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Danielak A, Magierowski M. Obesity and mitochondrial uncoupling - an opportunity for the carbon monoxide-based pharmacology of metabolic diseases. Pharmacol Res 2025; 215:107741. [PMID: 40252782 DOI: 10.1016/j.phrs.2025.107741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 04/16/2025] [Accepted: 04/16/2025] [Indexed: 04/21/2025]
Abstract
Obesity, a chronic and progressive disease with a complex etiology, remains a significant global health challenge. Despite advancements in lifestyle interventions, pharmacological therapies, and bariatric surgery, substantial barriers to effective and sustained obesity management persist. Resistance to weight loss and gradual weight regain are commonly reported, limiting the long-term success of both non-pharmacological and pharmacological strategies. A possible contributor is metabolic adaptation, a phenomenon characterized by reduced metabolic rate and energy expenditure following weight loss, which hinders therapeutic efficacy. To address these challenges, increasing attention has been directed toward strategies that counteract maladaptive mechanisms by modulating metabolic rate and enhancing energy expenditure. One promising approach involves mitochondrial uncoupling, where electron transport and oxygen consumption are disconnected from ATP synthesis, promoting energy dissipation. Preclinical studies have demonstrated the potential of various chemical compounds with uncoupling activity as anti-obesity agents. Additionally, carbon monoxide (CO) has emerged as a significant gaseous signaling molecule in human physiology, with anti-inflammatory, antioxidative, and cytoprotective properties. Advances in CO-based pharmacology have led to the development of controlled-release CO donors, enabling precise therapeutic application. Experimental studies suggest that CO modulates mitochondrial bioenergetics, induces mild mitochondrial uncoupling, and regulates mitochondrial biogenesis. By integrating these findings, this review uniquely connects scientific threads, offering a comprehensive synthesis of current knowledge while proposing innovative directions in mitochondrial, metabolic and CO-based pharmacological research. It highlights the potential of CO-based pharmacology to regulate metabolic rate, support weight loss, and address obesity-related dysfunctions, thus suggesting novel pathways for advancing obesity treatment.
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Affiliation(s)
- Aleksandra Danielak
- Center for Biomedicine and Interdisciplinary Sciences, Jagiellonian University - Medical College, Krakow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University - Medical College, Krakow, Poland
| | - Marcin Magierowski
- Center for Biomedicine and Interdisciplinary Sciences, Jagiellonian University - Medical College, Krakow, Poland.
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2
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Lee WH, Kipp ZA, Pauss SN, Martinez GJ, Bates EA, Badmus OO, Stec DE, Hinds TD. Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics. Clin Sci (Lond) 2025; 139:CS20242825. [PMID: 39873298 DOI: 10.1042/cs20242825] [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: 10/29/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 01/30/2025]
Abstract
Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.
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Affiliation(s)
- Wang-Hsin Lee
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Zachary A Kipp
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sally N Pauss
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Genesee J Martinez
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Evelyn A Bates
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Olufunto O Badmus
- Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, USA
| | - David E Stec
- Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, USA
| | - Terry D Hinds
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
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3
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Dayarathne LA, Ko SC, Yim MJ, Lee JM, Kim JY, Oh GW, Kim CH, Kim KW, Lee DS, Jung WK, Je JY. Purple Butter Clam ( Saxidomus Purpurata) as a Potential Functional Food Source for Obesity Treatment. J Med Food 2024; 27:1038-1049. [PMID: 39382491 DOI: 10.1089/jmf.2024.k.0169] [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] [Indexed: 10/10/2024] Open
Abstract
Saxidomus purpurata extract (SPE) is a highly consumable seafood worldwide with known health-related benefits. However, there are no reports of its' anti-obesity effect. This study explores the potential of SPE for anti-obesity effects by modulating adipogenesis and lipolysis. SPE reduced intracellular lipid and triglyceride accumulation while increasing free glycerol release in adipocytes. SPE inhibited lipogenesis protein expressions and increased the phosphorylation of hormone-sensitive lipase and Adenosine monophosphate-activated protein kinase (AMPK) to promote lipolysis. In addition, SPE suppressed adipogenesis by downregulating protein expression of key adipogenic markers, peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP1) via Wnt/β-catenin signaling. SPE augmented the heme oxygenase-1 (HO-1) expression. Thus, pharmacological intervention with Zinc protoporphyrin (ZnPP-HO-1 antagonist) was employed to validate the HO-1 role. The presence of ZnPP increased the lipid accumulation and reduced the free glycerol release. At the molecular level, adipogenic transcription factors (PPARγ, C/EBPα, and SREBP1) expressions were restored in the presence of ZnPP. GC-MS analysis revealed that SPE was comprised of several fatty acids, contributing to its anti-obesity activity. SPE is an effective nutraceutical that can be used to reduce the progression of obesity. HO-1 expression during adipogenesis might be the mechanism of action for the anti-obesity effect of SPE.
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Affiliation(s)
- Lakshi A Dayarathne
- Department of Food and Nutrition, Pukyong National University, Busan, Republic of Korea
| | - Seok-Chun Ko
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Mi-Jin Yim
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Jeong Min Lee
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Ji-Yul Kim
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Gun-Woo Oh
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Chul Hwan Kim
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Kyung Woo Kim
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Dae-Sung Lee
- National Marine Biodiversity of Korea (MABIK), Seochun, Korea
| | - Won-Kyo Jung
- Major of Biomedical Engineering, Division of Smart Healthcare, Pukyong National University, Busan, Korea
| | - Jae-Young Je
- Major of Human Bioconvergence, Division of Smart Healthcare, Pukyong National University, Busan, Korea
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Padda I, Sethi Y, Das M, Fabian D, Ralhan T, Aziz D, Sexton J, Johal G. Heme Oxygenase-1, Cardiac Senescence, and Myocardial Infarction: A Critical Review of the Triptych. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07590-0. [PMID: 38940935 DOI: 10.1007/s10557-024-07590-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/24/2024] [Indexed: 06/29/2024]
Abstract
PURPOSE Heme oxygenase-1 (HO-1) is a crucial enzyme in heme metabolism, facilitating the breakdown of heme into biliverdin, carbon monoxide, and free iron. Renowned for its potent cytoprotective properties, HO-1 showcases notable antioxidant, anti-inflammatory, and anti-apoptotic effects. In this review, the authors aim to explore the profound impact of HO-1 on cardiac senescence and its potential implications in myocardial infarction (MI). RESULTS Recent research has unveiled the intricate role of HO-1 in cellular senescence, characterized by irreversible growth arrest and functional decline. Notably, cardiac senescence has emerged as a pivotal factor in the development of various cardiovascular conditions, including MI. Notably, cardiac senescence has emerged as an important factor in the development of various cardiovascular conditions, including myocardial infarction (MI). The accumulation of senescent cells, spanning vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, and progenitor cells, poses a significant risk for cardiovascular diseases such as vascular aging, atherosclerosis, myocardial infarction, and ventricular remodeling. Inhibition of cardiomyocyte senescence not only reduces senescence-associated inflammation but also impacts other myocardial lineages, hinting at a broader mechanism of propagation in pathological remodeling. HO-1 has been shown to improve heart function and mitigate cardiomyocyte senescence induced by ischemic injury and aging. Furthermore, HO-1 induction has been found to alleviate H2O2-induced cardiomyocyte senescence. As we grow in our understanding of antiproliferative, antiangiogenic, anti-aging, and vascular effects of HO-1, we see the potential to exploit potential links between individual susceptibility to cardiac senescence and myocardial infarction. CONCLUSIONS This review investigates strategies for upregulating HO-1, including gene targeting and pharmacological agents, as potential therapeutic approaches. By synthesizing compelling evidence from diverse experimental models and clinical investigations, this study elucidates the therapeutic potential of targeting HO-1 as an innovative strategy to mitigate cardiac senescence and improve outcomes in myocardial infarction, emphasizing the need for further research in this field.
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Affiliation(s)
- Inderbir Padda
- Richmond University Medical Center/Mount Sinai, Staten Island, NY, USA
- PearResearch, Dehradun, India
| | - Yashendra Sethi
- PearResearch, Dehradun, India.
- Government Doon Medical College, Dehradun, Uttarakhand, India.
| | - Maumita Das
- School of Medicine, St. George's University, True Blue, Grenada
| | - Daniel Fabian
- Richmond University Medical Center/Mount Sinai, Staten Island, NY, USA
| | - Tushar Ralhan
- Department of Internal Medicine, Robert Wood Johnson Medical School, RutgersNew Brunswick, NJ, USA
| | - Daniel Aziz
- Department of Internal Medicine, Robert Wood Johnson Medical School, RutgersNew Brunswick, NJ, USA
| | - Jaime Sexton
- Department of Internal Medicine, Robert Wood Johnson Medical School, RutgersNew Brunswick, NJ, USA
| | - Gurpreet Johal
- Valley Medical Center, University of Washington, Seattle, USA
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Charoensaensuk V, Huang BR, Huang ST, Lin C, Xie SY, Chen CW, Chen YC, Cheng HT, Liu YS, Lai SW, Shen CK, Lin HJ, Yang LY, Lu DY. LPS priming-induced immune tolerance mitigates LPS-stimulated microglial activation and social avoidance behaviors in mice. J Pharmacol Sci 2024; 154:225-235. [PMID: 38485340 DOI: 10.1016/j.jphs.2024.02.006] [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: 11/13/2023] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
In this study, we investigated the regulatory mechanisms underlying the effects of LPS tolerance on the inflammatory homeostasis of immune cells. LPS priming-induced immune tolerance downregulated cyclooxygenase-2, and lowered the production of prostaglandin-E2 in microglial cells. In addition, LPS tolerance downregulated the expression of suppressor of cytokine signaling 3, and inducible nitric oxide synthase/nitric oxide; suppressed the LPS-mediated induction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1; and reduced reactive oxygen species production in microglial cells. LPS stimulation increased the levels of the adaptive response-related proteins heme oxygenase-1 and superoxide dismutase 2, and the levels of heme oxygenase-1 (HO-1) enhanced after LPS priming. Systemic administration of low-dose LPS (0.5 mg/kg) to mice for 4 consecutive days attenuated high-dose LPS (5 mg/kg)-induced inflammatory response, microglial activation, and proinflammatory cytokine expression. Moreover, repeated exposure to low-dose LPS suppressed the recruitment of peripheral monocytes or macrophages to brain regions and downregulated the expression of proinflammatory cytokines. Notably, LPS-induced social avoidance behaviors in mice were mitigated by immune tolerance. In conclusion, immune tolerance may reduce proinflammatory cytokine expression and reactive oxygen species production. Our findings provide insights into the effects of endotoxin tolerance on innate immune cells and social behaviors.
