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Kim EY, Lee JM. Liver Metabolism at the Crossroads: The Reciprocal Control of Nutrient-Sensing Nuclear Receptors and Autophagy. Int J Mol Sci 2025; 26:5825. [PMID: 40565288 DOI: 10.3390/ijms26125825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2025] [Revised: 06/11/2025] [Accepted: 06/17/2025] [Indexed: 06/28/2025] Open
Abstract
Peroxisome proliferator-activated receptor α (PPARα, encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are the two prominent nutrient-sensing nuclear receptors essential for maintaining hepatic metabolism during fasting and fed states, respectively. These nuclear receptors comprehensively regulate the transcription of numerous genes involved in fatty acid oxidation (FAO), ketogenesis, bile acid (BA) biosynthesis, and other metabolic processes critical for liver energy homeostasis. These receptors have been shown to have opposite impacts on autophagy, which is triggered by PPARα activation but inhibited by FXR activation. Recent studies have further revealed that liver-specific genetic ablation of key autophagic genes tremendously impairs the activation of these nuclear receptors, thereby profoundly affecting hepatic metabolism in both fasting and feeding states. This review explores the roles and mechanisms of PPARα and FXR in regulating liver metabolism and autophagy, highlighting the necessity of basal autophagic activity in ensuring the proper signaling of these nutrient-sensing nuclear receptors. Finally, we examine the potential therapeutic strategies that leverage the interplay between PPARα, FXR, and autophagy for the treatment of metabolic liver disorders. We also delve into the clinical implications of this complex relationship, emphasizing its significance for translational medicine and future therapeutic interventions.
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Affiliation(s)
- Eun Young Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Daegu 41944, Republic of Korea
| | - Jae Man Lee
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Daegu 41944, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
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Kien CL, Dumas JA. How the Dietary Saturated/Monounsaturated Fatty Acid Ratio Modulates Brain Function in Older Adults. Nutrients 2025; 17:1897. [PMID: 40507166 PMCID: PMC12157107 DOI: 10.3390/nu17111897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2025] [Revised: 05/28/2025] [Accepted: 05/28/2025] [Indexed: 06/16/2025] Open
Abstract
Palmitic acid (PA) and oleic acid (OA) are, respectively, the most prevalent saturated and monounsaturated fatty acids (SFAs, MUFAs) in the human diet. The objective of this brief review is to explore how this ratio affects brain function. In two double-masked crossover trials in young adults, physical activity was greater and systemic inflammatory tone was diminished under a diet with a lower dietary PA/OA ratio compared to that of the typical North American Diet, and anger and total mood disturbance were diminished under the low- compared to the higher-PA/OA diet. In another diet trial in young women, functional magnetic resonance imaging showed that lowering the dietary PA/OA ratio decreased brain activation in regions of the basal ganglia, suggesting that brain function was reversibly altered by the dietary PA/OA ratio. Recently, a crossover trial in older adults showed that a lower dietary PA/OA ratio decreased systemic inflammatory tone and caused the greater activation of a working memory network. As people age, there are declines in cognition that impact functional abilities and independence, but the preservation of structural aspects of the brain in normal aging implies that there is the possibility of slowing, stopping, or reversing cognitive changes that impact daily life. Reducing pro-inflammatory cytokine secretion by lowering habitual PA intake for even brief periods of time may be one modality to improve cognitive function in older adults, not only in those with typical cognitive aging but in those with dementia as well.
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Affiliation(s)
- C. Lawrence Kien
- Department of Pediatrics, Larner College of Medicine, University of Vermont, Burlington, VT 05402, USA
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05402, USA
| | - Julie A. Dumas
- Department of Psychiatry, Larner College of Medicine, University of Vermont, Burlington, VT 05401, USA
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3
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Fecho K, Tucker N, Beasley JM, Auerbach SS, Bizon C, Tropsha A. Elucidating the mechanistic relationships between peroxisome proliferator-activated receptors and hepatic fibrosis using the ROBOKOP knowledge graph. FRONTIERS IN TOXICOLOGY 2025; 7:1549268. [PMID: 40330554 PMCID: PMC12052891 DOI: 10.3389/ftox.2025.1549268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/14/2025] [Indexed: 05/08/2025] Open
Abstract
We developed the Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways (ROBOKOP) application as an open-source knowledge graph system to support evidence-based biomedical discovery and hypothesis generation. This study aimed to apply ROBOKOP to suggest biological mechanisms that might explain the hypothesized relationship between exposure to the herbicide and lipid-lowering drug clofibrate, an activator of peroxisome proliferator-activated receptor-α (PPARA), and hepatic fibrosis. We queried ROBOKOP to first establish that it could demonstrate a relationship between clofibrate and PPARA as a validation test and second to identify intermediary genes and biological processes or activities that might relate the activation of PPARA by clofibrate to hepatic fibrosis. Queries of ROBOKOP returned several paths relating clofibrate, PPARA, and hepatic fibrosis. One path suggested the following: clofibrate - affects / increases_ expression_ of / increases_ activity_ of / increases_ response_ to / decreases_ response_ to / is_ related_ to - PPARA - is_ actively_ involved_ in - cellular response to lipid - actively_ involves - CCL2 - is_ genetically_ associated_ with - hepatic fibrosis. This result established a relationship between clofibrate and PPARA and further suggested that PPARA is actively involved in the cellular response to lipids, which actively involves the chemokine ligand CCL2, a gene genetically associated with hepatic fibrosis; thus, we can infer that PPARA, upon activation by clofibrate, plays a role in hepatic fibrosis. We conclude that ROBOKOP can be used to derive insights into biological mechanisms that might explain relationships between environmental exposures and liver toxicity.
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Affiliation(s)
- Karamarie Fecho
- Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Copperline Professional Solutions, LLC, Pittsboro, NC, United States
| | - Nyssa Tucker
- UNC Eshelman School of Pharmacy and Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jon-Michael Beasley
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Scott S. Auerbach
- Division of Translational Toxicology, National Institute of Environmental Health Sciences, Durham, NC, United States
| | - Chris Bizon
- Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Alexander Tropsha
- Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Predictive, LLC, Raleigh, NC, United States
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4
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Alharbi AM, Kafl HE, Abdelaziz RR, Suddek GM. Saroglitazar ameliorates 5- Fluorouracil-induced hepatorenal damage in rats. Int Immunopharmacol 2024; 143:113407. [PMID: 39423659 DOI: 10.1016/j.intimp.2024.113407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/23/2024] [Accepted: 10/11/2024] [Indexed: 10/21/2024]
Abstract
RATIONALE Hepatotoxicity and nephrotoxicity are significant adverse effects caused in cancer patients treated with 5-Flurouracil (5-FU), a pyrimidine analogue anti-metabolite anticancer drug. The purpose of this research was to evaluate the impact of PPAR α/γ agonist (Saroglitazar; SARO) on 5-FU-induced hepatorenal damage in rats. METHODS Male rats were randomly assigned to four groups: control, 5-FU, 5-FU + SARO (2 mg/kg), and 5-FU + SARO (4 mg/kg). Rats received 75 mg/kg 5-FU intraperitoneally once weekly for three weeks. Saroglitazar (2 and 4 mg/kg/day) was orally supplied by oral syringe for three consecutive weeks. On day 22, rats were euthanized and their livers and kidneys were subjected to morphological, biochemical, histological, and immunohistochemical analysis. RESULTS Saroglitazar treatment significantly decreased serum liver and kidney function biomarkers. In addition, it successfully modulated liver and kidney levels of inflammatory mediators and markers (NF-κB P65, TNF-α, cleaved caspase-1, IL-1β and p-p38 MAPK) and oxidative stress-related parameters (MDA, GSH, SOD, Keap1, Nrf-2 and HO-1) in a dose dependent manner. Furthermore, SARO could attenuate 5-FU-induced activation of cleaved caspase-3 as well as improved histopathological examination of both liver and kidney tissues. SIGNIFICANCE Saroglitazar may be a viable therapy option for 5-FU toxicity as it halts the interaction network of NF-kB and Nrf2 signaling pathways and apoptosis.
