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Higa M, Naito K, Sato T, Tomii A, Hitsuda Y, Tahara M, Ishii K, Ichisaka Y, Sugiyama H, Kobayashi R, Sakamoto F, Watanabe K, Yoshikiyo K, Shimizu H. Hexaraphane Affects the Activation of Hepatic PPARα Signaling: Impact on Plasma Triglyceride Levels and Hepatic Senescence with Aging. Nutrients 2025; 17:1768. [PMID: 40507037 PMCID: PMC12158025 DOI: 10.3390/nu17111768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 05/15/2025] [Accepted: 05/19/2025] [Indexed: 06/16/2025] Open
Abstract
Background/Objectives: Hexaraphane, also known as 6-methylsulfinylhexyl isothiocyanate, derived from wasabi (Eutrema japonicum), increases heme oxygenase-1 (HO-1) and aldehyde dehydrogenase 2 (ALDH2) mRNA expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2) in both HepG2 cells and the mouse liver. Given the presence of a peroxisome proliferator-activated receptor (PPAR) response element (PPRE) in the HO-1 and ALDH2 promoters, the present study aimed to determine the effects of hexaraphane on PPARα-associated genes, age-related weight gain, plasma triglyceride levels, and hepatic senescence. Methods: HepG2 cells were treated with hexaraphane to evaluate PPARα target gene expression and PPRE transcriptional activity. Male C57BL/6J young control, aged control, and aged mice administered with hexaraphane for 16 weeks were assessed for food and water intake, body and tissue weights, plasma parameters, and hepatic PPARα-related gene expression. Results: Hexaraphane increased HO-1 mRNA expression levels in HepG2 cells, which was inhibited by GW6471, a PPARα antagonist. It elevated PPRE transcriptional activity and increased carnitine palmitoyltransferase 1A (CPT1A) mRNA expression levels, indicating PPARα activation. In aged mice, hexaraphane intake reduced body weight gain by decreasing the adipose tissue weight. Increased CPT1A expression levels and a tendency toward increased acyl-CoA oxidase 1 (ACOX1) expression levels in the liver of aged mice administered hexaraphane were associated with reduced plasma triglyceride levels and body weight gain. Increased hepatic Sirt1 expression levels in aged mice administered hexaraphane was associated with lower plasma triglyceride levels. Increased hepatic PPARα mRNA expression levels in aged mice administered hexaraphane suggest a positive feedback loop between PPARα and Sirt1. The expression levels of hepatic p21 mRNA, a senescence marker regulated by Sirt1, were upregulated in aged mice but suppressed by hexaraphane intake. Conclusions: Hexaraphane may prevent age-related body weight gain, elevated plasma triglyceride levels, and hepatic senescence by activating PPARα, potentially contributing to longevity.
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Affiliation(s)
- Manami Higa
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Kazuma Naito
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan
| | - Takenari Sato
- Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Ayame Tomii
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Yuuka Hitsuda
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Miyu Tahara
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Katsunori Ishii
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Yu Ichisaka
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Hikaru Sugiyama
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Rin Kobayashi
- Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Fuzuki Sakamoto
- Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Kazuhisa Watanabe
- Faculty of Nutrition, Tokyo Kasei University, 1-18-1 Kaga, Itabashi 173-8602, Tokyo, Japan
| | - Keisuke Yoshikiyo
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan
- Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Hidehisa Shimizu
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan
- Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Estuary Research Center, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
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Zheng Y, Shao M, Zheng Y, Sun W, Qin S, Sun Z, Zhu L, Guan Y, Wang Q, Wang Y, Li L. PPARs in atherosclerosis: The spatial and temporal features from mechanism to druggable targets. J Adv Res 2025; 69:225-244. [PMID: 38555000 PMCID: PMC11954843 DOI: 10.1016/j.jare.2024.03.020] [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: 01/17/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Atherosclerosis is a chronic and complex disease caused by lipid disorder, inflammation, and other factors. It is closely related to cardiovascular diseases, the chief cause of death globally. Peroxisome proliferator-activated receptors (PPARs) are valuable anti-atherosclerosis targets that showcase multiple roles at different pathological stages of atherosclerosis and for cell types at different tissue sites. AIM OF REVIEW Considering the spatial and temporal characteristics of the pathological evolution of atherosclerosis, the roles and pharmacological and clinical studies of PPARs were summarized systematically and updated under different pathological stages and in different vascular cells of atherosclerosis. Moreover, selective PPAR modulators and PPAR-pan agonists can exert their synergistic effects meanwhile reducing the side effects, thereby providing novel insight into future drug development for precise spatial-temporal therapeutic strategy of anti-atherosclerosis targeting PPARs. KEY SCIENTIFIC Concepts of Review: Based on the spatial and temporal characteristics of atherosclerosis, we have proposed the importance of stage- and cell type-dependent precision therapy. Initially, PPARs improve endothelial cells' dysfunction by inhibiting inflammation and oxidative stress and then regulate macrophages' lipid metabolism and polarization to improve fatty streak. Finally, PPARs reduce fibrous cap formation by suppressing the proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, research on the cell type-specific mechanisms of PPARs can provide the foundation for space-time drug treatment. Moreover, pharmacological studies have demonstrated that several drugs or compounds can exert their effects by the activation of PPARs. Selective PPAR modulators (that specifically activate gene subsets of PPARs) can exert tissue and cell-specific effects. Furthermore, the dual- or pan-PPAR agonist could perform a better role in balancing efficacy and side effects. Therefore, research on cells/tissue-specific activation of PPARs and PPAR-pan agonists can provide the basis for precision therapy and drug development of PPARs.
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Affiliation(s)
- Yi Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mingyan Shao
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yanfei Zheng
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255000, China
| | - Si Qin
- Lab of Food Function and Nutrigenomics, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Ziwei Sun
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Linghui Zhu
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yuanyuan Guan
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qi Wang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Yong Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China.
| | - Lingru Li
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
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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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Bai Y, Tan D, Deng Q, Miao L, Wang Y, Zhou Y, Yang Y, Wang S, Vong CT, Cheang WS. Cinnamic acid alleviates endothelial dysfunction and oxidative stress by targeting PPARδ in obesity and diabetes. Chin Med 2025; 20:13. [PMID: 39856769 PMCID: PMC11760083 DOI: 10.1186/s13020-025-01064-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE Cinnamic acid (CA) is a bioactive compound isolated from cinnamon. It has been demonstrated to ameliorate inflammation and metabolic diseases, which are associated with endothelial dysfunction. This study was aimed to study the potential protective effects of CA against diabetes-associated endothelial dysfunction and its underlying mechanisms. METHODS High-fat diet (HFD) with 60 kcal% fat was used to induce obesity/diabetes in C57BL/6 mice for 12 weeks. These diet-induced obese (DIO) mice were orally administered with CA at 20 or 40 mg/kg/day, pioglitazone (PIO) at 20 mg/kg/day or same volume of vehicle during the last 4 weeks. Isolated mouse aortic segments and primary culture rat aortic endothelial cells (RAECs) were induced with high glucose (HG) to mimic hyperglycemia and co-treated with different concentrations of CA. RESULTS In DIO mice, four-week administration of CA, particularly at 40 mg/kg/day, diminished the body weights, blood pressure, fasting blood glucose and plasma lipid levels, and ameliorated endothelium-dependent relaxations (EDRs) and oxidative stress in aortas. The beneficial effects of CA were comparable to the positive control group, PIO. Western blotting results indicated that CA treatment upregulated the expression of peroxisome proliferator-activated receptor delta (PPARδ), and activated nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) and AMP-activated protein kinase (AMPK)/ protein kinase B (Akt)/ endothelial nitric oxide synthase (eNOS) signaling pathways in mouse aortas in vivo and ex vivo. HG stimulation impaired EDRs in mouse aortas and inhibited nitric oxide (NO) production but elevated reactive oxygen species (ROS) levels in RAECs. CA reversed these impairments. Importantly, PPARδ antagonist GSK0660 abolished the vasoprotective effects of CA. Molecular docking analysis suggested a high likelihood of mutual binding between CA and PPARδ. CONCLUSION CA protects against endothelial dysfunction and oxidative stress in diabetes and obesity by targeting PPARδ through Nrf2/HO-1 and Akt/eNOS signaling pathways.
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Affiliation(s)
- Yizhen Bai
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Dechao Tan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Qiaowen Deng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Lingchao Miao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yuehan Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yan Zhou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yifan Yang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macao SAR, China
| | - Chi Teng Vong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macao SAR, China.
| | - Wai San Cheang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
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Feng H, Li Z, Zheng R. Bexarotene ameliorated the pulmonary inflammation and M1 polarization of alveolar macrophages induced by cigarette smoke via PPARγ/HO-1. Respir Res 2024; 25:431. [PMID: 39696251 DOI: 10.1186/s12931-024-03064-x] [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: 06/09/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Alveolar macrophages (AMs) modulate pulmonary inflammation in chronic obstructive pulmonary disease (COPD), contributing to its progression. The PPARγ/RXRα heterodimer influences AM polarization induced by cigarette smoke (CS). Although PPARγ agonists suppress CS-induced M1 macrophage polarization, the impact of RXRα agonists on this process has not been determined. This study explored the effects and mechanisms of the RXRα agonist bexarotene on macrophage polarization in a COPD mouse model. METHODS C57BL/6 mice were assigned to the control, model, bexarotene, or model + bexarotene group. The COPD model was induced by CS exposure and intraperitoneal injection of cigarette smoke extract (CSE), followed by intraperitoneal administration of bexarotene. Additionally, MH-S cells were exposed to CSE and bexarotene. Lung tissues were subjected to hematoxylin-eosin staining, and emphysema and inflammatory scores were assessed. Cytokine levels and cell differentials in bronchoalveolar lavage fluid were measured, and macrophage polarization was evaluated using immunohistochemistry, flow cytometry, and qPCR. RESULTS Bexarotene effectively reduced inflammatory scores, cytokine levels, and neutrophil counts and ameliorated emphysema and M1 polarization of AMs in COPD model mice. Furthermore, while CSE exposure reduced PPARγ expression and the transcriptional activity of AMs, bexarotene enhanced the transcriptional response of PPARγ to CSE. HO-1 was identified as a potential target of PPARγ; its levels were assessed in AMs, revealing that bexarotene mitigated the CSE-induced reduction in HO-1. Notably, the effect of bexarotene was partially inhibited by the PPARγ inhibitor. CONCLUSIONS Our results indicated that bexarotene may curb inflammation and M1 polarization in COPD through activation of the PPARγ/HO-1 pathway.
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Affiliation(s)
- Haoshen Feng
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, Liaoning, China
| | - Zhe Li
- Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, PR China
| | - Rui Zheng
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, 110004, Liaoning, China.