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Affiliation(s)
- Vichuda Charoensaensuk
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Bor-Ren Huang
- Department of Neurosurgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Sian-Ting Huang
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chingju Lin
- Department of Physiology, School of Medicine, China Medical University, Taichung, 404328, Taiwan
| | - Sheng-Yun Xie
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Chao-Wei Chen
- Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | - Yen-Chang Chen
- Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | - Han-Tsung Cheng
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Shu Liu
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Sheng-Wei Lai
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Ching-Kai Shen
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Hui-Jung Lin
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Liang-Yo Yang
- Department of Physiology, School of Medicine, China Medical University, Taichung, 404328, Taiwan; Laboratory for Neural Repair, China Medical University Hospital, Taichung, 404327, Taiwan; Biomedical Technology R&D Center, China Medical University Hospital, Taichung, 404327, Taiwan.
| | - Dah-Yuu Lu
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan.
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6
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Engin AB, Engin A. MicroRNAs as Epigenetic Regulators of Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:595-627. [PMID: 39287866 DOI: 10.1007/978-3-031-63657-8_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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Satarug S. Is Environmental Cadmium Exposure Causally Related to Diabetes and Obesity? Cells 2023; 13:83. [PMID: 38201287 PMCID: PMC10778334 DOI: 10.3390/cells13010083] [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: 11/28/2023] [Revised: 12/27/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Cadmium (Cd) is a pervasive toxic metal, present in most food types, cigarette smoke, and air. Most cells in the body will assimilate Cd, as its charge and ionic radius are similar to the essential metals, iron, zinc, and calcium (Fe, Zn, and Ca). Cd preferentially accumulates in the proximal tubular epithelium of the kidney, and is excreted in urine when these cells die. Thus, excretion of Cd reflects renal accumulation (body burden) and the current toxicity of Cd. The kidney is the only organ other than liver that produces and releases glucose into the circulation. Also, the kidney is responsible for filtration and the re-absorption of glucose. Cd is the least recognized diabetogenic substance although research performed in the 1980s demonstrated the diabetogenic effects of chronic oral Cd administration in neonatal rats. Approximately 10% of the global population are now living with diabetes and over 80% of these are overweight or obese. This association has fueled an intense search for any exogenous chemicals and lifestyle factors that could induce excessive weight gain. However, whilst epidemiological studies have clearly linked diabetes to Cd exposure, this appears to be independent of adiposity. This review highlights Cd exposure sources and levels associated with diabetes type 2 and the mechanisms by which Cd disrupts glucose metabolism. Special emphasis is on roles of the liver and kidney, and cellular stress responses and defenses, involving heme oxygenase-1 and -2 (HO-1 and HO-2). From heme degradation, both HO-1 and HO-2 release Fe, carbon monoxide, and a precursor substrate for producing a potent antioxidant, bilirubin. HO-2 appears to have also anti-diabetic and anti-obese actions. In old age, HO-2 deficient mice display a symptomatic spectrum of human diabetes, including hyperglycemia, insulin resistance, increased fat deposition, and hypertension.
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Affiliation(s)
- Soisungwan Satarug
- Kidney Disease Research Collaborative, Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia
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Puerto-Carranza E, Nuevo-Casals S, Roca-Portella B, Mas-Parés B, Gómez-Vilarrubla A, Carreras-Badosa G, Niubó M, Prats-Puig A, de Zegher F, Ibáñez L, Bassols J, López-Bermejo A. Total bilirubin and bilirubin-to-triglycerides ratio predict changes in glycated hemoglobin in healthy children. Front Endocrinol (Lausanne) 2023; 14:1303597. [PMID: 38107514 PMCID: PMC10722262 DOI: 10.3389/fendo.2023.1303597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
Objective Bilirubin and triglycerides can regulate insulin secretion and glucose uptake. The aim of our study is to analyze associations between total bilirubin (TB) and the bilirubin-to-triglycerides ratio (BTR) with metabolic markers in healthy prepubertal children. Methods Subjects were 246 healthy children (mean age 8), of whom 142 (58%) were reevaluated 4 years later (mean age 12). The subjects were stratified according to age into three groups (<7.8 years; 7.8-9.6 years; and >9.6 years; n=82 each) at baseline and into two groups (<12.9 years and ≥12.9 years; n=71 each) at follow-up. Anthropometrics and laboratory parameters [TB and its fractions (direct and indirect bilirubin), triglycerides, HDL-cholesterol, glucose, insulin, HOMA-IR, HOMA-B and glycated hemoglobin (HbA1c)] were assessed at both baseline and follow-up. Results TB and BTR showed independent and negative association with baseline and follow-up HbA1c. These associations were stronger for BTR and in the highest age group. No independent associations were observed with HOMA-IR or HOMA-B. Conclusion TB and BTR are independently associated with HbA1c and predict its changes over time in healthy children. Our results indicate that TB and BTR may be useful parameters in studies of glucose tolerance in healthy children.
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Affiliation(s)
- Elsa Puerto-Carranza
- Pediatric Endocrinology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Spain
- Pediatrics, Dr. Trueta University Hospital, Girona, Spain
| | | | | | - Berta Mas-Parés
- Pediatric Endocrinology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Spain
| | | | - Gemma Carreras-Badosa
- Pediatric Endocrinology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Spain
| | - Maria Niubó
- Maternal-Fetal Metabolic Group, Girona Biomedical Research Institute (IDIBGI), Salt, Spain
| | - Anna Prats-Puig
- University School of Health and Sport (EUSES), University of Girona, Girona, Spain
| | - Francis de Zegher
- Department of Development & Regeneration, University of Leuven, Leuven, Belgium
| | - Lourdes Ibáñez
- Endocrinology, Pediatric Research Institute, Sant Joan de Déu Children’s Hospital, Esplugues, Barcelona, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), ISCIII, Madrid, Spain
| | - Judit Bassols
- Maternal-Fetal Metabolic Group, Girona Biomedical Research Institute (IDIBGI), Salt, Spain
| | - Abel López-Bermejo
- Pediatric Endocrinology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Spain
- Pediatrics, Dr. Trueta University Hospital, Girona, Spain
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9
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Xu H, Wen Q, Xu X, Liu Z, Liu S, Wang H, Zhang C, Wan D, Liu K, Du L, Yuan C, Song L. Induction of heme oxygenase-1 antagonizes PM2.5-induced pulmonary VEGFA expression through regulating HIF-1α. J Biochem Mol Toxicol 2023; 37:e23494. [PMID: 37563788 DOI: 10.1002/jbt.23494] [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: 12/15/2022] [Revised: 06/19/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023]
Abstract
Particulate matter (PM) 2.5 has long been regarded as a major risk factor of the respiratory system, which constitutes a threat to human health. Although the positive relationship between PM2.5 exposure and the development of respiratory diseases has been well established, limited studies investigate the intrinsic self-protection mechanisms against PM2.5-induced respiratory injuries. Excessive pulmonary inflammation served as a key pathogenic mechanism in PM2.5-induced airway dysfunction, and we have previously shown that PM2.5 induced the production of vascular endothelial growth factor A (VEGFA) in the bronchial epithelial cells, which subsequently led to pulmonary inflammatory responses. In the current study, we found that PM2.5 also concurrently induced the expression of the stress-responsive protein heme oxygenase-1 (HO-1) along with VEGFA in the bronchial epithelial cells both in vivo and in vitro. Importantly, knocking down of HO-1 expression significantly increased the synthesis and secretion of VEGFA; while overexpression of HO-1 showed the opposite effects, indicating that HO-1 induction can antagonize VEGFA production in the bronchial epithelial cells upon PM2.5 exposure. Mechanistically, HO-1 inhibited PM2.5-evoked VEGFA induction through modulating hypoxia-inducible factor 1 alpha (HIF-1α), which was the upstream transcriptional factor of VEGFA. More specifically, HO-1 could not only inhibit HIF-1α expression, but also suppress its transactivity. Taken together, our results suggested that HO-1 was an intrinsic protective factor against PM2.5-induced pulmonary VEGFA production with a mechanism relating to HIF-1α, thus providing a potential treatment strategy against PM2.5 triggered airway injuries.