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Affiliation(s)
- Alhomedy M Alharbi
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt
| | - Hoda E Kafl
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt
| | - Rania R Abdelaziz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt
| | - Ghada M Suddek
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.
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Xiong Y, Zhong J, Chen W, Li X, Liu H, Li Y, Xiong W, Li H. Neferine alleviates acute kidney injury by regulating the PPAR-α/NF-κB pathway. Clin Exp Nephrol 2024; 28:969-987. [PMID: 38658442 DOI: 10.1007/s10157-024-02504-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 04/07/2024] [Indexed: 04/26/2024]
Abstract
Acute kidney injury (AKI) is a cluster of clinical syndromes with diverse etiologies that ultimately result in a swift decline in kidney function. Regrettably, AKI lacks effective therapeutic agents at present. Neferine, a bioactive alkaloid derived from Lotus Plumule, has been reported to alleviate AKI triggered by cisplatin, ischemia/reperfusion (I/R), and sepsis by inhibiting inflammatory pathways. However, the precise molecular mechanisms underpinning its renoprotective effects remain elusive. Peroxisome proliferator-activated receptor alpha (PPAR-α), a regulator of lipid metabolism with anti-inflammatory properties, was investigated in this study to examine its role in neferine's renoprotective effects in cellular and mouse models of AKI. We found that neferine pretreatment in both I/R- or lipopolysaccharide (LPS)-induced AKI models inhibited the activation of the NF-κB inflammatory pathway and reversed PPAR-α deficiency. In NRK-52E cells exposed to hypoxia/reoxygenation (H/R) or LPS, overexpression of PPAR-α resulted in inhibition of the NF-κB pathway and TNF-α production, while PPAR-α silencing via siRNA transfection negated neferine's anti-inflammatory effects. Furthermore, pretreatment with neferine not only reduced lipid accumulation but also reversed the downregulation of FAO-related enzymes induced by LPS. Our findings suggest that neferine's renoprotective effects against AKI are partially mediated through the reversal of renal PPAR-α deficiency and subsequent inhibition of the inflammatory NF-κB pathway. Therefore, regulating renal PPAR-α expression by neferine could represent a promising therapeutic strategy for AKI.
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Affiliation(s)
- Yanying Xiong
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Jin Zhong
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Wenhang Chen
- Department of Nephropathy, Xiangya Hospital Central-South University, Changsha, Hunan, China
| | - Xuan Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Hong Liu
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Ying Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Weijian Xiong
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China
| | - Huihui Li
- Department of Nephropathy, Chongqing Hospital of Traditional Chinese Medicine, Jiangbei District, Chongqing, China.
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Hopkin SJ, Nathan P, Pezhman L, Begum J, Manning JE, Quinn LM, Rainger GE, McGettrick HM, Iqbal AJ, Chimen M. Rejuvenation of leukocyte trafficking in aged mice through PEPITEM intervention. NPJ AGING 2024; 10:33. [PMID: 39025913 PMCID: PMC11258258 DOI: 10.1038/s41514-024-00160-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/24/2024] [Indexed: 07/20/2024]
Abstract
Inflammageing leads to uncontrolled leukocyte trafficking in response to inflammatory insults. Here, we used a zymosan-induced peritonitis mouse model on inflammation to investigate the role of the PEPITEM pathway on leukocyte migration in ageing. We then analysed whether PEPITEM could modulate leukocyte migration in older adults. We observed a loss of functionality in the PEPITEM pathway, which normally controls leukocyte trafficking in response to inflammation, in older adults and aged mice and show that this can be rescued by supplementation with PEPITEM. Thus, leading to the exciting possibility that PEPITEM supplementation may represent a potential pre-habilitation geroprotective agent to rejuvenate immune functions.
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Affiliation(s)
- Sophie J Hopkin
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Poppy Nathan
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Laleh Pezhman
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Jenefa Begum
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Julia E Manning
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
| | - Lauren M Quinn
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - G Ed Rainger
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Helen M McGettrick
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK.
| | - Asif J Iqbal
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
| | - Myriam Chimen
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK.
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Wang X, Zhao J, Lin Z, Li J, Li X, Xu X, Wang Y, Lv G, Lin H, Lin Z. Analysis of Polyphenol Extract from Hazel Leaf and Ameliorative Efficacy and Mechanism against Hyperuricemia Zebrafish Model via Network Pharmacology and Molecular Docking. Molecules 2024; 29:317. [PMID: 38257230 PMCID: PMC10820926 DOI: 10.3390/molecules29020317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/01/2024] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Hazel leaf, a by-product of hazelnuts, is commonly used in traditional folk medicine in Portugal, Sweden, Iran and other regions for properties such as vascular protection, anti-bleeding, anti-edema, anti-infection, and pain relief. Based on our previous studies, the polyphenol extract from hazel leaf was identified and quantified via HPLC fingerprint. The contents of nine compounds including kaempferol, chlorogenic acid, myricetin, caffeic acid, p-coumaric acid, resveratrol, luteolin, gallic acid and ellagic acid in hazel leaf polyphenol extract (ZP) were preliminary calculated, among which kaempferol was the highest with 221.99 mg/g, followed by chlorogenic acid with 8.23 mg/g. The inhibition of ZP on α-glucosidase and xanthine oxidase activities was determined via the chemical method, and the inhibition on xanthine oxidase was better. Then, the effect of ZP on hyperuricemia zebrafish was investigated. It was found that ZP obviously reduced the levels of uric acid, xanthine oxidase, urea nitrogen and creatinine, and up-regulated the expression ofOAT1 and HPRT genes in hyperuricemia zebrafish. Finally, the targeted network pharmacological analysis and molecular docking of nine polyphenol compounds were performed to search for relevant mechanisms for alleviating hyperuricemia. These results will provide a valuable basis for the development and application of hazel leaf polyphenols as functional ingredients.
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Affiliation(s)
| | | | | | | | | | | | | | | | - He Lin
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.W.); (J.Z.); (Z.L.); (J.L.); (X.L.); (X.X.); (Y.W.); (G.L.)
| | - Zhe Lin
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China; (X.W.); (J.Z.); (Z.L.); (J.L.); (X.L.); (X.X.); (Y.W.); (G.L.)
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8
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Wu S, Chen R, Chen J, Yang N, Li K, Zhang Z, Zhang R. Study of the Anti-Inflammatory Mechanism of β-Carotene Based on Network Pharmacology. Molecules 2023; 28:7540. [PMID: 38005265 PMCID: PMC10673508 DOI: 10.3390/molecules28227540] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
β-carotene is known to have pharmacological effects such as anti-inflammatory, antioxidant, and anti-tumor properties. However, its main mechanism and related signaling pathways in the treatment of inflammation are still unclear. In this study, component target prediction was performed by using literature retrieval and the SwissTargetPrediction database. Disease targets were collected from various databases, including DisGeNET, OMIM, Drug Bank, and GeneCards. A protein-protein interaction (PPI) network was constructed, and enrichment analysis of gene ontology and biological pathways was carried out for important targets. The analysis showed that there were 191 unique targets of β-carotene after removing repeat sites. A total of 2067 targets from the three databases were integrated, 58 duplicate targets were removed, and 2009 potential disease action targets were obtained. Biological function enrichment analysis revealed 284 biological process (BP) entries, 31 cellular component (CC) entries, 55 molecular function (MF) entries, and 84 cellular pathways. The biological processes were mostly associated with various pathways and their regulation, whereas the cell components were mainly membrane components. The main molecular functions included RNA polymerase II transcription factor activity, DNA binding specific to the ligand activation sequence, DNA binding, steroid binding sequence-specific DNA binding, enzyme binding, and steroid hormone receptors. The pathways involved in the process included the TNF signaling pathway, sphingomyelin signaling pathway, and some disease pathways. Lastly, the anti-inflammatory signaling pathway of β-carotene was systematically analyzed using network pharmacology, while the molecular mechanism of β-carotene was further explored by molecular docking. In this study, the anti-inflammatory mechanism of β-carotene was preliminarily explored and predicted by bioinformatics methods, and further experiments will be designed to verify and confirm the predicted results, in order to finally reveal the anti-inflammatory mechanism of β-carotene.
