity through its metabolic regulation of lipids and carbohydrates in adipocytes.
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Affiliation(s)
- Ryogo Furuhata
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
- Department of Orthopaedic[s] Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yasuaki Kabe
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
| | - Ayaka Kanai
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yuki Sugiura
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hitoshi Tsugawa
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Eiji Sugiyama
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Miwa Hirai
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Takehiro Yamamoto
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Ikko Koike
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Noritada Yoshikawa
- Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hirotoshi Tanaka
- Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masahiro Koseki
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
| | - Jun Nakae
- Department of Physiology, International University of Health and Welfare School of Medicine, Narita, 286-8686, Japan
| | - Morio Matsumoto
- Department of Orthopaedic[s] Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopaedic[s] Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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26
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Waldman M, Arad M, Abraham NG, Hochhauser E. The Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1α-Heme Oxygenase 1 Axis, a Powerful Antioxidative Pathway with Potential to Attenuate Diabetic Cardiomyopathy. Antioxid Redox Signal 2020; 32:1273-1290. [PMID: 32027164 PMCID: PMC7232636 DOI: 10.1089/ars.2019.7989] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
Significance: From studies of diabetic animal models, the downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)-heme oxygenase 1 (HO-1) axis appears to be a crucial event in the development of obesity and diabetic cardiomyopathy (DCM). In this review, we discuss the role of metabolic and biochemical stressors in the rodent and human pathophysiology of DCM. A crucial contributor for many cardiac pathologies is excessive production of reactive oxygen species (ROS) pathologies, which lead to extensive cellular damage by impairing mitochondrial function and directly oxidizing DNA, proteins, and lipid membranes. We discuss the role of ROS production and inflammatory pathways with multiple contributing and confounding factors leading to DCM. Recent Advances: The relevant biochemical pathways that are critical to a therapeutic approach to treat DCM, specifically caloric restriction and its relation to the PGC-1α-HO-1 axis in the attenuation of DCM, are elucidated. Critical Issues: The increased prevalence of diabetes mellitus type 2, a major contributor to unique cardiomyopathy characterized by cardiomyocyte hypertrophy with no effective clinical treatment. This review highlights the role of mitochondrial dysfunction in the development of DCM and potential oxidative targets to attenuate oxidative stress and attenuate DCM. Future Directions: Targeting the PGC-1α-HO-1 axis is a promising approach to ameliorate DCM through improvement in mitochondrial function and antioxidant defenses. A pharmacological inducer to activate PGC-1α and HO-1 described in this review may be a promising therapeutic approach in the clinical setting.
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Affiliation(s)
- Maayan Waldman
- Cardiac Research Laboratory, Felsenstein Medical Research Institute at Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
- Cardiac Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Michael Arad
- Cardiac Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Nader G. Abraham
- Department of Pharmacology, New York Medical College, Valhalla, New York, USA
| | - Edith Hochhauser
- Cardiac Research Laboratory, Felsenstein Medical Research Institute at Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
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27
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Arad M, Waldman M, Abraham NG, Hochhauser E. Therapeutic approaches to diabetic cardiomyopathy: Targeting the antioxidant pathway. Prostaglandins Other Lipid Mediat 2020; 150:106454. [PMID: 32413571 DOI: 10.1016/j.prostaglandins.2020.106454] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/23/2020] [Accepted: 05/06/2020] [Indexed: 12/25/2022]
Abstract
The global epidemic of cardiovascular disease continues unabated and remains the leading cause of death both in the US and worldwide. We hereby summarize the available therapies for diabetes and cardiovascular disease in diabetics. Clearly, the current approaches to diabetic heart disease often target the manifestations and certain mediators but not the specific pathways leading to myocardial injury, remodeling and dysfunction. Better understanding of the molecular events determining the evolution of diabetic cardiomyopathy will provide insight into the development of specific and targeted therapies. Recent studies largely increased our understanding of the role of enhanced inflammatory response, ROS production, as well as the contribution of Cyp-P450-epoxygenase-derived epoxyeicosatrienoic acid (EET), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α (PGC-1α), Heme Oxygenase (HO)-1 and 20-HETE in pathophysiology and therapy of cardiovascular disease. PGC-1α increases production of the HO-1 which has a major role in protecting the heart against oxidative stress, microcirculation and mitochondrial dysfunction. This review describes the potential drugs and their downstream targets, PGC-1α and HO-1, as major loci for developing therapeutic approaches beside diet and lifestyle modification for the treatment and prevention of heart disease associated with obesity and diabetes.
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Affiliation(s)
- Michael Arad
- Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Maayan Waldman
- Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel Aviv University, Tel Aviv, Israel
| | - Nader G Abraham
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
| | - Edith Hochhauser
- Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel Aviv University, Tel Aviv, Israel.
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28
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Bellner L, Lebovics NB, Rubinstein R, Buchen YD, Sinatra E, Sinatra G, Abraham NG, McClung JA, Thompson EA. Heme Oxygenase-1 Upregulation: A Novel Approach in the Treatment of Cardiovascular Disease. Antioxid Redox Signal 2020; 32:1045-1060. [PMID: 31891663 PMCID: PMC7153645 DOI: 10.1089/ars.2019.7970] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: Heme oxygenase (HO) plays a pivotal role in both vascular and metabolic functions and is involved in many physiological and pathophysiological processes in vascular endothelial cells (ECs) and adipocytes. Recent Advances: From the regulation of adipogenesis in adipose tissue to the adaptive response of vascular tissue in the ECs, HO plays a critical role in the capability of the vascular system to respond and adjust to insults in homeostasis. Recent studies show that HO-1 through regulation of adipocyte and adipose tissue functions ultimately aid not only in local but also in systemic maintenance of homeostasis. Critical Issues: Recent advances have revealed the existence of a cross talk between vascular ECs and adipocytes in adipose tissue. In the pathological state of obesity, this cross talk contributes to the condition's adverse chronic effects, and we propose that specific targeting of the HO-1 gene can restore signaling pathways and improve both vascular and adipose functions. Future Directions: A complete understanding of the role of HO-1 in regulation of cardiovascular homeostasis is important to comprehend the homeostatic regulation as well as in cardiovascular disease. Efforts are required to highlight the effects and the ability to target the HO-1 gene in models of obesity with an emphasis on the role of pericardial fat on cardiovascular health.