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Affiliation(s)
- Huan Xu
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China
| | - Qing Wen
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Xiuduan Xu
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China
| | - Zhihui Liu
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- College of Life Science, Henan Normal University, Xinxiang, People's Republic of China
| | - Shasha Liu
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Hongli Wang
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University, Kaifeng, People's Republic of China
| | - Chongchong Zhang
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University, Kaifeng, People's Republic of China
| | - Delian Wan
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Kun Liu
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Lina Du
- Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Chao Yuan
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
| | - Lun Song
- Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China
- School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China
- College of Life Science, Henan Normal University, Xinxiang, People's Republic of China
- School of Pharmacy, Jiamusi University, Jiamusi, People's Republic of China
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10
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Ruck L, Wiegand S, Kühnen P. Relevance and consequence of chronic inflammation for obesity development. Mol Cell Pediatr 2023; 10:16. [PMID: 37957462 PMCID: PMC10643747 DOI: 10.1186/s40348-023-00170-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Increasing prevalence of morbid obesity accompanied by comorbidities like type 2 diabetes mellitus (T2DM) led to a demand for improving therapeutic strategies and pharmacological intervention options. Apart from genetics, inflammation processes have been hypothesized to be of importance for the development of obesity and related aspects like insulin resistance. MAIN TEXT Within this review, we provide an overview of the intricate interplay between chronic inflammation of the adipose tissue and the hypothalamus and the development of obesity. Further understanding of this relationship might improve the understanding of the underlying mechanism and may be of relevance for the establishment of new treatment strategies.
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Affiliation(s)
- Lisa Ruck
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany.
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany.
| | - Susanna Wiegand
- Abteilung Interdisziplinär, Sozial-Pädiatrisches Zentrum, Charité Universitätsmedizin, Berlin, Germany
| | - Peter Kühnen
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany
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11
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Jayanti S, Dalla Verde C, Tiribelli C, Gazzin S. Inflammation, Dopaminergic Brain and Bilirubin. Int J Mol Sci 2023; 24:11478. [PMID: 37511235 PMCID: PMC10380707 DOI: 10.3390/ijms241411478] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Dopamine is a well-known neurotransmitter due to its involvement in Parkinson's disease (PD). Dopamine is not only involved in PD but also controls multiple mental and physical activities, such as the pleasure of food, friends and loved ones, music, art, mood, cognition, motivation, fear, affective disorders, addiction, attention deficit disorder, depression, and schizophrenia. Dopaminergic neurons (DOPAn) are susceptible to stressors, and inflammation is a recognized risk for neuronal malfunctioning and cell death in major neurodegenerative diseases. Less is known for non-neurodegenerative conditions. Among the endogenous defenses, bilirubin, a heme metabolite, has been shown to possess important anti-inflammatory activity and, most importantly, to prevent DOPAn demise in an ex vivo model of PD by acting on the tumor necrosis factor-alpha (TNFα). This review summarizes the evidence linking DOPAn, inflammation (when possible, specifically TNFα), and bilirubin as an anti-inflammatory in order to understand what is known, the gaps that need filling, and the hypotheses of anti-inflammatory strategies to preserve dopamine homeostasis with bilirubin included.
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Affiliation(s)
- Sri Jayanti
- Italian Liver Foundation, Liver Brain Unit “Rita Moretti”, Area Science Park, Bldg. Q, SS 14, Km 163,5, 34149 Trieste, Italy; (S.J.); (C.D.V.); (S.G.)
- Eijkman Research Centre for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Cibinong 16915, Indonesia
| | - Camilla Dalla Verde
- Italian Liver Foundation, Liver Brain Unit “Rita Moretti”, Area Science Park, Bldg. Q, SS 14, Km 163,5, 34149 Trieste, Italy; (S.J.); (C.D.V.); (S.G.)
| | - Claudio Tiribelli
- Italian Liver Foundation, Liver Brain Unit “Rita Moretti”, Area Science Park, Bldg. Q, SS 14, Km 163,5, 34149 Trieste, Italy; (S.J.); (C.D.V.); (S.G.)
| | - Silvia Gazzin
- Italian Liver Foundation, Liver Brain Unit “Rita Moretti”, Area Science Park, Bldg. Q, SS 14, Km 163,5, 34149 Trieste, Italy; (S.J.); (C.D.V.); (S.G.)
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12
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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: 4] [Impact Index Per Article: 2.0] [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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13
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Kabach I, Bouchmaa N, Zouaoui Z, Ennoury A, El Asri S, Laabar A, Oumeslakht L, Cacciola F, El Majdoub YO, Mondello L, Zyad A, Nhiri N, Nhiri M, Ben Mrid R. Phytochemical profile and antioxidant capacity, α-amylase and α-glucosidase inhibitory activities of Oxalis pes-caprae extracts in alloxan-induced diabetic mice. Biomed Pharmacother 2023; 160:114393. [PMID: 36774725 DOI: 10.1016/j.biopha.2023.114393] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Diabetes and its complications are closely correlated with chronic hyperglycemia, causing severe oxidative stress and leading to glycation reaction with formation of advanced glycation end products. However, medicinal plants are still a source of inspiration for the discovery of new treatments of several diseases, including diabetes. The present study was aimed to evaluate the antioxidant and antidiabetic properties of Oxalis pes-caprae flowers extract in alloxan-induced diabetic mice. The phytochemical and antioxidant activities of both aqueous and methanolic extracts were assessed by in-vitro testing such as free radical scavenging assays (DPPH and ABTS+), ferrous ions (Fe2+) chelating activity and reducing power assay. Additionally, the detection of Amadori products and advanced glycation end products was used to determine the antiglycation potential. α-glucosidase and α-amylase inhibitory assessment was employed to determine the antidiabetic effect, while alloxan-induced diabetic mice were used to measure the in-vivo activities of antioxidants and carbohydrates enzymes. The effect of the methanolic extract on body weight and blood glucose level of extract-treated diabetic mice were also investigated. Among the tested extract, the methanolic extract was the richest in phenolic compounds which is directly related with their remarkable antioxidant, enzyme inhibitory and antiglycation activity. The oral administration of the two doses of Oxalis pes-caprae flowers (150 mg/kg and 250 mg/kg) daily for 3 weeks resulted in hypoglycemic effect compared to the reference drug, glibenclamide (10 mg/kg). Furthermore, the extract was shown to significantly increase the activities of antioxidants and glycolysis enzymes in the liver, kidney and spleen of diabetic mice, compared to diabetic control group. Therefore, Oxalis pes-caprae extract effectively exhibited hypoglycemic and antidiabetic effects as indicated by in-vitro and in-vivo studies, confirming the protective effects on hyperglycemia and oxidative damage.
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Affiliation(s)
- Imad Kabach
- Laboratory of Biochemistry and Molecular Genetics, Faculty of Sciences and Technologies of Tangier, BP 416, 90000 Tangier, Morocco
| | - Najat Bouchmaa
- Institute of Biological Sciences (ISSB-P), UM6P-Faculty of Medical Sciences (UM6P-FMS), Mohammed VI Polytechnic University, Ben-Guerir, Morocco; Team of Experimental Oncology and Natural Substances, Cellular and Molecular Immuno-pharmacology, Faculty of Science and Technology, Sultan Moulay Slimane University, Beni-Mellal, Morocco
| | - Zakia Zouaoui
- Laboratory of Biochemistry and Molecular Genetics, Faculty of Sciences and Technologies of Tangier, BP 416, 90000 Tangier, Morocco
| | - Abdelhamid Ennoury
- Laboratory of Biochemistry and Molecular Genetics, Faculty of Sciences and Technologies of Tangier, BP 416, 90000 Tangier, Morocco
| | - Sara El Asri
- Laboratory of Biochemistry and Molecular Genetics, Faculty of Sciences and Technologies of Tangier, BP 416, 90000 Tangier, Morocco
| | - Abdelmounaim Laabar
- Laboratory of Pharmacology and Toxicology, Biopharmaceutical and Toxicological Analysis Research Team, Faculty of Medicine and Pharmacy, University Mohammed V of Rabat, Morocco
| | - Loubna Oumeslakht
- Institute of Biological Sciences (ISSB-P), UM6P-Faculty of Medical Sciences (UM6P-FMS), Mohammed VI Polytechnic University, Ben-Guerir, Morocco
| | - Francesco Cacciola
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy.
| | - Yassine Oulad El Majdoub
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy
| | - Luigi Mondello
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy; Chromaleont s.r.l., c/o Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy; Department of Sciences and Technologies for Human and Environment, University Campus Bio-Medico of Rome, 00128 Rome, Italy
| | - Abdelmajid Zyad
- Team of Experimental Oncology and Natural Substances, Cellular and Molecular Immuno-pharmacology, Faculty of Science and Technology, Sultan Moulay Slimane University, Beni-Mellal, Morocco
| | - Naima Nhiri
- Institute for the Chemistry of Natural Substances, CNRS, Paris Saclay University, 91190 Gif-Sur-Yvette, France
| | - Mohamed Nhiri
- Laboratory of Biochemistry and Molecular Genetics, Faculty of Sciences and Technologies of Tangier, BP 416, 90000 Tangier, Morocco
| | - Reda Ben Mrid
- Laboratory of Biochemistry and Molecular Genetics, Faculty of Sciences and Technologies of Tangier, BP 416, 90000 Tangier, Morocco; Institute of Biological Sciences (ISSB-P), UM6P-Faculty of Medical Sciences (UM6P-FMS), Mohammed VI Polytechnic University, Ben-Guerir, Morocco.