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Affiliation(s)
- Shilin Wu
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Ran Chen
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Jingyun Chen
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Ning Yang
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Kun Li
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Zhen Zhang
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
| | - Rongqing Zhang
- Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
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Demirdağ F, Yavuzer S, Cengiz M, Yavuzer H, Kara Z, Ayvacı A, Avcı S, Yürüyen M, Uzun H, Altıparmak MR, Döventaş A, Erdinçler DS. The Role of NF-κB, PPAR-α, and PPAR-γ in Older Adults with Metabolic Syndrome. Horm Metab Res 2023; 55:733-740. [PMID: 37308136 DOI: 10.1055/a-2109-1958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The etiopathogenesis of metabolic syndrome (MetS) has not been fully understood yet, and chronic low-grade inflammation is thought to be associated with the development of complications related to MetS. We aimed to investigate the role of Nuclear factor Kappa B ( NF-κB ), Peroxisome Proliferator-Activated Receptor- α and γ (PPAR-α, and PPAR-γ) which are the main markers of inflammation in older adults with MetS. A total of 269 patients aged≥18, 188 patients with MetS who met the diagnostic criteria of the International Diabetes Federation, and 81 controls who applied to geriatrics and general internal medicine outpatient clinics for various reasons were included in the study. Patients were separated into four groups: young with MetS (< 60, n=76), elderly with MetS (≥60, n=96), young control (< 60, n=31), elderly controls (≥60, n=38). Carotid intima-media thickness (CIMT) and NF-κB , PPAR-α, and PPAR-γ plasma levels were measured in all of the participants. Age and sex distribution were similar between MetS and control groups. C-reactive protein (CRP), NF-κB levels (p=0.001) and CIMT (p<0,001) of MetS group were significantly higher than in the control groups. On the other hand, the PPAR-γ (p=0.008) and PPAR-α (p=0.003) levels were significantly lower in MetS. ROC analysis revealed that the NF-κB, PPAR-α, and PPAR-γ could be used to indicate MetS in younger adults (AUC: 0.735, p<0.000; AUC: 0.653, p=0.003), whereas it could not be an indicator in older adults (AUC: 0.617, p=0.079; AUC:0.530, p=0.613). It seems that these markers have important roles in MetS-related inflammation. In our results, suggest that the indicator feature of NF-κB , PPAR-α and PPAR-γ in recognizing MetS in young individuals is lost in older adults with Mets.
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Affiliation(s)
- Filiz Demirdağ
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
- Division of Geriatrics, Department of Internal Medicine, Istanbul Medeniyet University, School of Medicine Istanbul, Turkey
| | - Serap Yavuzer
- Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Mahir Cengiz
- Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Hakan Yavuzer
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Zehra Kara
- Division of Endocrinology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Adnan Ayvacı
- Department of Radiology, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Suna Avcı
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Mehmet Yürüyen
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Hafize Uzun
- Department of Biochemistry, Istanbul Atlas University, School of Medicine, Istanbul, Turkey
| | - Mehmet Rıza Altıparmak
- Division of Nephrology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Alper Döventaş
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Deniz Suna Erdinçler
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
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10
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Ibáñez C, Acuña T, Quintanilla ME, Pérez-Reytor D, Morales P, Karahanian E. Fenofibrate Decreases Ethanol-Induced Neuroinflammation and Oxidative Stress and Reduces Alcohol Relapse in Rats by a PPAR-α-Dependent Mechanism. Antioxidants (Basel) 2023; 12:1758. [PMID: 37760061 PMCID: PMC10525752 DOI: 10.3390/antiox12091758] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
High ethanol consumption triggers neuroinflammation, implicated in sustaining chronic alcohol use. This inflammation boosts glutamate, prompting dopamine release in reward centers, driving prolonged drinking and relapse. Fibrate drugs, activating peroxisome proliferator-activated receptor alpha (PPAR-α), counteract neuroinflammation in other contexts, prompting investigation into their impact on ethanol-induced inflammation. Here, we studied, in UChB drinker rats, whether the administration of fenofibrate in the withdrawal stage after chronic ethanol consumption reduces voluntary intake when alcohol is offered again to the animals (relapse-type drinking). Furthermore, we determined if fenofibrate was able to decrease ethanol-induced neuroinflammation and oxidative stress in the brain. Animals treated with fenofibrate decreased alcohol consumption by 80% during post-abstinence relapse. Furthermore, fenofibrate decreased the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukins IL-1β and IL-6, and of an oxidative stress-induced gene (heme oxygenase-1), in the hippocampus, nucleus accumbens, and prefrontal cortex. Animals treated with fenofibrate showed an increase M2-type microglia (with anti-inflammatory proprieties) and a decrease in phagocytic microglia in the hippocampus. A PPAR-α antagonist (GW6471) abrogated the effects of fenofibrate, indicating that they are dependent on PPAR-α activation. These findings highlight the potential of fenofibrate, an FDA-approved dyslipidemia medication, as a supplementary approach to alleviating relapse severity in individuals with alcohol use disorder (AUD) during withdrawal.
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Affiliation(s)
- Cristina Ibáñez
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago 8910060, Chile; (C.I.); (D.P.-R.)
- Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders, Santiago 8910060, Chile;
| | - Tirso Acuña
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - María Elena Quintanilla
- Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders, Santiago 8910060, Chile;
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Diliana Pérez-Reytor
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago 8910060, Chile; (C.I.); (D.P.-R.)
| | - Paola Morales
- Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders, Santiago 8910060, Chile;
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
- Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Eduardo Karahanian
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago 8910060, Chile; (C.I.); (D.P.-R.)
- Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders, Santiago 8910060, Chile;
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11
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Zhao X, Zhou S, Liu Y, Gong C, Xiang L, Li S, Wang P, Wang Y, Sun L, Zhang Q, Yang Y. Parishin alleviates vascular ageing in mice by upregulation of Klotho. J Cell Mol Med 2023; 27:1398-1409. [PMID: 37032511 PMCID: PMC10183705 DOI: 10.1111/jcmm.17740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 04/11/2023] Open
Abstract
Senescence of vascular endothelial cells is the major risk of vascular dysfunction and disease among elderly people. Parishin, which is a phenolic glucoside derived from Gastrodia elata, significantly prolonged yeast lifespan. However, the action of parishin in vascular ageing remains poorly understood. Here, we treated human coronary artery endothelial cells (HCAEC) and naturally aged mice by parishin. Parishin alleviated HCAEC senescence and general age-related features in vascular tissue in naturally aged mice. Network pharmacology approach was applied to determine the compound-target networks of parishin. Our analysis indicated that parishin had a strong binding affinity for Klotho. Expression of Klotho, a protein of age-related declines, was upregulated by parishin in serum and vascular tissue in naturally aged mice. Furthermore, FoxO1, on Klotho/FoxO1 signalling pathway, was increased in the parishin-intervened group, accompanied by the downregulated phosphorylated FoxO1. Taken together, parishin can increase Klotho expression to alleviate vascular endothelial cell senescence and vascular ageing.