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Affiliation(s)
- Lars Bellner
- Department of Pharmacology and New York Medical College, Valhalla, New York
| | - Nachum B Lebovics
- Department of Pharmacology and New York Medical College, Valhalla, New York
| | | | - Yosef D Buchen
- Department of Pharmacology and New York Medical College, Valhalla, New York
| | - Emilia Sinatra
- Department of Pharmacology and New York Medical College, Valhalla, New York
| | - Giuseppe Sinatra
- Department of Pharmacology and New York Medical College, Valhalla, New York
| | - Nader G Abraham
- Department of Pharmacology and New York Medical College, Valhalla, New York.,Department of Medicine, New York Medical College, Valhalla, New York
| | - John A McClung
- Department of Medicine, New York Medical College, Valhalla, New York
| | - Ellen A Thompson
- Department of Medicine, Marshall University, Joan C. Edwards School of Medicine, Huntington, West Virginia
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Petelin A, Jurdana M, Jenko Pražnikar Z, Žiberna L. SERUM BILIRUBIN CORRELATES WITH SERUM ADIPOKINES IN NORMAL WEIGHT AND OVERWEIGHT ASYMPTOMATIC ADULTS. Acta Clin Croat 2020; 59:19-29. [PMID: 32724271 PMCID: PMC7382891 DOI: 10.20471/acc.2020.59.01.03] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Overweight and obesity are considered as chronic low-grade inflammation accompanied by imbalanced production of adipokines. The aim of this study was to elucidate the relationship between serum bilirubin, which is an endogenous antioxidant with anti-inflammatory activity, and pro- and anti-inflammatory serum adipokines in asymptomatic normal weight and overweight individuals. Healthy men and women aged 25-49 participated in this cross-sectional study. All participants underwent fasting serological measurements of adipokines, interleukin-6, tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), total and direct serum bilirubin, and other biochemical parameters. Participants were divided into normal weight and overweight groups. We found a significant negative association between total bilirubin and CRP, TNF-α, visfatin and resistin values, and a significant positive association between total bilirubin and adiponectin values in both normal-weight and overweight groups. Importantly, after adjusting for body mass index, we also found a significant negative association between total serum bilirubin levels and both visfatin and CRP serum levels. Moreover, visfatin, resistin and CRP were predictors of the total serum bilirubin levels.
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Affiliation(s)
| | - Mihaela Jurdana
- 1Faculty of Health Sciences, University of Primorska, Izola, Slovenia; 2Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Zala Jenko Pražnikar
- 1Faculty of Health Sciences, University of Primorska, Izola, Slovenia; 2Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Lovro Žiberna
- 1Faculty of Health Sciences, University of Primorska, Izola, Slovenia; 2Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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30
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Lamas CA, Kido LA, Montico F, Collares-Buzato CB, Maróstica MR, Cagnon VHA. A jaboticaba extract prevents prostatic damage associated with aging and high-fat diet intake. Food Funct 2020; 11:1547-1559. [DOI: 10.1039/c9fo02621e] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Jaboticaba extract prevented the prostatic lesion development in aging and/or overweight mice, mainly interfering in cell proliferation, hormonal and angiogenesis pathways.
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Affiliation(s)
- C. A. Lamas
- Department of Structural and Functional Biology
- Institute of Biology
- University of Campinas
- São Paulo
- Brazil
| | - L. A. Kido
- Department of Structural and Functional Biology
- Institute of Biology
- University of Campinas
- São Paulo
- Brazil
| | - F. Montico
- Department of Structural and Functional Biology
- Institute of Biology
- University of Campinas
- São Paulo
- Brazil
| | - C. B. Collares-Buzato
- Department of Biochemistry and Tissue Biology
- Biology Institute
- University of Campinas
- São Paulo
- Brazil
| | - M. R. Maróstica
- Department of Food and Nutrition
- School of Food Engineering
- University of Campinas
- São Paulo
- Brazil
| | - V. H. A. Cagnon
- Department of Structural and Functional Biology
- Institute of Biology
- University of Campinas
- São Paulo
- Brazil
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Adipocyte Specific HO-1 Gene Therapy is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model. Antioxidants (Basel) 2020; 9:antiox9010040. [PMID: 31906399 PMCID: PMC7022335 DOI: 10.3390/antiox9010040] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/25/2019] [Accepted: 12/30/2019] [Indexed: 12/31/2022] Open
Abstract
Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.