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14
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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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15
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Qian R, Chen H, Lin H, Jiang Y, He P, Ding Y, Wu H, Peng Y, Wang L, Chen C, Wang D, Ji W, Guo X, Shan X. The protective roles of allicin on type 1 diabetes mellitus through AMPK/mTOR mediated autophagy pathway. Front Pharmacol 2023; 14:1108730. [PMID: 36817124 PMCID: PMC9937553 DOI: 10.3389/fphar.2023.1108730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 01/25/2023] [Indexed: 02/05/2023] Open
Abstract
Background: Type 1 diabetes mellitus (T1DM) is one of the most common endocrine and metabolic diseases in children. Pancreatic β cells are thought to be critical cells involved in the progression of T1DM, and their injury would directly lead to impaired insulin secretion. Purpose: To investigate the protective effects of allicin on pancreatic β cell injury and elucidate the underlying mechanism. Methods: The streptozotocin (STZ)-induced mouse T1DM model in vivo and STZ-induced pancreatic β cell Min6 model in vitro were used to explore the effects of allicin on T1DM. The experiments include fasting blood glucose test, oral glucose tolerance detection, HE staining, immunohistochemistry, immunofluorescence, TUNEL staining, western blot, real-time quantitative PCR (RT-qPCR), and flow cytometry. Results: Allicin could significantly decrease blood glucose level, improve islet structure and insulin expression, and inhibit apoptosis to reduce STZ-induced pancreatic β cell injury and loss through activating AMPK/mTOR mediated autophagy pathway. Conclusion: Allicin treatment significantly reduced STZ-induced T1DM progression, suggesting that allicin may be a potential therapy option for T1DM patients.
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Affiliation(s)
- Rengcheng Qian
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huihui Chen
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hongzhou Lin
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yalan Jiang
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pingping He
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yinjuan Ding
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huilan Wu
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yongmiao Peng
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lingfei Wang
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Congde Chen
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Children Genitourinary Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Structural Malformations in Children of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Dexuan Wang
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Children Genitourinary Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Structural Malformations in Children of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weiping Ji
- Department of General Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Weiping Ji, ; Xiaoling Guo, ; Xiaoou Shan,
| | - Xiaoling Guo
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Children Genitourinary Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Structural Malformations in Children of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Basic Medical Research Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Weiping Ji, ; Xiaoling Guo, ; Xiaoou Shan,
| | - Xiaoou Shan
- Department of Pediatrics, The Second Schoozl of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Children Genitourinary Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,Key Laboratory of Structural Malformations in Children of Zhejiang Province, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Weiping Ji, ; Xiaoling Guo, ; Xiaoou Shan,
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16
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Hong J, Kim Y. Fatty Liver/Adipose Tissue Dual-Targeting Nanoparticles with Heme Oxygenase-1 Inducer for Amelioration of Obesity, Obesity-Induced Type 2 Diabetes, and Steatohepatitis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2203286. [PMID: 36209391 PMCID: PMC9685446 DOI: 10.1002/advs.202203286] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/15/2022] [Indexed: 05/28/2023]
Abstract
Persistent uptake of high-calorie diets induces the storage of excessive lipid in visceral adipose tissue. Lipids secreted from obese adipose tissue are accumulated in peripheral tissues such as the liver, pancreas, and muscle, and impair insulin sensitivity causing type 2 diabetes mellitus (T2DM). Furthermore, the accumulation of inflammatory cytokines and lipids in the liver induces apoptosis and fibrogenesis, and ultimately causes nonalcoholic steatohepatitis (NASH). To modulate obese tissue environments, it is challenged to selectively deliver inducers of heme oxygenase-1 (HO-1) to adipose tissue with the aid of a prohibitin targeting drug delivery system. Prohibitin binding peptide (PBP), an oligopeptide targeting prohibitin rich in adipose tissue, is conjugated on the surface of Hemin- or CoPP-loaded poly(lactide-co-glycolide) nanoparticles (PBP-NPs). PBP-NPs efficiently differentiate lipid storing white adipocytes into energy-generating brown adipocytes in T2DM and NASH models. In addition, PBP-NPs are found to target prohibitin overexpressed fatty liver in the NASH model and inhibit hepatic uptake of circulating lipids. Furthermore, PBP-NPs switch phenotypes of inflammatory macrophages in damaged organs and lower inflammation. Taken together, dual-targeted induction of HO-1 in fatty adipose and liver tissues is proven to be a promising therapeutic strategy to ameliorate obesity, insulin resistance, and steatohepatitis by lowering lipids and cytokines.
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Affiliation(s)
- Juhyeong Hong
- Department of BioengineeringInstitute for Bioengineering and Biopharmaceutical Research Hanyang UniversitySeoul04763South Korea
- Education and Research Group for Biopharmaceutical Innovation LeaderHanyang UniversitySeoul04763South Korea
| | - Yong‐Hee Kim
- Department of BioengineeringInstitute for Bioengineering and Biopharmaceutical Research Hanyang UniversitySeoul04763South Korea
- Education and Research Group for Biopharmaceutical Innovation LeaderHanyang UniversitySeoul04763South Korea
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17
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Ye T, Zhang J, Wu D, Shi J, Kuang Z, Ma Y, Xu Q, Chen B, Kan C, Sun X, Han F. Empagliflozin Attenuates Obesity-Related Kidney Dysfunction and NLRP3 Inflammasome Activity Through the HO-1-Adiponectin Axis. Front Endocrinol (Lausanne) 2022; 13:907984. [PMID: 35784553 PMCID: PMC9248377 DOI: 10.3389/fendo.2022.907984] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/12/2022] [Indexed: 01/17/2023] Open
Abstract
Empagliflozin (EMPA) is a novel sodium-glucose cotransporter 2 inhibitor (SGLT2i) that produces protective cardiovascular-renal outcomes in patients with diabetes. However, the effects of EMPA on obesity-related kidney disease have not been determined. The heme oxygenase-1 (HO-1)-adiponectin axis is an essential antioxidant system with anti-apoptotic and anti-inflammatory properties. This study explored whether EMPA improves obesity-related kidney disease through regulation of the renal HO-1-mediated adiponectin axis. C57BL/6J mice were assigned to control, high-fat diet (HFD) groups, and EMPA (10 mg/kg) groups. HFD mice showed metabolic abnormality and renal injury, including increased urinary albumin excretion, morphologic changes, and lipid accumulation. EMPA treatment improved metabolic disorders and attenuated lipotoxicity-induced renal injury. Furthermore, EMPA treatment ameliorated renal NLRP3 inflammasome activity and upregulated the HO-1-adiponectin axis. Our findings indicate that EMPA improves obesity-related kidney disease through reduction of NLRP3 inflammasome activity and upregulation of the HO-1-adiponectin axis, suggesting a novel mechanism for SGLT2i-mediated renal protection in obesity.
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Affiliation(s)
- Tongtong Ye
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Jingwen Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Di Wu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Junfeng Shi
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zengguang Kuang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yuting Ma
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Qian Xu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Bing Chen
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
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18
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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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19
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Topical application of sustained released-carbon monoxide promotes cutaneous wound healing in diabetic mice. Biochem Pharmacol 2022; 199:115016. [PMID: 35331735 DOI: 10.1016/j.bcp.2022.115016] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 01/13/2023]
Abstract
Clinical incidences of pressure ulcers in the elderly and intractable skin ulcers in diabetic patients are increasing because of the aging population and an increase in the number of diabetic patients worldwide. Although various agents are used to treat pressure and skin ulcers, these ulcers are often refractory and deteriorate the patients' quality of life. Therefore, a novel therapeutic agent with a novel mechanism of action is required. Carbon monoxide (CO) contributes to many physiological and pathophysiological processes, including anti-inflammatory activity; therefore, it can be a therapeutic gaseous molecule. Recent studies have revealed that CO accelerates wound healing in gastrointestinal tract injuries. However, it remains unclear whether CO promotes cutaneous wound healing. Therefore, we aimed to evaluate the therapeutic effects of topical application of a CO-containing solution and elucidate the underlying mechanism. A full-thickness skin wound generated on the back of diabetic mice was treated topically with CO or vehicle. Sustained release of CO was achieved using polyacrylic acid (PAA) as a thickener. The administration of CO-containing PAA aqueous solution resulted in a significant acceleration in wound recovery without elevating serum CO levels in association with increased angiogenesis and supported by elevated expression of vascular endothelial growth factor mRNA in the wound granulomatous tissues. These data suggest that CO might represent a novel therapeutic agent for the treatment of cutaneous wounds.
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Reactive Oxygen Species (ROS) and Antioxidants as Immunomodulators in Exercise: Implications for Heme Oxygenase and Bilirubin. Antioxidants (Basel) 2022; 11:antiox11020179. [PMID: 35204062 PMCID: PMC8868548 DOI: 10.3390/antiox11020179] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/12/2022] [Accepted: 01/14/2022] [Indexed: 02/07/2023] Open
Abstract
Exercise is commonly prescribed as a lifestyle treatment for chronic metabolic diseases as it functions as an insulin sensitizer, cardio-protectant, and essential lifestyle tool for effective weight maintenance. Exercise boosts the production of reactive oxygen species (ROS) and subsequent transient oxidative damage, which also upregulates counterbalancing endogenous antioxidants to protect from ROS-induced damage and inflammation. Exercise elevates heme oxygenase-1 (HO-1) and biliverdin reductase A (BVRA) expression as built-in protective mechanisms, which produce the most potent antioxidant, bilirubin. Together, these mitigate inflammation and adiposity. Moderately raising plasma bilirubin protects in two ways: (1) via its antioxidant capacity to reduce ROS and inflammation, and (2) its newly defined function as a hormone that activates the nuclear receptor transcription factor PPARα. It is now understood that increasing plasma bilirubin can also drive metabolic adaptions, which improve deleterious outcomes of weight gain and obesity, such as inflammation, type II diabetes, and cardiovascular diseases. The main objective of this review is to describe the function of bilirubin as an antioxidant and metabolic hormone and how the HO-1-BVRA-bilirubin-PPARα axis influences inflammation, metabolic function and interacts with exercise to improve outcomes of weight management.