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Bellver-Sanchis A, Ávila-López PA, Tic I, Valle-García D, Ribalta-Vilella M, Labrador L, Banerjee DR, Guerrero A, Casadesus G, Poulard C, Pallàs M, Griñán-Ferré C. Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128. Neural Regen Res 2024; 19:2532-2542. [PMID: 38526289 PMCID: PMC11090428 DOI: 10.4103/1673-5374.393102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 12/17/2023] [Accepted: 12/28/2023] [Indexed: 03/26/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202419110-00033/figure1/v/2024-03-08T184507Z/r/image-tiff Dysregulation of G9a, a histone-lysine N-methyltransferase, has been observed in Alzheimer's disease and has been correlated with increased levels of chronic inflammation and oxidative stress. Likewise, microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis, especially in multifactorial diseases such as Alzheimer's disease. Therefore, our aim has been to provide partial insights into the interconnection between G9a, microRNAs, oxidative stress, and neuroinflammation. To better understand the biology of G9a, we compared the global microRNA expression between senescence-accelerated mouse-prone 8 (SAMP8) control mice and SAMP8 treated with G9a inhibitor UNC0642. We found a downregulation of miR-128 after a G9a inhibition treatment, which interestingly binds to the 3' untranslated region (3'-UTR) of peroxisome-proliferator activator receptor γ (PPARG) mRNA. Accordingly, Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group. We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor. To confirm these antioxidant effects, we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult. In this setting, treatment with G9a inhibitor increases both cell survival and antioxidant enzymes. Moreover, up-regulation of PPARγ by G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis. In addition, we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression. Finally, PPARγ/GADD45α potentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition. Altogether, we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due, at least in part, by the modulation of PPARγ-dependent pathways by miR-128.
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Affiliation(s)
- Aina Bellver-Sanchis
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - Pedro A. Ávila-López
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Iva Tic
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - David Valle-García
- Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca, Mexico
| | - Marta Ribalta-Vilella
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - Luis Labrador
- Department of Pharmacology and Therapeutics, Health Science Center-University of Florida, Gainesville, FL, USA
| | - Deb Ranjan Banerjee
- Department of Chemistry, National Institute of Technology Durgapur, M G Avenue, Durgapur, West Bengal, India
| | - Ana Guerrero
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
| | - Gemma Casadesus
- Department of Pharmacology and Therapeutics, Health Science Center-University of Florida, Gainesville, FL, USA
| | - Coralie Poulard
- Cancer Research Cancer Lyon, Université de Lyon, Lyon, France
- Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- CNRS UMR5286, Centre de Recherche en Cancérlogie de Lyon, Lyon, France
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
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Huang HC, Shi YJ, Vo TLT, Hsu TH, Song TY. The Anti-Inflammatory Effects and Mechanism of the Submerged Culture of Ophiocordyceps sinensis and Its Possible Active Compounds. J Fungi (Basel) 2024; 10:523. [PMID: 39194849 DOI: 10.3390/jof10080523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/04/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024] Open
Abstract
The pharmacological effects of the fruiting body of Ophiocordyceps sinensis (O. sinensis) such as antioxidant, anti-virus, and immunomodulatory activities have already been described, whereas the anti-inflammatory effects and active components of the submerged culture of O. sinesis (SCOS) still need to be further verified. This study aimed to investigate the active compounds in the fermented liquid (FLOS), hot water (WEOS), and 50-95% (EEOS-50, EEOS-95) ethanol extracts of SCOS and their anti-inflammatory effects and potential mechanisms in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. The results demonstrated that all of the SCOS extracts could inhibit NO production in BV2 cells. EEOS-95 exhibited the strongest inhibitory effects (71% inhibitory ability at 500 µg/mL), and its ergosterol, γ-aminobutyric acid (GABA), total phenolic, and total flavonoid contents were significantly higher than those of the other extracts (18.60, 18.60, 2.28, and 2.14 mg/g, p < 0.05, respectively). EEOS-95 also has a strong inhibitory ability against IL-6, IL-1β, and TNF-α with an IC50 of 617, 277, and 507 µg/mL, respectively, which is higher than that of 1 mM melatonin. The anti-inflammatory mechanism of EEOS-95 seems to be associated with the up-regulation of PPAR-γ/Nrf-2/HO-1 antioxidant-related expression and the down-regulation of NF-κB/COX-2/iNOS pro-inflammatory expression signaling. In summary, we demonstrated that EEOS-95 exhibits neuroinflammation-mediated neurodegenerative disorder activities in LPS-induced inflammation in brain microglial cells.
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Affiliation(s)
- Hsien-Chi Huang
- PhD Program of Biotechnology and Bioindustry, College of Biotechnology and Bioresources, Da-Yeh University, Changhua 515, Taiwan
| | - Yu-Juan Shi
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua 515, Taiwan
| | - Thuy-Lan-Thi Vo
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua 515, Taiwan
| | - Tai-Hao Hsu
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua 515, Taiwan
| | - Tuzz-Ying Song
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua 515, Taiwan
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Chiang YT, Seow KM, Chen KH. The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms. Int J Mol Sci 2024; 25:4532. [PMID: 38674114 PMCID: PMC11050545 DOI: 10.3390/ijms25084532] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/12/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.
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Affiliation(s)
- Yi-Ting Chiang
- Department of Medical Education, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, Taipei 231, Taiwan;
| | - Kok-Min Seow
- Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan;
- Department of Obstetrics and Gynecology, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan
| | - Kuo-Hu Chen
- Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, Taipei 231, Taiwan
- School of Medicine, Tzu-Chi University, Hualien 970, Taiwan
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9
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Alhakamy NA, Alamoudi AJ, Asfour HZ, Ahmed OAA, Abdel-Naim AB, Aboubakr EM. L-arginine mitigates bleomycin-induced pulmonary fibrosis in rats through regulation of HO-1/PPAR-γ/β-catenin axis. Int Immunopharmacol 2024; 131:111834. [PMID: 38493696 DOI: 10.1016/j.intimp.2024.111834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/26/2024] [Accepted: 03/07/2024] [Indexed: 03/19/2024]
Abstract
Pulmonary fibrosis is a chronic and progressively deteriorating lung condition that can be replicated in laboratory animals by administering bleomycin, a chemotherapeutic antibiotic known for its lung fibrosis-inducing side effects. L-arginine, a semi-essential amino acid, is recognized for its diverse biological functions, including its potential to counteract fibrosis. This study aimed to evaluate the antifibrotic properties of L-arginine on bleomycin-induced pulmonary fibrosis in rats. The administration of a single intratracheal dose of bleomycin resulted in visible and microscopic damage to lung tissues, an uptick in oxidative stress markers, and an elevation in inflammatory, apoptotic, and fibrotic indicators. A seven-day treatment with L-arginine post-bleomycin exposure markedly improved the gross and histological architecture of the lungs, prevented the rise of malondialdehyde and carbonyl content, and enhanced total antioxidant capacity alongside the activities of antioxidant enzymes. Also, L-arginine attenuated the expression of the pro-fibrotic factors, transforming growth factor-β and lactate dehydrogenase in bronchoalveolar lavage fluid. In the lung tissue, L-arginine reduced collagen deposition, hydroxyproline concentration, and mucus production, along with decreasing expression of α-smooth muscle actin, tumor necrosis factor-α, caspase-3, matrix metalloproteinase-9, and β-catenin. Moreover, it boosted levels of nitric oxide and upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), heme oxygenase-1 (HO-1), and E-cadherin and downregulating the expression of β-catenin. These findings suggest that L-arginine has preventive activities against bleomycin-induced pulmonary fibrosis. This effect can be attributed to the increased production of nitric oxide, which modulates the HO-1/PPAR-γ/β-catenin axis.
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Affiliation(s)
- Nabil A Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulmohsin J Alamoudi
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Hani Z Asfour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt
| | - Osama A A Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ashraf B Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Esam M Aboubakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt
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10
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Kong M, Zhou J, Kang A, Kuai Y, Xu H, Li M, Miao X, Guo Y, Fan Z, Xu Y, Li Z. Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis. Gut 2024; 73:810-824. [PMID: 38176898 DOI: 10.1136/gutjnl-2023-329671] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 12/15/2023] [Indexed: 01/06/2024]
Abstract
OBJECTIVE Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis. DESIGN HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation. RESULTS We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme. CONCLUSIONS Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.
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Affiliation(s)
- Ming Kong
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Junjing Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of JiangnanUniversity, Wuxi, People's Republic of China
| | - Aoqi Kang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yameng Kuai
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Huihui Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Min Li
- Department of Pathophysiology, Jiangsu Health Vocational College, Nanjing, People's Republic of China
| | - Xiulian Miao
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, People's Republic of China
| | - Yan Guo
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, People's Republic of China
| | - Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People's Republic of China
| | - Yong Xu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
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11
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Yeudall S, Upchurch CM, Leitinger N. The clinical relevance of heme detoxification by the macrophage heme oxygenase system. Front Immunol 2024; 15:1379967. [PMID: 38585264 PMCID: PMC10995405 DOI: 10.3389/fimmu.2024.1379967] [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] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/11/2024] [Indexed: 04/09/2024] Open
Abstract
Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.
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Affiliation(s)
- Scott Yeudall
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States
- Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Clint M. Upchurch
- Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Norbert Leitinger
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States
- Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States
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12
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Lee IT, Yang CC, Yang CM. Harnessing peroxisome proliferator-activated receptor γ agonists to induce Heme Oxygenase-1: a promising approach for pulmonary inflammatory disorders. Cell Commun Signal 2024; 22:125. [PMID: 38360670 PMCID: PMC10868008 DOI: 10.1186/s12964-024-01501-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/27/2024] [Indexed: 02/17/2024] Open
Abstract
The activation of peroxisome proliferator-activated receptor (PPAR)-γ has been extensively shown to attenuate inflammatory responses in conditions such as asthma, acute lung injury, and acute respiratory distress syndrome, as demonstrated in animal studies. However, the precise molecular mechanisms underlying these inhibitory effects remain largely unknown. The upregulation of heme oxygenase-1 (HO-1) has been shown to confer protective effects, including antioxidant, antiapoptotic, and immunomodulatory effects in vitro and in vivo. PPARγ is highly expressed not only in adipose tissues but also in various other tissues, including the pulmonary system. Thiazolidinediones (TZDs) are highly selective agonists for PPARγ and are used as antihyperglycemic medications. These observations suggest that PPARγ agonists could modulate metabolism and inflammation. Several studies have indicated that PPARγ agonists may serve as potential therapeutic candidates in inflammation-related diseases by upregulating HO-1, which in turn modulates inflammatory responses. In the respiratory system, exposure to external insults triggers the expression of inflammatory molecules, such as cytokines, chemokines, adhesion molecules, matrix metalloproteinases, and reactive oxygen species, leading to the development of pulmonary inflammatory diseases. Previous studies have demonstrated that the upregulation of HO-1 protects tissues and cells from external insults, indicating that the induction of HO-1 by PPARγ agonists could exert protective effects by inhibiting inflammatory signaling pathways and attenuating the development of pulmonary inflammatory diseases. However, the mechanisms underlying TZD-induced HO-1 expression are not well understood. This review aimed to elucidate the molecular mechanisms through which PPARγ agonists induce the expression of HO-1 and explore how they protect against inflammatory and oxidative responses.
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Affiliation(s)
- I-Ta Lee
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 110301, Taiwan
| | - Chien-Chung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, 333008, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, 333323, Taiwan
| | - Chuen-Mao Yang
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, 242062, Taiwan.