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Singh SP, McClung JA, Thompson E, Glick Y, Greenberg M, Acosta‐Baez G, Edris B, Shapiro JI, Abraham NG. Cardioprotective Heme Oxygenase-1-PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice. Obesity (Silver Spring) 2019; 27:1634-1643. [PMID: 31441604 PMCID: PMC6756945 DOI: 10.1002/oby.22608] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE This study investigated whether levels of signaling pathways and inflammatory adipokines in epicardial fat regulate cardiovascular risks in humans and mice. METHODS Epicardial fat was obtained from the hearts of patients with heart failure requiring coronary artery bypass surgery, and signaling pathways were compared with visceral fat. The genetic profile of epicardial and visceral fat from humans was also compared with genetic profiles of epicardial and visceral fat in obese mice. Left ventricular (LV) fractional shortening was measured in obese mice before and after treatment with inducers of mitochondrial signaling heme oxygenase 1 (HO-1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). An RNA array/heat map on 88 genes that regulate adipose tissue function was used to identify a target gene network. RESULTS Human epicardial fat gene profiling showed decreased levels of mitochondrial signaling of HO-1-PGC1α and increased levels of the inflammatory adipokine CCN family member 3. Similar observations were seen in epicardial and visceral fat of obese mice. Improvement in LV function was linked to the increase in mitochondrial signaling in epicardial fat of obese mice. CONCLUSIONS There is a link between cardiac ectopic fat deposition and cardiac function in humans that is similar to that which is described in obese mice. An increase of mitochondrial signaling pathway gene expression in epicardial fat attenuates cardiometabolic dysfunction and LV fractional shortening in obese mice.
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Affiliation(s)
| | - John A. McClung
- Department of MedicineNew York Medical CollegeValhallaNew YorkUSA
| | - Ellen Thompson
- Department of CardiologyJoan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest VirginiaUSA
| | - Yosef Glick
- Department of PharmacologyNew York Medical CollegeValhallaNew YorkUSA
| | | | - Giancarlo Acosta‐Baez
- Department of CardiologyJoan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest VirginiaUSA
| | - Basel Edris
- Department of CardiologyJoan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest VirginiaUSA
| | - Joseph I. Shapiro
- Department of Internal MedicineJoan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest VirginiaUSA
| | - Nader G. Abraham
- Department of PharmacologyNew York Medical CollegeValhallaNew YorkUSA
- Department of MedicineNew York Medical CollegeValhallaNew YorkUSA
- Department of Internal MedicineJoan C. Edwards School of Medicine, Marshall UniversityHuntingtonWest VirginiaUSA
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Drummond GS, Baum J, Greenberg M, Lewis D, Abraham NG. HO-1 overexpression and underexpression: Clinical implications. Arch Biochem Biophys 2019; 673:108073. [PMID: 31425676 DOI: 10.1016/j.abb.2019.108073] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/23/2019] [Accepted: 08/10/2019] [Indexed: 12/11/2022]
Abstract
In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on vascular disease. In a few instances e.g., neonatal jaundice, overproduction of HO-1 and increased HO activity results in elevated levels of bilirubin requiring clinical intervention with inhibitors of HO activity. In contrast HO-1 levels and HO activity are low in obesity and the HO system responds to mitigate the deleterious effects of oxidative stress through increased levels of bilirubin (anti-inflammatory) and CO (anti-apoptotic) and decreased levels of heme (pro-oxidant). Site specific HO-1 overexpression diminishes adipocyte terminal differentiation and lipid accumulation of obesity mediated release of inflammatory molecules. A series of diverse strategies have been implemented that focus on increasing HO-1 and HO activity that are central to reversing the clinical complications associated with diseases including, obesity, metabolic syndrome and vascular disease.
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Affiliation(s)
- George S Drummond
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Jeffrey Baum
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Menachem Greenberg
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - David Lewis
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25701, USA.
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Beneficial Role of HO-1-SIRT1 Axis in Attenuating Angiotensin II-Induced Adipocyte Dysfunction. Int J Mol Sci 2019; 20:ijms20133205. [PMID: 31261892 PMCID: PMC6650875 DOI: 10.3390/ijms20133205] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/24/2019] [Accepted: 06/24/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Angiotensin II (Ang II), released by the renin–angiotensin–aldosterone system (RAAS), contributes to the modulatory role of the RAAS in adipose tissue dysfunction. Investigators have shown that inhibition of AngII improved adipose tissue function and insulin resistance in mice with metabolic syndrome. Heme Oxygenase-1 (HO-1), a potent antioxidant, has been demonstrated to improve oxidative stress and adipocyte phenotype. Molecular effects of high oxidative stress include suppression of sirtuin-1 (SIRT1), which is amenable to redox manipulations. The mechanisms involved, however, in these metabolic effects of the RAAS remain incompletely understood. Hypothesis: We hypothesize that AngII-induced oxidative stress has the potential to suppress adipocyte SIRT1 via down regulation of HO-1. This effect of AngII will, in turn, upregulate mineralocorticoid receptor (MR). The induction of HO-1 will rescue SIRT1, hence improving oxidative stress and adipocyte phenotype. Methods and Results: We examined the effect of AngII on lipid accumulation, oxidative stress, and inflammatory cytokines in mouse pre-adipocytes in the presence and absence of cobalt protoporphyrin (CoPP), HO-1 inducer, tin mesoporphyrin (SnMP), and HO-1 inhibitor. Our results show that treatment of mouse pre-adipocytes with AngII increased lipid accumulation, superoxide levels, inflammatory cytokine levels, interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), and adiponectin levels. This effect was attenuated by HO-1 induction, which was further reversed by SnMP, suggesting HO-1 mediated improvement in adipocyte phenotype. AngII-treated pre-adipocytes also showed upregulated levels of MR and suppressed SIRT1 that was rescued by HO-1. Subsequent treatment with CoPP and SIRT1 siRNA in mouse pre-adipocytes increased lipid accumulation and fatty acid synthase (FAS) levels, suggesting that beneficial effects of HO-1 are mediated via SIRT1. Conclusion: Our study demonstrates for the first time that HO-1 has the ability to restore cellular redox, rescue SIRT1, and prevent AngII-induced impaired effects on adipocytes and the systemic metabolic profile.
