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Wadan AHS, Moshref AS, Emam AM, Bakry YG, Khalil BO, Chaurasia A, Ibrahim RAH, Badawy T, Mehanny SS. Mitochondrial dysfunction as a key player in aggravating periodontitis among diabetic patients: review of the current scope of knowledge. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04025-x. [PMID: 40272516 DOI: 10.1007/s00210-025-04025-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/05/2025] [Indexed: 04/25/2025]
Abstract
Periodontitis is a prevalent inflammatory disease that leads to significant periodontal tissue destruction and compromised dental health, with its severity exacerbated in individuals with Diabetes Mellitus (DM). This review explores the complex relationship between mitochondrial dysfunction and periodontitis in diabetic patients. Recent studies indicate that the excessive production of reactive oxygen species (ROS), primarily generated by dysfunctional mitochondrial electron transport chain (ETC) complexes, contributes to oxidative stress (OS) and subsequent periodontal tissue damage. The interplay between impaired mitochondrial biogenesis, apoptosis of periodontal cells, and ROS accumulation highlights a critical area of concern in understanding the pathophysiology of diabetic periodontitis. Furthermore, altered glycemic control due to inflammatory processes associated with periodontitis may perpetuate a cyclical detriment to oral and systemic health. This review aims to highlight the mechanistic roles of mitochondrial dysfunction in the aggravation of periodontitis among diabetic patients, emphasizing further research to identify potential therapeutic targets and improve treatment efficacy for this dual pathology.
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Affiliation(s)
- Al-Hassan Soliman Wadan
- Department of Oral Biology, Faculty of Dentistry, Galala University, Galala City, Suez, Egypt.
| | | | | | | | | | - Akhilanand Chaurasia
- Department of Oral Medicine and Radiology, King George'S Medical University, Lucknow, India
| | - Reham A H Ibrahim
- Department of Oral Biology, Faculty of Dentistry, Galala University, Galala City, Suez, Egypt
| | - Tamer Badawy
- Department of Oral Biology, Faculty of Dentistry, Galala University, Galala City, Suez, Egypt
- Department of Oral Biology, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Samah S Mehanny
- Department of Oral Biology, Faculty of Dentistry, Galala University, Galala City, Suez, Egypt
- Department of Oral Biology, Faculty of Dentistry, Cairo University, Cairo, Egypt
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Lin MH, Wu WT, Chen YC, Chien WC, Lin TK, Chou YC, Hsu PS, Sun CA. Association Between Clinical Use of Lansoprazole and the Risk of Coronary Heart Disease: A Nationwide Pharmacoepidemiological Cohort Study. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07643-4. [PMID: 39671131 DOI: 10.1007/s10557-024-07643-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2024] [Indexed: 12/14/2024]
Abstract
PURPOSE Proton pump inhibitors (PPIs) are widely prescribed for gastrointestinal disorders. Lansoprazole, a PPI, has been recognized for its potential effects of improving insulin resistance, reduction of oxidative stress, and improvement in atherosclerosis through peroxisome proliferator-activated receptor gamma (PPARγ) induction. This study aims to investigate whether lansoprazole poses a distinct risk of coronary heart disease (CHD) compared to other PPIs. METHODS A retrospective cohort study utilized data from the National Health Insurance Research Database in Taiwan spanning from 2000 to 2013. The exposed cohort included 1666 patients with lansoprazole use, while the comparison cohort comprised 6664 patients using other PPIs. The primary outcome was incident CHD. Cox regression models were employed to assess the association between lansoprazole use and CHD risk, presenting hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS Patients prescribed lansoprazole demonstrated a significantly reduced risk of CHD compared to those undergoing other PPI treatments in individuals without a history of CHD. Lansoprazole users exhibited a 25% lower risk of developing CHD compared to other PPI users (adjusted HR 0.75; 95% CI 0.65-0.87). Intriguingly, this inverse association between lansoprazole use and CHD risk was consistent across genders and various age groups. CONCLUSION This study suggests that lansoprazole is associated with a decreased risk of CHD in comparison to other PPIs in patients without a history of CHD. Further research is warranted to elucidate the clinical implications of these findings.
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Affiliation(s)
- Ming-Hsun Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wen-Tung Wu
- Department of Pharmacy, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei, 114, Taiwan
| | - Yong-Chen Chen
- Data Science Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei City, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Tsung-Kun Lin
- Department of Pharmacy, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei, 114, Taiwan
| | - Yu-Ching Chou
- School of Public Health National Defense Medical Center, Taipei City, Taiwan
| | - Po-Shun Hsu
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, 4F, No.325, Cheng-Kung Rd, Sec2, Taipei, 114, Taiwan.
| | - Chien-An Sun
- Data Science Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, No.510, Zhongzheng Road , Xinzhuang District, New Taipei City, 24205, Taiwan.
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Li Y, Pan Y, Zhao X, Wu S, Li F, Wang Y, Liu B, Zhang Y, Gao X, Wang Y, Zhou H. Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression. Clin Nutr 2024; 43:332-345. [PMID: 38142478 DOI: 10.1016/j.clnu.2023.12.005] [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: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/26/2023]
Abstract
Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling and cellular function. One of the key hallmarks of cancer is the reprogramming of metabolic pathways, especially abnormal lipid metabolism. Alterations in lipid uptake, lipid desaturation, de novo lipogenesis, lipid droplets, and fatty acid oxidation in cancer cells all contribute to cell survival in a changing microenvironment by regulating feedforward oncogenic signals, key oncogenic functions, oxidative and other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated by fatty acids and act as core lipid sensors involved in the regulation of lipid homeostasis and cell fate. In addition to regulating whole-body energy homeostasis in physiological states, PPARs play a key role in lipid metabolism in cancer, which is receiving increasing research attention, especially the fundamental molecular mechanisms and cancer therapies targeting PPARs. In this review, we discuss how cancer cells alter metabolic patterns and regulate lipid metabolism to promote their own survival and progression through PPARs. Finally, we discuss potential therapeutic strategies for targeting PPARs in cancer based on recent studies from the last five years.
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Affiliation(s)
- Yunkuo Li
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yujie Pan
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Xiaodong Zhao
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Shouwang Wu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Faping Li
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yuxiong Wang
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yanghe Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China
| | - Xin Gao
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China.
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China.
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Fuior EV, Zvintzou E, Filippatos T, Giannatou K, Mparnia V, Simionescu M, Gafencu AV, Kypreos KE. Peroxisome Proliferator-Activated Receptor α in Lipoprotein Metabolism and Atherosclerotic Cardiovascular Disease. Biomedicines 2023; 11:2696. [PMID: 37893070 PMCID: PMC10604751 DOI: 10.3390/biomedicines11102696] [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: 08/23/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator of plasma lipid and lipoprotein metabolism, with pluripotent effects influencing the lipid and apolipoprotein cargo of both atherogenic and antiatherogenic lipoproteins and their functionality. Clinical evidence supports an important role of PPARα agonists (fibric acid derivatives) in the treatment of hypertriglyceridemia and/or low high-density lipoprotein (HDL) cholesterol levels, although the effects of clinical trials are contradictory and point to a reduction in the risk of nonfatal and fatal myocardial infarction events. In this manuscript, we provide an up-to-date critical review of the existing relevant literature.
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Affiliation(s)
- Elena Valeria Fuior
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
| | - Evangelia Zvintzou
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
| | - Theodosios Filippatos
- Internal Medicine Clinic, Department of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Katerina Giannatou
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
| | - Victoria Mparnia
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
| | - Maya Simionescu
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
| | - Anca Violeta Gafencu
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
| | - Kyriakos E. Kypreos
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
- Department of Life Sciences, School of Sciences, European University Cyprus, 2404 Nicosia, Cyprus
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Miao M, Wang X, Liu T, Li YJ, Yu WQ, Yang TM, Guo SD. Targeting PPARs for therapy of atherosclerosis: A review. Int J Biol Macromol 2023:125008. [PMID: 37217063 DOI: 10.1016/j.ijbiomac.2023.125008] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 05/24/2023]
Abstract
Atherosclerosis, a chief pathogenic factor of cardiovascular disease, is associated with many factors including inflammation, dyslipidemia, and oxidative stress. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are widely expressed with tissue- and cell-specificity. They control multiple genes that are involved in lipid metabolism, inflammatory response, and redox homeostasis. Given the diverse biological functions of PPARs, they have been extensively studied since their discovery in 1990s. Although controversies exist, accumulating evidence have demonstrated that PPAR activation attenuates atherosclerosis. Recent advances are valuable for understanding the mechanisms of action of PPAR activation. This article reviews the recent findings, mainly from the year of 2018 to present, including endogenous molecules in regulation of PPARs, roles of PPARs in atherosclerosis by focusing on lipid metabolism, inflammation, and oxidative stress, and synthesized PPAR modulators. This article provides information valuable for researchers in the field of basic cardiovascular research, for pharmacologists that are interested in developing novel PPAR agonists and antagonists with lower side effects as well as for clinicians.
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Affiliation(s)
- Miao Miao
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Xue Wang
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Tian Liu
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Yan-Jie Li
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Wen-Qian Yu
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Tong-Mei Yang
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Shou-Dong Guo
- Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of Pharmacy, Weifang Medical University, Weifang 261053, China.
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ElKhatib MAW, Isse FA, El-Kadi AOS. Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy. Drug Metab Rev 2022; 55:50-74. [PMID: 36573379 DOI: 10.1080/03602532.2022.2162075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The incidence of heart failure (HF) is generally preceded by cardiac hypertrophy (CH), which is the enlargement of cardiac myocytes in response to stress. During CH, the metabolism of arachidonic acid (AA), which is present in the cell membrane phospholipids, is modulated. Metabolism of AA gives rise to hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) via cytochrome P450 (CYP) ω-hydroxylases and CYP epoxygenases, respectively. A plethora of studies demonstrated the involvement of CYP-mediated AA metabolites in the pathogenesis of CH. Also, inflammation is known to be a characteristic hallmark of CH. In this review, our aim is to highlight the impact of inflammation on CYP-derived AA metabolites and CH. Inflammation is shown to modulate the expression of various CYP ω-hydroxylases and CYP epoxygenases and their respective metabolites in the heart. In general, HETEs such as 20-HETE and mid-chain HETEs are pro-inflammatory, while EETs are characterized by their anti-inflammatory and cardioprotective properties. Several mechanisms are implicated in inflammation-induced CH, including the modulation of NF-κB and MAPK. This review demonstrated the inflammatory modulation of cardiac CYPs and their metabolites in the context of CH and the anti-inflammatory strategies that can be employed in the treatment of CH and HF.