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13
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Cho W, Oh H, Choi SW, Abd El-Aty AM, Yeşilyurt F, Jeong JH, Jung TW. Musclin Mitigates the Attachment of HUVECs to THP-1 Monocytes in Hyperlipidemic Conditions through PPARα/HO-1-Mediated Attenuation of Inflammation. Inflammation 2024; 47:1-12. [PMID: 37737929 DOI: 10.1007/s10753-023-01904-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/31/2023] [Accepted: 09/11/2023] [Indexed: 09/23/2023]
Abstract
Musclin, a myokine, undergoes modulation during exercise and has demonstrated anti-inflammatory effects in cardiomyocytes and glomeruli. However, its role in atherosclerotic responses remains unclear. This study aimed to explore the impact of musclin on inflammatory responses and the interaction between endothelial cells and monocytes under hyperlipidemic conditions. The attachment levels of THP-1 monocytes on cultured HUVECs were examined. Inflammation and the expression of cell adhesion molecules were also evaluated. To explore the molecular mechanisms of musclin, PPARα or heme oxygenase 1 (HO-1) siRNA transfection was performed in HUVECs. The results revealed that treatment with recombinant musclin effectively suppressed the attachment of palmitate-induced HUVECs to THP-1 cells and reduced the expression of cell adhesion proteins (ICAM-1, VCAM-1, and E-selectin) in HUVECs. Furthermore, musclin treatment ameliorated the expression of inflammation markers (phosphorylated NFκB and IκB) in both HUVECs and THP-1 monocytes, as well as the release of TNFα and MCP-1 from HUVECs and THP-1 monocytes. Notably, musclin treatment augmented the expression levels of PPARα and HO-1. However, when PPARα or HO-1 siRNA was employed, the beneficial effects of musclin on inflammation, cell attachment, and adhesion molecule expression were abolished. These findings indicate that musclin exerts anti-inflammatory effects via the PPARα/HO-1 pathway, thereby mitigating the interaction between endothelial cells and monocytes. This study provides evidence supporting the important role of musclin in ameliorating obesity-related arteriosclerosis and highlights its potential as a therapeutic agent for treating arteriosclerosis.
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Affiliation(s)
- Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, 221, Heuksuk-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea
| | - Heeseung Oh
- Department of Pharmacology, College of Medicine, Chung-Ang University, 221, Heuksuk-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea
| | - Sung Woo Choi
- Department of Pharmacology, College of Medicine, Chung-Ang University, 221, Heuksuk-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Fatma Yeşilyurt
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, 221, Heuksuk-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, 221, Heuksuk-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea.
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14
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Liang J, Yang C, Li P, Zhang M, Xie X, Xie X, Chen Y, Wang Q, Zhou L, Luo X. Astragaloside IV inhibits AOM/DSS-induced colitis-associated tumorigenesis via activation of PPARγ signaling in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 121:155116. [PMID: 37776619 DOI: 10.1016/j.phymed.2023.155116] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/15/2023] [Accepted: 09/21/2023] [Indexed: 10/02/2023]
Abstract
BACKGROUND Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD), resulting from long-term inflammation in the intestines. The primary cause of CAC is the imbalance of oxidative metabolism in intestinal cells, triggered by excessive reactive oxygen (ROS) and nitrogen (NO) species production due to prolonged intestinal inflammation. This imbalance leads to genomic instability caused by DNA damage, eventually resulting in the development of intestinal cancer. Previous studies have demonstrated that astragaloside IV is effective in treating dextran sulfate sodium salt (DSS)-induced colitis, but there is currently no relevant research on its efficacy in treating CAC. METHODS To investigate the effect of astragaloside IV against CAC and the underlying mechanism, C57 mice were treated with (20, 40, 80 mg/kg) astragaloside IV while CAC was induced by intraperitoneal injection of 10 mg/kg azoxymethane (AOM) and ad libitum consumption of 2% dextran sulfate sodium salt (DSS). We re-verified the activating effects of astragaloside IV on PPARγ signaling in IEC-6 cells, which were reversed by GW9662 (the PPARγ inhibitor). RESULTS Our results showed that astragaloside IV significantly improved AOM/DSS-induced CAC mice by inhibiting colonic shortening, preventing intestinal mucosal damage, reducing the number of tumors and, the expression of Ki67 protein. In addition, astragaloside IV could activate PPARγ signaling, which not only promoted the expression of Nrf2 and HO-1, restored the level of SOD, CAT and GSH, but also inhibited the expression of iNOS and reduced the production of NO in the intestine and IEC-6 cells. And this effect could be reversed by GW9662 in vitro. Astragaloside IV thus decreased the level of ROS and NO in the intestinal tract of mice, as well as reduced the damage of DNA, and therefore inhibited the occurrence of CAC. CONCLUSION Astragaloside IV can activate PPARγ signaling in intestinal epithelial cells and reduces DNA damage caused by intestinal inflammation, thereby inhibiting colon tumourigenesis. The novelty of this study is to use PPARγ as the target to inhibit DNA damage to prevent the occurrence of CAC.
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Affiliation(s)
- Junjie Liang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China; Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital)
| | - Caiyi Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Pengcheng Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Meiling Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Xueqian Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Xuting Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Yunliang Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Qing Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China
| | - Lian Zhou
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China.
| | - Xia Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No. 232 Outer Ring Road, Panyu District, Guangzhou, Guang Dong 510006, China.
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15
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Ni S, Yi N, Yuan H, Li D, Chen X, Zhuang C. Angelica sinensis polysaccharide improves mitochondrial metabolism of osteoarthritis chondrocytes through PPARγ/SOD2/ROS pathways. Phytother Res 2023; 37:5394-5406. [PMID: 37632225 DOI: 10.1002/ptr.7979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/26/2023] [Accepted: 07/27/2023] [Indexed: 08/27/2023]
Abstract
Osteoarthritis (OA) is a common degenerative joint disease, which is characterized by wear of articular cartilage and narrow joint space, resulting in joint movement disorder. At present, accurate molecular mechanisms and effective interventions are still being explored. Here, we propose that angelica sinensis polysaccharide (ASP) alleviates OA progression by activating peroxisome proliferator-activated receptor gamma (PPARγ). Therapeutic effect of ASP improving mitochondrial metabolism of OA chondrocytes was evaluated in vitro and in vivo, respectively. During cell experiments, the concentration and time response of tert butyl hydroperoxide (TBHP) and ASP were determined by cell viability. Apoptosis was detected by flow cytometry. Mitochondrial metabolism was detected by reactive oxygen species (ROS), mitochondrial membrane potential (MMP), release of cytochrome C, adenosine triphosphate (ATP) production, and superoxide dismutase 2 (SOD2) activity. Expressions of Aggrecan, collagen type II (Col2a1), PPARγ, and SOD2 were detected by qRT-PCR and western blot. In animal experiments, we detected cell apoptosis and target protein expression separately through terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) staining and immunohistochemistry. Pretreatment of ASP significantly activated PPARγ and SOD2 in rat chondrocytes incubated with TBHP, cleared ROS, improved mitochondrial metabolism, increased chondrocytes viability, and alleviated chondrocytes apoptosis. In vivo, the administration of ASP could effectively ameliorate cartilage degeneration in OA rats, promote extracellular matrix synthesis, and decelerate the progress of OA. Our research identifies the role of ASP in mitochondrial metabolism of OA chondrocytes through PPARγ/SOD2/ROS pathways, which provides a new idea for the treatment of OA.
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Affiliation(s)
- Su Ni
- Laboratory of Clinical Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
- Bone Disease Research and Clinical Rehabilitation Center, Changzhou Medical Center, NanjingMedicalUniversity, Changzhou, China
| | - Ning Yi
- Laboratory of Clinical Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
- Graduate School of Dalian Medical University, Dalian, China
| | - Hang Yuan
- Laboratory of Clinical Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
- Graduate School of Bengbu Medical College, Bengbu, China
| | - Dong Li
- Department of Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Xu Chen
- Laboratory of Clinical Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
- Department of Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Chao Zhuang
- Department of Orthopedics, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
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16
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Pu Y, Cheng CK, Zhang H, Luo JY, Wang L, Tomlinson B, Huang Y. Molecular mechanisms and therapeutic perspectives of peroxisome proliferator-activated receptor α agonists in cardiovascular health and disease. Med Res Rev 2023; 43:2086-2114. [PMID: 37119045 DOI: 10.1002/med.21970] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 04/30/2023]
Abstract
The prevalence of cardiovascular disease (CVD) has been rising due to sedentary lifestyles and unhealthy dietary patterns. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor regulating multiple biological processes, such as lipid metabolism and inflammatory response critical to cardiovascular homeostasis. Healthy endothelial cells (ECs) lining the lumen of blood vessels maintains vascular homeostasis, where endothelial dysfunction associated with increased oxidative stress and inflammation triggers the pathogenesis of CVD. PPARα activation decreases endothelial inflammation and senescence, contributing to improved vascular function and reduced risk of atherosclerosis. Phenotypic switch and inflammation of vascular smooth muscle cells (VSMCs) exacerbate vascular dysfunction and atherogenesis, in which PPARα activation improves VSMC homeostasis. Different immune cells participate in the progression of vascular inflammation and atherosclerosis. PPARα in immune cells plays a critical role in immunological events, such as monocyte/macrophage adhesion and infiltration, macrophage polarization, dendritic cell (DC) embedment, T cell activation, and B cell differentiation. Cardiomyocyte dysfunction, a major risk factor for heart failure, can also be alleviated by PPARα activation through maintaining cardiac mitochondrial stability and inhibiting cardiac lipid accumulation, oxidative stress, inflammation, and fibrosis. This review discusses the current understanding and future perspectives on the role of PPARα in the regulation of the cardiovascular system as well as the clinical application of PPARα ligands.
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Affiliation(s)
- Yujie Pu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Hongsong Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jiang-Yun Luo
- Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Brian Tomlinson
- Faculty of Medicine, Macau University of Science & Technology, Macau, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
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Zhou B, Wang X, Wang Y, Liu D. FNDC5 Attenuates Atherosclerotic Plaque Formation and Regulates PPARα/HO-1 in ApoE-/- Mice. J Vasc Res 2023; 60:172-182. [PMID: 37586354 DOI: 10.1159/000531585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 06/10/2023] [Indexed: 08/18/2023] Open
Abstract
INTRODUCTION This study attempted to observe the role of fibronectin type III domain-containing protein 5 (FNDC5) in atherosclerosis development and the underlying mechanism. METHODS After being fed a high-fat diet (HFD), ApoE-/- mice were injected with saline, control adenovirus (Ad-vector), or FNDC5 overexpressing adenovirus (Ad-FNDC5). ApoE-/- mice fed with a chow diet were considered the control. After 12 weeks of treatment, the levels of serum high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and irisin were detected by commercial kits. RESULTS Compared with the control, the serum TG, TC, and LDL-C levels, aortic plaque area, and weight were significantly increased, while serum HDL-C and irisin levels were reduced in HFD mice. Treating with Ad-FNDC5 could alleviate these changes in HFD mice and cause the activation of PPARα/HO-1 signaling in aortic tissue. After co-treating with GW6471, a PPARα antagonist, the effects of Ad-FNDC5 on the weight, serum LDL-C, TC, TG, and HDL-C levels, and aortic plaque of HFD mice were partly blocked. CONCLUSION Elevated FNDC5 has a delaying effect on atherosclerotic plaque formation, which may be related to the upregulation of PPARα/HO-1 signaling.