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Tsai YC, Cheng PY, Chen JH, Lee YM, Yen MH. Raspberry ketone promotes FNDC5 protein expression via HO-1 upregulation in 3T3-L1 adipocytes. CHINESE J PHYSIOL 2022; 65:80-86. [DOI: 10.4103/cjp.cjp_95_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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22
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Rong X, Peng Y, Liu C, Li M, Shi J, Yu M, Ba S, Sheng W, Zhu B. A novel highly sensitive fluorescent probe for imaging endogenous CO. NEW J CHEM 2022. [DOI: 10.1039/d2nj04920a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
A highly sensitive and selective fluorescent probe was constructed to detect carbon monoxide in living cells and zebrafish.
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Affiliation(s)
- Xiaodi Rong
- School of Water Conservancy and Environment, University of Jinan, Jinan 250022, China
| | - Yiyuan Peng
- School of Water Conservancy and Environment, University of Jinan, Jinan 250022, China
| | - Caiyun Liu
- School of Water Conservancy and Environment, University of Jinan, Jinan 250022, China
| | - Mingzhu Li
- School of Water Conservancy and Environment, University of Jinan, Jinan 250022, China
| | - Jiafan Shi
- School of Water Conservancy and Environment, University of Jinan, Jinan 250022, China
| | - Miaohui Yu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250103, China
| | - Shuaikang Ba
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250103, China
| | - Wenlong Sheng
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250103, China
| | - Baocun Zhu
- School of Water Conservancy and Environment, University of Jinan, Jinan 250022, China
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23
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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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24
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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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25
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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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26
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Stec DE, Abraham NG. Pharmacological and Clinical Significance of Heme Oxygenase-1. Antioxidants (Basel) 2021; 10:antiox10060854. [PMID: 34071751 PMCID: PMC8227735 DOI: 10.3390/antiox10060854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 05/25/2021] [Indexed: 11/16/2022] Open
Affiliation(s)
- David E. Stec
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA
- Correspondence: (D.E.S.); (N.G.A.); Tel.: +1-914-594-3121 (N.G.A.)
| | - 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
- Correspondence: (D.E.S.); (N.G.A.); Tel.: +1-914-594-3121 (N.G.A.)
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27
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Rahman S, Jan G, Jan FG, Rahim HU. Phytochemical Screening and Antidiabetic, Antihyperlipidemic, and Antioxidant Effects of Leptopus Cordifolius Decne. In Diabetic Mice. Front Pharmacol 2021; 12:643242. [PMID: 33897432 PMCID: PMC8060645 DOI: 10.3389/fphar.2021.643242] [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: 12/17/2020] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
Plants are well known in traditional herbal medicines for their hypoglycemic and hypolipidemic activities and are often used due to their accessibility, affordability, and corollary effects. Leptopus cordifolius has been reported to control diabetes in folkloric medicine, but no known scientific research has been conducted to assess the plausibility of this assertion. Therefore, the current study is aimed to investigate the antidiabetic and hypolipidemic effects of Leptopus cordifolius leaves in alloxan-induced diabetic mice. The antidiabetic and antihyperlipidemic evaluation was conducted in Swiss albino mice at doses of 150-250°mg/kg for 15°days. The blood glucose, total cholesterol, triglyceride, LDL, HDL, creatinine, ALP, SGPT, and SGOT levels were estimated according to standard procedures. Phytochemicals of leaves were analyzed using GC-MS analysis. Enzymatic antioxidant activity of the plant was investigated spectrophotometrically by carrying out superoxide dismutase, peroxidase, and catalase assays. The membrane stabilization potential of L. cordifolius leaf extracts was carried out using an in vitro haemolytic assay. The results revealed a dose response effect with the methanolic extract of L. cordifolius which had significant antihyperglycemic effects at 150-250°mg/kg in alloxan treated mice, although less than the positive control (glibenclamide). Hyperlipidemic activity was significant at 250 mg/kg. The biochemical parameters, such as total cholesterol, triglyceride, LDL, HDL, creatinine, ALP, SGPT, and SGOT, were significantly improved (p < 0.01) by the methanolic extract of 250 mg/kg compared to the diabetic group. Treatment for 15 days showed significant elevation (p < 0.01) of antioxidant enzymes. GC-MS analysis provided tentative identifications of 52 compounds in the methanolic extract of L. cordifolius, of which 12 compounds have reported antidiabetic activity. In conclusion, methanolic extract of L. cordifolius of 150 and 250°mg/kg body weight showed significant antidiabetic and antihyperlipidemic activities in alloxan-induced diabetic mice and, with further work, has the potential to be used to manage blood glucose and cholesterol levels.
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Affiliation(s)
- Shahid Rahman
- Pharmacology Lab, Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Gul Jan
- Pharmacology Lab, Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Farzana Gul Jan
- Pharmacology Lab, Department of Botany, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Hafeez Ur Rahim
- Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), School of Environmental Science and Technology, Dalian University of Technology, Dalian, China
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28
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James TJ, Corbett J, Cummings M, Allard S, Young JS, Towse J, Carey-Jones K, Eglin C, Hopkins B, Morgan C, Tipton M, Saynor ZL, Shepherd AI. Timing of acute passive heating on glucose tolerance and blood pressure in people with type 2 diabetes: a randomized, balanced crossover, control trial. J Appl Physiol (1985) 2021; 130:1093-1105. [PMID: 33411640 DOI: 10.1152/japplphysiol.00747.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and progressive insulin resistance, leading to macro and microvascular dysfunction. Passive heating has potential to improve glucose homeostasis and act as an exercise mimetic. We assessed the effect of acute passive heating before or during an oral glucose tolerance test (OGTT) in people with T2DM. Twelve people with T2DM were randomly assigned to the following three conditions: 1) 3-h OGTT (control), 2) 1-h passive heating (40°C water) 30 min before an OGTT (HOT-OGTT), and 3) 1-h passive heating (40°C water) 30 min after commencing an OGTT (OGTT-HOT). Blood glucose concentration, insulin sensitivity, extracellular heat shock protein 70 (eHSP70), total energy expenditure (TEE), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. Passive heating did not alter blood glucose concentration [control: 1,677 (386) arbitrary units (AU), HOT-OGTT: 1,797 (340) AU, and OGTT-HOT: 1,662 (364) AU, P = 0.28], insulin sensitivity (P = 0.15), or SBP (P = 0.18) but did increase eHSP70 concentration in both heating conditions [control: 203.48 (110.81) pg·mL-1; HOT-OGTT: 402.47 (79.02) pg·mL-1; and OGTT-HOT: 310.00 (60.53) pg·mL-1, P < 0.001], increased TEE (via fat oxidation) in the OGTT-HOT condition [control: 263 (33) kcal, HOT-OGTT: 278 (40) kcal, and OGTT-HOT: 304 (38) kcal, P = 0.001], increased HR in both heating conditions (P < 0.001), and reduced DBP in the OGTT-HOT condition (P < 0.01). Passive heating in close proximity to a glucose challenge does not alter glucose tolerance but does increase eHSP70 concentration and TEE and reduce blood pressure in people with T2DM.NEW & NOTEWORTHY This is the first study to investigate the timing of acute passive heating on glucose tolerance and extracellular heat shock protein 70 concentration ([eHSP70]) in people with type 2 diabetes. The principal novel findings from this study were that both passive heating conditions: 1) did not reduce the area under the curve or peak blood glucose concentration, 2) elevated heart rate, and 3) increased [eHSP70], which was blunted by glucose ingestion, while passive heating following glucose ingestion, 4) increased total energy expenditure, and 5) reduced diastolic blood pressure.
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Affiliation(s)
- Thomas J James
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - Jo Corbett
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Michael Cummings
- Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - Sharon Allard
- Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - John S Young
- School of Pharmacy and Biomedical Sciences, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Jonathan Towse
- School of Pharmacy and Biomedical Sciences, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Kathryn Carey-Jones
- School of Biological Sciences, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Oaks Healthcare, Cowplain Family Practice, Waterlooville, United Kingdom
| | - Clare Eglin
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Billy Hopkins
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Connor Morgan
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Michael Tipton
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Zoe L Saynor
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - Anthony I Shepherd
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
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Darwish MA, Abdel-Bakky MS, Messiha BAS, Abo-Saif AA, Abo-Youssef AM. Resveratrol mitigates pancreatic TF activation and autophagy-mediated beta cell death via inhibition of CXCL16/ox-LDL pathway: A novel protective mechanism against type 1 diabetes mellitus in mice. Eur J Pharmacol 2021; 901:174059. [PMID: 33794215 DOI: 10.1016/j.ejphar.2021.174059] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/08/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022]
Abstract
The role of CXC chemokine ligand 16 (CXCL16), oxidized LDL (ox-LDL), tissue factor (TF) and autophagy-induced beta cell death in type 1 diabetes mellitus (T1DM) pathogenesis is still unclear. We examined the therapeutic potential and mechanism of resveratrol (RES) against T1DM. Diabetes was induced in Balb/c mice by i. p. injection of 55 mg/kg streptozotocin (STZ) for five consecutive days. The control group received vehicles. RES or (RES + STZ) groups received RES (50 mg/kg, i. p.) daily for 12 days starting from the fourth day of buffer or STZ injections, respectively. Blood glucose, serum insulin, beta cell mass, serum lipid profiles, histological changes, oxidative stress biomarkers were determined. Moreover, CXCL16, TF, ox-LDL, P62 and LC3 tissue expression were also analyzed. Diabetic mice showed a marked deterioration in biochemical, physical and oxidative stress parameters. Interestingly, immunofluorescence analysis showed a remarkable elevation in CXCL16 (12 folds), ox-LDL (9 folds), TF (8.3 folds) in pancreatic B-cells. Moreover, western blotting revealed a profound increase in ox-LDL (2.6 folds), TF (3.2 folds), while a significant decline in P62 (0.34) and LC3 (0.25) when compared to control. RES mitigated biochemical, physical, oxidative imbalance and distorted pancreatic architecture in T1DM mice. Intriguingly, CXCL16, ox-LDL, TF and autophagic markers were also restored after RES treatment. Our data give the first direct evidence that beta cell-specific CXCL16/ox-LDL pathway activation is a potential trigger of TF activation and autophagic beta cell death in T1DM. Moreover, RES may have potential therapeutic applications for prevention of T1DM mainly via ameliorating this pathway.