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Affiliation(s)
| | - Fadumo Ahmed Isse
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada
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Cardoso TC, Rocha MA, Monteiro MMLV, Alves VS, Savio LEB, Silva CLM. The blockage of downstream P2Y 2 receptor signaling inhibits the prostate cancer cell adhesion to endothelial cells. Life Sci 2022; 306:120793. [PMID: 35850244 DOI: 10.1016/j.lfs.2022.120793] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/20/2022] [Accepted: 07/06/2022] [Indexed: 11/26/2022]
Abstract
AIMS Prostate cancer is the second most frequently malignancy in men worldwide. Most deaths are caused by metastasis, and tumor cell dissemination involves the interaction with endothelial cells. However, the endothelial cell signaling involved in such interaction is not entirely understood. The tumor microenvironment contains extracellular ATP, an endogenous agonist of the purinergic P2Y2 receptor (P2Y2R). P2Y2R signaling changes endothelial cell phenotype, which may be relevant to cancer pathophysiology. Therefore, we hypothesized that P2Y2R activation could favor the metastatic prostate cancer cells adhesion to endothelial cells. MAIN METHODS For adhesion assays, confluent endothelial cells EA.hy926 were treated with P2Y2R agonists before adding and imaging stained DU-145 cells. Alternatively, fluorescent probes and antibodies were used to determine intracellular endothelial Ca2+, nitric oxide (NO), and flow cytometry assays. KEY FINDINGS Endothelial P2Y2R activation with ATP, UTP, or the selective agonist 2-thio-UTP increased DU-145 cell adhesion to EA.hy926 cells. This effect required endothelial cell Ca2+ mobilization and relied on the endothelial expression of VCAM-1 and ICAM-1. Conversely, inhibiting this proadhesive endothelial phenotype could impair DU-145 cell adhesion. To evaluate this, we chose atorvastatin based on its notable improvement of endothelial cell dysfunction. Atorvastatin blocked UTP-induced DU-145 cell adhesion to endothelial cell monolayer in a NO-dependent manner, unveiling a P2Y2R and NO signaling crosstalk. SIGNIFICANCE Endothelial P2Y2R signaling contributes to the adhesion of metastatic prostate cancer cells suggesting that the downstream signaling blockade by statins could be a putative mechanism to reduce prostate cancer metastasis.
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Affiliation(s)
- Tassya Cataldi Cardoso
- Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil
| | - Marianna Araujo Rocha
- Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil
| | - Matheus M L V Monteiro
- Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil
| | - Vinícius Santos Alves
- Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil
| | - Luiz Eduardo Baggio Savio
- Laboratório de Imunofisiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil
| | - Claudia Lucia Martins Silva
- Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil.
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Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium. Basic Res Cardiol 2022; 117:30. [PMID: 35674847 PMCID: PMC9177477 DOI: 10.1007/s00395-022-00937-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 01/31/2023]
Abstract
Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12-CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe-/- mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3's role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.
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Liu SY, Huang CC, Huang SF, Liao TL, Kuo NR, Yang YY, Li TH, Liu CW, Hou MC, Lin HC. Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats. Cells 2021; 10:3044. [PMID: 34831270 PMCID: PMC8616474 DOI: 10.3390/cells10113044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 01/23/2023] Open
Abstract
Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.
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Affiliation(s)
- Szu-Yu Liu
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Chia-Chang Huang
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Shiang-Fen Huang
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Tsai-Ling Liao
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 11217, Taiwan
| | - Nai-Rong Kuo
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Ying-Ying Yang
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Foundation, Taipei 11217, Taiwan
| | - Chih-Wei Liu
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Han-Chieh Lin
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
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Cho SK, Chong BF. SnapshotDx Quiz: October 2021. J Invest Dermatol 2021. [DOI: 10.1016/j.jid.2021.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Patel J, Maddukuri S, Li Y, Bax C, Werth VP. Highly Multiplexed Mass Cytometry Identifies the Immunophenotype in the Skin of Dermatomyositis. J Invest Dermatol 2021; 141:2151-2160. [PMID: 33766508 PMCID: PMC8384654 DOI: 10.1016/j.jid.2021.02.748] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/31/2021] [Accepted: 02/17/2021] [Indexed: 01/06/2023]
Abstract
Dermatomyositis (DM) is a rare, systemic autoimmune disease that most frequently affects the skin, muscles, and lungs. The inflammatory infiltrate in the skin has not been fully characterized, and, in this study, we took a single-cell, unbiased approach using imaging mass cytometry. Substantial monocyte‒macrophage diversity was observed, with the CD14+ population correlating positively with Cutaneous Dermatomyositis Disease Area and Severity Index scores (P = 0.031). The T-cell compartment revealed CD4+ T, CD8+ T, and FOXP3+ T cells. Activated (CD69+) circulating memory T cells correlated positively with Cutaneous Dermatomyositis Disease Area and Severity Index scores (P = 0.0268). IFN-β protein was highly upregulated in the T-cell, macrophage, dendritic cell, and endothelial cell populations of DM skin. Myeloid dendritic cells expressed phosphorylated peroxisome proliferator‒activated receptor γ, phosphorylated IRF3, IL-4, and IL-31, and their quantity correlated with itch as measured in Skindex-29. Plasmacytoid dendritic cells colocalized with IFN-γ in addition to the known colocalization with IFN-β. Nuclear phosphorylated peroxisome proliferator‒activated receptor γ expression was found in the DM endothelium. Imaging mass cytometry allows us to characterize single cells in the immune cell population and identify upregulated cytokines and inflammatory pathways in DM. These findings have important implications for the development of future targeted therapies for DM.
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Affiliation(s)
- Jay Patel
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Spandana Maddukuri
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yubin Li
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Christina Bax
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Victoria P Werth
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, USA; Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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12
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Khorshidi-Sedehi S, Aryaeian N, Shahram F, Akhlaghi M, Mahmoudi M, Motevalian M, Asgari -Taee F, Hosseini A. Effects of hydroalcoholic extract of Berberis integerrima on the clinical signs, hs-CRP, TNFα, and ESR in active rheumatoid arthritis patients. J Herb Med 2021. [DOI: 10.1016/j.hermed.2021.100444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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13
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Paredes A, Santos-Clemente R, Ricote M. Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease. Int J Mol Sci 2021; 22:ijms22157775. [PMID: 34360540 PMCID: PMC8346021 DOI: 10.3390/ijms22157775] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/13/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology.
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Mannan A, Garg N, Singh TG, Kang HK. Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-ɣ): Molecular Effects and Its Importance as a Novel Therapeutic Target for Cerebral Ischemic Injury. Neurochem Res 2021; 46:2800-2831. [PMID: 34282491 DOI: 10.1007/s11064-021-03402-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
Cerebral ischemic injury is a leading cause of death and long-term disability throughout the world. Peroxisome proliferator-activated receptor gamma (PPAR-ɣ) is a ligand-activated nuclear transcription factor that is a member of the PPAR family. PPAR-ɣ has been shown in several in vitro and in vivo models to prevent post-ischemic inflammation and neuronal damage by negatively controlling the expression of genes modulated by cerebral ischemic injury, indicating a neuroprotective effect during cerebral ischemic injury. A extensive literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on the mechanistic role of Peroxisome proliferator activated receptor gamma and its modulation in Cerebral ischemic injury. PPAR-ɣ can interact with specific DNA response elements to control gene transcription and expression when triggered by its ligand. It regulates lipid metabolism, improves insulin sensitivity, modulates antitumor mechanisms, reduces oxidative stress, and inhibits inflammation. This review article provides insights on the current state of research into the neuroprotective effects of PPAR-ɣ in cerebral ischemic injury, as well as the cellular and molecular mechanisms by which these effects are modulated, such as inhibition of inflammation, reduction of oxidative stress, suppression of pro-apoptotic production, modulation of transcription factors, and restoration of injured tissue through neurogenesis and angiogenesis.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Nikhil Garg
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | | | - Harmeet Kaur Kang
- Chitkara School of Health Sciences, Chitkara University, Punjab, India
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15
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Li C, Li J, Loreno EG, Miriyala S, Panchatcharam M, Lu X, Sun H. Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice. Int J Mol Sci 2021; 22:ijms22105121. [PMID: 34066125 PMCID: PMC8150922 DOI: 10.3390/ijms22105121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 01/17/2023] Open
Abstract
Ischemic stroke is one of the leading causes of death and permanent disability in adults. Recently, we found that light alcohol consumption (LAC) suppresses post-ischemic inflammatory response, which plays an important role in ischemic brain damage. Our goal was to determine the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in the anti-inflammatory effect of LAC against transient focal cerebral ischemia. In in vivo study, male C57BL/6J wild type (WT) and endothelial-specific conditional PPARγ knockout mice were gavage fed with 0.7 g/kg/day ethanol or volume-matched water daily for 8 weeks. From the 7th week, 3 mg/kg/day GW9662 (a selective PPARγ antagonist) was intraperitoneally given for two weeks. Cerebral ischemia/reperfusion (I/R) injury and expression of manganese superoxide dismutase (MnSOD) and adhesion molecules, neutrophil infiltration, and microglial activation in the cerebral cortex before and following a 90 min unilateral middle cerebral artery occlusion (MCAO)/24 h reperfusion were evaluated. In in vitro study, the impact of chronic alcohol exposure on expression of PPARγ and MnSOD in C57BL/6J mouse brain microvascular endothelial cells (MBMVECs) was measured. PPARγ and MnSOD were significantly upregulated in the cerebral cortex of ethanol-fed WT mice and low-concentration ethanol-exposed C57BL/6J MBMVECs. GW9662 significantly inhibited alcohol-induced upregulation of MnSOD. Eight-week ethanol feeding significantly reduced cerebral I/R injury and alleviated the post-ischemic inflammatory response (upregulation of intercellular adhesion molecule-1 (ICAM-1) and E-selectin, microglial activation, and neutrophil infiltration). Treatment with GW9662 and endothelial-specific conditional knockout of PPARγ did not alter cerebral I/R injury and the inflammatory response in the control mice but abolish the neuroprotective effect in ethanol-fed mice. In addition, GW9662 and endothelial-specific conditional knockout of PPARγ diminished the inhibitory effect of LAC on the post-ischemic expression of adhesion molecules and neutrophil infiltration. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing the post-ischemic inflammation via activation of PPARγ.