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Affiliation(s)
- Bo Zhou
- Institute of Medical Science, Guizhou Medical University, Guiyang, China
- The First People's Hospital of Bijie City, Bijie, China
| | - Xiang Wang
- Institute of Medical Science, Guizhou Medical University, Guiyang, China
| | - Yao Wang
- Institute of Medical Science, Guizhou Medical University, Guiyang, China
| | - Danan Liu
- Institute of Medical Science, Guizhou Medical University, Guiyang, China
- Department of Cardiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
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18
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Hassanein EHM, Saleh FM, Ali FEM, Rashwan EK, Atwa AM, Abd El-Ghafar OAM. Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1-7 signals. Immunopharmacol Immunotoxicol 2023; 45:304-316. [PMID: 36326099 DOI: 10.1080/08923973.2022.2143371] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVES Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor, is an anti-hyperglycemic drug that has been approved to treat diabetes. This study evaluated the beneficial effects of CAN on cerebral cortex intoxication induced by cisplatin (CIS). MATERIALS AND METHODS Rats were allocated into four groups: normal control, CAN (10 mg/kg, P.O.) for 10 days, CIS (8 mg/kg, i.p.) as a single dose on the 5th day of the experiment, and CAN + CIS group. RESULTS In comparison with CIS control rats, CAN significantly mitigated CIS-induced cortical changes in rats' behavior in the open field and forced swimming assessment as well as histological structure. Biochemically, CAN administration efficiently decreased lipid peroxidation biomarkers MDA and boosted the antioxidant status via a remarkable increase in the cortical reduced glutathione (GSH) content as well as enzymatic activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase (CAT), and glutathione peroxidase (GPx) mediated by up-regulation of heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptors (PPARγ), and silent information regulator (SIRT1)/forkhead box-O3 (FOXO-3) signals. Additionally, pretreatment with CAN significantly decreased cortical myeloperoxidase (MPO), nitrite (NO2-), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels. At the same time, it elevated the IL-10 level associated with the downregulation of Jun N-terminal kinase (JNK)/activator protein 1 (AP-1), TLR4/inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and Ang II/Ang 1-7 signals. CONCLUSIONS Due to the potent antioxidant and anti-inflammatory properties of CAN, our findings showed that CAN could be a good candidate for the protection against CIS-induced cortical intoxication in the patient receiving CIS.
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Affiliation(s)
- Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Fayez M Saleh
- Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Eman K Rashwan
- Department of Physiology, College of Medicine, Al-Azhar University, Assiut, Egypt
| | - Ahmed M Atwa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Omnia A M Abd El-Ghafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
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Saha S, Saso L, Trofimov AV, Yablonskaya OI. Chemical, Biological and Biomedical Aspects of Bioantioxidants. Biomedicines 2023; 11:biomedicines11051377. [PMID: 37239048 DOI: 10.3390/biomedicines11051377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 04/27/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
Bioantioxidants are biologically important antioxidants, a heterogeneous variety of molecules, which are difficult to classify using commonly shared structural features [...].
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Affiliation(s)
- Sarmistha Saha
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura 281406, Uttar Pradesh, India
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, 00185 Rome, Italy
| | - Aleksei V Trofimov
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Ul. Kosygina 4, 119334 Moscow, Russia
- Moscow Institute of Physics and Technology, National Research University, Institutskii per. 9, 141701 Moscow, Russia
| | - Olga I Yablonskaya
- Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Ul. Kosygina 4, 119334 Moscow, Russia
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20
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Venkataraman B, Almarzooqi S, Raj V, Bhongade BA, Patil RB, Subramanian VS, Attoub S, Rizvi TA, Adrian TE, Subramanya SB. Molecular Docking Identifies 1,8-Cineole (Eucalyptol) as A Novel PPARγ Agonist That Alleviates Colon Inflammation. Int J Mol Sci 2023; 24:ijms24076160. [PMID: 37047133 PMCID: PMC10094723 DOI: 10.3390/ijms24076160] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023] Open
Abstract
Inflammatory bowel disease, comprising Crohn's disease (CD) and ulcerative colitis (UC), is often debilitating. The disease etiology is multifactorial, involving genetic susceptibility, microbial dysregulation, abnormal immune activation, and environmental factors. Currently, available drug therapies are associated with adverse effects when used long-term. Therefore, the search for new drug candidates to treat IBD is imperative. The peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in the colon. PPARγ plays a vital role in regulating colonic inflammation. 1,8-cineole, also known as eucalyptol, is a monoterpene oxide present in various aromatic plants which possess potent anti-inflammatory activity. Molecular docking and dynamics studies revealed that 1,8-cineole binds to PPARγ and if it were an agonist, that would explain the anti-inflammatory effects of 1,8-cineole. Therefore, we investigated the role of 1,8-cineole in colonic inflammation, using both in vivo and in vitro experimental approaches. Dextran sodium sulfate (DSS)-induced colitis was used as the in vivo model, and tumor necrosis factor-α (TNFα)-stimulated HT-29 cells as the in vitro model. 1,8-cineole treatment significantly decreased the inflammatory response in DSS-induced colitis mice. 1,8-cineole treatment also increased nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus to induce potent antioxidant effects. 1,8-cineole also increased colonic PPARγ protein expression. Similarly, 1,8-cineole decreased proinflammatory chemokine production and increased PPARγ protein expression in TNFα-stimulated HT-29 cells. 1,8-cineole also increased PPARγ promoter activity time-dependently. Because of its potent anti-inflammatory effects, 1,8-cineole may be valuable in treating IBD.
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Affiliation(s)
- Balaji Venkataraman
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Saeeda Almarzooqi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Vishnu Raj
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bhoomendra A Bhongade
- Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical & Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Rajesh B Patil
- Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Vadgaon (BK), Pune 411 041, India
| | | | - Samir Attoub
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Tahir A Rizvi
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Thomas E Adrian
- Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai P.O. Box 505055, United Arab Emirates
| | - Sandeep B Subramanya
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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Zivkovic S, Maric G, Cvetinovic N, Lepojevic-Stefanovic D, Bozic Cvijan B. Anti-Inflammatory Effects of Lipid-Lowering Drugs and Supplements-A Narrative Review. Nutrients 2023; 15:nu15061517. [PMID: 36986246 PMCID: PMC10053759 DOI: 10.3390/nu15061517] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Cardiovascular diseases (CVD) are the leading cause of death worldwide. Since the establishment of the "lipid hypothesis", according to which, cholesterol level is directly correlated to the risk of CVD, many different lipid-lowering agents have been introduced in clinical practice. A majority of these drugs, in addition to their lipid-lowering properties, may also exhibit some anti-inflammatory and immunomodulatory activities. This hypothesis was based on the observation that a decrease in lipid levels occurs along with a decrease in inflammation. Insufficient reduction in the inflammation during treatment with lipid-lowering drugs could be one of the explanations for treatment failure and recurrent CVD events. Thus, the aim of this narrative review was to evaluate the anti-inflammatory properties of currently available lipid-lowering medications including statins, ezetimibe, bile acid sequestrants (BAS), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fibrates, omega-3 fatty acids, and niacin, as well as dietary supplements and novel drugs used in modern times.
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Affiliation(s)
- Stefan Zivkovic
- Department of Cardiovascular Disease, Zvezdara University Medical Center, 11000 Belgrade, Serbia
| | - Gorica Maric
- Faculty of Medicine, Institute of Epidemiology, University of Belgrade, Dr. Subotica 8, 11000 Belgrade, Serbia
| | - Natasa Cvetinovic
- Department of Cardiovascular Disease, University Medical Center "Dr Dragisa Misovic-Dedinje", 11000 Belgrade, Serbia
| | | | - Bojana Bozic Cvijan
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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Heme Oxygenase-1 and Blood Bilirubin Are Gradually Activated by Oral D-Glyceric Acid. Antioxidants (Basel) 2022; 11:antiox11122319. [PMID: 36552529 PMCID: PMC9774343 DOI: 10.3390/antiox11122319] [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: 10/27/2022] [Revised: 11/10/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022] Open
Abstract
It has been shown that small doses of oral D-glyceric acid (DGA) activate mitochondrial metabolism and reduce inflammation among 50-60-year-old healthy volunteers. The present results with the same small doses reveal that after a 4-day DGA regimen, a dose of DGA activated the HO-1 pathway acutely, while enhanced inflammatory status after the 4-day DGA regimen seemed to be able to downregulate the HO-1 pathway in non-acute measurement. Blood bilirubin was strongly upregulated towards the end of the altogether 21-day study period with positive associations towards improved inflammation and reduced blood triglycerides. After the 4-day DGA regimen, hepatic inflow of blood bilirubin with albumin as the carrier was clearly upregulated in the lower-aerobic-capacity persons. At the same time also, blood triglycerides were down, pointing possibly to the activation of liver fatty acid oxidation. The combination of activated aerobic energy metabolism with transient HO-1 pathway activation and the upregulation of blood bilirubin may reduce the risks of chronic diseases, especially in aging. Furthermore, there exist certain diseases with unsatisfactorily-met medical needs, such as fatty and cholestatic liver diseases, and Parkinson's disease, that can be possibly ameliorated with the whole-body mechanism of the action of the DGA regimen.
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23
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Mohan UP, Tirupathi Pichiah PB, Kunjiappan S, Arunachalam S. A Hypothesis Concerning the role of PPAR family on Cardiac Energetics in Adriamycin-Induced Cardiomyopathy. J Appl Toxicol 2022; 42:1910-1920. [PMID: 35944906 DOI: 10.1002/jat.4374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/06/2022] [Accepted: 08/06/2022] [Indexed: 11/10/2022]
Abstract
Adriamycin is an effective anti-neoplastic drug against a variety of cancer types. However, the drug causes adverse side-effects in a number of organ systems. Cardiomyopathy is one of the life-threatening side-effects of Adriamycin. In the current work, we have derived the possible involvement of PPAR family members in the development of Adriamycin-induced cardiomyopathy. Dysregulation of PPAR family by Adriamycin causes impairment in the transport and β-oxidation of fatty acids, the key substrate for ATP synthesis in heart. Evidences suggest that dysregulation of PPAR family results in alters the recruitment of glucose transporters. Furthermore, Hemeoxygenase-1 is a crucial enzyme regulating the iron homeostasis in the heart whose expression is regulated by PPAR family. Inverse relationship exists between the expression levels of PPARγ and hemeoxygenase-1. Adriamycin upregulates the expression of hemeoxygenase-1 which in turn disrupts the iron homeostasis in cardiomyocytes. Our molecular docking results show that Adriamycin has high affinity for iron binding sites of hemeoxygenase-1, thereby hindering formation of iron-sulfur complex. Lack of iron-sulfur complex impairs the electron transport chain. In addition, succinate dehydrogenase subunit A is downregulated by Adriamycin. The lack of this subunit uncouples Krebs cycle from ETC. Further lack of this subunit causes increases the concentration of succinate which further alters the mitochondrial membrane potential. Overall, in the present work we hypothesize that alteration in the expression of PPAR family members is one of the major causes of metabolic chaos and oxidative stress caused by Adriamycin during the development of cardiomyopathy.