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Peterson SJ, Rubinstein R, Faroqui M, Raza A, Boumaza I, Zhang Y, Stec D, Abraham NG. Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy. Int J Mol Sci 2019; 20:ijms20102514. [PMID: 31121826 PMCID: PMC6566770 DOI: 10.3390/ijms20102514] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/17/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022] Open
Abstract
Objective: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. Method: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control. Results: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP. Conclusion: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the “crosstalk” between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.
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Affiliation(s)
- Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA.
| | - Rochelle Rubinstein
- Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
| | - Mouzam Faroqui
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA.
| | - Adnan Raza
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA.
| | - Imene Boumaza
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA.
| | - Yilun Zhang
- Tufts University School of Medicine, Boston, MA 02111, USA.
| | - David Stec
- Department of Physiology and Biophysics at the University of Mississippi Medical Center, Jackson, MI 39216, USA.
| | - Nader G Abraham
- Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
- Department of Pharmacology, Physiology and Toxicology, Marshall University, Joan Edwards School of Medicine, Huntington, WV 25701, USA.
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Rizzetti DA, Corrales P, Piagette JT, Uranga-Ocio JA, Medina-Gomez G, Peçanha FM, Vassallo DV, Miguel M, Wiggers GA. Chronic mercury at low doses impairs white adipose tissue plasticity. Toxicology 2019; 418:41-50. [PMID: 30807803 DOI: 10.1016/j.tox.2019.02.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/31/2019] [Accepted: 02/23/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The toxic effects of mercury (Hg) are involved in homeostasis of energy systems such as lipid and glucose metabolism, and white adipose tissue dysfunction is considered as a central mechanism leading to metabolic disorders. OBJECTIVE The aim of this study was to determine the effects of chronic inorganic Hg exposure at low doses on the lipid and glycemic metabolism. METHODS Male Wistar rats were divided into two groups and treated for 60 days with: saline solution, i.m. (Untreated) and mercury chloride, i.m. - 1st dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/day - (Mercury). Histological analyses, Hg levels measurement and GRP78, CHOP, PPARα, PPARγ, leptin, adiponectin and CD11 mRNA expressions were performed in epididymal white adipose tissue (eWAT). Glucose, triglycerides, total cholesterol and insulin plasma levels were also measured. RESULTS Hg exposure reduced the absolute and relative eWAT weights, adipocyte size, plasma insulin levels, glucose tolerance, antioxidant defenses and increased plasma glucose and triglyceride levels. In addition, CHOP, GRP78, PPARα, PPARγ, leptin and adiponectin mRNA expressions were increased in Hg-treated animals. No differences in Hg concentration were found in eWAT between the untreated and Hg groups. These results suggest that the reduction in adipocyte size is related to the impaired antioxidant defenses, endoplasmic reticulum (ER) stress, the disrupted PPARs and adipokines mRNA expression induced by the metal in eWAT. These disturbances possibly induced a decrease in circulating insulin levels, an imbalance between lipolysis and lipogenesis mechanisms in eWAT, with an increase in fatty acids mobilization, a reduction in glucose uptake and an activation of pro-apoptotic pathways, leading to hyperglycemia and hyperlipidemia. CONCLUSIONS Hg is a powerful environmental WAT disruptor that influences signaling events and impairs metabolic activity and hormonal balance of adipocytes.
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Affiliation(s)
- Danize Aparecida Rizzetti
- Cardiovascular Physiology Laboratory, Universidade Federal do Pampa, BR 472, Km 592, Uruguaiana, Rio Grande do Sul, Brazil; Polytechnic School, Federal University of Santa Maria, Av. Roraima, n° 1000, Santa Maria, Rio Grande do Sul, Brazil.
| | - Patricia Corrales
- Department of Basic Health Sciences, Universidad Rey Juan Carlos, Antenas s/n, Alcorcón, Spain.
| | - Janaina Trindade Piagette
- Cardiovascular Physiology Laboratory, Universidade Federal do Pampa, BR 472, Km 592, Uruguaiana, Rio Grande do Sul, Brazil.
| | | | - Gema Medina-Gomez
- Department of Basic Health Sciences, Universidad Rey Juan Carlos, Antenas s/n, Alcorcón, Spain.
| | - Franck Maciel Peçanha
- Cardiovascular Physiology Laboratory, Universidade Federal do Pampa, BR 472, Km 592, Uruguaiana, Rio Grande do Sul, Brazil.
| | - Dalton Valentim Vassallo
- Cardiac Electromechanical and Vascular Reactivity Laboratory, Universidade Federal do Espírito Santo, Marechal Campos, 1468, Vitória, Espírito Santo, Brazil.
| | - Marta Miguel
- Bioactivity and Food Analysis Laboratory, Instituto de Investigación en Ciencias de la Alimentación, Nicolás Cabrera, 9, Campus Universitario de Cantoblanco, Madrid, Spain.
| | - Giulia Alessandra Wiggers
- Cardiovascular Physiology Laboratory, Universidade Federal do Pampa, BR 472, Km 592, Uruguaiana, Rio Grande do Sul, Brazil.