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Affiliation(s)
- Xinxiu Zhao
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Shixian Zhou
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Yang Liu
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Caixia Gong
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Lan Xiang
- College of Pharmaceutical SciencesZhejiang University866 Yu Hang Tang RoadHangzhouChina
| | - Shumin Li
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Peixia Wang
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Yuejun Wang
- Zhejiang Aged Care HospitalHangzhou Normal UniversityHangzhouZhejiangChina
| | - Linlin Sun
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Qin Zhang
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Yunmei Yang
- Department of Geriatrics, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Diagnosis and Treatment of Aging and Physic‐chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
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12
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Kokabiyan Z, Yaghmaei P, Jameie SB, Hajebrahimi Z. Effect of eugenol on lipid profile, oxidative stress, sex hormone, liver injury, ovarian failure, and expression of COX-2 and PPAR-α genes in a rat model of diabetes. Mol Biol Rep 2023; 50:3669-3679. [PMID: 36829079 DOI: 10.1007/s11033-022-08108-3] [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: 08/27/2022] [Accepted: 11/09/2022] [Indexed: 02/26/2023]
Abstract
BACKGROUND Diabetes is among the leading causes of reproductive system failure and infertility in both women and men. Inflammation and oxidative stress have a main role in the development of diabetes. Eugenol or clove oil is a phenolic monoterpenoid with antioxidant and anti-inflammatory properties. Here, the effects of eugenol on diabetes features and ovarian function were investigated. METHODS AND RESULTS Streptozotocin-induced diabetes rats were treated with 12 and 24 mg/kg of eugenol for 4 weeks. The biochemical and histological assay was done to evaluate the effects of eugenol on ovary and pancreas function, liver injury, oxidative status, sex hormones, lipid profile, and mRNA levels of cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor alpha (PPAR-α) genes. Streptozotocin increased levels of serum glucose, total cholesterol, triglyceride, low-density lipoprotein, aspartate transaminase, alanine transaminase, alkaline phosphatase, malondialdehyde, pancreas necrosis and inflammation, COX-2 expression, ovarian cystic, and anovulation. It decreased the levels of insulin, high-density lipoprotein, Superoxide dismutase, estradiol, progesterone, testosterone, luteinizing hormone, follicle-stimulating hormone, and PPAR-α expression. Eugenol administration ameliorated diabetes features through the improvement of lipid profile, oxidative status, insulin and glucose levels, sex hormone levels, liver markers, COX-2 and PPAR-α expression, and pancreas histology. It had no effect on ovarian cystic and follicular development. CONCLUSIONS Therefore, eugenol may be useful for ameliorating some adverse features of diabetes and used as an adjunct treatment or protective agent accompany by other chemicals in diabetes patients.
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Affiliation(s)
- Zahra Kokabiyan
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parichehreh Yaghmaei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Seyed Behnamedin Jameie
- Department of Anatomy, Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Hajebrahimi
- A&S Research Institute, Ministry of Science Research and Technology, Tehran, Iran
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13
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Gallucci GM, Alsuwayt B, Auclair AM, Boyer JL, Assis DN, Ghonem NS. Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis. Inflammation 2022; 45:2570-2581. [PMID: 35838934 PMCID: PMC10853883 DOI: 10.1007/s10753-022-01713-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 07/01/2022] [Indexed: 11/05/2022]
Abstract
Chronic liver diseases, e.g., cholestasis, are negatively impacted by inflammation, which further aggravates liver injury. Pharmacotherapy targeting the peroxisome proliferator-activated receptor alpha (PPARα), e.g., fenofibrate, has recently become an off-label therapeutic option for patients with refractory cholestasis. Clinical studies show that fibrates can reduce some pro-inflammatory cytokines in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); however, its anti-inflammatory mechanisms have not been established. Numerous cytokines are regulated by the transcription factor nuclear receptor kappa B (NF-κB), and PPARα has been shown to interfere with NF-κB signaling. This study investigates the anti-inflammatory mechanism of fenofibrate by inhibiting NF-κB signaling in human macrophages and clinical outcomes in patients with PBC. For adult patients with PBC and an incomplete biochemical response to ursodiol (13-15 mg/kg/day), the addition of fenofibrate (145-160 mg/day) reduced serum levels of TNF-α, IL-17A, IL-1β, IL-6, IL-8, and MCP-1 and increased IL-10. In THP-1 cells, pretreatment with fenofibrate (125 μM) reduced LPS-stimulated peak concentrations of IL-1β (- 63%), TNF-α (- 88%), and IL-8 (- 54%), in a PPARα-dependent manner. Treatment with fenofibrate prior to LPS significantly decreased nuclear NF-κB p50 and p65 subunit binding by 49% and 31%, respectively. Additionally, fenofibrate decreased nuclear NF-κB p50 and p65 protein expression by 66% and 55% and increased cytoplasmic levels by 53% and 54% versus LPS alone, respectively. Lastly, fenofibrate increased IκBα levels by 2.7-fold (p < 0.001) vs. LPS. These data demonstrate that fenofibrate reduces pro-inflammatory cytokines section by inhibiting in NF-κB signaling, which likely contribute to its anti-inflammatory effects during chronic liver diseases.
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Affiliation(s)
- Gina M Gallucci
- College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA
| | - Bader Alsuwayt
- School of Pharmacy, Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
| | - Adam M Auclair
- College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA
| | - James L Boyer
- Yale School of Medicine, Liver Center, New Haven, CT, USA
| | - David N Assis
- Yale School of Medicine, Liver Center, New Haven, CT, USA
| | - Nisanne S Ghonem
- College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Avedisian Hall, Kingston, RI 02881, USA.
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14
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Macrophages Are Polarized toward an Inflammatory Phenotype by their Aged Microenvironment in the Human Skin. J Invest Dermatol 2022; 142:3136-3145.e11. [PMID: 35850208 DOI: 10.1016/j.jid.2022.06.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 06/09/2022] [Accepted: 06/11/2022] [Indexed: 01/05/2023]
Abstract
Aging of the skin is accompanied by cellular as well as tissue environmental changes, ultimately reducing the ability of the tissue to regenerate and adequately respond to external stressors. Macrophages are important gatekeepers of tissue homeostasis, and it has been reported that their number and phenotype change during aging in a site-specific manner. How aging affects human skin macrophages and what implications this has for the aging process in the tissue are still not fully understood. Using single-cell RNA-sequencing analysis, we show that there is at least a 50% increase of macrophages in human aged skin, which appear to have developed from monocytes and exhibit more proinflammatory M1-like characteristics. In contrast, the cell-intrinsic ability of aged monocytes to differentiate into M1 macrophages was reduced. Using coculture experiments with aged dermal fibroblasts, we show that it is the aged microenvironment that drives a more proinflammatory phenotype of macrophages in the skin. This proinflammatory M1-like phenotype in turn negatively influenced the expression of extracellular matrix proteins by fibroblasts, emphasizing the impact of the aged macrophages on the skin phenotype.
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15
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Landim-Vieira M, Kahmini AR, Engel M, Cannon EN, Amat-Alarcon N, Judge DP, Pinto JR, Chelko SP. Efficacy and Safety of Angiotensin Receptor Blockers in a Pre-Clinical Model of Arrhythmogenic Cardiomyopathy. Int J Mol Sci 2022; 23:13909. [PMID: 36430389 PMCID: PMC9697954 DOI: 10.3390/ijms232213909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Arrhythmogenic Cardiomyopathy (ACM) is a familial heart disease, characterized by contractile dysfunction, ventricular arrhythmias (VAs), and the risk of sudden cardiac death. Currently, implantable cardioverter defibrillators and antiarrhythmics are the mainstays in ACM therapeutics. Angiotensin receptor blockers (ARBs) have been highlighted in the treatment of heart diseases, including ACM. Yet, recent research has additionally implicated ARBs in the genesis of VAs and myocardial lipolysis via the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. The latter is of particular interest, as fibrofatty infiltration is a pathological hallmark in ACM. Here, we tested two ARBs, Valsartan and Telmisartan, and the PPAR agonist, Rosiglitazone, in an animal model of ACM, homozygous Desmoglein-2 mutant mice (Dsg2mut/mut). Cardiac function, premature ventricular contractions (PVCs), fibrofatty scars, PPARα/γ protein levels, and PPAR-mediated mRNA transcripts were assessed. Of note, not a single mouse treated with Rosiglitazone made it to the study endpoint (i.e., 100% mortality: n = 5/5). Telmisartan-treated Dsg2mut/mut mice displayed the preservation of contractile function (percent ejection fraction [%EF]; 74.8 ± 6.8%EF) compared to Vehicle- (42.5 ± 5.6%EF) and Valsartan-treated (63.1 ± 4.4%EF) mice. However, Telmisartan-treated Dsg2mut/mut mice showed increased cardiac wall motion abnormalities, augmented %PVCs, electrocardiographic repolarization/depolarization abnormalities, larger fibrotic lesions, and increased expression of PPARy-regulated gene transcripts compared to their Dsg2mut/mut counterparts. Alternatively, Valsartan-treated Dsg2mut/mut mice harbored fewer myocardial scars, reduced %PVC, and increased Wnt-mediated transcripts. Considering our findings, caution should be taken by physicians when prescribing medications that may increase PPARy signaling in patients with ACM.