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Affiliation(s)
- Chun Li
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Jiyu Li
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Ethyn G. Loreno
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Sumitra Miriyala
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Manikandan Panchatcharam
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Xiaohong Lu
- Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71130, USA;
| | - Hong Sun
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
- Correspondence: ; Tel.: +1-(318)-675-4566; Fax: +1-(318)-675-5889
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16
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Schön C, Allegrini P, Engelhart-Jentzsch K, Riva A, Petrangolini G. Grape Seed Extract Positively Modulates Blood Pressure and Perceived Stress: A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Volunteers. Nutrients 2021; 13:nu13020654. [PMID: 33671310 PMCID: PMC7922661 DOI: 10.3390/nu13020654] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/08/2021] [Accepted: 02/13/2021] [Indexed: 12/13/2022] Open
Abstract
It is well established that maintaining healthy blood pressure is fundamental in order to avoid disorders to the heart and blood vessels. In prevention, and alongside pharmacological therapy, the use of natural substances has been proven to be extremely helpful for pre- and mild hypertensive subjects. Our study was therefore focused on the effects, both in vitro and in humans, of a grape seed extract, Enovita (GSEe), a highly standardized extract in polyphenols of Vitis vinifera L. The in vitro human umbilical vein endothelial cells (HUVEC) model was chosen to explore the extract properties related to vascular inflammation/vasodilation. A significant reduction of both soluble Inter-Cellular Adhesion Molecule-1 (sICAM) and endothelin-1 secretion/release was induced by GSEe in HUVEC cells. A randomized, double-blind, placebo-controlled clinical study in healthy volunteers was further performed to investigate GSEe benefits. In healthy volunteers, both supplementations significantly modulated blood pressure, with a pronounced effect after GSEe tablets (300 mg/day for 16 weeks) in respect to placebo. In the male gender subgroup, no placebo effect was observed as it was for the female group. As an additional outcome, an overall GSEe positive modulation emerged on mood related to stress perception. Thus, GSEe resulted in a benefit of modulating endothelial functionality and blood pressure. It was noteworthy that GSEe relieved the perceived stress, promising new future perspectives on mood comfort.
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Affiliation(s)
- Christiane Schön
- BioTeSys GmbH, Schelztorstr. 54–56, 73728 Esslingen, Germany;
- Correspondence:
| | - Pietro Allegrini
- Research and Development Department, Indena SpA, 20139 Milan, Italy; (P.A.); (A.R.); (G.P.)
| | | | - Antonella Riva
- Research and Development Department, Indena SpA, 20139 Milan, Italy; (P.A.); (A.R.); (G.P.)
| | - Giovanna Petrangolini
- Research and Development Department, Indena SpA, 20139 Milan, Italy; (P.A.); (A.R.); (G.P.)
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17
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Locatelli L, Fedele G, Castiglioni S, Maier JA. Magnesium Deficiency Induces Lipid Accumulation in Vascular Endothelial Cells via Oxidative Stress-The Potential Contribution of EDF-1 and PPARγ. Int J Mol Sci 2021; 22:ijms22031050. [PMID: 33494333 PMCID: PMC7865876 DOI: 10.3390/ijms22031050] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 12/21/2022] Open
Abstract
Background: Magnesium deficiency contributes to atherogenesis partly by promoting the dysfunction of endothelial cells, which are critical in vascular homeostasis and diseases. Since EDF-1 and PPARγ regulate crucial endothelial activities, we investigated the modulation of these proteins involved in lipogenesis as well the deposition of lipids in human endothelial cells cultured in different concentrations of magnesium. Methods: Human endothelial cells from the umbilical vein were cultured in medium containing from 0.1 to 5 mM magnesium for 24 h. The levels of EDF-1 and PPARγ were visualized by Western blot. Reactive oxygen species (ROS) were measured by DCFDA. Lipids were detected after O Red Oil staining. Results: Magnesium deficiency leads to the accumulation of ROS which upregulate EDF-1. Further, PPARγ is increased after culture in low magnesium, but independently from ROS. Moreover, lipids accumulate in magnesium-deficient cells. Conclusions: Our results suggest that magnesium deficiency leads to the deposition of lipids by inducing EDF-1 and PPARγ. The increase in intracellular lipids might be interpreted as an adaptive response of endothelial cells to magnesium deficiency.
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Affiliation(s)
- Laura Locatelli
- Department Biomedical and Clinical Sciences L. Sacco, Università di Milano, Via GB Grassi 74, 20157 Milano, Italy; (L.L.); (G.F.); (S.C.)
| | - Giorgia Fedele
- Department Biomedical and Clinical Sciences L. Sacco, Università di Milano, Via GB Grassi 74, 20157 Milano, Italy; (L.L.); (G.F.); (S.C.)
| | - Sara Castiglioni
- Department Biomedical and Clinical Sciences L. Sacco, Università di Milano, Via GB Grassi 74, 20157 Milano, Italy; (L.L.); (G.F.); (S.C.)
| | - Jeanette A. Maier
- Department Biomedical and Clinical Sciences L. Sacco, Università di Milano, Via GB Grassi 74, 20157 Milano, Italy; (L.L.); (G.F.); (S.C.)
- Interdisciplinary Centre for Nanostructured Materials and Interfaces (CIMaINa), Università di Milano, 20133 Milano, Italy
- Correspondence:
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18
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Chang G, Wang J, Song J, Zhang Z, Zhang L. Efficacy and safety of pioglitazone for treatment of plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials. J DERMATOL TREAT 2020; 31:680-686. [PMID: 31116619 DOI: 10.1080/09546634.2019.1610552] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 04/10/2019] [Indexed: 02/07/2023]
Abstract
Background: A growing number of studies have shown that thiazolidinediones (TZD) can be antipsoriatic. Pioglitazone is a representative of the class of antidiabetic drugs known as TZD. TZD can activate nuclear peroxisome proliferator-activated receptors (PPAR)-c. PPARs are expressed on epidermal keratinocytes and exert their effects by promoting the terminal differentiation of keratinocytes, inhibiting epidermal growth, and reducing inflammatory responses. These observations suggest that TZD have potential benefits in the treatment of cutaneous and metabolic pathologies associated with psoriasis.Objective: A systematic review and meta-analysis was carried out to evaluate the efficacy of combined pioglitazone treatment. We point out three controversial side effects from administration of pioglitazone in psoriasis: elevated liver enzymes, weight gain, and nausea.Study selection: Randomized, single blind, or double blind, published studies of pioglitazone compared with placebo given to patients with plaque psoriasis for 10 weeks or 12 weeks were considered for inclusion in this review. The primary outcomes were 75% or greater improvement in the Psoriasis Area and Severity Index score from baseline (PASI 75) with pioglitazone.Data collection and analysis: The systematic literature search was conducted in the PubMed, Embase, Google Scholar, and Cochrane databases from inception up to December 20 2018. Data analysis was done using Revman 5.3 Haymarket, London, United Kingdom.Main results: We included six studies (three publications of pioglitazone only; three publications of pioglitazone combination therapy) comprising a total of 294 patients (n = 149 with pioglitazone only and n = 145 with pioglitazone combination therapy) in the analysis. There was a significant PASI 75 response, in the pioglitazone only subgroup as compared to placebo (OR = 8.74, 95% CI 3.76-20.31, p < .00001), and the pioglitazone combination subgroup as compared to placebo (OR = 4.64, 95% CI 2.03-10.60, p < .00001), others, the total of pioglitazone as compared to placebo (OR = 6.37, 95% CI 3.55-11.43, p < .00001), and tests of subgroup differences show: p = .29, I2 = 9.5%. The incidence rate of elevated liver enzymes (OR = 3.70, 95% CI 0.56-24.31, p = .99), weight gain (OR = 1.44, 95% CI 0.60-3.47, p = .41), and nausea (OR = 0.76, 95% CI 0.23-2.49, p = .65) were not significantly different compared with the control group.Conclusion: Pioglitazone has efficacy for the treatment of plaque psoriasis. There is no significant difference between patients treated with pioglitazone only or in combination with other therapies. The incidence rate of side effects associated with pioglitazone treatment such as elevated liver enzymes, weight gain, and nausea were not significantly different compared with the control group.
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Affiliation(s)
- Guizhen Chang
- Dermatology and Venereology, Graduate School of Tianjin Medical University, Tianjin, China
| | - Jin Wang
- Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine of Affiliated Hospital, Tianjin, China
| | - Jingxin Song
- Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine of Affiliated Hospital, Tianjin, China
| | - Zhilong Zhang
- Department of Dermatology, Binhai Hospital of Tianjin Medical University General Hospital, Tianjin, China
| | - Litao Zhang
- Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine of Affiliated Hospital, Tianjin, China
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19
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Holowatyj AN, Haffa M, Lin T, Scherer D, Gigic B, Ose J, Warby CA, Himbert C, Abbenhardt-Martin C, Achaintre D, Boehm J, Boucher KM, Gicquiau A, Gsur A, Habermann N, Herpel E, Kauczor HU, Keski-Rahkonen P, Kloor M, von Knebel-Doeberitz M, Kok DE, Nattenmüller J, Schirmacher P, Schneider M, Schrotz-King P, Simon T, Ueland PM, Viskochil R, Weijenberg MP, Scalbert A, Ulrich A, Bowers LW, Hursting SD, Ulrich CM. Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer. Cancer Prev Res (Phila) 2020; 13:817-828. [PMID: 32655010 PMCID: PMC7877796 DOI: 10.1158/1940-6207.capr-19-0538] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 05/28/2020] [Accepted: 07/06/2020] [Indexed: 12/18/2022]
Abstract
Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition-as in fibrosis and metastasis-and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted.See related spotlight by Colacino et al., p. 803.