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Varga C, Veszelka M, Kupai K, Börzsei D, Deim Z, Szabó R, Török S, Priksz D, Gesztelyi R, Juhász B, Radák Z, Pósa A. The Effects of Exercise Training and High Triglyceride Diet in an Estrogen Depleted Rat Model: The Role of the Heme Oxygenase System and Inflammatory Processes in Cardiovascular Risk. J Sports Sci Med 2018; 17:580-588. [PMID: 30479526 PMCID: PMC6243614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 08/31/2018] [Indexed: 06/09/2023]
Abstract
Cardiovascular morbidity and mortality of premenopausal women are significantly lower compared to men of similar age. However, this protective effect evidently decreases after the onset of menopause. We hypothesized that physical exercise could be a potential therapeutic strategy to improve inflammatory processes and cardiovascular antioxidant homeostasis, which can be affected by the loss of estrogen and the adverse environmental factors, such as overnutrition. Ovariectomized (OVX, n= 40) and sham-operated (SO, n= 40) female Wistar rats were randomized to exercising (R) and non-exercising (NR) groups. Feeding parameters were chosen to make a standard chow (CTRL) or a high triglyceride diet (HT) for 12 weeks. Aortic and cardiac heme oxygenase (HO) activity and HO-1 concentrations significantly decreased in all of the NR OVX and SO HT groups. However, the 12-week physical exercise was found to improve HO-1 values. Plasma IL-6 concentrations were higher in the NR OVX animals and rats fed HT diet compared to SO CTRL rats. TNF-α concentrations were significantly higher in the NR OVX groups. 12 weeks of exercise significantly reduced the concentrations of both TNF-α and IL-6 compared to the NR counterparts. The activity of myeloperoxidase enzyme (MPO) was significantly increased as a result of OVX and HT diet, however voluntary wheel-running exercise restored the elevated values. Our results show that estrogen deficiency and HT diet caused a significant decrease in the activity and concentration of HO enzyme, as well as the concentrations of TNF-α, IL-6, and the activity of MPO. However, 12 weeks of voluntary wheel-running exercise is a potential non-pharmacological therapy to ameliorate these disturbances, which determine the life expectancy of postmenopausal women.
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Affiliation(s)
- Csaba Varga
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Médea Veszelka
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Krisztina Kupai
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Denise Börzsei
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Zoltán Deim
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Renáta Szabó
- University of Szeged, Interdisciplinary Excellence Centre, Department of Physiology, Anatomy and Neuroscience
| | - Szilvia Török
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary
| | - Dániel Priksz
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Rudolf Gesztelyi
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Béla Juhász
- Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary
| | - Zsolt Radák
- Institute of Sport Science, Faculty of Physical Education and Sport Science, Semmelweis University, Budapest, Hungary
| | - Anikó Pósa
- University of Szeged, Interdisciplinary Excellence Centre, Department of Physiology, Anatomy and Neuroscience
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Braud L, Pini M, Muchova L, Manin S, Kitagishi H, Sawaki D, Czibik G, Ternacle J, Derumeaux G, Foresti R, Motterlini R. Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice. JCI Insight 2018; 3:123485. [PMID: 30429365 DOI: 10.1172/jci.insight.123485] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/16/2018] [Indexed: 12/15/2022] Open
Abstract
Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents.
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Affiliation(s)
- Laura Braud
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
| | - Maria Pini
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Lucie Muchova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Sylvie Manin
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
| | - Hiroaki Kitagishi
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto, Japan
| | - Daigo Sawaki
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Gabor Czibik
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Julien Ternacle
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Geneviève Derumeaux
- Faculty of Medicine, University Paris-Est, Créteil, France.,Inserm U955, Team 8, Créteil, France
| | - Roberta Foresti
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
| | - Roberto Motterlini
- Inserm U955, Team 12, Créteil, France.,Faculty of Medicine, University Paris-Est, Créteil, France
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Liu L, Puri N, Raffaele M, Schragenheim J, Singh SP, Bradbury JA, Bellner L, Vanella L, Zeldin DC, Cao J, Abraham NG. Ablation of soluble epoxide hydrolase reprogram white fat to beige-like fat through an increase in mitochondrial integrity, HO-1-adiponectin in vitro and in vivo. Prostaglandins Other Lipid Mediat 2018; 138:1-8. [PMID: 30041041 DOI: 10.1016/j.prostaglandins.2018.07.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/11/2018] [Accepted: 07/20/2018] [Indexed: 01/07/2023]
Abstract
We have shown that epoxyeicosatrienoic acids (EETs), specifically 11,12- and 14,15-EETs, reduce adipogenesis in human mesenchymal stem cells and mouse preadipocytes (3T-3L1). In this study, we explore the effects of soluble epoxide hydrolase (sEH) deletion on various aspects of adipocyte-function, including programing for white vs. beige-like fat, and mitochondrial and thermogenic gene-expressions. We further hypothesize that EETs and heme-oxygenase 1 (HO-1) form a synergistic, functional module whose effects on adipocyte and vascular function is greater than the effects of sEH deletion alone. In in vitro studies, we examined the effect of sEH inhibitors on MSC-derived adipocytes. MSC-derived adipocytes exposed to AUDA, an inhibitor of sEH, exhibit an increased number of small and healthy adipocytes, an effect reproduced by siRNA for sEH. in vivo studies indicate that sEH deletion results in a significant decrease in adipocyte size, inflammatory adipokines NOV, TNFα, while increasing adiponectin (p < 0.05). These findings are associated with a decrease in body weight (p < 0.05), and visceral fat (p < 0.05). Importantly, sEH deletion was associated with a significant increase in Mfn1, COX 1, UCP1 and adiponectin (p < 0.03). sEH deletion was manifested by a significant increase in EETs isomers 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET and an increased EETs/DHETEs ratio. Notably, activation of HO-1 gene expression further increased the levels of EETs, suggesting that the antioxidant HO-1 system protects EETs from degradation by ROS. These results are novel in that sEH deletion, while increasing EET levels, resulted in reprograming of white fat to express mitochondrial and thermogenic genes, a phenotype characteristic of beige-fat. Thus, EETs agonist(s) and sEH inhibitors may have therapeutic potential in the treatment of metabolic syndrome and obesity.