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Affiliation(s)
- Uma Priya Mohan
- Centre for Cardiovascular and Adverse Drug Reactions, Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India
| | | | - Selvaraj Kunjiappan
- Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India
| | - Sankarganesh Arunachalam
- Centre for Cardiovascular and Adverse Drug Reactions, Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Tamilnadu, India
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Lee Y, Lim JW, Kim H. α‑lipoic acid inhibits cerulein/resistin‑induced expression of interleukin‑6 by activating peroxisome proliferator‑activated receptor‑γ in pancreatic acinar cells. Mol Med Rep 2022; 26:264. [PMID: 35730599 PMCID: PMC9260878 DOI: 10.3892/mmr.2022.12780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/09/2022] [Indexed: 11/06/2022] Open
Abstract
Cerulein‑induced pancreatitis resembles human acute pancreatitis in terms of pathological events, such as enzymatic activation and inflammatory cell infiltration in the pancreas. Cerulein is a cholecystokinin analog that increases levels of reactive oxygen species (ROS) and interleukin‑6 (IL‑6) expression level in pancreatic acinar cells. Serum levels of resistin, which is secreted from adipocytes, are reportedly higher in patients with acute pancreatitis than in healthy individuals. Previously, it was shown that the adipokine resistin can aggravate the cerulein‑induced increase in ROS levels and IL‑6 expression level in pancreatic acinar cells. Peroxisome proliferator‑activated receptor‑gamma (PPAR‑γ) is a key regulator of the transcription and expression of antioxidant enzymes, including heme oxygenase 1 (HO‑1) and catalase. α‑lipoic acid, a naturally occurring dithiol antioxidant, can prevent cerulein‑induced pancreatic damage in rats. In the present study, it was aimed to investigate whether α‑lipoic acid can attenuate the cerulein/resistin‑induced increase in IL‑6 expression and ROS levels via PPAR‑γ activation in pancreatic acinar AR42J cells. The anti‑inflammatory mechanism of α‑lipoic acid was determined using reverse transcription‑quantitative PCR, western blot analysis, enzyme‑linked immunosorbent assay, immunofluorescence staining and fluorometry. Treatment with cerulein and resistin increased ROS levels and IL‑6 expression level, which were inhibited by α‑lipoic acid in pancreatic acinar cells. α‑lipoic acid increased the nuclear translocation and expression level of PPAR‑γ and the expression levels of its target genes: HO‑1 and catalase. The PPAR‑γ antagonist GW9662 and HO‑1 inhibitor zinc protoporphyrin reversed the inhibitory effect of α‑lipoic acid on cerulein/resistin‑induced increase in ROS and IL‑6 levels. In conclusion, α‑lipoic acid inhibits the cerulein/resistin‑induced increase in ROS production and IL‑6 expression levels by activating PPAR‑γ and inducing the expression of HO‑1 and catalase in pancreatic acinar cells.
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Affiliation(s)
- Yujin Lee
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Joo Weon Lim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Hyeyoung Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
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Guixé‐Muntet S, Biquard L, Szabo G, Dufour J, Tacke F, Francque S, Rautou P, Gracia‐Sancho J. Review article: vascular effects of PPARs in the context of NASH. Aliment Pharmacol Ther 2022; 56:209-223. [PMID: 35661191 PMCID: PMC9328268 DOI: 10.1111/apt.17046] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/04/2021] [Accepted: 05/08/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to regulate glucose and fatty acid metabolism, inflammation, endothelial function and fibrosis. PPAR isoforms have been extensively studied in metabolic diseases, including type 2 diabetes and cardiovascular diseases. Recent data extend the key role of PPARs to liver diseases coursing with vascular dysfunction, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). AIM This review summarises and discusses the pathobiological role of PPARs in cardiovascular diseases with a special focus on their impact and therapeutic potential in NAFLD and NASH. RESULTS AND CONCLUSIONS PPARs may be attractive for the treatment of NASH due to their liver-specific effects but also because of their efficacy in improving cardiovascular outcomes, which may later impact liver disease. Assessment of cardiovascular disease in the context of NASH trials is, therefore, of the utmost importance, both from a safety and efficacy perspective.
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Affiliation(s)
- Sergi Guixé‐Muntet
- Liver Vascular Biology Research GroupIDIBAPS Biomedical Research Institute & CIBEREHDBarcelonaSpain
| | - Louise Biquard
- Université de Paris, Inserm, CNRSCentre de recherche sur l'InflammationUMR1149ParisFrance
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMassachusettsUSA
| | - Jean‐François Dufour
- Department of Visceral Surgery and Medicine & Department for Biomedical ResearchInselspital, University of BernBernSwitzerland
| | - Frank Tacke
- Department of Hepatology & GastroenterologyCharité Universitätsmedizin Berlin, Campus Virchow‐Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Sven Francque
- Department of Gastroenterology and HepatologyAntwerp University HospitalAntwerpBelgium,Translational Sciences in Inflammation and ImmunologyInflaMed Centre of Excellence, Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of AntwerpAntwerpBelgium
| | - Pierre‐Emmanuel Rautou
- Université de Paris, AP‐HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGESTCentre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE‐LIVER, Centre de recherche sur l'inflammationParisFrance
| | - Jordi Gracia‐Sancho
- Liver Vascular Biology Research GroupIDIBAPS Biomedical Research Institute & CIBEREHDBarcelonaSpain,Department of Visceral Surgery and Medicine & Department for Biomedical ResearchInselspital, University of BernBernSwitzerland
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Heme Oxygenase 1/Peroxisome Proliferator-Activated Receptor Gamma Pathway Protects Intimal Hyperplasia and Mitigates Arteriovenous Fistula Dysfunction by Regulating Oxidative Stress and Inflammatory Response. Cardiovasc Ther 2022; 2022:7576388. [PMID: 35812724 PMCID: PMC9207017 DOI: 10.1155/2022/7576388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/28/2022] [Indexed: 11/25/2022] Open
Abstract
Purpose An arteriovenous fistula (AVF) is the preferred vascular access mode for maintenance hemodialysis, and access stenosis and thrombosis are the primary causes of AVF dysfunction. This study is aimed at exploring the molecular mechanisms underlying AVF development and the roles of the heme oxygenase 1/peroxisome proliferator-activated receptor gamma (HO-1/PPAR-γ) pathway in AVF. Method AVF model mice were established, and the vascular tissues from the arteriovenous anastomosis site were sent for mRNA sequencing. Differentially expressed mRNAs (DEmRNAs) were screened and subjected to functional analysis. Thereafter, the mice with HO-1 knockdown and coprotoporphyrin IX chloride (COPP) pretreatment were used to investigate the roles of the HO-1/PPAR-γ pathway in AVF. Results By sequencing, 2514 DEmRNAs, including 1323 upregulated and 1191 downregulated genes, were identified. These DEmRNAs were significantly enriched in the PPAR signaling pathway, AMPK signaling pathway, glucagon signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway. High expression of HO-1 and PPAR-γ reduced endothelial damage and intimal hyperplasia during AVF maturation. After AVF was established, the levels of transforming growth factor-β (TGF-β), interleukin-1β (IL-1β), interleukin-18 (IL-18), and reactive oxygen species (ROS) were significantly increased (P < 0.05), and HO-1 normal expression and COPP pretreatment evidently decreased their levels in AVF (P < 0.05). Additionally, AVF significantly upregulated HO-1 and PPAR-γ and downregulated MMP9, and COPP pretreatment and HO-1 normal expression further upregulated and downregulated their expression. Conclusion The HO-1/PPAR-γ pathway may suppress intimal hyperplasia induced by AVF and protect the intima of blood vessels by regulating MMP9 and ROS, thus mitigating AVF dysfunction.
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Heme Oxygenase-1 Inhibits the Proliferation of Hepatic Stellate Cells by Activating PPARγ and Suppressing NF-κB. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8920861. [PMID: 35047060 PMCID: PMC8763483 DOI: 10.1155/2022/8920861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 11/22/2022]
Abstract
Background Hepatic stellate cells (HSCs) are reported to play significant roles in the development of liver fibrosis. Heme oxygenase-1 (HO-1) is a key rate-limiting enzyme, which could decrease collagen synthesis and liver damage. Nevertheless, it was yet elusive towards the function and mechanism of HO-1. Methods An HO-1 inducer Hemin or an HO-1 inhibitor ZnPP-IX was used to treat the activated HSC-T6, respectively. MTT assay was adopted to detect cell proliferation. Immunocytochemical staining was employed to test the levels of alpha-smooth muscle actin (α-SMA), peroxisome proliferator-activated receptor-γ (PPARγ), and nuclear factor-kappa B (NF-kappa B) levels in HSC-T6. HO-1, PPARγ, and NF-κB expression levels were measured by qRT-PCR and Western blotting. ELISA was then used to detect the levels of transforming growth factor- (TGF-) beta 1 (TGF-β1), interleukin-6 (IL-6), serum hyaluronic acid (HA), and serum type III procollagen aminopeptide (PIIIP). Results HSC-T6 proliferation was inhibited in Hemin-treated HSCs. The levels of α-SMA, HA, and PIIIP and the production of ECM were lower in Hemin-treated HSCs, whereas those could be rescued by ZnPP-IX. NF-κB activation was decreased, but PPARγ expression was increased after HO-1 upregulation. Furthermore, the levels of TGF-β1 and IL-6, which were downstream of activated NF-κB in HSC-T6, were reduced. The PPAR-specific inhibitor GW9662 could block those mentioned effects. Conclusions Our data demonstrated that HO-1 induction could inhibit HSC proliferation and activation by regulating PPARγ expression and NF-κB activation directly or indirectly, which makes it a promising therapeutic target for liver fibrosis.
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Lin C, Lai SW, Shen CK, Chen CW, Tsai CF, Liu YS, Lu DY, Huang BR. Fenofibrate inhibits hypoxia-inducible factor-1 alpha and carbonic anhydrase expression through activation of AMP-activated protein kinase/HO-1/Sirt1 pathway in glioblastoma cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:2551-2561. [PMID: 34520103 DOI: 10.1002/tox.23369] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 08/27/2021] [Accepted: 08/29/2021] [Indexed: 06/13/2023]
Abstract
Cancer and its associated conditions have significant impacts on public health at many levels worldwide, and cancer is the leading cause of death among adults. Peroxisome proliferator-activated receptor α (PPARα)-specific agonists, fibrates, have been approved by the Food and Drug Administration for managing hyperlipidemia. PPARα-specific agonists exert anti-cancer effects in many human cancer types, including glioblastoma (GBM). Recently, we have reported that the hypoxic state in GBM stabilizes hypoxia-inducible factor-1 alpha (HIF-1α), thus contributing to tumor escape from immune surveillance by activating the expression of the pH-regulating protein carbonic anhydrase IX (CA9). In this study, we aimed to study the regulatory effects of the PPARα agonist fibrate on the regulation of HIF-1α expression and its downstream target protein in GBM. Our findings showed that fenofibrate is the high potency compound among the various fibrates that inhibit hypoxia-induced HIF-1α and CA9 expression in GBM. Moreover, fenofibrate-inhibited HIF-1α expression is mediated by HO-1 activation in GBM cells through the AMP-activated protein kinase (AMPK) pathway. In addition, fenofibrate-enhanced HO-1 upregulation activates SIRT1 and leads to subsequent accumulation of SIRT1 in the nucleus, which further promotes HIF-1α deacetylation and inhibits CA9 expression. Using a protein synthesis inhibitor, cycloheximide, we also observed that fenofibrate inhibited HIF-1α protein synthesis. In addition, the administration of the proteasome inhibitor MG132 showed that fenofibrate promoted HIF-1α protein degradation in GBM. Hence, our results indicate that fenofibrate is a useful anti-GBM agent that modulates hypoxia-induced HIF-1α expression through multiple cellular pathways.
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Affiliation(s)
- Chingju Lin
- Department of Physiology, 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
| | - Chao-Wei Chen
- Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | - Cheng-Fang Tsai
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
| | - Yu-Shu Liu
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, 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
| | - 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
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Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 2021; 20:689-709. [PMID: 34194012 PMCID: PMC8243062 DOI: 10.1038/s41573-021-00233-1] [Citation(s) in RCA: 1395] [Impact Index Per Article: 348.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2021] [Indexed: 02/06/2023]
Abstract
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.