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Affiliation(s)
- Maicon Landim-Vieira
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Aida Rahimi Kahmini
- Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32306, USA
| | - Morgan Engel
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Elisa Nicole Cannon
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Nuria Amat-Alarcon
- Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21215, USA
| | - Daniel P. Judge
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - José Renato Pinto
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Stephen P. Chelko
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
- Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21215, USA
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16
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Skoglund O, Walhelm T, Thyberg I, Eriksson P, Sjöwall C. Fighting Fatigue in Systemic Lupus Erythematosus: Experience of Dehydroepiandrosterone on Clinical Parameters and Patient-Reported Outcomes. J Clin Med 2022; 11:jcm11185300. [PMID: 36142945 PMCID: PMC9505355 DOI: 10.3390/jcm11185300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Manifestations related to ongoing inflammation in systemic lupus erythematosus (SLE) are often adequately managed, but patient-reported outcome measures (PROMs) support that fatigue and low quality of life (QoL) in the absence of raised disease activity remain major burdens. The adrenal hormone dehydroepiandrosterone (DHEA) has shown potential as a pharmacological agent for managing fatigue in mild SLE. We retrospectively evaluated data on dosage, disease activity, corticosteroid doses, concomitant antirheumatic drugs, and PROMs regarding pain intensity, fatigue, and well-being (visual analogue scales), QoL (EQ-5D-3L) and functional disability. A total of 15 patients with SLE were exposed to DHEA and 15 sex- and age-matched non-exposed SLE patients served as comparators. At baseline, 83% of the DHEA-exposed patients had subnormal DHEA concentration. The 15 subjects prescribed DHEA were exposed during a median time of 12 months (IQR 16.5) [range 3–81] and used a median daily dose of 50 mg of DHEA (IQR 25.0) [range 25–200]. Neither disease activity, nor damage accrual, changed significantly over time among patients using DHEA, and no severe adverse events were observed. Numerical improvements of all evaluated PROMs were seen in the DHEA-treated group, but none reached statistical significance. For DHEA-exposed patients, a non-significant trend was found regarding fatigue comparing baseline and 36 months (p = 0.068). In relation to SLE controls, the DHEA-exposed group initially reported significantly worse fatigue, pain, and well-being, but the differences diminished over time. In conclusion, DHEA was safe, but evidence for efficacy of DHEA supplementation in relation to PROMs were not found. Still, certain individuals with mild SLE, plagued by fatigue and absence of increased disease activity, appear to benefit from DHEA in terms of improved fatigue and QoL. Testing of DHEA concentration in blood should be performed before initiation, and investigation of other conditions, or reasons responsible for fatigue, must always be considered first.
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17
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Sucajtys-Szulc E, Debska-Slizien A, Rutkowski B, Szolkiewicz M, Swierczynski J, Smolenski RT. Hepatocyte Nuclear Factor 1α Proinflammatory Effect Linked to the Overexpression of Liver Nuclear Factor–κB in Experimental Model of Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23168883. [PMID: 36012158 PMCID: PMC9408856 DOI: 10.3390/ijms23168883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/06/2022] [Indexed: 11/18/2022] Open
Abstract
Chronic kidney disease (CKD) is associated with low-grade inflammation that activates nuclear factor–κB (NF–κB), which upregulates the expression of numerous NF–κB responsive genes, including the genes encoding IL-6, ICAM-1, VCAM-1, and MCP-1. Herein, we found the coordinated overexpression of genes encoding RelA/p65 (a subunit of NF–κB) and HNF1α in the livers of chronic renal failure (CRF) rats—an experimental model of CKD. The coordinated overexpression of RelA/p65 and HNF1α was associated with a significant increase in IL-6, ICAM-1, VCAM-1, and MCP-1 gene expressions. A positive correlation between liver RelA/p65 mRNA levels and a serum concentration of creatinine and BUN suggest that RelA/p65 gene transcription is tightly related to the progression of renal failure. The knockdown of HNF1α in the HepG2 cell line by siRNA led to a decrease in Rel A/p65 mRNA levels. This was associated with a decrease in IL-6, ICAM-1, VCAM-1, and MCP-1 gene expressions. The simultaneous repression of HNF-1α and RelA/p65 by clofibrate is tightly associated with the downregulation of IL-6, ICAM-1, VCAM-1, and MCP-1 gene expression. In conclusion, our findings suggest that NF–κB could be a downstream component of the HNF1α-initiated signaling pathway in the livers of CRF rats.
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Affiliation(s)
- Elzbieta Sucajtys-Szulc
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland
| | - Alicja Debska-Slizien
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland
| | - Boleslaw Rutkowski
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland
| | - Marek Szolkiewicz
- Department of Nephrology, Transplantology, and Internal Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland
- Department of Cardiology and Interventional Angiology, Kashubian Center for Heart and Vascular Diseases in Wejherowo, Pomeranian Hospitals, 84-200 Wejherowo, Poland
| | - Julian Swierczynski
- Koszalin State Higher Vocational School, Lesna 1, 75-582 Koszalin, Poland
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | - Ryszard Tomasz Smolenski
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
- Correspondence: ; Tel.: +48-58-3491460
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18
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Wagner N, Wagner KD. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells 2022; 11:cells11152432. [PMID: 35954274 PMCID: PMC9368267 DOI: 10.3390/cells11152432] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
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Affiliation(s)
- Nicole Wagner
- Correspondence: (N.W.); (K.-D.W.); Tel.: +33-489-153-713 (K.-D.W.)
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19
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Hu C, Zhang Z, Song G, Zhu L, Wang R, Ruan Z. Jujuboside A Ameliorates Myocardial Apoptosis and Inflammation in Rats with Coronary Heart Disease by Inhibiting PPAR- α Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:2285728. [PMID: 35783519 PMCID: PMC9249489 DOI: 10.1155/2022/2285728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 11/17/2022]
Abstract
Background Coronary heart disease (CHD) is a chronic disease caused by atherosclerosis (AS), which can cause myocardial ischemia, hypoxia, or necrosis, seriously threatening human health. There is an urgent need for effective treatments and drugs to reduce the various risk factors for coronary heart disease and relieve symptoms of angina pectoris and myocardial infarction in patients. Jujuboside A (JuA) is a triterpenoid saponin extracted from jujube seeds, which has various biological activities such as antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective effects. We study the function of JuA in myocardial injury, dyslipidemia, and inflammation in the CHD rat model, to explore its potential mechanism of improving CHD. Methods A rat model of CHD was established by feeding a high-fat diet. The rats were randomly divided into 5 groups (n = 6): control group, CHD group, JuA 25 mg/kg group, JuA 50 mg/kg group, and JuA 75 mg/kg group. Echocardiography was used to detect the cardiac function parameters of rats in each group, and then, hematoxylin and eosin staining was used to assess the histopathological injury in myocardial tissues. Levels of blood lipids, myocardial injury indexes, and inflammatory factors of rats in each group were measured by biochemical tests and enzyme linked immunosorbent assay, and the levels of Bax, Bcl-2, c-caspase-3, PPAR-α, p65, p-p65, IκBα, and p-IκBα protein expression in myocardial tissues were detected by western blot. Results Compared with the CHD group, JuA therapy significantly improved injury in myocardial tissue and endothelial tissue. It also strengthened cardiac function, while decreasing total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol levels in the serum and increasing high-density lipoprotein cholesterol levels. In addition, JuA also restrained cardiomyocytes apoptosis and inhibited the inflammatory reaction by reducing TNF-α, IL-1β, and IL-6 expression in myocardial tissues. Furthermore, administration of JuA inhibited the activation of PPAR-α pathway by preventing the phosphorylation of p65 and IκBα in myocardial tissues of CHD rats. Conclusion JuA may improve cardiac function, alleviate myocardial and endothelial injury, and also ameliorate dyslipidemia and inflammatory reaction in rats with CHD, where JuA probably plays a protective role by inhibiting the activation of PPAR-α pathway.