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Affiliation(s)
- Mostafa A Darwish
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Mohamed S Abdel-Bakky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim, Saudi Arabia
| | - Basim A S Messiha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
| | - Ali A Abo-Saif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; Department of Pharmacology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Amira M Abo-Youssef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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30
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Chen Y, Huang H, He X, Duan W, Mo X. Sex differences in the link between blood cobalt concentrations and insulin resistance in adults without diabetes. Environ Health Prev Med 2021; 26:42. [PMID: 33773581 PMCID: PMC8005238 DOI: 10.1186/s12199-021-00966-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/17/2021] [Indexed: 01/17/2023] Open
Abstract
Background Little is known about the effects of environmental cobalt exposure on insulin resistance (IR) in the general adult population. We investigated the association between cobalt concentration and IR. Methods A total of 1281 subjects aged more than 20 years with complete blood cobalt data were identified from the National Health and Nutrition Examination Survey (NHANES) 2015–2016 cycle. Blood cobalt levels were analyzed for their association with IR among all populations and subgroups by sex. Regression coefficients and 95% confidence intervals (CIs) of blood cobalt concentrations in association with fasting glucose, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) were estimated using multivariate linear regression after adjusting for age, sex, ethnicity, alcohol consumption, body mass index, education level, and household income. A multivariate generalized linear regression analysis was further carried out to explore the association between cobalt exposure and IR. Results A negative association between blood cobalt concentration (coefficient = − 0.125, 95% CI − 0.234, − 0.015; P = 0.026) and HOMA-IR in female adults in the age- and sex-adjusted model was observed. However, no associations with HOMA-IR, fasting glucose, or insulin were found in the overall population. In the generalized linear models, participants with the lowest cobalt levels had a 2.74% (95% CI 0.04%, 5.50%) increase in HOMA-IR (P for trend = 0.031) compared with subjects with the highest cobalt levels. Restricted cubic spline regression suggested that a non-linear relationship may exist between blood cobalt and HOMA-IR. Conclusions These results provide epidemiological evidence that low levels of blood cobalt are negatively associated with HOMA-IR in female adults. Supplementary Information The online version contains supplementary material available at 10.1186/s12199-021-00966-w.
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Affiliation(s)
- Yong Chen
- Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China
| | - Haobin Huang
- Department of Cardiovascular Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Xiaowei He
- Department of Endocrinology and Metabolism/Diabetes Care and Research Center, Nanjing Medical University Affiliated Geriatric Hospital/Jiangsu Province Geriatric Hospital, Jiangsu Province Official Hospital/Jiangsu Province Institute of Geriatrics, Nanjing, China
| | - Weiwei Duan
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China.
| | - Xuming Mo
- Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China.
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31
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Role of HO-1 against Saturated Fatty Acid-Induced Oxidative Stress in Hepatocytes. Nutrients 2021; 13:nu13030993. [PMID: 33808635 PMCID: PMC8003531 DOI: 10.3390/nu13030993] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/11/2021] [Accepted: 03/16/2021] [Indexed: 01/24/2023] Open
Abstract
Increased circulating levels of free fatty acids, especially saturated ones, are involved in disease progression in the non-alcoholic fatty liver. Although the mechanism of saturated fatty acid-induced toxicity in the liver is not fully understood, oxidative stress may be deeply involved. We examined the effect of increased palmitic acid, the most common saturated fatty acid in the blood, on the liver of BALB/c mice via tail vein injection with palmitate. After 24 h, among several anti-oxidative stress response genes, only heme oxygenase-1 (HO-1) was significantly upregulated in palmitate-injected mice compared with that in vehicle-injected mice. Elevation of HO-1 mRNA was also observed in the fatty liver of high-fat-diet-fed mice. To further investigate the role of HO-1 on palmitic acid-induced oxidative stress, in vitro experiments were performed to expose palmitate to HepG2 cells. SiRNA-mediated knockdown of HO-1 significantly increased the oxidative stress induced by palmitate, whereas pre-treatment with SnCl2, a well-known HO-1 inducer, significantly decreased it. Moreover, SB203580, a selective p38 inhibitor, reduced HO-1 mRNA expression and increased palmitate-induced oxidative stress in HepG2 cells. These results suggest that the HO-1-mediated anti-oxidative stress compensatory reaction plays an essential role against saturated fatty acid-induced lipotoxicity in the liver.
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Dietary vitamin D equilibrium in serum ameliorates direct bilirubin associated diabetes mellitus. Chem Biol Interact 2021; 337:109399. [PMID: 33503443 DOI: 10.1016/j.cbi.2021.109399] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/21/2021] [Indexed: 01/05/2023]
Abstract
Diabetes mellitus (DM), a non-communicable endocrine disease that is marked by a differing degree of tolerance to insulin and dysfunction. The connection between diabetes and liver failure important to doctors in general practice diabetologists and hepatologists. DM is linked with an elevated risk of hepatic consequences and mortality of liver cirrhosis patients. DM may facilitate to insult the liver by inducing inflammation and fibrosis by elevating mitochondrial oxidative stress. The conventional liver function indices are bilirubin including Indirect Bilirubin (IBil), Direct Bilirubin (DBil), and Total Bilirubin (TBil). DBil, IBil, and TBil, have diverse clinical implications as the standard index of liver disorder. An elevated level of DBil may suggest damage to the hepatic cell whereas TBil is within the normal range. Thus, increased liver enzymes are correlated with hepatic insulin resistance in healthy subjects. Notably, a significant correlation between DBil levels and Insulin resistance risk could indicate a connection between liver dysfunction and diabetes mellitus risk. Thus, our primary goal via the current review to examine the impact of dietary vitamin D (VitD) in serum mediated risk reduction of insulin resistance and further incidence of DM through inflammatory liver associated high DBil. Therefore, modifying these inflammatory pathways may be a therapeutic alternative approach for diabetes treatment.
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Hahn D, Shin SH, Bae JS. Natural Antioxidant and Anti-Inflammatory Compounds in Foodstuff or Medicinal Herbs Inducing Heme Oxygenase-1 Expression. Antioxidants (Basel) 2020; 9:E1191. [PMID: 33260980 PMCID: PMC7761319 DOI: 10.3390/antiox9121191] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
Heme oxygenase-1 (HO-1) is an inducible antioxidant enzyme that catalyzes heme group degradation. Decreased level of HO-1 is correlated with disease progression, and HO-1 induction suppresses development of metabolic and neurological disorders. Natural compounds with antioxidant activities have emerged as a rich source of HO-1 inducers with marginal toxicity. Here we discuss the therapeutic role of HO-1 in obesity, hypertension, atherosclerosis, Parkinson's disease and hepatic fibrosis, and present important signaling pathway components that lead to HO-1 expression. We provide an updated, comprehensive list of natural HO-1 inducers in foodstuff and medicinal herbs categorized by their chemical structures. Based on the continued research in HO-1 signaling pathways and rapid development of their natural inducers, HO-1 may serve as a preventive and therapeutic target for metabolic and neurological disorders.
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Affiliation(s)
- Dongyup Hahn
- School of Food Science and Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Korea;
- Department of Integrative Biology, Kyungpook National University, Daegu 41566, Korea
| | - Seung Ho Shin
- Department of Food and Nutrition, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea;
| | - Jong-Sup Bae
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Korea
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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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Yao H, Peterson AL, Li J, Xu H, Dennery PA. Heme Oxygenase 1 and 2 Differentially Regulate Glucose Metabolism and Adipose Tissue Mitochondrial Respiration: Implications for Metabolic Dysregulation. Int J Mol Sci 2020; 21:ijms21197123. [PMID: 32992485 PMCID: PMC7582259 DOI: 10.3390/ijms21197123] [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: 09/02/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 12/15/2022] Open
Abstract
Heme oxygenase (HO) consists of inducible (HO-1) and constitutive (HO-2) isoforms that are encoded by Hmox1 and Hmox2 genes, respectively. As an anti-inflammatory and antioxidant molecule, HO participates in the development of metabolic diseases. Whether Hmox deficiency causes metabolic abnormalities under basal conditions remains unclear. We hypothesized that HO-1 and HO-2 differentially affect global and adipose tissue metabolism. To test this hypothesis, we determined insulin sensitivity, glucose tolerance, energy expenditure, and respiratory exchange ratio in global Hmox1-/- and Hmox2-/- mice. Body weight was reduced in female but not male Hmox1-/- and Hmox2-/- mice. Reduced insulin sensitivity and physical activity were observed in Hmox1-/- but not Hmox2-/- mice. Deletion of either Hmox1 or Hmox2 had no effects on glucose tolerance, energy expenditure or respiratory exchange ratio. Mitochondrial respiration was unchanged in gonadal fat pads (white adipose tissue, WAT) of Hmox1-/- mice. Hmox2 deletion increased proton leak and glycolysis in gonadal, but not interscapular fat tissues (brown adipose tissue, BAT). Uncoupling protein and Hmox1 genes were unchanged in gonadal fat pads of Hmox2-/- mice. Conclusively, HO-1 maintains insulin sensitivity, while HO-2 represses glycolysis and proton leak in the WAT under basal condition. This suggests that HO-1 and HO-2 differentially modulate metabolism, which may impact the metabolic syndrome.