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Affiliation(s)
- Lu Liu
- Department of Cardiology, Nanlou Division, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Nitin Puri
- Joan Edward School of Medicine, Marshall University, Huntington, WV, 25701, USA
| | - Marco Raffaele
- Department of Drug Sciences, University of Catania, Catania, Italy
| | - Joseph Schragenheim
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Shailendra P Singh
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - J Alyce Bradbury
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA
| | - Lars Bellner
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Luca Vanella
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Department of Drug Sciences, University of Catania, Catania, Italy
| | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA
| | - Jian Cao
- Department of Cardiology, Nanlou Division, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.
| | - Nader G Abraham
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan Edward School of Medicine, Marshall University, Huntington, WV, 25701, USA.
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Ibuki A, Minematsu T, Yoshida M, Iizaka S, Matsumoto M, Sugama J, Sanada H. Microsatellite polymorphism in the Heme oxygenase-1 gene promoter is associated with dermal collagen density in Japanese obese male subjects. PLoS One 2018; 13:e0199994. [PMID: 30024897 PMCID: PMC6053161 DOI: 10.1371/journal.pone.0199994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 06/18/2018] [Indexed: 11/19/2022] Open
Abstract
We previously reported elevated oxidative stress-related mechanical vulnerabilities of the skin as sparse distributions of hyperechoic areas. Although this helped establish a personalized skin care system to prevent skin disorders related to mechanical stress, obesity-related skin vulnerability involves individual differences. Here, we hypothesized that individual differences are caused by polymorphisms of GT repetitive sequences in the heme oxygenase1 (HMOX1) promoter region, which encodes an antioxidant enzyme. This cross-sectional study enrolled healthy male volunteers in a walking classroom aimed at weight control. Subjects with a body mass index <25 kg/m2 were classified as non-obese and those with body mass index ≥25 kg/m2 were classified as obese. Subject skin was categorized into sparse dermis or normal groups according to the distribution of hyperechoic areas by high-resolution skin ultrasonography (20 MHz). Genomic DNA and mRNA extracted from three body hairs with attached follicle cells were used to analyze GT repetitive sequences of the HMOX1 promoter, HMOX1 mRNA expression levels, and oxidative stress levels (8-hydroxy-2’-deoxyguanosine). Classifications of GT repetitive sequence of HMOX1 promoter were Short (<27 times) and Long (≥27 times). Higher numbers of subjects with sparse dermis were in the obese group compared with the non-obese group. In obese subjects, the number of subjects that had the Long allele of the HMOX1 promoter with sparse dermis was significantly higher compared with the normal group, whereas no association was observed between the polymorphism and ultrasonographic features in non-obese subjects. Thus, HMOX1 polymorphisms detected a risk of low collagen density in Japanese obese male subjects.
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Affiliation(s)
- Ai Ibuki
- Department of Biological Science and Nursing, School of Medicine, Yokohama City University, Kanagawa, Japan
- Department of Gerontological Nursing/ Wound Care Management, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeo Minematsu
- Department of Skincare Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mikako Yoshida
- Department of Imaging Nursing Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shinji Iizaka
- School of Nutrition, College of Nursing and Nutrition, Shukutoku University, Chiba, Japan
| | - Masaru Matsumoto
- Department of Imaging Nursing Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junko Sugama
- Advanced Health Care Science Research Unit Innovative Integrated Bio-Research Core Institute for Frontier Science Initiative, Kanazawa University, Ishikawa, Japan
| | - Hiromi Sanada
- Department of Gerontological Nursing/ Wound Care Management, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- * E-mail:
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Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress. Int J Hepatol 2018; 2018:3484107. [PMID: 30057822 PMCID: PMC6051135 DOI: 10.1155/2018/3484107] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/30/2018] [Accepted: 05/15/2018] [Indexed: 12/30/2022] Open
Abstract
AIM Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. METHODS Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. RESULTS NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. CONCLUSIONS These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH.
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Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes. Biochem Biophys Res Commun 2018; 502:129-136. [PMID: 29787756 DOI: 10.1016/j.bbrc.2018.05.133] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 05/18/2018] [Indexed: 01/11/2023]
Abstract
Although Fibronectin Type III Domain Containing 4 (FNDC4) has been reported to be involved in the modulation of inflammation in macrophages, its effects on inflammation and insulin resistance in adipose tissue are unknown. In the current study, we investigated the effects of FNDC4 on hyperlipidemia-mediated endoplasmic reticulum (ER) stress, inflammation, and insulin resistance in adipocytes via the AMP-activated protein kinase (AMPK)/heme oxygenase-1 (HO-1)-mediated pathway. Hyperlipidemia-induced nuclear factor κB (NFκB), inhibitory κBα (IκBα) phosphorylation, and pro-inflammatory cytokines such as TNFα and MCP-1 were markedly mitigated by FNDC4. Furthermore, FNDC4 treatment attenuated impaired insulin signaling in palmitate-treated differentiated 3T3-L1 cells and in subcutaneous adipose tissue of HFD-fed mice. FNDC4 administration ameliorated glucose intolerance and reduced HFD-induced body weight gain in mice. However, FNDC4 treatment did not affect calorie intake. Additionally, treatment with FNDC4 attenuated hyperlipidemia-induced phosphorylation or expression of ER stress markers such as IRE-1, eIF2α, and CHOP in 3T3-L1 adipocytes and in subcutaneous adipose tissue of mice. FNDC4 treatment stimulated AMPK phosphorylation and HO-1 expression in 3T3-L1 adipocytes and in subcutaneous adipose tissue of mice. siRNA-mediated suppression of AMPK and HO-1 abrogated the suppressive effects of FNDC4 on palmitate-induced ER stress, inflammation, and insulin resistance. In conclusion, our results show that FNDC4 ameliorates insulin resistance via AMPK/HO-1-mediated suppression of inflammation and ER stress, indicating that FNDC4 may be a novel therapeutic agent for treating insulin resistance and type 2 diabetes.