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Affiliation(s)
- Chunfang Hu
- Cardiovascular MedicineCardiovascular Medicine, Taizhou People's Hospital, Taizhou 225399, Jiangsu, China
- Dalian Medical University, Dalian 116000, Liaoning, China
| | - Zhiyuan Zhang
- Cardiovascular MedicineCardiovascular Medicine, Taizhou People's Hospital, Taizhou 225399, Jiangsu, China
| | - Guixian Song
- Cardiovascular MedicineCardiovascular Medicine, Taizhou People's Hospital, Taizhou 225399, Jiangsu, China
| | - Li Zhu
- Cardiovascular MedicineCardiovascular Medicine, Taizhou People's Hospital, Taizhou 225399, Jiangsu, China
| | - Ruzhu Wang
- Cardiovascular MedicineCardiovascular Medicine, Taizhou People's Hospital, Taizhou 225399, Jiangsu, China
| | - Zhongbao Ruan
- Cardiovascular MedicineCardiovascular Medicine, Taizhou People's Hospital, Taizhou 225399, Jiangsu, China
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20
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Huang Y, Li P, Li Z, Zhu D, Fan Y, Wang X, Zhao C, Jiao J, Du X, Wang S. Red yeast rice dietary intervention reduces oxidative stress-related inflammation and improves intestinal microbiota. Food Funct 2022; 13:6583-6595. [PMID: 35621018 DOI: 10.1039/d1fo03776e] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Inflammation and oxidative stress play key roles in the aging process, while red yeast rice (RYR), a traditional Chinese fermented food, has anti-oxidant and anti-inflammatory effects. To understand the anti-aging function of RYR in vivo, this study established a D-galactose-induced aging mouse model to verify the positive effects of RYR dietary intervention on aging and explore the related underlying mechanism. Eight weeks of RYR dietary intervention was shown to have a significant inhibitory effect on cognitive decline and hippocampal damage. The molecular mechanistic studies showed that the anti-aging effects of RYR were achieved by (i) improving the oxidative stress-related damage (increasing SOD, CAT, and GSH, and reducing MDA), (ii) regulating the NF-κB inflammation pathway induced by oxidative stress (decreasing the pro-inflammatory cytokines IL-6, TNF-α, IFN-γ, iNOs, and IL-1β, increasing the anti-inflammatory cytokine IL-10, and decreasing the expression of the NF-κB protein), (iii) slowing down apoptosis caused by oxidative stress (reducing the expression of P21 and P53), (iv) restoring the abundance of Lactobacillus, Lachnospiraceae and Rikenellaceae downregulated by D-galactose, and (v) reducing the abundance of Akkermansia and Helicobacter enriched by D-galactose. Mass spectrometry revealed orange pigments (rubropunctatin and monascorubrin) as the main antioxidant components in RYR, which might play key roles in aging inhibition. This study provides theoretical support for the wide application of orange pigments as an antioxidant dietary supplement.
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Affiliation(s)
- Yaping Huang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Ping Li
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Zhengang Li
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Dongdong Zhu
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Yufei Fan
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Xiaoyi Wang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Chumin Zhao
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Jingbo Jiao
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Xinjun Du
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.
| | - Shuo Wang
- State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China. .,Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, China
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21
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Su M, Zhao W, Xu S, Weng J. Resveratrol in Treating Diabetes and Its Cardiovascular Complications: A Review of Its Mechanisms of Action. Antioxidants (Basel) 2022; 11:antiox11061085. [PMID: 35739982 PMCID: PMC9219679 DOI: 10.3390/antiox11061085] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/21/2022] [Accepted: 05/27/2022] [Indexed: 02/01/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most prevalent chronic diseases worldwide. High morbidity and mortality caused by DM are closely linked to its complications in multiple organs/tissues, including cardiovascular complications, diabetic nephropathy, and diabetic neuropathy. Resveratrol is a plant-derived polyphenolic compound with pleiotropic protective effects, ranging from antioxidant and anti-inflammatory to hypoglycemic effects. Recent studies strongly suggest that the consumption of resveratrol offers protection against diabetes and its cardiovascular complications. The protective effects of resveratrol involve the regulation of multiple signaling pathways, including inhibition of oxidative stress and inflammation, enhancement of insulin sensitivity, induction of autophagy, regulation of lipid metabolism, promotion of GLUT4 expression, and translocation, and activation of SIRT1/AMPK signaling axis. The cardiovascular protective effects of resveratrol have been recently reviewed in the literature, but the role of resveratrol in preventing diabetes mellitus and its cardiovascular complications has not been systematically reviewed. Therefore, in this review, we summarize the pharmacological effects and mechanisms of action of resveratrol based on in vitro and in vivo studies, highlighting the therapeutic potential of resveratrol in the prevention and treatment of diabetes and its cardiovascular complications.
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22
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PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH). BIOLOGY 2022; 11:biology11050792. [PMID: 35625520 PMCID: PMC9138523 DOI: 10.3390/biology11050792] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 12/31/2022]
Abstract
Simple Summary In the context of liver disease, one of the more growing public health problems is the transition from simple steatosis to non-alcoholic steatohepatitis. Profound metabolic dysregulations linked to inflammation and hepatic injury are features of non-alcoholic steatohepatitis. Since the peroxisomal-proliferator-activated receptor alpha has long been considered one of the key transcriptional factors in hepatic metabolism, its role in the pathogenesis of non-alcoholic steatohepatitis is discussed in this review. Abstract The strong relationship between metabolic alterations and non-alcoholic steatohepatitis (NASH) suggests a pathogenic interplay. However, many aspects have not yet been fully clarified. Nowadays, NASH is becoming the main cause of liver-associated morbidity and mortality. Therefore, an effort to understand the mechanisms underlying the pathogenesis of NASH is critical. Among the nuclear receptor transcription factors, peroxisome-proliferator-activated receptor alpha (PPARα) is highly expressed in the liver, where it works as a pivotal transcriptional regulator of the intermediary metabolism. In this context, PPARα’s function in regulating the lipid metabolism is essential for proper liver functioning. Here, we review metabolic liver genes under the control of PPARα and discuss how this aspect can impact the inflammatory condition and pathogenesis of NASH.
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23
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Galli F, Bonomini M, Bartolini D, Zatini L, Reboldi G, Marcantonini G, Gentile G, Sirolli V, Di Pietro N. Vitamin E (Alpha-Tocopherol) Metabolism and Nutrition in Chronic Kidney Disease. Antioxidants (Basel) 2022; 11:989. [PMID: 35624853 PMCID: PMC9137556 DOI: 10.3390/antiox11050989] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/07/2022] [Accepted: 05/10/2022] [Indexed: 01/27/2023] Open
Abstract
Vitamin E (alpha-tocopherol) is an essential micronutrient and fat-soluble antioxidant with proposed role in protecting tissues from uncontrolled lipid peroxidation. This vitamin has also important protein function and gene modulation effects. The metabolism of vitamin E depends on hepatic binding proteins that selectively retain food alpha-tocopherol for incorporation into nascent VLDL and tissue distribution together with esterified cholesterol and triglycerides. Chronic kidney disease (CKD) is a condition of oxidative stress and increased lipid peroxidation, that are associated with alterations of alpha-tocopherol metabolism and function. Specific changes have been reported for the levels of its enzymatic metabolites, including both short-chain and long-chain metabolites, the latter being endowed with regulatory functions on enzymatic and gene expression processes important for the metabolism of lipids and xenobiotics detoxification, as well as for the control of immune and inflammatory processes. Vitamin E therapy has been investigated in CKD using both oral vitamin E protocols and vitamin E-coated hemodialyzers, showing promising results in the secondary prevention of cardiovascular disease, as well as of immune and hematological complications. These therapeutic approaches are reviewed in the present article, together with a narrative excursus on the main findings indicating CKD as a condition of relative deficiency and impaired metabolism of vitamin E.