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Affiliation(s)
- Hongwei Yao
- Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI 02860, USA; (H.Y.); (A.L.P.)
| | - Abigail L. Peterson
- Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI 02860, USA; (H.Y.); (A.L.P.)
| | - Jie Li
- Department of Epidemiology, Brown University, Providence, RI 02860, USA; (J.L.); (H.X.)
| | - Haiyan Xu
- Department of Epidemiology, Brown University, Providence, RI 02860, USA; (J.L.); (H.X.)
| | - Phyllis A. Dennery
- Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI 02860, USA; (H.Y.); (A.L.P.)
- Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI 02860, 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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Verheijen N, Suttorp CM, van Rheden REM, Regan RF, Helmich MPAC, Kuijpers-Jagtman AM, Wagener FADTG. CXCL12-CXCR4 Interplay Facilitates Palatal Osteogenesis in Mice. Front Cell Dev Biol 2020; 8:771. [PMID: 32974338 PMCID: PMC7471603 DOI: 10.3389/fcell.2020.00771] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 07/22/2020] [Indexed: 12/19/2022] Open
Abstract
Cranial neural crest cells (CNCCs), identified by expression of transcription factor Sox9, migrate to the first branchial arch and undergo proliferation and differentiation to form the cartilage and bone structures of the orofacial region, including the palatal bone. Sox9 promotes osteogenic differentiation and stimulates CXCL12-CXCR4 chemokine-receptor signaling, which elevates alkaline phosphatase (ALP)-activity in osteoblasts to initiate bone mineralization. Disintegration of the midline epithelial seam (MES) is crucial for palatal fusion. Since we earlier demonstrated chemokine-receptor mediated signaling by the MES, we hypothesized that chemokine CXCL12 is expressed by the disintegrating MES to promote the formation of an osteogenic center by CXCR4-positive osteoblasts. Disturbed migration of CNCCs by excess oxidative and inflammatory stress is associated with increased risk of cleft lip and palate (CLP). The cytoprotective heme oxygenase (HO) enzymes are powerful guardians harnessing injurious oxidative and inflammatory stressors and enhances osteogenic ALP-activity. By contrast, abrogation of HO-1 or HO-2 expression promotes pregnancy pathologies. We postulate that Sox9, CXCR4, and HO-1 are expressed in the ALP-activity positive osteogenic regions within the CNCCs-derived palatal mesenchyme. To investigate these hypotheses, we studied expression of Sox9, CXCL12, CXCR4, and HO-1 in relation to palatal osteogenesis between E15 and E16 using (immuno)histochemical staining of coronal palatal sections in wild-type (wt) mice. In addition, the effects of abrogated HO-2 expression in HO-2 KO mice and inhibited HO-1 and HO-2 activity by administrating HO-enzyme activity inhibitor SnMP at E11 in wt mice were investigated at E15 or E16 following palatal fusion. Overexpression of Sox9, CXCL12, CXCR4, and HO-1 was detected in the ALP-activity positive osteogenic regions within the palatal mesenchyme. Overexpression of Sox9 and CXCL12 by the disintegrating MES was detected. Neither palatal fusion nor MES disintegration seemed affected by either HO-2 abrogation or inhibition of HO-activity. Sox9 progenitors seem important to maintain the CXCR4-positive osteoblast pool to drive osteogenesis. Sox9 expression may facilitate MES disintegration and palatal fusion by promoting epithelial-to-mesenchymal transformation (EMT). CXCL12 expression by the MES and the palatal mesenchyme may promote osteogenic differentiation to create osteogenic centers. This study provides novel evidence that CXCL12-CXCR4 interplay facilitates palatal osteogenesis and palatal fusion in mice.
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Affiliation(s)
- Nanne Verheijen
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Christiaan M Suttorp
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - René E M van Rheden
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Raymond F Regan
- Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Maria P A C Helmich
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Anne Marie Kuijpers-Jagtman
- Department of Orthodontics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland.,Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Frank A D T G Wagener
- Department of Dentistry - Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, Netherlands.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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Tun S, Spainhower CJ, Cottrill CL, Lakhani HV, Pillai SS, Dilip A, Chaudhry H, Shapiro JI, Sodhi K. Therapeutic Efficacy of Antioxidants in Ameliorating Obesity Phenotype and Associated Comorbidities. Front Pharmacol 2020; 11:1234. [PMID: 32903449 PMCID: PMC7438597 DOI: 10.3389/fphar.2020.01234] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been a worldwide epidemic for decades. Despite the abundant increase in knowledge regarding the etiology and pathogenesis of obesity, the prevalence continues to rise with estimates predicting considerably higher numbers by the year 2030. Obesity is characterized by an abnormal lipid accumulation, however, the physiological consequences of obesity are far more concerning. The development of the obesity phenotype constitutes dramatic alterations in adipocytes, along with several other cellular mechanisms which causes substantial increase in systemic oxidative stress mediated by reactive oxygen species (ROS). These alterations promote a chronic state of inflammation in the body caused by the redox imbalance. Together, the systemic oxidative stress and chronic inflammation plays a vital role in maintaining the obese state and exacerbating onset of cardiovascular complications, Type II diabetes mellitus, dyslipidemia, non-alcoholic steatohepatitis, and other conditions where obesity has been linked as a significant risk factor. Because of the apparent role of oxidative stress in the pathogenesis of obesity, there has been a growing interest in attenuating the pro-oxidant state in obesity. Hence, this review aims to highlight the therapeutic role of antioxidants, agents that negate pro-oxidant state of cells, in ameliorating obesity and associated comorbidities. More specifically, this review will explore how various antioxidants target unique and diverse pathways to exhibit an antioxidant defense mechanism.
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Affiliation(s)
- Steven Tun
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Caleb James Spainhower
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Cameron Lee Cottrill
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Hari Vishal Lakhani
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Sneha S Pillai
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Anum Dilip
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Hibba Chaudhry
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Joseph I Shapiro
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Komal Sodhi
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
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Zhu P, Qi T, Huang ZS, Li H, Wang B, Feng JX, Ma S, Xiao HJ, Tang YX, Liu W, Chen J. Proteomic analysis of oxidative stress response in human umbilical vein endothelial cells (HUVECs): role of heme oxygenase 1 (HMOX1) in hypoxanthine-induced oxidative stress in HUVECs. Transl Androl Urol 2020; 9:218-231. [PMID: 32420127 PMCID: PMC7215041 DOI: 10.21037/tau.2020.03.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background Erectile dysfunction (ED) is a well-known complication of diabetes, affecting up to 75% of diabetic men. Although the etiology of diabetic ED is multifactorial, endothelial dysfunction is considered to be a pillar of its pathophysiology. Endothelial dysfunction is caused by the harmful effects of high glucose levels and increased oxidative stress on the endothelial cells that comprise the vascular endothelium. The aim of this study was to identify the proteomic changes caused by high glucose-induced oxidative stress and explore the role of heme oxygenase 1 (HMOX1) in it. Methods The cellular proteomic response to hypoxanthine-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) was analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) were analyzed through Network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Further validation assays was performed to validate the role of HMOX1. Results The results showed that 66 and 76 DEPs were markedly upregulated and downregulated, respectively, for HUVECs oxidative stress. Among these proteins, we verified eight dysregulated genes by quantitative reverse transcription PCR, including nucleolin (NCL), X-ray repair cross-complementing protein 6 (XRCC6), ubiquinol-cytochrome C reductase binding protein (UQCRB), non-POU domain containing octamer binding (NONO), heme oxygenase 1 (HMOX1), nucleobindin 1 (NUCB1), DEK, and chromatin target of prmt1 (CHTOP). Further, using overexpression and genetic knockdown approaches, we found that HMOX1 was critical for the oxidative stress response in HUVECs. Conclusions We found that HMOX1 was closely related to the oxidative stress response induced by hypoxanthine. To the best of our knowledge, this study is the first overview of the responses of HUVECs to oxidative stress. The findings will contribute to analyses of the detailed molecular mechanisms involved in the pathogenesis of endothelial dysfunction and related molecular mechanisms in ED patients.
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Affiliation(s)
- Pei Zhu
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Tao Qi
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zhan-Sen Huang
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Hao Li
- Department of Urology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
| | - Bo Wang
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jia-Xin Feng
- Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Shuai Ma
- Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Heng-Jun Xiao
- Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Yu-Xin Tang
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Wei Liu
- Guangdong Provincial Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Jun Chen
- Department of Infertility and Sexual Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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40
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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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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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Peterson SJ, Dave N, Kothari J. The Effects of Heme Oxygenase Upregulation on Obesity and the Metabolic Syndrome. Antioxid Redox Signal 2020; 32:1061-1070. [PMID: 31880952 DOI: 10.1089/ars.2019.7954] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Obesity is a chronic condition that is characterized by inflammation and oxidative stress with consequent cardiovascular complications of hypertension, dyslipidemia, and vascular dysfunction. Obesity-induced metabolic syndrome remains an epidemic of global proportions. Recent Advances: Gene targeting of the endothelium with a retrovirus using an endothelium-specific promoter vascular endothelium cadherin (VECAD)-HO-1 offers a potential long-term solution to adiposity by targeting the endothelium. This has resulted in improvements of both vascular function and adiposity attenuation. Critical Issues: Heme oxygenase plays an ever-increasing role in the understanding of human biology in the complex conditions of obesity and the metabolic syndrome. The heme oxygenase 1 (HO-1) system creates biliverdin/bilirubin, which functions as an antioxidant, and carbon monoxide, which has antiapoptotic properties. Future Directions: Upregulation of HO-1 has been shown to improve adiposity as well as vascular function in both animal and human studies.