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Tirado R, Masdeu MJ, Vigil L, Rigla M, Luna A, Rebasa P, Pareja R, Hurtado M, Caixàs A. Impact of Bariatric Surgery on Heme Oxygenase-1, Inflammation, and Insulin Resistance in Morbid Obesity with Obstructive Sleep Apnea. Obes Surg 2018; 27:2338-2346. [PMID: 28283920 DOI: 10.1007/s11695-017-2635-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Morbid obesity and obstructive sleep apnea (OSA) interact at an inflammatory level. Bariatric surgery reduces inflammatory responses associated with obesity. Heme oxygenase-1 (HO-1) is an enzyme with anti-inflammatory properties, which might be increased in morbid obesity or OSA. We studied morbidly obese patients with OSA to determine: (a) HO-1 plasma concentrations according to OSA severity and their relationship with insulin resistance and inflammation and (b) the impact of bariatric surgery on HO-1 and parameters of insulin resistance and inflammation. MATERIAL AND METHODS We analyzed the homeostasis model insulin resistance index (HOMA) and plasma concentrations of HO-1, tumor necrosis factor alpha, interleukin-6, interleukin-1-beta, C reactive protein (CRP), and adiponectin according to polysomnography findings in 66 morbidly obese patients before bariatric surgery and 12 months after surgery. RESULTS Before surgery, HO-1 plasma concentrations were similar in three groups of patients with mild, moderate, and severe OSA, and correlated with HOMA (r = 0.27, p = 0.02). Twelve months after surgery, low-grade inflammation and insulin resistance had decreased in all the groups, but HO-1 plasma concentration had decreased only in the severe OSA group (p = 0.02). In this group, the reduction in HO-1 correlated with a reduction in CRP concentrations (r = 0.43, p = 0.04) and with improved HOMA score (r = 0.37, p = 0.03). CONCLUSIONS Bariatric surgery decreases HO-1 concentrations in morbid obesity with severe OSA, and this decrease is associated with decreases in insulin resistance and in inflammation.
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Affiliation(s)
- Raquel Tirado
- Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Maria José Masdeu
- Pneumology Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Laura Vigil
- Pneumology Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, Ciber de Enfermedades Respiratorias-Ciberes, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Mercedes Rigla
- Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Alexis Luna
- Surgery Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Pere Rebasa
- Surgery Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Rocío Pareja
- Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Marta Hurtado
- Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain
| | - Assumpta Caixàs
- Endocrinology and Nutrition Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Universitat Autònoma de Barcelona, c/ Parc Taulí no 1, 08208, Sabadell, Barcelona, Spain.
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Bereczki D, Balla J, Bereczki D. Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke. Curr Pharm Des 2018; 24:2229-2235. [PMID: 30014798 PMCID: PMC6302555 DOI: 10.2174/1381612824666180717101104] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/02/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023]
Abstract
Stroke is the second-leading cause of death and a leading cause of serious long-term disability worldwide, with an increasing global burden due to the growing and aging population. However, strict eligibility criteria for current treatment opportunities make novel therapeutic approaches desirable. Oxidative stress plays a pivotal role during cerebral ischemia, eventually leading to neuronal injury and cell death. The significant correlation between redox imbalance and ischemic stroke has led to various treatment strategies targeting the endogenous antioxidant system in order to ameliorate the adverse prognosis in patients with cerebral infarction. One of the most extensively investigated cellular defense pathway in this regard is the Nrf2-heme oxygenase-1 (HO-1) axis. In this review, our aim is to focus on the potential clinical relevance of targeting the HO-1 pathway in ischemic stroke.
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Affiliation(s)
- Daniel Bereczki
- Address correspondence to this author at the Department of Neurology, Medical Centre, Hungarian Defence Forces, Róbert Károly krt. 44., Budapest, H-1134, Hungary; Tel: +36-70-701-0671; E-mail:
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The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice. Int J Mol Sci 2017; 18:ijms18112268. [PMID: 29143802 PMCID: PMC5713238 DOI: 10.3390/ijms18112268] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 10/25/2017] [Accepted: 10/27/2017] [Indexed: 01/19/2023] Open
Abstract
The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes.
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Ling K, Men F, Wang WC, Zhou YQ, Zhang HW, Ye DW. Carbon Monoxide and Its Controlled Release: Therapeutic Application, Detection, and Development of Carbon Monoxide Releasing Molecules (CORMs). J Med Chem 2017; 61:2611-2635. [PMID: 28876065 DOI: 10.1021/acs.jmedchem.6b01153] [Citation(s) in RCA: 197] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described.
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Affiliation(s)
- Ken Ling
- Cancer Center, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China.,Department of Anesthesiology, Union Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China
| | - Fang Men
- College of Chemistry and Molecular Sciences , Wuhan University , Wuhan 430072 , China
| | - Wei-Ci Wang
- Department of Vascular Surgery, Union Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China
| | - Ya-Qun Zhou
- Anesthesiology Institute, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China
| | - Hao-Wen Zhang
- Cancer Center, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China
| | - Da-Wei Ye
- Cancer Center, Tongji Hospital, Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , China
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Nagami M, Ito Y, Nagasawa T. Phenethyl isothiocyanate protects against H 2O 2-induced insulin resistance in 3T3-L1 adipocytes. Biosci Biotechnol Biochem 2017; 81:2195-2203. [PMID: 28899227 DOI: 10.1080/09168451.2017.1372181] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Obesity is associated with systemic oxidative stress and leads to insulin resistance. Phenethyl isothiocyanate (PEITC), a natural dietary isothiocyanate, has been shown to have beneficial effects in improving cellular defense activities against oxidative stress through activation of nuclear factor erythroid-2 related factor 2 (Nrf2) pathway. However, little evidence exists if the antioxidative activity has beneficial effects on glucose metabolism. Here, we tested the preventive potential of PEITC for impaired insulin-induced glucose uptake by oxidative stress in 3T3-L1 adipocytes. Treatment with PEITC increased the expression of antioxidative enzymes regulated by Nrf2 such as γ-glutamylcysteine-synthetase, heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase, and reduced oxidative stress induced by H2O2. Furthermore, PEITC restored impaired insulin-stimulated glucose uptake, translocation of glucose transporter 4 and insulin signaling by H2O2. These results indicate that PEITC protected insulin-regulated glucose metabolism impaired by oxidative stress through the antioxidative activity in 3T3-L1 adipocytes.