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Affiliation(s)
- Henry Jay Forman
- University of California Merced, Merced, CA, USA.
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
| | - Hongqiao Zhang
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
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Li J, Quan X, Lei S, Huang Z, Wang Q, Xu P. PFOS Inhibited Normal Functional Development of Placenta Cells via PPARγ Signaling. Biomedicines 2021; 9:biomedicines9060677. [PMID: 34203907 PMCID: PMC8232579 DOI: 10.3390/biomedicines9060677] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 01/13/2023] Open
Abstract
Perfluorooctane sulfonic acid (PFOS), a persistent environmental pollutant, has adverse effects on gestation pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is involved in angiogenesis, metabolic processes, anti-inflammatory, and reproductive development. However, the function of PPARγ in PFOS evoked disadvantageous effects on the placenta remain uncertain. Here, we explored the role of PPARγ in PFOS-induced placental toxicity. Cell viability, cell migration, angiogenesis, and mRNA expression were monitored by CCK-8 assay, wound healing assay, tube formation assay, and real-time PCR, respectively. Activation and overexpression of PPARγ were conducted by rosiglitazone or pcDNA-PPARγ, and inhibition and knockdown of PPARγ were performed by GW9662 or si-PPARγ. Results revealed that PFOS decreased cell growth, migration, angiogenesis, and increased inflammation in human HTR-8/SVneo and JEG-3 cells. Placenta diameter and fetal weight decreased in mice treated with PFOS (12.5 mg/kg). In addition, rosiglitazone or pcDNA-PPARγ rescued cell proliferation, migration, angiogenesis, and decreased inflammation induced by PFOS in HTR8/SVneo and JEG-3 cells. Furthermore, GW9662 or si-PPARγ exacerbated the inhibition of cell viability, migration, angiogenesis, and aggravated inflammation induced by PFOS in HTR-8/SVneo and JEG-3 cells. Meanwhile, the results of mRNA expression level were consistent with the cell representation. In conclusion, our findings revealed that PFOS induced placenta cell toxicity and functional damage through PPARγ pathway.
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Affiliation(s)
- Jing Li
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, China; (J.L.); (X.Q.); (Z.H.); (Q.W.)
| | - Xiaojie Quan
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, China; (J.L.); (X.Q.); (Z.H.); (Q.W.)
| | - Saifei Lei
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA;
| | - Zhenyao Huang
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, China; (J.L.); (X.Q.); (Z.H.); (Q.W.)
| | - Qi Wang
- School of Public Health, Xuzhou Medical University, Xuzhou 221002, China; (J.L.); (X.Q.); (Z.H.); (Q.W.)
| | - Pengfei Xu
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA;
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Correspondence: ; Tel.: +1-412-708-4694
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Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection: a theoretical perspective. Pharmacol Rep 2021; 73:712-727. [PMID: 33880743 PMCID: PMC8057922 DOI: 10.1007/s43440-021-00255-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/14/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. Drug Suggestion Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. Conclusion The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.
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Macrophage metabolic adaptation to heme detoxification involves CO-dependent activation of the pentose phosphate pathway. Blood 2021; 136:1535-1548. [PMID: 32556090 DOI: 10.1182/blood.2020004964] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 05/08/2020] [Indexed: 02/07/2023] Open
Abstract
Heme is an essential cofactor for numerous cellular functions, but release of free heme during hemolysis results in oxidative tissue damage, vascular dysfunction, and inflammation. Macrophages play a key protective role in heme clearance; however, the mechanisms that regulate metabolic adaptations that are required for effective heme degradation remain unclear. Here we demonstrate that heme loading drives a unique bioenergetic switch in macrophages, which involves a metabolic shift from oxidative phosphorylation toward glucose consumption. Metabolomic and transcriptional analysis of heme-loaded macrophages revealed that glucose is funneled into the pentose phosphate pathway (PPP), which is indispensable for efficient heme detoxification and is required to maintain redox homeostasis. We demonstrate that the metabolic shift to the PPP is controlled by heme oxygenase-dependent generation of carbon monoxide (CO). Finally, we show that PPP upregulation occurs in vivo in organ systems central to heme clearance and that PPP activity correlates with heme levels in mouse sickle cell disease (SCD). Together, our findings demonstrate that metabolic adaptation to heme detoxification in macrophages requires a shift to the PPP that is induced by heme-derived CO, suggesting pharmacologic targeting of macrophage metabolism as a novel therapeutic strategy to improve heme clearance in patients with hemolytic disorders.
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Yang CC, Yang CM. Chinese Herbs and Repurposing Old Drugs as Therapeutic Agents in the Regulation of Oxidative Stress and Inflammation in Pulmonary Diseases. J Inflamm Res 2021; 14:657-687. [PMID: 33707963 PMCID: PMC7940992 DOI: 10.2147/jir.s293135] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Several pro-inflammatory factors and proteins have been characterized that are involved in the pathogenesis of inflammatory diseases, including acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, induced by oxidative stress, cytokines, bacterial toxins, and viruses. Reactive oxygen species (ROS) act as secondary messengers and are products of normal cellular metabolism. Under physiological conditions, ROS protect cells against oxidative stress through the maintenance of cellular redox homeostasis, which is important for proliferation, viability, cell activation, and organ function. However, overproduction of ROS is most frequently due to excessive stimulation of either the mitochondrial electron transport chain and xanthine oxidase or reduced nicotinamide adenine dinucleotide phosphate (NADPH) by pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor α. NADPH oxidase activation and ROS overproduction could further induce numerous inflammatory target proteins that are potentially mediated via Nox/ROS-related transcription factors triggered by various intracellular signaling pathways. Thus, oxidative stress is considered important in pulmonary inflammatory processes. Previous studies have demonstrated that redox signals can induce pulmonary inflammatory diseases. Thus, therapeutic strategies directly targeting oxidative stress may be effective for pulmonary inflammatory diseases. Therefore, drugs with anti-inflammatory and anti-oxidative properties may be beneficial to these diseases. Recent studies have suggested that traditional Chinese medicines, statins, and peroxisome proliferation-activated receptor agonists could modulate inflammation-related signaling processes and may be beneficial for pulmonary inflammatory diseases. In particular, several herbal medicines have attracted attention for the management of pulmonary inflammatory diseases. Therefore, we reviewed the pharmacological effects of these drugs to dissect how they induce host defense mechanisms against oxidative injury to combat pulmonary inflammation. Moreover, the cytotoxicity of oxidative stress and apoptotic cell death can be protected via the induction of HO-1 by these drugs. The main objective of this review is to focus on Chinese herbs and old drugs to develop anti-inflammatory drugs able to induce HO-1 expression for the management of pulmonary inflammatory diseases.
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Affiliation(s)
- Chien-Chung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan, 33302, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, 33302, Taiwan
| | - Chuen-Mao Yang
- Department of Pharmacology, College of Medicine, China Medical University, Taichung, 40402, Taiwan.,Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, 40402, Taiwan.,Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Taichung, 41354, Taiwan
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de Carvalho MV, Gonçalves-de-Albuquerque CF, Silva AR. PPAR Gamma: From Definition to Molecular Targets and Therapy of Lung Diseases. Int J Mol Sci 2021; 22:E805. [PMID: 33467433 PMCID: PMC7830538 DOI: 10.3390/ijms22020805] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/18/2020] [Accepted: 09/24/2020] [Indexed: 12/15/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate the expression of genes related to lipid and glucose metabolism and inflammation. There are three members: PPARα, PPARβ or PPARγ. PPARγ have several ligands. The natural agonists are omega 9, curcumin, eicosanoids and others. Among the synthetic ligands, we highlight the thiazolidinediones, clinically used as an antidiabetic. Many of these studies involve natural or synthetic products in different pathologies. The mechanisms that regulate PPARγ involve post-translational modifications, such as phosphorylation, sumoylation and ubiquitination, among others. It is known that anti-inflammatory mechanisms involve the inhibition of other transcription factors, such as nuclear factor kB(NFκB), signal transducer and activator of transcription (STAT) or activator protein 1 (AP-1), or intracellular signaling proteins such as mitogen-activated protein (MAP) kinases. PPARγ transrepresses other transcription factors and consequently inhibits gene expression of inflammatory mediators, known as biomarkers for morbidity and mortality, leading to control of the exacerbated inflammation that occurs, for instance, in lung injury/acute respiratory distress. Many studies have shown the therapeutic potentials of PPARγ on pulmonary diseases. Herein, we describe activities of the PPARγ as a modulator of inflammation, focusing on lung injury and including definition and mechanisms of regulation, biological effects and molecular targets, and its role in lung diseases caused by inflammatory stimuli, bacteria and virus, and molecular-based therapy.
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Affiliation(s)
- Márcia V. de Carvalho
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil;
- Programa de Pós-Graduação em Biologia Celular e Molecular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Cassiano F. Gonçalves-de-Albuquerque
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil;
- Laboratório de Imunofarmacologia, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro 20211-010, Brazil
- Programa de Pós-Graduação em Biologia Molecular e Celular, Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro 20211-010, Brazil
| | - Adriana R. Silva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil;
- Programa de Pós-Graduação em Biologia Celular e Molecular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
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Jang HY, Hong OY, Youn HJ, Kim MG, Kim CH, Jung SH, Kim JS. 15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism. BMB Rep 2021. [PMID: 31964465 PMCID: PMC7196191 DOI: 10.5483/bmbrep.2020.53.4.164] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and over-expressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPARγ. In this study, we investigated the effects of induction of HO-1 by PPARγ on TPA-induced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-μB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPARγ ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP-9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPARγ/HO-1 signaling-pathway inhibition may be beneficial for prevention and treatment of breast cancer.
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Affiliation(s)
- Hye-Yeon Jang
- Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - On-Yu Hong
- Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - Hyun Jo Youn
- Department of Surgery, Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University and Biomedical Research Institute, Jeonju 54907, Korea
| | - Min-Gul Kim
- Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - Cheorl-Ho Kim
- Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sung Kyun Kwan University, Suwon 16419, Korea
| | - Sung Hoo Jung
- Department of Surgery, Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University and Biomedical Research Institute, Jeonju 54907, Korea
| | - Jong-Suk Kim
- Department of Biochemistry, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54907, Korea
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Prashantha Kumar BR, Kumar AP, Jose JA, Prabitha P, Yuvaraj S, Chipurupalli S, Jeyarani V, Manisha C, Banerjee S, Jeyabalan JB, Mohankumar SK, Dhanabal SP, Justin A. Minutes of PPAR-γ agonism and neuroprotection. Neurochem Int 2020; 140:104814. [PMID: 32758586 DOI: 10.1016/j.neuint.2020.104814] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/25/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPAR-γ) is one of the ligand-activated transcription factors which regulates a number of central events and considered as a promising target for various neurodegenerative disease conditions. Numerous reports implicate that PPAR-γ agonists have shown neuroprotective effects by regulating genes transcription associated with the pathogenesis of neurodegeneration. In regards, this review critically appraises the recent knowledge of PPAR-γ receptors in neuroprotection in order to hypothesize potential neuroprotective mechanism of PPAR-γ agonism in chronic neurological conditions. Of note, the PPAR-γ's interaction dynamics with PPAR-γ coactivator-1α (PGC-1α) has gained significant attention for neuroprotection. Likewise, a plethora of studies suggest that the PPAR-γ pathway can be actuated by the endogenous ligands present in the CNS and thus identification and development of novel agonist for the PPAR-γ receptor holds a vow to prevent neurodegeneration. Together, the critical insights of this review enlighten the translational possibilities of developing novel neuroprotective therapeutics targeting PPAR-γ for various neurodegenerative disease conditions.