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Affiliation(s)
- Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, New York.,New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York
| | - Niel Dave
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York
| | - Janish Kothari
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York
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Gasier HG, Yu T, Swift JM, Metzger CE, McNerny EM, Swallow EA, Piantadosi CA, Allen MR. Carbon Monoxide and Exercise Prevents Diet-Induced Obesity and Metabolic Dysregulation Without Affecting Bone. Obesity (Silver Spring) 2020; 28:924-931. [PMID: 32237119 DOI: 10.1002/oby.22768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 01/28/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Carbon monoxide (CO) may counteract obesity and metabolic dysfunction in rodents consuming high-fat diets, but the skeletal effects are not understood. This study investigated whether low-dose inhaled CO (250 ppm) with or without moderate intensity aerobic exercise (3 h/wk) would limit diet-induced obesity and metabolic dysregulation and preserve bone health. METHODS Obesity-resistant (OR) rats served as controls, and obesity-prone (OP) rats were randomized to sedentary, sedentary plus CO, exercise, or CO plus exercise. For 10 weeks, OP rats consumed a high-fat, high-sucrose diet, whereas OR rats consumed a low-fat control diet. Measurements included indicators of obesity and metabolism, bone turnover markers, femoral geometry and microarchitecture, bone mechanical properties, and tibial morphometry. RESULTS A high-fat, high-sucrose diet led to obesity, hyperinsulinemia, and hyperleptinemia, without impacting bone. CO alone led only to a modest reduction in weight gain. Exercise attenuated weight gain and improved the metabolic profile; however, bone fragility increased. Combined CO and exercise led to body mass reduction and a metabolic state similar to control OR rats and prevented the exercise-induced increase in bone fragility. CONCLUSIONS CO and aerobic exercise training prevent obesity and metabolic sequelae of nutrient excess while stabilizing bone physiology.
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Affiliation(s)
- Heath G Gasier
- Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Tianzheng Yu
- Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Joshua M Swift
- Warfighter Performance, Office of Naval Research, Arlington, Virginia, USA
| | - Corrine E Metzger
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Erin M McNerny
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Elizabeth A Swallow
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Claude A Piantadosi
- Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Matthew R Allen
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
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Functional Role of Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work. Int J Mol Sci 2020; 21:ijms21093104. [PMID: 32354030 PMCID: PMC7247152 DOI: 10.3390/ijms21093104] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/23/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND On the 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown origin detected in Wuhan City, Hubei Province, China. The infection spread first in China and then in the rest of the world, and on the 11th of March, the WHO declared that COVID-19 was a pandemic. Taking into consideration the mortality rate of COVID-19, about 5-7%, and the percentage of positive patients admitted to intensive care units being 9-11%, it should be mandatory to consider and take all necessary measures to contain the COVID-19 infection. Moreover, given the recent evidence in different hospitals suggesting IL-6 and TNF-α inhibitor drugs as a possible therapy for COVID-19, we aimed to highlight that a dietary intervention could be useful to prevent the infection and/or to ameliorate the outcomes during therapy. Considering that the COVID-19 infection can generate a mild or highly acute respiratory syndrome with a consequent release of pro-inflammatory cytokines, including IL-6 and TNF-α, a dietary regimen modification in order to improve the levels of adiponectin could be very useful both to prevent the infection and to take care of patients, improving their outcomes.
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Behnammanesh G, Durante GL, Khanna YP, Peyton KJ, Durante W. Canagliflozin inhibits vascular smooth muscle cell proliferation and migration: Role of heme oxygenase-1. Redox Biol 2020; 32:101527. [PMID: 32278282 PMCID: PMC7152682 DOI: 10.1016/j.redox.2020.101527] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/20/2020] [Accepted: 03/27/2020] [Indexed: 12/14/2022] Open
Abstract
Recent cardiovascular outcome trials found that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular disease and mortality in type 2 diabetic patients; however, the underlying mechanisms are not fully known. Since the proliferation and migration of vascular smooth muscle cells (SMCs) contributes to the development of arterial lesions, we hypothesized that SGLT2 inhibitors may exert their beneficial cardiovascular effects by inhibiting the growth and movement of vascular SMCs. Treatment of rat or human aortic SMCs with clinically relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin, inhibited cell proliferation and migration. The inhibition of SMC growth by canagliflozin occurred in the absence of cell death, and was associated with the arrest of SMCs in the G0/G1 phase of the cell cycle and diminished DNA synthesis. Canagliflozin also resulted in the induction of heme oxygenase-1 (HO-1) expression, and a rise in HO activity in vascular SMCs, whereas, empagliflozin or dapagliflozin had no effect on HO activity. Canagliflozin also activated the HO-1 promoter and this was abrogated by mutating the antioxidant responsive element or by overexpressing dominant-negative NF-E2-related factor-2 (Nrf2). The induction of HO-1 by canagliflozin relied on reactive oxygen species (ROS) formation and was negated by antioxidants. Finally, silencing HO-1 expression partially rescued the proliferative and migratory response of canagliflozin-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the present study identifies canagliflozin as a novel inhibitor of vascular SMC proliferation and migration. Moreover, it demonstrates that canagliflozin stimulates the expression of HO-1 in vascular SMCs via the ROS-Nrf2 pathway, and that the induction of HO-1 contributes to the cellular actions of canagliflozin. The ability of canagliflozin to exert these pleiotropic effects may contribute to the favorable clinical actions of the drug and suggest an extra potential benefit of canagliflozin relative to other SGLT2 inhibitors.
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Affiliation(s)
- Ghazaleh Behnammanesh
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Giovanna L Durante
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Yash P Khanna
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Kelly J Peyton
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - William Durante
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, USA.
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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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Effects of stress-induced increases of corticosterone on circulating triglyceride levels, biliverdin concentration, and heme oxygenase expression. Comp Biochem Physiol A Mol Integr Physiol 2020; 240:110608. [DOI: 10.1016/j.cbpa.2019.110608] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022]
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Pratt R, Lakhani HV, Zehra M, Desauguste R, Pillai SS, Sodhi K. Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis. Int J Mol Sci 2019; 21:ijms21010087. [PMID: 31877680 PMCID: PMC6982200 DOI: 10.3390/ijms21010087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 02/07/2023] Open
Abstract
Obesity is a multifaceted pathophysiological condition that has been associated with lipid accumulation, adipocyte dysfunction, impaired mitochondrial biogenesis and an altered metabolic profile. Redox imbalance and excessive release of inflammatory mediators have been intricately linked in obesity-associated phenotypes. Hence, understanding the mechanisms of redox signaling pathways and molecular targets exacerbating oxidative stress is crucial in improving health outcomes. The activation of Na/K-ATPase/Src signaling, and its downstream pathways, by reactive oxygen species (ROS) has been recently implicated in obesity and subsequent nonalcoholic steatohepatitis (NASH), which causes further production of ROS creating an oxidant amplification loop. Apart from that, numerous studies have also characterized antioxidant properties of heme oxygenase 1 (HO-1), which is suppressed in an obese state. The induction of HO-1 restores cellular redox processes, which contributes to inhibition of the toxic milieu. The novelty of these independent mechanisms presents a unique opportunity to unravel their potential as molecular targets for redox regulation in obesity and NASH. The attenuation of oxidative stress, by understanding the underlying molecular mechanisms and associated mediators, with a targeted treatment modality may provide for improved therapeutic options to combat clinical disorders.
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Affiliation(s)
| | | | | | | | | | - Komal Sodhi
- Correspondence: ; Tel.: +1-(304)-691-1704; Fax: +1-(914)-347-4956
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Hagisawa K, Ayaori M, Ikewaki K, Nakajima M, Morimoto Y. 5-Aminolevulinic Acid Attenuates Atherosclerotic Plaque Progression in Low-Density Lipoprotein Receptor-Deficient Mice by Heme Oxygenase-1 Induction. Circ Rep 2019; 2:60-68. [PMID: 33693175 PMCID: PMC7929702 DOI: 10.1253/circrep.cr-19-0089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background:
Recently, 5-aminolevulinic acid (ALA) has been reported to modulate inflammatory development via an antioxidant effect. Hence, the aim of this study was to determine the anti-atherosclerotic effect of ALA. Methods and Results:
Low-density lipoprotein (LDL) receptor knockout mice were fed the following diets for 24 weeks: normal diet (n=6); 1.25% cholesterol diet (high-cholesterol diet, HCD; n=7); HCD+ALA (46 mg/kg/day; n=10); and HCD+ezetimibe (5 mg/kg/day; n=10). At 40 weeks, HCD+ALA had reduced LDL cholesterol (320±68 vs. 379±49 mg/dL), triglyceride (141±44 vs. 195±49 mg/dL) and oxidized LDL (380±40 vs. 422±64 pg/mL) compared with HCD only. En face lesion area for the entire aortic surface was significantly smaller in mice that received HCD+ALA than in mice that received only HCD (32±5% vs. 39±4%, P<0.05). ALA intake exogenously increased tissue heme oxygenase-1 (HO-1) level in plaque composite tissue of the carotid arterial wall compared with HCD only (18±8 vs. 12±3 pg/μL, P<0.05), and HO-1-positive plaque showed modest NADPH oxidase 4 expression. Conclusions:
ALA intake induces exogenous production of HO-1 at plaque sites, and improves lipid profiles and attenuation of atherosclerotic plaque progression in vivo.
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Affiliation(s)
- Kohsuke Hagisawa
- Department of Physiology, National Defense Medical College Tokorozawa Japan
| | - Makoto Ayaori
- Division of Cardiology, Tokorozawa Heart Center Tokorozawa Japan
| | - Katsunori Ikewaki
- Department of Internal Medicine, National Defense Medical College Tokorozawa Japan
| | | | - Yuji Morimoto
- Department of Physiology, National Defense Medical College Tokorozawa Japan
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50
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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: 27] [Impact Index Per Article: 4.5] [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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