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Affiliation(s)
- Andreana N Holowatyj
- Huntsman Cancer Institute, Salt Lake City, Utah.
- University of Utah, Salt Lake City, Utah
- Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Mariam Haffa
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Tengda Lin
- Huntsman Cancer Institute, Salt Lake City, Utah
- University of Utah, Salt Lake City, Utah
| | | | | | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, Utah
- University of Utah, Salt Lake City, Utah
| | - Christy A Warby
- Huntsman Cancer Institute, Salt Lake City, Utah
- University of Utah, Salt Lake City, Utah
| | - Caroline Himbert
- Huntsman Cancer Institute, Salt Lake City, Utah
- University of Utah, Salt Lake City, Utah
| | - Clare Abbenhardt-Martin
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - David Achaintre
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Juergen Boehm
- Huntsman Cancer Institute, Salt Lake City, Utah
- University of Utah, Salt Lake City, Utah
| | | | - Audrey Gicquiau
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Andrea Gsur
- Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Nina Habermann
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Esther Herpel
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
- University Hospital, Heidelberg, Germany
| | | | | | - Matthias Kloor
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | | | | | | | - Peter Schirmacher
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | | | - Petra Schrotz-King
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | | | - Per M Ueland
- Maastricht University, Maastricht, the Netherlands
| | - Richard Viskochil
- Huntsman Cancer Institute, Salt Lake City, Utah
- University of Utah, Salt Lake City, Utah
| | | | | | | | - Laura W Bowers
- Purdue University, West Lafayette, Indiana
- University of North Carolina, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
| | - Stephen D Hursting
- University of North Carolina, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Salt Lake City, Utah.
- University of Utah, Salt Lake City, Utah
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20
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Advanced Glycation End Products Induce Vascular Smooth Muscle Cell-Derived Foam Cell Formation and Transdifferentiate to a Macrophage-Like State. Mediators Inflamm 2020; 2020:6850187. [PMID: 32831637 PMCID: PMC7428884 DOI: 10.1155/2020/6850187] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 07/06/2020] [Accepted: 07/11/2020] [Indexed: 12/18/2022] Open
Abstract
Background Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown. Methods Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA. Results In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors. Conclusions CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.
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21
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Luo H, Li QQ, Wu N, Shen YG, Liao WT, Yang Y, Dong E, Zhang GM, Liu BR, Yue XZ, Tang XQ, Yang HS. Chronological in vivo imaging reveals endothelial inflammation prior to neutrophils accumulation and lipid deposition in HCD-fed zebrafish. Atherosclerosis 2019; 290:125-135. [DOI: 10.1016/j.atherosclerosis.2019.09.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/20/2022]
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Tseng V, Sutliff RL, Hart CM. Redox Biology of Peroxisome Proliferator-Activated Receptor-γ in Pulmonary Hypertension. Antioxid Redox Signal 2019; 31:874-897. [PMID: 30582337 PMCID: PMC6751396 DOI: 10.1089/ars.2018.7695] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Peroxisome proliferator-activated receptor-gamma (PPARγ) maintains pulmonary vascular health through coordination of antioxidant defense systems, inflammation, and cellular metabolism. Insufficient PPARγ contributes to pulmonary hypertension (PH) pathogenesis, whereas therapeutic restoration of PPARγ activity attenuates PH in preclinical models. Recent Advances: Numerous studies in the past decade have elucidated the complex mechanisms by which PPARγ in the pulmonary vasculature and right ventricle (RV) protects against PH. The scope of PPARγ-interconnected pathways continues to expand and includes induction of antioxidant genes, transrepression of inflammatory signaling, regulation of mitochondrial biogenesis and bioenergetic integrity, control of cell cycle and proliferation, and regulation of vascular tone through interactions with nitric oxide and endogenous vasoactive molecules. Furthermore, PPARγ interacts with an extensive regulatory network of transcription factors and microRNAs leading to broad impact on cell signaling. Critical Issues: Abundant evidence suggests that targeting PPARγ exerts diverse salutary effects in PH and represents a novel and potentially translatable therapeutic strategy. However, progress has been slowed by an incomplete understanding of how specific PPARγ pathways are critically disrupted across PH disease subtypes and lack of optimal pharmacological ligands. Future Directions: Recent studies indicate that ligand-induced post-translational modifications of the PPARγ receptor differentially induce therapeutic benefits versus adverse side effects of PPARγ receptor activation. Strategies to selectively target PPARγ activity in diseased cells of pulmonary circulation and RV, coupled with development of ligands designed to specifically regulate post-translational PPARγ modifications, may unlock the full therapeutic potential of this versatile master transcriptional and metabolic regulator in PH.
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Affiliation(s)
- Victor Tseng
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.,Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - Roy L Sutliff
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.,Atlanta Veterans Affairs Medical Center, Decatur, Georgia
| | - C Michael Hart
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.,Atlanta Veterans Affairs Medical Center, Decatur, Georgia
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A Secreted Phospholipase A 2 Induces Formation of Smooth Muscle Foam Cells Which Transdifferentiate to Macrophage-Like State. Molecules 2019; 24:molecules24183244. [PMID: 31489892 PMCID: PMC6766822 DOI: 10.3390/molecules24183244] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/30/2019] [Accepted: 09/02/2019] [Indexed: 12/15/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) loaded with lipid droplets (LDs) are markers of atherosclerosis. In this disease, inflammatory Group IIA-secreted phospholipase A2s (GIIA sPLA2s) are highly expressed in VSMCs, but their actions in these cells are unknown. Here, we investigated the ability of myotoxin III (MT-III), an ophidian GIIA sPLA2 sharing structural and functional features with mammalian GIIA sPLA2s, to induce LD formation and lipid metabolism factors involved in this effect. Modulation of VSMC phenotypes by this sPLA2 was also evaluated. Incubation of VSMCs with MT-III significantly increased the number of LDs. MT-III upregulated scavenger receptor type 1 (SR-A1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) protein expression and enhanced acetylated-low density lipoprotein (acLDL) uptake by VSMCs, revealing the ability of a GIIA PLA2 to modulate scavenger receptor activities. MT-III induced translocation and protein expression of PPAR-γ and -β/δ. Inhibition of peroxisome proliferator-activated receptors (PPARs) and diacylglycerol O-acyltransferase (DGAT) and acyl-CoA:cholesterolacyltransferase (ACAT) enzymes abrogated MT-III-induced LD formation. Moreover, in response to MT-III, VSMCs acquired phagocytic activity and expressed macrophage markers CD68 and MAC-2. In conclusion, MT-III is able to stimulate VSMCs and recruit factors involved in lipid uptake and metabolism, leading to the formation of VSMC-derived foam cells with acquisition of macrophage-like markers and functions.
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24
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Eren E, Yılmaz N, Pençe S, Koçoğlu H, Göksu S, Kocabaş R, Kadayıfcı S. Diagnostic Value of C-Reactive Protein in Patients with Angiographically Documented Coronary Heart Disease. ACTA MEDICA (HRADEC KRÁLOVÉ) 2019. [DOI: 10.14712/18059694.2019.73] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Aim: The aim of this study was to evaluate the diagnostic value of serum C-reactive protein (CRP) level measurement in predicting coronary artery disease (CAD) that can be shown angiographically. Methods: CRP levels were determined in the blood of 198 patients (patients group, PG) with angiographically documented coronary artery disease and compared with that of 85 patients (control group, CG) who had a clinical indication for coronary angiography but have no angiographically determined coronary artery stenosis, as well as with that of 41 healthy volunteers as a healthy control group (HG) who did not have any complaint and did not have coronary angiography. CRP levels were measured 24 hours prior to angiography in PG and CG patients, and in the morning after not having eaten for same time. Any coronary artery stenosis or plaque formation was defined as CAD. Severity of the disease was assessed by both the number of diseased vessels (0 to 3) and the degree of stenosis (<50 % mild, 50–70 % moderate and >70 % severe). Results: Receiver Operating Characteristics (ROC) curves of CRP in angiographically documented CAD group showed a diagnostic value of 0.659 in female patients, followed by 0.542 in male patients, in predicting CAD. CRP levels were found to be significantly different between groups, higher in PG (6.2 ± 0.86 mg/L) than those of CG (3.7 ± 0.92 mg/L) and HG (0.854 ± 0.2 mg/L) (p<0.05). CRP levels were not associated with the number of diseased vessels, neither with the degree of the occlusion (p>0.05). Multiple logistic regression analysis after adjustment for the established coronary risk factors showed CRP as an independent discriminating risk factor for CAD. Conclusion: It is concluded that CRP measurement has a value in predicting the presence of angiographically documented CAD. However, CRP levels were not associated with the degree or severity of CAD.