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Affiliation(s)
- B R Prashantha Kumar
- Department of Pharmaceutical Chemistry, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Mysuru, Karnataka, India
| | - Ashwini Prem Kumar
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Jincy A Jose
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - P Prabitha
- Department of Pharmaceutical Chemistry, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Mysuru, Karnataka, India
| | - S Yuvaraj
- Department of Pharmaceutical Chemistry, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Mysuru, Karnataka, India
| | - Sandhya Chipurupalli
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Victoria Jeyarani
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Chennu Manisha
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Sayani Banerjee
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Jeyaram Bharathi Jeyabalan
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Suresh Kumar Mohankumar
- TIFAC CORE in HD, Department of Pharmacognosy, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - S P Dhanabal
- TIFAC CORE in HD, Department of Pharmacognosy, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Antony Justin
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India.
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Comparative study of the effects of ziram and disulfiram on human monocyte-derived macrophage functions and polarization: involvement of zinc. Cell Biol Toxicol 2020; 37:379-400. [PMID: 32712770 DOI: 10.1007/s10565-020-09540-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/03/2020] [Indexed: 10/23/2022]
Abstract
Ziram, a zinc dithiocarbamate is widely used worldwide as a fungicide in agriculture. In order to investigate ziram-induced changes in macrophage functions and polarization, human monocytes-derived macrophages in culture were treated with ziram at 0.01-10 μmol.L-1 for 4-24 h. To characterize zinc involvement in these changes, we also determined the effects of disulfiram alone (dithiocarbamate without zinc) or in co-incubation with ZnSO4. We have shown that ziram and disulfiram at 0.01 μmol.L-1 increased zymosan phagocytosis. In contrast, ziram at 10 μmol.L-1 completely inhibited this phagocytic process, the oxidative burst triggered by zymosan and the production of TNF-α, IL-1β, IL-6, and CCL2 triggered by LPS. Disulfiram had the same effects on these macrophages functions only when combined with zinc (10 μmol.L-1). In contrast, at 10 μmol.L-1 ziram and zinc associated-disulfiram induced expression of several antioxidants genes HMOX1, SOD2, and catalase, which could suggest the induction of oxidative stress. This oxidative stress could be involved in the increase in late apoptosis induced by ziram (10 μmol.L-1) and zinc associated-disulfiram. Concerning gene expression profiles of membrane markers of macrophage polarization, ziram at 10 μmol.L-1 had two opposite effects. It inhibited the gene expression of M2 markers (CD36, CD163) in the same way as the disulfiram-zinc co-treatment. Conversely, ziram induced gene expression of other M2 markers CD209, CD11b, and CD16 in the same way as treatment with zinc alone. Disulfiram-zinc association had no significant effects on these markers. These results taken together show that ziram via zinc modulates macrophages to M2-like anti-inflammatory phenotype which is often associated with various diseases.
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Abdalla HB, Napimoga MH, Lopes AH, de Macedo Maganin AG, Cunha TM, Van Dyke TE, Clemente Napimoga JT. Activation of PPAR-γ induces macrophage polarization and reduces neutrophil migration mediated by heme oxygenase 1. Int Immunopharmacol 2020; 84:106565. [DOI: 10.1016/j.intimp.2020.106565] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 04/30/2020] [Accepted: 05/03/2020] [Indexed: 01/11/2023]
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Comparative Study of PPAR γ Targets in Human Extravillous and Villous Cytotrophoblasts. PPAR Res 2020; 2020:9210748. [PMID: 32308672 PMCID: PMC7152979 DOI: 10.1155/2020/9210748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/26/2020] [Accepted: 02/11/2020] [Indexed: 12/15/2022] Open
Abstract
Trophoblasts, as the cells that make up the main part of the placenta, undergo cell differentiation processes such as invasion, migration, and fusion. Abnormalities in these processes can lead to a series of gestational diseases whose underlying mechanisms are still unclear. One protein that has proven to be essential in placentation is the peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in the nuclei of extravillous cytotrophoblasts (EVCTs) in the first trimester and villous cytotrophoblasts (VCTs) throughout pregnancy. Here, we aimed to explore the genome-wide effects of PPARγ on EVCTs and VCTs via treatment with the PPARγ-agonist rosiglitazone. EVCTs and VCTs were purified from human chorionic villi, cultured in vitro, and treated with rosiglitazone. The transcriptomes of both types of cells were then quantified using microarray profiling. Differentially expressed genes (DEGs) were filtered and submitted for gene ontology (GO) annotation and pathway analysis with ClueGO. The online tool STRING was used to predict PPARγ and DEG protein interactions, while iRegulon was used to predict the binding sites for PPARγ and DEG promoters. GO and pathway terms were compared between EVCTs and VCTs with clusterProfiler. Visualizations were prepared in Cytoscape. From our microarray data, 139 DEGs were detected in rosiglitazone-treated EVCTs (RT-EVCTs) and 197 DEGs in rosiglitazone-treated VCTs (RT-VCTs). Downstream annotation analysis revealed the similarities and differences between RT-EVCTs and RT-VCTs with respect to the biological processes, molecular functions, cellular components, and KEGG pathways affected by the treatment, as well as predicted binding sites for both protein-protein interactions and transcription factor-target gene interactions. These results provide a broad perspective of PPARγ-activated processes in trophoblasts; further analysis of the transcriptomic signatures of RT-EVCTs and RT-VCTs should open new avenues for future research and contribute to the discovery of possible drug-targeted genes or pathways in the human placenta.
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Ahn S, Basavana Gowda M, Lee M, Masagalli JN, Mailar K, Choi WJ, Noh M. Novel linked butanolide dimer compounds increase adiponectin production during adipogenesis in human mesenchymal stem cells through peroxisome proliferator-activated receptor γ modulation. Eur J Med Chem 2020; 187:111969. [DOI: 10.1016/j.ejmech.2019.111969] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/28/2019] [Accepted: 12/11/2019] [Indexed: 12/15/2022]
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Nitti M, Furfaro AL, Mann GE. Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment? Front Physiol 2020; 11:23. [PMID: 32082188 PMCID: PMC7000760 DOI: 10.3389/fphys.2020.00023] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
Among antioxidants in the human body, bilirubin has been recognized over the past 20 years to afford protection against different chronic conditions, including inflammation and cardiovascular disease. Moderate increases in plasma concentration and cellular bilirubin generation from metabolism of heme via heme oxygenase (HMOX) in virtually all tissues can modulate endothelial and vascular function and exert antioxidant and anti-inflammatory roles. This review aims to provide an up-to-date and critical overview of the molecular mechanisms by which bilirubin derived from plasma or from HMOX1 activation in vascular cells affects endothelial function. Understanding the molecular actions of bilirubin may critically improve the management not only of key cardiovascular diseases, but also provide insights into a broad spectrum of pathologies driven by endothelial dysfunction. In this context, therapeutic interventions aimed at mildly increasing serum bilirubin as well as bilirubin generated endogenously by endothelial HMOX1 should be considered.
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Affiliation(s)
- Mariapaola Nitti
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Anna Lisa Furfaro
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Giovanni E Mann
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
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Gui F, You Z, Fu S, Wu H, Zhang Y. Endothelial Dysfunction in Diabetic Retinopathy. Front Endocrinol (Lausanne) 2020; 11:591. [PMID: 33013692 PMCID: PMC7499433 DOI: 10.3389/fendo.2020.00591] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/20/2020] [Indexed: 12/21/2022] Open
Abstract
Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.
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Baghcheghi Y, Salmani H, Beheshti F, Shafei MN, Sadeghnia HR, Soukhtanloo M, Ebrahimzadeh Bideskan A, Hosseini M. Effects of PPAR-γ agonist, pioglitazone on brain tissues oxidative damage and learning and memory impairment in juvenile hypothyroid rats. Int J Neurosci 2019; 129:1024-1038. [PMID: 31215278 DOI: 10.1080/00207454.2019.1632843] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 05/19/2019] [Accepted: 06/11/2019] [Indexed: 12/20/2022]
Abstract
Aim: The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on the brain tissues oxidative damage and learning and memory impairment in the juvenile hypothyroid rats was evaluated. Main methods: Rats were classified as: ( 1 ) Control; (2) Propylthiouracil (PTU); (3) PTU-Pio 10 and (4) PTU-Pio 20. PTU was given in drinking water (0.05%) during 6 weeks. Pioglitazone (10 or 20 mg/kg) was daily injected intraperitoneally. Passive avoidance (PA) and Morris water maze (MMW) were conducted. Later, the animals were sacrificed and the brain tissues were removed for biochemical measurements. Key funding: The results indicated that in the MWM escape latency as well as traveled path increased in the PTU group as compared to the control group. Also, the time spent in the target quadrant in the probe test of MWM and step-through latency in the PA test were decreased in the PTU group as compared to the control group. Pioglitazone reversed all the negative behavioral effects of hypothyroidism. Administration of PTU attenuated thiol and superoxide dismutase (SOD), and catalase (CAT) activities in the brain tissues, whereas increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. PPARγ agonist improved thiol, SOD and CAT, while diminished MDA concentration. Significance: Our finding in the present study indicated that PPARγ agonist pioglitazone prevented the brain tissues from oxidative damage and learning and memory impairments in juvenile hypothyroid rats.
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Affiliation(s)
- Yousef Baghcheghi
- Student Research Committee, Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Hossein Salmani
- Student Research Committee, Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Farimah Beheshti
- Department of Medical Basic Sciences and Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences , Torbat Heydariyeh , Iran
| | - Mohammad Naser Shafei
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Hamid Reza Sadeghnia
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Mohammad Soukhtanloo
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Alireza Ebrahimzadeh Bideskan
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Mahmoud Hosseini
- Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences , Mashhad , Iran
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Zhu X, Chen F, Lu K, Wei A, Jiang Q, Cao W. PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice. Ann Rheum Dis 2019; 78:1420-1429. [PMID: 31239244 DOI: 10.1136/annrheumdis-2018-214940] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/31/2019] [Accepted: 06/03/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Osteoarthritis (OA) is the most common degenerative joint disease in aged population and its development is significantly influenced by aberrant epigenetic modifications of numerous OA susceptible genes; however, the precise mechanisms that DNA methylation alterations affect OA pathogenesis remain undefined. This study investigates the critical role of epigenetic PPARγ (peroxisome proliferator-activated receptor-gamma) suppression in OA development. METHODS Articular cartilage expressions of PPARγ and bioactive DNA methyltransferases (DNMTs) from OA patients and mice incurred by DMM (destabilisation of medial meniscus) were examined. DNA methylation status of both human and mouse PPARγ promoters were assessed by methylated specific PCR and/or bisulfite-sequencing PCR. OA protections by a pharmacological DNA demethylating agent 5Aza (5-Aza-2'-deoxycytidine) were compared between wild type and PPARγ knockout mice. RESULTS Articular cartilages from both OA patients and DMM mice display substantial PPARγ suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPARγ promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPARγ promoter hypermethylation, recovered the PPARγ loss and effectively attenuated the cartilage damage in OA mice. 5Aza also inhibited the OA-associated excessive inflammatory cytokines and deficit anti-oxidant enzymes, which were blocked by a specific PPARγ inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPARγ knockout mice. CONCLUSION Epigenetic PPARγ suppression plays a key role in OA development and PPARγ preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.