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Affiliation(s)
- Francesco Galli
- Department of Pharmaceutical Science, University of Perugia, 06126 Perugia, Italy; (D.B.); (L.Z.); (G.M.)
| | - Mario Bonomini
- Department of Medicine and Aging, G. d’Annunzio University Chieti-Pescara, 66100 Chieti, Italy; (M.B.); (V.S.)
| | - Desirée Bartolini
- Department of Pharmaceutical Science, University of Perugia, 06126 Perugia, Italy; (D.B.); (L.Z.); (G.M.)
| | - Linda Zatini
- Department of Pharmaceutical Science, University of Perugia, 06126 Perugia, Italy; (D.B.); (L.Z.); (G.M.)
| | - Gianpaolo Reboldi
- Department of Medicine and Surgery, Centro di Ricerca Clinica e Traslazionale, CERICLET, University of Perugia, 06126 Perugia, Italy;
| | - Giada Marcantonini
- Department of Pharmaceutical Science, University of Perugia, 06126 Perugia, Italy; (D.B.); (L.Z.); (G.M.)
| | - Giorgio Gentile
- Royal Cornwall Hospitals, NHS Trust, Cornwall, Truro TR1 3LJ, UK;
- Department of Nephrology, University of Exeter Medical School, Exeter EX1 2HZ, UK
| | - Vittorio Sirolli
- Department of Medicine and Aging, G. d’Annunzio University Chieti-Pescara, 66100 Chieti, Italy; (M.B.); (V.S.)
| | - Natalia Di Pietro
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, G. d’Annunzio University Chieti-Pescara, 66100 Chieti, Italy;
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24
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Chatterton RT. Functions of dehydroepiandrosterone in relation to breast cancer. Steroids 2022; 179:108970. [PMID: 35122788 DOI: 10.1016/j.steroids.2022.108970] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/17/2022] [Accepted: 01/31/2022] [Indexed: 11/20/2022]
Abstract
Although DHEA sulfate (DS) is the most abundant steroid in the circulation, breast fluid contains an approximately 80-fold greater concentration than serum. Transport of DS into cells requires organic anion transporting polypeptides (OATPs), which are specific for cell type, cell location, and substrate, but may have a broader specificity for housekeeping functions. Specific classes, which may be modified by soluble factors including neutral steroids, have been identified in the breast. After transport, DS may be cleaved to DHEA by ubiquitous sulfatases, which may be modified by the cell milieu, or DHEA may enter by diffusion. Synthesis from cholesterol does not occur because CYP17B12 and cytochrome b5 are lacking in breast tissues. Case-control studies reveal a positive association of serum DS with risk of breast cancer. The association is even greater with DHEA, particularly in postmenopausal women with HR + invasive tumors. Metabolites of DHEA, androstenedione and testosterone, are associated with breast cancer but DHEA is likely to have an independent role as well. Mechanisms by which DHEA may promote breast cancer relate to its effect in increasing circulating IGF-I, by inhibiting the suppressive effect of glucocorticoids, and by promoting retention of pre-adipocytes with aromatase activity. In addition, DHEA may interact with the G-protein coupled receptor GPER for stimulation of miR-21 and subsequent activation of the MAPK pathway. DHEA also has antitumor properties that relate to stimulation of immunity, suppression of inflammation, and elevation of adipose tissue adiponectin synthesis. The net effect may depend on the which factors predominate.
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Affiliation(s)
- Robert T Chatterton
- Department of Obstetrics and Gynecology and the Robert H Lurie Comprehensive Cancer Center of Northwestern, Northwestern University Feinberg Medical School. Chicago, IL 60911, USA.
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25
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Amin SV, Khanna S, Parvar SP, Shaw LT, Dao D, Hariprasad SM, Skondra D. Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature. Exp Biol Med (Maywood) 2022; 247:317-329. [PMID: 35068220 PMCID: PMC8899338 DOI: 10.1177/15353702211069986] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin's potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin's role in management of posterior segment disorders. However, given metformin's proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.
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Affiliation(s)
- Shivam V Amin
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Saira Khanna
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Seyedeh P Parvar
- Islamic Azad University Tehran Faculty of Medicine, Tehran QCGM+X9, Tehran Province, Iran
| | - Lincoln T Shaw
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - David Dao
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Seenu M Hariprasad
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Dimitra Skondra
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
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26
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Weatherly LM, Shane HL, Lukomska E, Baur R, Anderson SE. Systemic toxicity induced by topical application of heptafluorobutyric acid (PFBA) in a murine model. Food Chem Toxicol 2021; 156:112528. [PMID: 34474067 DOI: 10.1016/j.fct.2021.112528] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/10/2021] [Accepted: 08/28/2021] [Indexed: 01/19/2023]
Abstract
Heptafluorobutyric acid (PFBA) is a synthetic chemical belonging to the per- and polyfluoroalkyl substances (PFAS) group that includes over 5000 chemicals incorporated into numerous products. PFBA is a short-chain PFAS (C4) labeled as a safer alternative to legacy PFAS which have been linked to numerous health effects. Despite the high potential for dermal exposure, occupationally and environmentally, dermal exposure studies are lacking. Using a murine model, this study analyzed serum chemistries, histology, immune phenotyping, and gene expression to evaluate the systemic toxicity of sub-chronic dermal PFBA 15-day (15% v/v or 375 mg/kg/dose) or 28-day (3.75-7.5% v/v or 93.8-187.5 mg/kg/dose) exposures. PFBA exposure produced significant increases in liver and kidney weights and altered serum chemistries (all exposure levels). Immune-cell phenotyping identified significant increases in draining lymph node B-cells (15%) and CD11b + cells (3.75-15%) and skin T-cells (3.75-15%) and neutrophils (7.5-15%). Histopathological and gene expression changes were observed in both the liver and skin after dermal PFBA exposure. The findings indicate PFBA induces liver toxicity and alterations of PPAR target genes, suggesting a role of a PPAR pathway. These results demonstrate that sustained dermal exposure to PFBA induces systemic effects and raise concerns of short-chain PFAS being promoted as safer alternatives.
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Affiliation(s)
- Lisa M Weatherly
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA.
| | - Hillary L Shane
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA
| | - Ewa Lukomska
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA
| | - Rachel Baur
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA
| | - Stacey E Anderson
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA
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27
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Noise-Induced Cochlear Damage Involves PPAR Down-Regulation through the Interplay between Oxidative Stress and Inflammation. Antioxidants (Basel) 2021; 10:antiox10081188. [PMID: 34439436 PMCID: PMC8388985 DOI: 10.3390/antiox10081188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
The cross-talk between oxidative stress and inflammation seems to play a key role in noise-induced hearing loss. Several studies have addressed the role of PPAR receptors in mediating antioxidant and anti-inflammatory effects and, although its protective activity has been demonstrated in several tissues, less is known about how PPARs could be involved in cochlear dysfunction induced by noise exposure. In this study, we used an in vivo model of noise-induced hearing loss to investigate how oxidative stress and inflammation participate in cochlear dysfunction through PPAR signaling pathways. Specifically, we found a progressive decrease in PPAR expression in the cochlea after acoustic trauma, paralleled by an increase in oxidative stress and inflammation. By comparing an antioxidant (Q-ter) and an anti-inflammatory (Anakinra) treatment, we demonstrated that oxidative stress is the primary element of damage in noise-induced cochlear injury and that increased inflammation can be considered a consequence of PPAR down-regulation induced by ROS production. Indeed, by decreasing oxidative stress, PPARs returned to control values, reactivating the negative control on inflammation in a feedback loop.