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García-Martín A, Garrido-Rodríguez M, Navarrete C, del Río C, Bellido ML, Appendino G, Calzado MA, Muñoz E. EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis. Biochem Pharmacol 2018; 157:304-313. [DOI: 10.1016/j.bcp.2018.07.047] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 07/31/2018] [Indexed: 01/07/2023]
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26
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Huang L, Zhang L, Li T, Liu YW, Wang Y, Liu BJ. Human Plasma Metabolomics Implicates Modified 9-cis-Retinoic Acid in the Phenotype of Left Main Artery Lesions in Acute ST-Segment Elevated Myocardial Infarction. Sci Rep 2018; 8:12958. [PMID: 30154509 PMCID: PMC6113282 DOI: 10.1038/s41598-018-30219-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 07/23/2018] [Indexed: 12/18/2022] Open
Abstract
The detection of left main coronary artery disease (LMCAD) is crucial before ST-segment elevated myocardial infarction (STEMI) or sudden cardiac death. The aim of this study was to identify characteristic metabolite modifications in the LMCAD phenotype, using the metabolomics technique. Metabolic profiles were generated based on ultra-performance liquid chromatography and mass spectrometry, combined with multivariate statistical analysis. Plasma samples were collected prospectively from a propensity-score matched cohort including 44 STEMI patients (22 consecutive LMCAD and 22 non-LMCAD), and 22 healthy controls. A comprehensive metabolomics data analysis was performed with Metaboanalyst 3.0 version. The retinol metabolism pathway was shown to have the strongest discriminative power for the LMCAD phenotype. According to biomarker analysis through receiver-operating characteristic curves, 9-cis-retinoic acid (9cRA) dominated the first page of biomarkers, with area under the curve (AUC) value 0.888. Next highest were a biomarker panel consisting of 9cRA, dehydrophytosphingosine, 1H-Indole-3-carboxaldehyde, and another seven variants of lysophosphatidylcholines, exhibiting the highest AUC (0.933). These novel data propose that the retinol metabolism pathway was the strongest differential pathway for the LMCAD phenotype. 9cRA was the most critical biomarker of LMCAD, and a ten-metabolite plasma biomarker panel, in which 9cRA remained the weightiest, may help develop a potent predictive model for LMCAD in clinic.
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Affiliation(s)
- Lei Huang
- Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, P.R. China
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, P.R. China
| | - Lei Zhang
- Tianjin Institute of Hepatobiliary Disease, Tianjin, P.R. China
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, P.R. China
- Department of Clinical Laboratory, Tianjin Third Central Hospital, Tianjin, P.R. China
| | - Tong Li
- Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China.
- Tianjin Institute of Hepatobiliary Disease, Tianjin, P.R. China.
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, P.R. China.
| | - Ying-Wu Liu
- Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, P.R. China
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, P.R. China
| | - Yu Wang
- Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, P.R. China
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, P.R. China
| | - Bo-Jiang Liu
- Heart Center, Tianjin Third Central Hospital, Tianjin, P.R. China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, P.R. China
- Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, P.R. China
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27
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Ma X, Chen Z, Wang L, Wang G, Wang Z, Dong X, Wen B, Zhang Z. The Pathogenesis of Diabetes Mellitus by Oxidative Stress and Inflammation: Its Inhibition by Berberine. Front Pharmacol 2018; 9:782. [PMID: 30100874 PMCID: PMC6072898 DOI: 10.3389/fphar.2018.00782] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 06/27/2018] [Indexed: 12/17/2022] Open
Abstract
A substantial knowledge on the pathogenesis of diabetes mellitus (DM) by oxidative stress and inflammation is available. Berberine is a biologically active botanical that can combat oxidative stress and inflammation and thus ameliorate DM, especially type 2 DM. This article describes the potential of berberine against oxidative stress and inflammation with special emphasis on its mechanistic aspects. In diabetic animal studies, the modified levels of proinflammatory cytokines and oxidative stress markers were observed after administering berberine. In renal, fat, hepatic, pancreatic and several others tissues, berberine-mediated suppression of oxidative stress and inflammation was noted. Berberine acted against oxidative stress and inflammation through a very complex mechanism consisting of several kinases and signaling pathways involving various factors, including NF-κB (nuclear factor-κB) and AMPK (AMP-activated protein kinases). Moreover, MAPKs (mitogen-activated protein kinases) and Nrf2 (nuclear factor erythroid-2 related factor 2) also have mechanistic involvement in oxidative stress and inflammation. In spite of above advancements, the mechanistic aspects of the inhibitory role of berberine against oxidative stress and inflammation in diabetes mellitus still necessitate additional molecular studies. These studies will be useful to examine the new prospects of natural moieties against DM.
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Affiliation(s)
- Xueling Ma
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhongjun Chen
- Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Le Wang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Gesheng Wang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Zihui Wang
- Chaoyang Hospital, Capital Medical University, Beijing, China
| | - XiaoBo Dong
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Binyu Wen
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Zhichen Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
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28
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Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family and plays an important role in adipocyte differentiation, glucose homeostasis, and insulin sensitivity. Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have been used for the treatment of diabetes mellitus for two decades. TZDs were expected to be amazing drugs not only for type 2 diabetes but also for metabolic syndrome and atherosclerotic vascular disease because they can reduce both insulin resistance and inflammation in experimental studies. However, serious unwanted effects pushed TZDs back to an optional second-tier drug for type 2 diabetes. Nevertheless, PPARγ is still one of the most important targets for the treatment of insulin resistance and diabetes mellitus, and novel strategies to modulate PPARγ activity to enhance its beneficial effects and reduce unwanted adverse effects are anticipated. Recent studies showed that post-translational modification (PTM) of PPARγ regulates PPARγ activity or stability and may be a novel way to optimize PPARγ activity with reduced adverse effects. In this review, we will focus on recent advances in PTM of PPARγ and the mechanisms regulating PPARγ function as well as in the development of PPARγ modulators or agonists.
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Affiliation(s)
- Sung Hee Choi
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sung Soo Chung
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
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29
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Li J, Liu YP. The roles of PPARs in human diseases. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2018; 37:361-382. [PMID: 30036119 DOI: 10.1080/15257770.2018.1475673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Peroxisome proliferator-activated receptors (PPARs), as members of nuclear hormone receptor superfamily, can be activated by binding natural or synthetic ligands. The use of related ligands has revealed many potential roles for PPARs in the pathogenesis of some human metabolic disorders and inflammatory-related disease. Based on the previous studies, this review primarily concluded the current progress of knowledge regarding the specific biological activity of PPARs in cancers, atherosclerosis, and type 2 diabetes mellitus, providing a foundation for the potential therapeutic use of PPAR ligands in human diseases.
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Affiliation(s)
- Jingjing Li
- a Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province , Sichuan Agricultural University , Chengdu , China
| | - Yi-Ping Liu
- a Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province , Sichuan Agricultural University , Chengdu , China
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30
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Silva JC, de Oliveira EM, Turato WM, Trossini GHG, Maltarollo VG, Pitta MGR, Pitta IR, de Las Heras B, Boscá L, Rudnicki M, Abdalla DSP. GQ-11: A new PPAR agonist improves obesity-induced metabolic alterations in LDLr -/- mice. Int J Obes (Lond) 2018; 42:1062-1072. [PMID: 29453462 DOI: 10.1038/s41366-018-0011-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 11/29/2017] [Accepted: 12/10/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Obesity and insulin resistance/diabetes are important risk factors for cardiovascular diseases and demand safe and efficacious therapeutics. OBJECTIVE To assess the effects of a new thiazolidine compound-GQ-11-on obesity and insulin resistance induced by a diabetogenic diet in LDL receptor-deficient (LDLr-/-) mice. METHODS Molecular docking simulations of GQ-11, PPARα and PPARγ structures were performed. Male C57BL/6J LDLr-/- mice fed a diabetogenic diet for 24 weeks were treated with vehicle, GQ-11 or pioglitazone or (20 mg/kg/day) for 28 days by oral gavage. Glucose tolerance test, insulin, HOMA-IR, adipokines (leptin, adiponectin) and the lipid profile were assessed after treatment. Adipose tissue was analysed by X-ray analysis and morphometry; gene and protein expression were evaluated by real-time PCR and western blot, respectively. RESULTS GQ-11 showed partial agonism to PPARγ and PPARα. In vivo, treatment with GQ-11 ameliorated insulin sensitivity and did not modify subcutaneous adipose tissue and body weight gain. In addition, GQ-11 restored adipokine imbalance induced by a diabetogenic diet and enhanced Glut-4 expression in the adipose tissue. Improved insulin sensitivity was also associated with lower levels of MCP-1 and higher levels of IL-10. Furthermore, GQ-11 reduced triglycerides and VLDL cholesterol and increased HDL-cholesterol by upregulation of Apoa1 and Abca1 gene expression in the liver. CONCLUSION GQ-11 is a partial/dual PPARα/γ agonist that demonstrates anti-diabetic effects. Additionally, it improves the lipid profile and ameliorates chronic inflammation associated with obesity in atherosclerosis-prone mice.
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Affiliation(s)
- Jacqueline C Silva
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Edson M de Oliveira
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Walter M Turato
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gustavo H G Trossini
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Vinícius G Maltarollo
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Marina G R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Ivan R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Beatriz de Las Heras
- Department of Pharmacology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Martina Rudnicki
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Dulcineia S P Abdalla
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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31
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Analysis of Drug Effects on Primary Human Coronary Artery Endothelial Cells Activated by Serum Amyloid A. Mediators Inflamm 2018; 2018:8237209. [PMID: 29670468 PMCID: PMC5833471 DOI: 10.1155/2018/8237209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 11/03/2017] [Accepted: 11/14/2017] [Indexed: 01/04/2023] Open
Abstract
Background RA patients have a higher incidence of cardiovascular diseases compared to the general population. Serum amyloid A (SAA) is an acute-phase protein, upregulated in sera of RA patients. Aim To determine the effects of medications on SAA-stimulated human coronary artery endothelial cells (HCAEC). Methods HCAEC were preincubated for 2 h with medications from sterile ampules (dexamethasone, methotrexate, certolizumab pegol, and etanercept), dissolved in medium (captopril) or DMSO (etoricoxib, rosiglitazone, meloxicam, fluvastatin, and diclofenac). Human recombinant apo-SAA was used to stimulate HCAEC at a final 1000 nM concentration for 24 hours. IL-6, IL-8, sVCAM-1, and PAI-1 were measured by ELISA. The number of viable cells was determined colorimetrically. Results SAA-stimulated levels of released IL-6, IL-8, and sVCAM-1 from HCAEC were significantly attenuated by methotrexate, fluvastatin, and etoricoxib. Both certolizumab pegol and etanercept significantly decreased PAI-1 by an average of 43%. Rosiglitazone significantly inhibited sVCAM-1 by 58%. Conclusion We observed marked influence of fluvastatin on lowering cytokine production in SAA-activated HCAEC. Methotrexate showed strong beneficial effects for lowering released Il-6, IL-8, and sVCAM-1. Interesting duality was observed for NSAIDs, with meloxicam exhibiting opposite-trend effects from diclofenac and etoricoxib. This represents unique insight into specific responsiveness of inflammatory-driven HCAEC relevant to atherosclerosis.