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Affiliation(s)
- Xiaobo Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, The Affiliated Drum Tower Hospital of Nanjing University School of Medicine, Nanjing, China
| | - Fang Chen
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Ke Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, The Affiliated Drum Tower Hospital of Nanjing University School of Medicine, Nanjing, China
| | - Ai Wei
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, The Affiliated Drum Tower Hospital of Nanjing University School of Medicine, Nanjing, China
- Model Animal Research Center, Nanjing University, Nanjing, China
| | - Wangsen Cao
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China
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Drummond GS, Baum J, Greenberg M, Lewis D, Abraham NG. HO-1 overexpression and underexpression: Clinical implications. Arch Biochem Biophys 2019; 673:108073. [PMID: 31425676 DOI: 10.1016/j.abb.2019.108073] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/23/2019] [Accepted: 08/10/2019] [Indexed: 12/11/2022]
Abstract
In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on vascular disease. In a few instances e.g., neonatal jaundice, overproduction of HO-1 and increased HO activity results in elevated levels of bilirubin requiring clinical intervention with inhibitors of HO activity. In contrast HO-1 levels and HO activity are low in obesity and the HO system responds to mitigate the deleterious effects of oxidative stress through increased levels of bilirubin (anti-inflammatory) and CO (anti-apoptotic) and decreased levels of heme (pro-oxidant). Site specific HO-1 overexpression diminishes adipocyte terminal differentiation and lipid accumulation of obesity mediated release of inflammatory molecules. A series of diverse strategies have been implemented that focus on increasing HO-1 and HO activity that are central to reversing the clinical complications associated with diseases including, obesity, metabolic syndrome and vascular disease.
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Affiliation(s)
- George S Drummond
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Jeffrey Baum
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Menachem Greenberg
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - David Lewis
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25701, USA.
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Lane SL, Dodson RB, Doyle AS, Park H, Rathi H, Matarrazo CJ, Moore LG, Lorca RA, Wolfson GH, Julian CG. Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction. FASEB J 2019; 33:8999-9007. [PMID: 31039323 PMCID: PMC6662983 DOI: 10.1096/fj.201900214r] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/08/2019] [Indexed: 12/11/2022]
Abstract
The hypoxia of high-altitude (HA) residence increases the risk of intrauterine growth restriction (IUGR) and preeclampsia 3-fold, augmenting perinatal morbidity and mortality and the risk for childhood and adult disease. Currently, no effective therapies exist to prevent these vascular disorders of pregnancy. The peroxisome proliferator-activated receptor γ (PPAR-γ) is an important regulator of uteroplacental vascular development and function and has been implicated in the pathogenesis of IUGR and preeclampsia. Here, we used a model of HA pregnancy in mice to determine whether hypoxia-induced fetal growth restriction reduces placental PPAR-γ protein expression and placental vascularization and, if so, to evaluate the effectiveness of the selective PPAR-γ agonist pioglitazone (PIO) for preventing hypoxia-induced IUGR. Hypoxia resulted in asymmetric IUGR, placental insufficiency, and reduced placental PPAR-γ expression; PIO prevented approximately half of the fetal growth restriction and attenuated placental insufficiency. PIO did not affect fetal growth under normoxia. Although PIO was beneficial for fetal growth, PIO treatment reduced placental vascular density of the labrynthine zone in normoxic and hypoxic (Hx) conditions, and mean vascular area was reduced in the Hx group. Our results suggest that pharmacological PPAR-γ activation is a potential strategy for preventing IUGR in pregnancies complicated by hypoxia, although further studies are needed to identify its likely metabolic or vascular mechanisms.-Lane, S. L., Dodson, R. B., Doyle, A. S., Park, H., Rathi, H., Matarrazo, C. J., Moore, L. G., Lorca, R. A., Wolfson, G. H., Julian, C. G. Pharmacological activation of peroxisome proliferator-activated receptor γ (PPAR-γ) protects against hypoxia-associated fetal growth restriction.
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Affiliation(s)
- Sydney L. Lane
- Integrated Physiology Program, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - R. Blair Dodson
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexandrea S. Doyle
- Department of Integrative Biology, University of Colorado Denver, Denver, Colorado, USA
| | - Haemin Park
- Colorado Undergraduate Research in Environmental Health Sciences, University of Colorado Denver, Denver, Colorado, USA
| | - Hinal Rathi
- Department of Integrative Biology, University of Colorado Denver, Denver, Colorado, USA
| | | | - Lorna G. Moore
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Ramón A. Lorca
- Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Gabriel H. Wolfson
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA; and
| | - Colleen G. Julian
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA; and
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2-Phenyl-8-(1-phenylallyl)-chromenone compounds have a pan-PPAR modulator pharmacophore. Bioorg Med Chem 2019; 27:2948-2958. [PMID: 31128991 DOI: 10.1016/j.bmc.2019.05.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/15/2019] [Accepted: 05/17/2019] [Indexed: 12/30/2022]
Abstract
Adiponectin is an adipocytokine with insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. Adiponectin secretion-inducing compounds have therapeutic potential in a variety of metabolic diseases. Phenotypic screening led to the discovery that 5,7-dihydroxy-8-(1-(4-hydroxy-3-methoxyphenyl)allyl)-2-phenyl-4H-chromen-4-one (compound 1) had adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Compound 1 was originally reported to be an anti-cancer chemical isolated from natural honeybee propolis, and its adiponectin secretion-inducing activity was found in non-cytotoxic concentrations. In a target identification study, compound 1 and its potent synthetic derivative compound 5 were shown to be novel pan-peroxisome proliferator-activator receptor (PPAR) modulators. Molecular docking models with PPARs have indicated that the binding modes of chromenone compounds preferentially interacted with the hydrophobic ligand binding pocket of PPARs. In addition, chromenone compounds have been shown to result in different phenotypic outcomes in the transcriptional regulation of lipid metabolic enzymes than those of selective PPAR mono-agonists for PPARα, PPARγ, and PPARδ. In line with the pharmacology of adiponectin and PPAR pan-modulators, compounds 1 and 5 may have diverse therapeutic potentials to treat cancer and metabolic diseases.
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Gordon DM, Blomquist TM, Miruzzi SA, McCullumsmith R, Stec DE, Hinds TD. RNA sequencing in human HepG2 hepatocytes reveals PPAR-α mediates transcriptome responsiveness of bilirubin. Physiol Genomics 2019; 51:234-240. [PMID: 31074682 DOI: 10.1152/physiolgenomics.00028.2019] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Bilirubin is a potent antioxidant that reduces inflammation and the accumulation of fat. There have been reports of gene responses to bilirubin, which was mostly attributed to its antioxidant function. Using RNA sequencing, we found that biliverdin, which is rapidly reduced to bilirubin, induced transcriptome responses in human HepG2 hepatocytes in a peroxisome proliferator-activated receptor (PPAR)-α-dependent fashion (398 genes with >2-fold change; false discovery rate P < 0.05). For comparison, a much narrower set of genes demonstrated differential expression when PPAR-α was suppressed via lentiviral shRNA knockdown (23 genes). Gene set enrichment analysis revealed the bilirubin-PPAR-α transcriptome mediates pathways for oxidation-reduction processes, mitochondrial function, response to nutrients, fatty acid oxidation, and lipid homeostasis. Together, these findings suggest that transcriptome responses from the generation of bilirubin are mostly PPAR-α dependent, and its antioxidant function regulates a smaller set of genes.
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Affiliation(s)
- Darren M Gordon
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine , Toledo, Ohio
| | - Thomas M Blomquist
- Department of Pathology, University of Toledo College of Medicine , Toledo, Ohio
| | - Scott A Miruzzi
- Department of Neuroscience, University of Toledo College of Medicine , Toledo, Ohio
| | - Robert McCullumsmith
- Department of Neuroscience, University of Toledo College of Medicine , Toledo, Ohio
| | - David E Stec
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center , Jackson, Mississippi
| | - Terry D Hinds
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine , Toledo, Ohio
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Armagan G, Sevgili E, Gürkan FT, Köse FA, Bilgiç T, Dagcı T, Saso L. Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3β in MPP⁺-Induced Cell Damage. Molecules 2019; 24:molecules24071377. [PMID: 30965670 PMCID: PMC6480928 DOI: 10.3390/molecules24071377] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/05/2019] [Accepted: 04/07/2019] [Indexed: 01/14/2023] Open
Abstract
Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3β (GSK-3β) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP⁺-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3β enzyme inhibition against MPP⁺. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3β enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3β along with PPARγ activation may be responsible for neuroprotection.
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Affiliation(s)
- Güliz Armagan
- Department of Biochemistry, Faculty of Pharmacy, Ege University, 35100 Bornova, Izmir, Turkey.
| | - Elvin Sevgili
- Department of Biochemistry, Faculty of Pharmacy, Ege University, 35100 Bornova, Izmir, Turkey.
| | - Fulya Tuzcu Gürkan
- Department of Physiology, School of Medicine, Ege University, 35100 Bornova, Izmir, Turkey.
| | - Fadime Aydın Köse
- Department of Biochemistry, Faculty of Pharmacy, Ege University, 35100 Bornova, Izmir, Turkey.
| | - Tuğçe Bilgiç
- Department of Physiology, School of Medicine, Ege University, 35100 Bornova, Izmir, Turkey.
| | - Taner Dagcı
- Department of Physiology, School of Medicine, Ege University, 35100 Bornova, Izmir, Turkey.
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, 00185 Rome, Italy.
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Korbecki J, Bobiński R, Dutka M. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm Res 2019; 68:443-458. [PMID: 30927048 PMCID: PMC6517359 DOI: 10.1007/s00011-019-01231-1] [Citation(s) in RCA: 259] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/24/2019] [Accepted: 03/22/2019] [Indexed: 12/14/2022] Open
Abstract
The peroxisome proliferator-activated receptor (PPAR) family includes three transcription factors: PPARα, PPARβ/δ, and PPARγ. PPAR are nuclear receptors activated by oxidised and nitrated fatty acid derivatives as well as by cyclopentenone prostaglandins (PGA2 and 15d-PGJ2) during the inflammatory response. This results in the modulation of the pro-inflammatory response, preventing it from being excessively activated. Other activators of these receptors are nonsteroidal anti-inflammatory drug (NSAID) and fatty acids, especially polyunsaturated fatty acid (PUFA) (arachidonic acid, ALA, EPA, and DHA). The main function of PPAR during the inflammatory reaction is to promote the inactivation of NF-κB. Possible mechanisms of inactivation include direct binding and thus inactivation of p65 NF-κB or ubiquitination leading to proteolytic degradation of p65 NF-κB. PPAR also exert indirect effects on NF-κB. They promote the expression of antioxidant enzymes, such as catalase, superoxide dismutase, or heme oxygenase-1, resulting in a reduction in the concentration of reactive oxygen species (ROS), i.e., secondary transmitters in inflammatory reactions. PPAR also cause an increase in the expression of IκBα, SIRT1, and PTEN, which interferes with the activation and function of NF-κB in inflammatory reactions.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 Str., 40-752, Katowice, Poland. .,Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa 2 Str., 43-309, Bielsko-Biała, Poland.
| | - Rafał Bobiński
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa 2 Str., 43-309, Bielsko-Biała, Poland
| | - Mieczysław Dutka
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa 2 Str., 43-309, Bielsko-Biała, Poland
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