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Affiliation(s)
- Moe Nagami
- a Department of Biological Chemistry and Food Science, Graduate School of Agriculture , Iwate University , Morioka , Japan
| | - Yoshiaki Ito
- a Department of Biological Chemistry and Food Science, Graduate School of Agriculture , Iwate University , Morioka , Japan
| | - Takashi Nagasawa
- a Department of Biological Chemistry and Food Science, Graduate School of Agriculture , Iwate University , Morioka , Japan
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Mišan A, Petelin A, Stubelj M, Mandić A, Šimurina O, Pojić M, Milovanović I, Jakus T, Filipčev B, Jenko Pražnikar Z. Buckwheat – enriched instant porridge improves lipid profile and reduces inflammation in participants with mild to moderate hypercholesterolemia. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.06.056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Murugesan V, Degerman E, Holmen-Pålbrink AK, Duner P, Knutsson A, Hultgårdh-Nilsson A, Rauch U. β-Sarcoglycan Deficiency Reduces Atherosclerotic Plaque Development in ApoE-Null Mice. J Vasc Res 2017; 54:235-245. [PMID: 28768281 DOI: 10.1159/000478014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 06/02/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Smooth muscle cells are important for atherosclerotic plaque stability. Their proper ability to communicate with the extracellular matrix is crucial for maintaining the correct tissue integrity. In this study, we have investigated the role of β-sarcoglycan within the matrix-binding dystrophin-glycoprotein complex in the development of atherosclerosis. RESULTS Atherosclerotic plaque development was significantly reduced in ApoE-deficient mice lacking β-sarcoglycan, and their plaques contained an increase in differentiated smooth muscle cells. ApoE-deficient mice lacking β-sarcoglycan showed a reduction in ovarian adipose tissue and adipocyte size, while the total weight of the animals was not significantly different. Western blot analysis of adipose tissues showed a decreased activation of protein kinase B, while that of AMP-activated kinase was increased in mice lacking β-sarcoglycan. Analysis of plasma in β-sarcoglycan-deficient mice revealed reduced levels of leptin, adiponectin, insulin, cholesterol, and triglycerides but increased levels of IL-6, IL-17, and TNF-α. CONCLUSIONS Our results indicate that the dystrophin-glycoprotein complex and β-sarcoglycan can affect the atherosclerotic process. Furthermore, the results show the effects of β-sarcoglycan deficiency on adipose tissue and lipid metabolism, which may also have contributed to the atherosclerotic plaque reduction.
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Affiliation(s)
- Vignesh Murugesan
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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Singh SP, Grant I, Meissner A, Kappas A, Abraham NG. Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice. Horm Mol Biol Clin Investig 2017; 31:hmbci-2017-0027. [PMID: 28763300 DOI: 10.1515/hmbci-2017-0027] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 06/23/2017] [Indexed: 12/15/2022]
Abstract
Background Hmox1 plays an important role in the regulation of mitochondrial bioenergetics and function by regulating cellular heme-derived CO and bilirubin. Previous studies have demonstrated that global disruption of HO-1 in humans and mice resulted in severe organ dysfunction. Methods We investigated the potential role of adipose-specific-HO-1 genetic ablation on adipose tissue function, mitochondrial quality control and energy expenditure by generating an adipo-HO-1 knockout mouse model (Adipo-HO-1-/-) and, in vitro, adipocyte cells in which HO activity was inhibited. Adiposity, signaling proteins, fasting glucose and oxygen consumption were determined and compared to adipocyte cultures with depressed levels of both HO-1/HO-2. Results Adipo-HO-1-/- female mice exhibited increased adipocyte size, and decreases in the mitochondrial fusion to fission ratio, PGC1, and SIRT3. Importantly, ablation of HO-1 in adipose tissue resulted in fat acquiring many properties of visceral fat such as decreases in thermogenic genes including pAMPK and PRDM16. Deletion of HO-1 in mouse adipose tissue led to complete metabolic dysfunction, an increase in white adipose tissue, a reduction of beige fat and associated increases in FAS, aP2 and hyperglycemia. Mechanistically, genetic deletion of HO-1 in adipose tissues decreased the mitochondrial fusion to fission ratio; disrupted the activity of the PGC1 transcriptional axis and thermogenic genes both in vitro and in vivo. Conclusion Ablation of adipose tissue-HO-1 abridged PGC1 expression promoted mitochondrial dysfunction and contributed to an increase of pro-inflammatory visceral fat and abrogated beige-cell like phenotype.
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Affiliation(s)
| | - Ilana Grant
- Department of Medicine, New York Medical College, NY, USA
| | - Aliza Meissner
- Department of Medicine, New York Medical College, NY, USA
| | - Attallah Kappas
- The Rockefeller University, New York, NY 10065, USA, Phone: 212-327-8494, Fax: 212-327-8690
| | - Nader G Abraham
- Department of Pharmacology, New York Medical College, NY, USA
- New York Medical College, Valhalla, NY 10595, USA, Phone: +914-594-3121, Fax: +914-347-4956
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