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Barcones MF, MacDowell KS, García-Bueno B, Bioque M, Gutiérrez-Galve L, González-Pinto A, Parellada MJ, Bobes J, Bernardo M, Lobo A, Leza JC. Cardiovascular Risk in Early Psychosis: Relationship with Inflammation and Clinical Features 6 Months after Diagnosis. Int J Neuropsychopharmacol 2017; 21:410-422. [PMID: 29228174 PMCID: PMC5932475 DOI: 10.1093/ijnp/pyx110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 11/18/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND We aimed to investigate the state of cardiovascular risk/protection factors in early psychosis patients. METHODS A total 119 subjects were recruited during the first year after their first episode of psychosis. Eighty-five of these subjects were followed during the next 6 months. Cardiovascular risk/protection factors were measured in plasma and co-variated by sociodemographic/clinical characteristics. Multiple linear regression models detected the change of each biological marker from baseline to follow-up in relation to clinical scales, antipsychotic medication, and pro-/antiinflammatory mediators. RESULTS Glycosylated hemoglobin is a state biomarker in first episode of psychosis follow-up patients and inversely correlated to the Global Assessment of Functioning scale. We found opposite alterations in the levels of VCAM-1 and E-selectin in first episode of psychosis baseline conditions compared with control that were absent in the first episode of psychosis follow-up group. Adiponectin levels decreased in a continuum in both pathological time points studied. E-Selectin plasma levels were inversely related to total antipsychotic equivalents and adiponectin levels inversely co-related to the Global Assessment of Functioning scale. Finally, adiponectin levels were directly related to antiinflammatory nuclear receptor PPARγ expression in first episode of psychosis baseline conditions and to proinflammatory nuclear factor nuclear factor κB activity in follow-up conditions, respectively. CONCLUSIONS Our results support the need for integrating cardiovascular healthcare very early after the first episode of psychosis.
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Affiliation(s)
| | - Karina Soledad MacDowell
- Department of Pharmacology, Faculty of Medicine, Complutense University, Instituto de Investigación Sanitaria Hospital, IUINQ, Madrid, Spain
| | - Borja García-Bueno
- FLAMM-PEPs* study, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain and Hospital Universitario Miguel Servet, Unidad de Medicina Familiar y Comunitaria, Department of Medicine and Psychiatry, University of Zaragoza Instituto de Investigación Sanitaria, Aragón, Spain,Department of Pharmacology, Faculty of Medicine, Complutense University, Instituto de Investigación Sanitaria Hospital, IUINQ, Madrid, Spain,Correspondence: Borja García Bueno, PhD, Department of Pharmacology, Faculty of Medicine, University Complutense, Av. Complutense s/n 28040, Madrid, Spain ()
| | - Miquel Bioque
- Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain
| | - Leticia Gutiérrez-Galve
- FLAMM-PEPs* study, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain and Hospital Universitario Miguel Servet, Unidad de Medicina Familiar y Comunitaria, Department of Medicine and Psychiatry, University of Zaragoza Instituto de Investigación Sanitaria, Aragón, Spain
| | | | - Maria José Parellada
- Child and Adolescent Psychiatry Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Julio Bobes
- Department of Psychiatry, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Miguel Bernardo
- Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain,Universitat de Barcelona, Barcelona, Spain
| | - Antonio Lobo
- Department of Medicine and Psychiatry, University of Zaragoza, Instituto de Investigación Sanitaria, Aragón, Spain
| | - Juan Carlos Leza
- Department of Pharmacology, Faculty of Medicine, Complutense University, Instituto de Investigación Sanitaria Hospital, IUINQ, Madrid, Spain
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Cai W, Yang T, Liu H, Han L, Zhang K, Hu X, Zhang X, Yin KJ, Gao Y, Bennett MVL, Leak RK, Chen J. Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair. Prog Neurobiol 2017; 163-164:27-58. [PMID: 29032144 DOI: 10.1016/j.pneurobio.2017.10.002] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/06/2017] [Accepted: 10/08/2017] [Indexed: 01/06/2023]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a widely expressed ligand-modulated transcription factor that governs the expression of genes involved in inflammation, redox equilibrium, trophic factor production, insulin sensitivity, and the metabolism of lipids and glucose. Synthetic PPARγ agonists (e.g. thiazolidinediones) are used to treat Type II diabetes and have the potential to limit the risk of developing brain injuries such as stroke by mitigating the influence of comorbidities. If brain injury develops, PPARγ serves as a master gatekeeper of cytoprotective stress responses, improving the chances of cellular survival and recovery of homeostatic equilibrium. In the acute injury phase, PPARγ directly restricts tissue damage by inhibiting the NFκB pathway to mitigate inflammation and stimulating the Nrf2/ARE axis to neutralize oxidative stress. During the chronic phase of acute brain injuries, PPARγ activation in injured cells culminates in the repair of gray and white matter, preservation of the blood-brain barrier, reconstruction of the neurovascular unit, resolution of inflammation, and long-term functional recovery. Thus, PPARγ lies at the apex of cell fate decisions and exerts profound effects on the chronic progression of acute injury conditions. Here, we review the therapeutic potential of PPARγ in stroke and brain trauma and highlight the novel role of PPARγ in long-term tissue repair. We describe its structure and function and identify the genes that it targets. PPARγ regulation of inflammation, metabolism, cell fate (proliferation/differentiation/maturation/survival), and many other processes also has relevance to other neurological diseases. Therefore, PPARγ is an attractive target for therapies against a number of progressive neurological disorders.
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Affiliation(s)
- Wei Cai
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Tuo Yang
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Huan Liu
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Lijuan Han
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Kai Zhang
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Xiaoming Hu
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh PA, USA
| | - Xuejing Zhang
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Ke-Jie Yin
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Yanqin Gao
- State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Michael V L Bennett
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Rehana K Leak
- Division of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA.
| | - Jun Chen
- Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA; State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh PA, USA.
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Ku YH, Cho BJ, Kim MJ, Lim S, Park YJ, Jang HC, Choi SH. Rosiglitazone increases endothelial cell migration and vascular permeability through Akt phosphorylation. BMC Pharmacol Toxicol 2017; 18:62. [PMID: 28854981 PMCID: PMC5577739 DOI: 10.1186/s40360-017-0169-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 08/11/2017] [Indexed: 02/06/2023] Open
Abstract
Background Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, exhibit anti-inflammatory and antioxidant properties and inhibit endothelial inflammation and dysfunction, which is anti-atherogenic. However, fluid retention, which may lead to congestive heart failure and peripheral edema, is also a concern, which may result from endothelial cell leakage. In the current study, we examined the effects of PPAR-γ agonists on vascular endothelial cell migration and permeability in order to determine its underlying mechanisms. Methods We used rosiglitazone and conducted cell migration assay and permeability assay using HUVEC cells and measured vascular permeability and leakage in male C57BL/6 mice. Results Rosiglitazone significantly promoted endothelial cell migration and induced permeability via activation of phosphatidylinositol-3-kinase (PI3K) – Akt or protein kinase C (PKC)β. In addition, rosiglitazone increased vascular endothelial growth factor (VEGF) expression and suppressed expression of tight junction proteins (JAM-A and ZO-1), which might promote neovascularization and vascular leakage. These phenomena were reduced by Akt inhibition. Conclusions Vascular endothelial cell migration and permeability change through Akt phosphorylation might be a mechanism of induced fluid retention and peripheral tissue edema by TZD.
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Affiliation(s)
- Yun Hyi Ku
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, South Korea
| | - Bong-Jun Cho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Min Joo Kim
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, South Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hak C Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea. .,, 166 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea.
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Abstract
Lipids are potent signaling molecules that regulate a multitude of cellular responses, including cell growth and death and inflammation/infection, via receptor-mediated pathways. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. This diversity arises from their synthesis, which occurs via discrete enzymatic pathways and because they elicit responses via different receptors. This review will collate the bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and role in inflammation. Specifically, lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins, and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins, and maresins) will be discussed herein.
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Chou PS, Ho BL, Yang YH. Effects of pioglitazone on the incidence of dementia in patients with diabetes. J Diabetes Complications 2017; 31:1053-1057. [PMID: 28254448 DOI: 10.1016/j.jdiacomp.2017.01.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 01/05/2017] [Accepted: 01/13/2017] [Indexed: 12/23/2022]
Abstract
AIMS Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists exert neuroprotective effects in the brain. Therefore, in this population-based cohort study, we investigated the effects of pioglitazone, a PPAR-γ agonist, on the risk of dementia. METHODS By using claims data from Taiwan's National Health Insurance Research Database, we included 6401 patients with diabetes who were treated with pioglitazone and 12,802 age- and sex-matched patients with diabetes who were never treated with pioglitazone from 2004 to 2009 and who were free of dementia at baseline. RESULTS In total, 113 (1.8%) and 323 (2.5%) patients in the pioglitazone-treated and comparison cohorts, respectively, developed dementia during the 5-year follow-up. The risk of dementia decreased by 23% in the pioglitazone-treated cohort compared with that in the comparison cohort after adjustment for age, sex, hypertension, and stroke (adjusted hazard ratio [HR], 0.77; 95% confidence interval [CI]=0.62-0.96). In addition, the adjusted HRs (95% CIs) for dementia were 0.50 (0.34-0.75, P=.001) in high-cumulative dose users, 0.53 (0.36-0.77, P<.001) in long-term users, and 0.66 (0.49-0.90, P=.009) in high-mean daily dose users. CONCLUSIONS Pioglitazone is a time- and dose-dependent protective factor against dementia in patients with diabetes. The risk of dementia is lower in long-term and high-dose pioglitazone users than in never users of pioglitazone.
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Affiliation(s)
- Ping-Song Chou
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Bo-Lin Ho
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yuan-Han Yang
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of and Master's Program in Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Lee A, Papangeli I, Park Y, Jeong HN, Choi J, Kang H, Jo HN, Kim J, Chun HJ. A PPARγ-dependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis. Sci Rep 2017; 7:2528. [PMID: 28566713 PMCID: PMC5451412 DOI: 10.1038/s41598-017-02852-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 04/20/2017] [Indexed: 12/22/2022] Open
Abstract
Activation of the endothelium by pro-inflammatory stimuli plays a key role in the pathogenesis of a multitude of vascular diseases. Angiogenesis is a crucial component of the vascular response associated with inflammatory signaling. The CD40/CD40 ligand dyad in endothelial cells (EC) has a central role in promoting vascular inflammatory response; however, the molecular mechanism underlying this component of inflammation and angiogenesis is not fully understood. Here we report a novel microRNA mediated suppression of endothelial CD40 expression. We found that CD40 is closely regulated by miR-424 and miR-503, which directly target its 3′ untranslated region. Pro-inflammatory stimuli led to increased endothelial CD40 expression, at least in part due to decreased miR-424 and miR-503 expression. In addition, miR-424 and miR-503 reduced LPS induced EC sprouting, migration and tube formation. Moreover, we found that miR-424 and miR-503 expression is directly regulated by peroxisome proliferator-activated receptor gamma (PPARγ), whose endothelial expression and activity are decreased in response to inflammatory factors. Finally, we demonstrate that mice with endothelial-specific deletion of miR-322 (miR-424 ortholog) and miR-503 have augmented angiogenic response to LPS in a Matrigel plug assay. Overall, these studies identify a PPARγ-dependent miR-424/503-CD40 signaling axis that is critical for regulation of inflammation mediated angiogenesis.
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Affiliation(s)
- Aram Lee
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea
| | - Irinna Papangeli
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Youngsook Park
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea
| | - Ha-Neul Jeong
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea
| | - Jihea Choi
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea
| | - Hyesoo Kang
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea
| | - Ha-Neul Jo
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea
| | - Jongmin Kim
- Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon-gil, Yongsan-gu, Seoul, 140-742, Korea. .,Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.
| | - Hyung J Chun
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.
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Bennett M, Gilroy DW. Lipid Mediators in Inflammation. MYELOID CELLS IN HEALTH AND DISEASE 2017:343-366. [DOI: 10.1128/9781555819194.ch19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Melanie Bennett
- Roche Products Limited, Shire Park; Welwyn Garden City AL7 1TW United Kingdom
| | - Derek W. Gilroy
- Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London; London WC1 E6JJ United Kingdom
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Alsalem M, Altarifi A, Kalbouneh H, Zer HA, Azab B, Salem KE. Role of PPARα and PPARγ in Mediating the Analgesic Properties of Ibuprofen in vivo and the Effects of Dual PPARα/γ Activation in Inflammatory Pain Model in the Rat. INT J PHARMACOL 2016. [DOI: 10.3923/ijp.2016.812.820] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Gómez-Hernández A, Beneit N, Díaz-Castroverde S, Escribano Ó. Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications. Int J Endocrinol 2016; 2016:1216783. [PMID: 27766104 PMCID: PMC5059561 DOI: 10.1155/2016/1216783] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 07/19/2016] [Accepted: 08/04/2016] [Indexed: 12/18/2022] Open
Abstract
This review focuses on the contribution of white, brown, and perivascular adipose tissues to the pathophysiology of obesity and its associated metabolic and vascular complications. Weight gain in obesity generates excess of fat, usually visceral fat, and activates the inflammatory response in the adipocytes and then in other tissues such as liver. Therefore, low systemic inflammation responsible for insulin resistance contributes to atherosclerotic process. Furthermore, an inverse relationship between body mass index and brown adipose tissue activity has been described. For these reasons, in recent years, in order to combat obesity and its related complications, as a complement to conventional treatments, a new insight is focusing on the role of the thermogenic function of brown and perivascular adipose tissues as a promising therapy in humans. These lines of knowledge are focused on the design of new drugs, or other approaches, in order to increase the mass and/or activity of brown adipose tissue or the browning process of beige cells from white adipose tissue. These new treatments may contribute not only to reduce obesity but also to prevent highly prevalent complications such as type 2 diabetes and other vascular alterations, such as hypertension or atherosclerosis.
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Affiliation(s)
- Almudena Gómez-Hernández
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
| | - Nuria Beneit
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
| | - Sabela Díaz-Castroverde
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
| | - Óscar Escribano
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
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Cariou B, Fruchart JC, Staels B. Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/14746514050050030301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
ardiovascular disease is significantly increased in patients with the metabolic syndrome and type 2 diabetes. A clustering of risk factors, including dyslipidaemia, insulin resistance, hypertension, inflammation and coagulation disorders are acting in concert to promote cardiovascular events in these patients. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that influence vascular function by altering gene expression in vascular tissue and indirectly via effects on other tissues. Indeed, PPAR activation displays beneficial effects on glucose homeostasis and lipid metabolism, and also on endothelial function and vessel wall inflammation. Clinically used PPARα agonists, such as fibrates, and PPARγ agonists, such as insulin-sensitising thiazolidinediones, may consequently alter the process of atherosclerosis, especially in subjects with the metabolic syndrome and type 2 diabetes. The present review highlights emerging evidence for beneficial effects of PPAR α and PPARγ in the prevention and treatment of atherosclerosis in such high-risk patients.
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Affiliation(s)
- Bertrand Cariou
- Département d'Athérosclérose, Institut Pasteur de Lille & Faculté de Pharmacie, Université de Lille2, Lille, France
| | - Jean-Charles Fruchart
- Département d'Athérosclérose, Institut Pasteur de Lille & Faculté de Pharmacie, Université de Lille2, Lille, France
| | - Bart Staels
- Département d'Athérosclérose, Institut Pasteur de Lille & Faculté de Pharmacie, Université de Lille2, Lille, France,
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Lakkappa N, Krishnamurthy PT, Hammock BD, Velmurugan D, Bharath MMS. Possible role of Epoxyeicosatrienoic acid in prevention of oxidative stress mediated neuroinflammation in Parkinson disorders. Med Hypotheses 2016; 93:161-5. [PMID: 27372879 PMCID: PMC4985172 DOI: 10.1016/j.mehy.2016.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/24/2016] [Accepted: 06/04/2016] [Indexed: 11/19/2022]
Abstract
Parkinson's disease (PD) is a multifactorial neurodegenerative disease involving oxidative stress, neuroinflammation and apoptosis. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites and they play a role in cytoprotection by modulating various cell signaling pathways. This cytoprotective role of EETs are well established in cerebral stroke, cardiac failure, and hypertension, and it is due to their ability to attenuate oxidative stress, endoplasmic reticulum stress, inflammation, caspase activation and apoptosis. The actions of EETs in brain closely parallel the effects which is observed in the peripheral tissues. Since many of these effects could potentially contribute to neuroprotection, EETs are, therefore, one of the potential therapeutic candidates in PD. Therefore, by increasing the half life of endogenous EETs in vivo via inhibition of sEH, its metabolizing enzyme can, therefore, constitutes an important therapeutic strategy in PD.
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Affiliation(s)
- Navya Lakkappa
- Department of Pharmacology, JSS College of Pharmacy (A Constituent College of JSS University, Mysore), Ootacamund, Tamilnadu, India
| | - Praveen T Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy (A Constituent College of JSS University, Mysore), Ootacamund, Tamilnadu, India.
| | - Bruce D Hammock
- Department of Entomology and Nematology, and Comprehensive Cancer Research Center, University of California, Davis, CA, USA
| | - D Velmurugan
- Department of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, India
| | - M M Srinivas Bharath
- Department of Neurochemistry, National Institute of Mental Health & Neuro Sciences, Bangalore, India
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Schindler C. Review: The metabolic syndrome as an endocrine disease: is there an effective pharmacotherapeutic strategy optimally targeting the pathogenesis? Ther Adv Cardiovasc Dis 2016; 1:7-26. [DOI: 10.1177/1753944707082662] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The metabolic syndrome (MetS) represents a combination of cardiovascular risk determinants such as obesity, insulin resistance and lipid abnormalities such as hypertriglyceridemia, increased free fatty acids, low high-density-cholesterol and hypertension. As a multiple component condition it imparts a doubling of relative risk for atherosclerotic cardiovascular disease (ASCVD). It is currently controversial which component of the syndrome carries what weight. There is even a considerable debate whether the risk for ASCVD is greater in patients diagnosed with MetS than that by the individual risk factors. At present, no unifying pathogenetic mechanism can explain the metabolic syndrome and there is no unique treatment for it. This review summarizes and critically reviews the currently available clinical and scientific evidence for the concept that the MetS is causally an endocrine disease and discusses pharmacotherapeutic strategies targeting the pathogenesis rather than single symptoms of the cluster.
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Affiliation(s)
- Christoph Schindler
- Institute of Clinical Pharmacology, Medical Faculty, Technical University of Dresden, Fiedlerstrasse 27, 01307 Dresden, Germany christoph.schindler@ tu-dresden.de
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Rudnicki M, Tripodi GL, Ferrer R, Boscá L, Pitta MGR, Pitta IR, Abdalla DSP. New thiazolidinediones affect endothelial cell activation and angiogenesis. Eur J Pharmacol 2016; 782:98-106. [PMID: 27108791 DOI: 10.1016/j.ejphar.2016.04.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 04/08/2016] [Accepted: 04/20/2016] [Indexed: 02/07/2023]
Abstract
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPARγ) agonists used in treating type 2 diabetes that may exhibit beneficial pleiotropic effects on endothelial cells. In this study, we characterized the effects of three new TZDs [GQ-32 (3-biphenyl-4-ylmethyl-5-(4-nitro-benzylidene)-thiazolidine-2,4-dione), GQ-169 (5-(4-chloro-benzylidene)-3-(2,6-dichloro-benzyl)-thiazolidine-2,4-dione), and LYSO-7 (5-(5-bromo-1H-indol-3-ylmethylene)-3-(4-chlorobenzyl)-thiazolidine-2,4-dione)] on endothelial cells. The effects of the new TZDs were evaluated on the production of nitric oxide (NO) and reactive oxygen species (ROS), cell migration, tube formation and the gene expression of adhesion molecules and angiogenic mediators in human umbilical vein endothelial cells (HUVECs). PPARγ activation by new TZDs was addressed with a reporter gene assay. The three new TZDs activated PPARγ and suppressed the tumor necrosis factor α-induced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. GQ-169 and LYSO-7 also inhibited the glucose-induced ROS production. Although NO production assessed with 4-amino-5-methylamino-2',7'-difluorofluorescein-FM probe indicated that all tested TZDs enhanced intracellular levels of NO, only LYSO-7 treatment significantly increased the release of NO from HUVEC measured by chemiluminescence analysis of culture media. Additionally, GQ-32 and GQ-169 induced endothelial cell migration and tube formation by the up-regulation of angiogenic molecules expression, such as vascular endothelial growth factor A and interleukin 8. GQ-169 also increased the mRNA levels of basic fibroblast growth factor, and GQ-32 enhanced transforming growth factor-β expression. Together, the results of this study reveal that these new TZDs act as partial agonists of PPARγ and modulate endothelial cell activation and endothelial dysfunction besides to stimulate migration and tube formation.
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Affiliation(s)
- Martina Rudnicki
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gustavo L Tripodi
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Renila Ferrer
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Marina G R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Ivan R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Dulcineia S P Abdalla
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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Desouza CV, Murthy SN, Diez J, Dunne B, Matta AS, Fonseca VA, McNamara DB. Differential Effects of Peroxisome Proliferator Activator Receptor-α and γ Ligands on Intimal Hyperplasia After Balloon Catheter-Induced Vascular Injury in Zucker Rats. J Cardiovasc Pharmacol Ther 2016; 8:297-305. [PMID: 14740079 DOI: 10.1177/107424840300800407] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background: Patients with type 2 diabetes mellitus have a higher rate of restenosis following angioplasty. Peroxisome proliferator activator receptor-x (PPAR) and y ligands such as fenofibrate and rosiglitazone, respectively, have been shown to have protective effects on the vessel wall. We studied the effect of fenofibrate and rosiglitazone on intimal hyperplasia in the Zucker rat, a model for insulin resistance and type 2 diabetes mellitus, following balloon catheter-induced injury. Methods and Results: Three groups of 13-week-old female fatty Zucker rats were administered an aqueous suspension of either 3 mg/kg/d rosiglitazone (n = 7) or 150 mg/kg/d fenofibrate (n = 6) by gavage, or served as controls (n = 9). In addition, two groups of 13-week-old female lean Zucker rats were either administered 3 mg/kg/d rosiglitazone (n = 6) or served as controls (n = 6). Carotid balloon injury was induced 1 week after the drugs were started. The drug administration was continued for 3 weeks. A 2-mm balloon catheter was introduced through the femoral artery to the left carotid. The balloon was inflated to 4 atmospheres for 20 seconds and then was deflated to 2 atmospheres and dragged down to the aorta. The rats were killed 3 weeks after the injury. The carotid intima/media ratio was calculated. Intimal hyperplasia after carotid balloon-induced injury in the fatty Zucker rats was significantly reduced in the group treated with rosiglitazone (0.18 ± 0.29) compared with the untreated group (0.97 ± 0.13; P < .01). Plasma glucose, triglyceride, and insulin levels were elevated, indicative of the presence of insulin resistance; rosiglitazone treatment significantly reduced insulin and triglyceride levels without decreasing glucose. Rosiglitazone treatment also reduced, but to a lesser extent, the intimal hyperplasia in the lean Zucker rats (0.57 ± 0.10 vs 1.06 ± 0.12 treated and untreated, respectively; P < .01); however, it had no effect on insulin, triglyceride, or glucose levels in this group. The intimal hyperplasia in the fatty Zucker rats treated with fenofibrate was not reduced compared with controls (0.84 ± 0.26 vs 0.97 ± 0.13, respectively); fenofibrate reduced insulin and triglyceride, but not glucose levels, in these animals. Conclusions: The PPAR-y ligand rosiglitazone, but not the PPAR-x ligand fenofibrate, decreases intimal hyperplasia following balloon injury in both fatty and lean Zucker rats. This effect of the PPAR-y ligand was independent of glycemia, insulin, and lipid levels, and was more pronounced in insulin-resistant rats.
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Affiliation(s)
- Cyrus V Desouza
- Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Silva JC, César FA, de Oliveira EM, Turato WM, Tripodi GL, Castilho G, Machado-Lima A, de Las Heras B, Boscá L, Rabello MM, Hernandes MZ, Pitta MGR, Pitta IR, Passarelli M, Rudnicki M, Abdalla DSP. New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice. Pharmacol Res 2016; 104:49-60. [PMID: 26706782 DOI: 10.1016/j.phrs.2015.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Revised: 12/01/2015] [Accepted: 12/08/2015] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.
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Affiliation(s)
- Jacqueline C Silva
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Fernanda A César
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Edson M de Oliveira
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Walter M Turato
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gustavo L Tripodi
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gabriela Castilho
- Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Adriana Machado-Lima
- Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Beatriz de Las Heras
- Department of Pharmacology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Marcelo M Rabello
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil
| | - Marcelo Z Hernandes
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil
| | - Marina G R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Ivan R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Marisa Passarelli
- Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Martina Rudnicki
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Dulcineia S P Abdalla
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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Shirpoor A, Norouzi L, Nemati S, Khadem Ansari MH. Protective effect of vitamin E against diabetes-induced oxidized LDL and aorta cell wall proliferation in rat. IRANIAN BIOMEDICAL JOURNAL 2016; 19:117-23. [PMID: 25864817 PMCID: PMC4412923 DOI: 10.6091/ibj.1449.2015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
UNLABELLED Hyperlipidemia and oxidized-low-density lipoproteins (Ox-LDL) are important independent cardiovascular risk factors that have been shown to stimulate vascular smooth muscle cell (VSMC) proliferation. The purpose of the present study was to investigate the effect of vitamin E on Ox-LDL, lipid profile, C-reactive protein (CRP), and VSMC proliferation of rat aorta. METHODS Male Wistar rats (n = 32) were divided into four groups namely: sham (SH), control (C), non-treated diabetic, and vitamin E-treated diabetic (VETD) groups. Ox-LDL, lipid profile, CRP and VSMC proliferation of aorta were measured after 42 days. RESULTS The results revealed that along with a significant increase in VSMC proliferation, the amount of CRP, Ox-LDL, and lipid profiles in diabetic rats. VSMC proliferation was significantly ameliorated, and elevated CRP, Ox-LDL, and lipid profiles were also restored to those of shams in VETD. CONCLUSIONS These findings strongly support the idea that diabetes induces Ox-LDL-mediated oxidative stress and VSMC proliferation in aorta of rat and imply that vitamin E has a strong protective effect as an antioxidant.
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Affiliation(s)
- Alireza Shirpoor
- Dept. of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Leila Norouzi
- Dept. of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Samira Nemati
- Dept. of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Mahajan VK. Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics. World J Dermatol 2016; 5:17. [DOI: 10.5314/wjd.v5.i1.17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 10/25/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
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Cicero AFG, Baggioni A. Berberine and Its Role in Chronic Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 928:27-45. [PMID: 27671811 DOI: 10.1007/978-3-319-41334-1_2] [Citation(s) in RCA: 160] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis [e.g. Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Berberis aristata (tree turmeric)], Hydrastis canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron amurense [2] (Amur corktree), Coptis chinensis (Chinese goldthread), Tinospora cordifolia, Argemone mexicana (prickly poppy) and Eschscholzia californica (Californian poppy). In vitro it exerts significant anti-inflammatory and antioxidant activities. In animal models berberine has neuroprotective and cardiovascular protective effects. In humans, its lipid-lowering and insulin-resistance improving actions have clearly been demonstrated in numerous randomized clinical trials. Moreover, preliminary clinical evidence suggest the ability of berberine to reduce endothelial inflammation improving vascular health, even in patients already affected by cardiovascular diseases. Altogether the available evidences suggest a possible application of berberine use in the management of chronic cardiometabolic disorders.
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Affiliation(s)
- Arrigo F G Cicero
- Cardiovascular Disease Prevention Research Unit, Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Via Albertoni 15, 40138, Bologna, Italy.
| | - Alessandra Baggioni
- Cardiovascular Disease Prevention Research Unit, Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Via Albertoni 15, 40138, Bologna, Italy
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Gupta M, Mahajan VK, Mehta KS, Chauhan PS, Rawat R. Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the 'future' in dermatology therapeutics? Arch Dermatol Res 2015; 307:767-780. [PMID: 25986745 DOI: 10.1007/s00403-015-1571-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 04/11/2015] [Accepted: 05/05/2015] [Indexed: 01/10/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and comprise three different isoforms namely PPARα, PPARγ, and PPARβ/δ with PPARβ/δ being the predominant subtype in human keratinocytes. After binding with specific ligands, PPARs regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorogenesis. PPARs also modulate a wide variety of skin functions including keratinocyte proliferation, epidermal barrier formation, wound healing, melanocyte proliferation, and sebum production. Recent studies have shown the importance of PPARs in the pathogenesis of many dermatological disorders. Clinical trials have suggested possible role of PPAR agonists in the management of various dermatoses ranging from acne vulgaris, psoriasis, hirsutism, and lipodystrophy to cutaneous malignancies including melanoma. This article is intended to be a primer for dermatologists in their understanding of clinical relevance of PPARs and PPAR agonists in dermatology therapeutics.
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Affiliation(s)
- Mrinal Gupta
- Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda, 176001, Himachal Pradesh, India
| | - Vikram K Mahajan
- Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda, 176001, Himachal Pradesh, India.
| | - Karaninder S Mehta
- Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda, 176001, Himachal Pradesh, India
| | - Pushpinder S Chauhan
- Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda, 176001, Himachal Pradesh, India
| | - Ritu Rawat
- Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda, 176001, Himachal Pradesh, India
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