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28
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Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas. Cancers (Basel) 2021; 13:cancers13153716. [PMID: 34359615 PMCID: PMC8345059 DOI: 10.3390/cancers13153716] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/29/2021] [Accepted: 07/21/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Primary aldosteronism is a common form of endocrine hypertension often caused by a hyper-secreting tumor of the adrenal cortex called an aldosterone-producing adenoma. Metabolic reprogramming plays a role in tumor progression and influences the tumor immune microenvironment by limiting immune-cell infiltration and suppressing its anti-tumor function. We hypothesized that the development of aldosterone-producing adenomas involves metabolic adaptations of its component tumor cells and intrinsically influences tumor pathogenesis. Herein, we use state-of-the-art computational tools for the comprehensive analysis of array-based gene expression profiles to demonstrate metabolic reprogramming and remodeling of the immune microenvironment in aldosterone-producing adenomas compared with paired adjacent adrenal cortical tissue. Our findings suggest metabolic alterations may function in the pathogenesis of aldosterone-producing adenomas by conferring survival advantages to their component tumor cells. Abstract Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid β-oxidation regulated by PPARα, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45+ immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid β-oxidation and glycolysis. Increased lipid metabolism via PPARα may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties.
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29
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Jiang T, Li P, Zhao J, Dai L, Sun D, Liu M, An L, Jia L, Jing X, Wang H, Wu S, Wang Y, Cheng Z. Long-chain polyunsaturated fatty acids improve airway pathological features and gut microbial imbalances in BALB/c mice with ovalbumin-induced asthma. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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30
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Villavicencio-Tejo F, Flores-Bastías O, Marambio-Ruiz L, Pérez-Reytor D, Karahanian E. Fenofibrate (a PPAR-α Agonist) Administered During Ethanol Withdrawal Reverts Ethanol-Induced Astrogliosis and Restores the Levels of Glutamate Transporter in Ethanol-Administered Adolescent Rats. Front Pharmacol 2021; 12:653175. [PMID: 33959021 PMCID: PMC8093785 DOI: 10.3389/fphar.2021.653175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/31/2021] [Indexed: 01/11/2023] Open
Abstract
High-ethanol intake induces a neuroinflammatory response, which has been proposed as responsible for the maintenance of chronic ethanol consumption. Neuroinflammation decreases glutamate transporter (GLT-1) expression, increasing levels of glutamate that trigger dopamine release at the corticolimbic reward areas, driving long-term drinking behavior. The activation of peroxisome proliferator-activated receptor alpha (PPARα) by fibrates inhibits neuroinflammation, in models other than ethanol consumption. However, the effect of fibrates on ethanol-induced neuroinflammation has not yet been studied. We previously reported that the administration of fenofibrate to ethanol-drinking rats decreased ethanol consumption. Here, we studied whether fenofibrate effects are related to a decrease in ethanol-induced neuroinflammation and to the normalization of the levels of GLT-1. Rats were administered ethanol on alternate days for 4 weeks (2 g/kg/day). After ethanol withdrawal, fenofibrate was administered for 14 days (50 mg/kg/day) and the levels of glial fibrillary acidic protein (GFAP), phosphorylated NF-κB-inhibitory protein (pIκBα) and GLT-1, were quantified in the prefrontal cortex, hippocampus, and hypothalamus. Ethanol treatment increased the levels of GFAP in the hippocampus and hypothalamus, indicating a clear astrocytic activation. Similarly, ethanol increased the levels of pIκBα in the three areas. The administration of fenofibrate decreased the expression of GFAP and pIκBα in the three areas. These results indicate that fenofibrate reverts both astrogliosis and NF-κB activation. Finally, ethanol decreased GLT-1 expression in the prefrontal cortex and hippocampus. Fenofibrate normalized the levels of GLT-1 in both areas, suggesting that its effect in reducing ethanol consumption could be due to the normalization of glutamatergic tone.
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Affiliation(s)
| | - Osvaldo Flores-Bastías
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
| | - Lucas Marambio-Ruiz
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
| | - Diliana Pérez-Reytor
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
| | - Eduardo Karahanian
- Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile
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31
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Bouchab H, Ishaq A, El Kebbaj R, Nasser B, Saretzki G. Protective effect of argan oil on DNA damage in vivo and in vitro. Biomarkers 2021; 26:425-433. [PMID: 33843382 DOI: 10.1080/1354750x.2021.1905068] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: Iron-overload is a well-known cause for the development of chronic liver diseases and known to induce DNA damage.Material and methods: The protective effect of argan oil (AO) from the Argania spinosa fruit and olive oil (OO) (6% AO or OO for 28 days) was evaluated on a mouse model of iron overload (3.5mg Fe2+/liter) and in human fibroblasts where DNA damage was induced via culture under hyperoxia (40% oxygen).Results: Iron treatment induced DNA damage in liver tissue while both oils were able to decrease it. We confirmed this effect in vitro in MRC-5 fibroblasts under hyperoxia. A cell-free ABTS assay suggested that improvement of liver toxicity by both oils might depend on a high content in tocopherol, phytosterol and polyphenol compounds known for their antioxidant potential. The antioxidant effect of AO was confirmed in fibroblasts by reduced intracellular peroxide levels after hyperoxia. However, we could not find a significant decrease of genes encoding pro-inflammatory cytokines (TNFα, IL-6, IL-1β, COX-2) or senescence markers (p16 and p21) for the oils in mouse liver.Conclusion: We found a striking effect of AO by ameliorating DNA damage after iron overload in a mouse liver model and in human fibroblasts by hyperoxia adding compelling evidence to the protective mechanisms of AO and OO.
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Affiliation(s)
- Habiba Bouchab
- Laboratoire Biochimie, Neurosciences, Ressources naturelles et Environnement, Faculté des Sciences et Techniques, Hassan First University of Settat, Settat, Morocco.,Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Abbas Ishaq
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Riad El Kebbaj
- Laboratoire Biochimie, Neurosciences, Ressources naturelles et Environnement, Faculté des Sciences et Techniques, Hassan First University of Settat, Settat, Morocco.,Laboratory of Health Sciences and Technologies, Hassan First University of Settat, Higher Institute of Health Sciences, Settat, Morocco
| | - Boubker Nasser
- Laboratoire Biochimie, Neurosciences, Ressources naturelles et Environnement, Faculté des Sciences et Techniques, Hassan First University of Settat, Settat, Morocco
| | - Gabriele Saretzki
- Campus for Ageing and Vitality, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
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32
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Fang S, Livergood MC, Nakagawa P, Wu J, Sigmund CD. Role of the Peroxisome Proliferator Activated Receptors in Hypertension. Circ Res 2021; 128:1021-1039. [PMID: 33793338 DOI: 10.1161/circresaha.120.318062] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nuclear receptors represent a large family of ligand-activated transcription factors which sense the physiological environment and make long-term adaptations by mediating changes in gene expression. In this review, we will first discuss the fundamental mechanisms by which nuclear receptors mediate their transcriptional responses. We will focus on the PPAR (peroxisome proliferator-activated receptor) family of adopted orphan receptors paying special attention to PPARγ, the isoform with the most compelling evidence as an important regulator of arterial blood pressure. We will review genetic data showing that rare mutations in PPARγ cause severe hypertension and clinical trial data which show that PPARγ activators have beneficial effects on blood pressure. We will detail the tissue- and cell-specific molecular mechanisms by which PPARs in the brain, kidney, vasculature, and immune system modulate blood pressure and related phenotypes, such as endothelial function. Finally, we will discuss the role of placental PPARs in preeclampsia, a life threatening form of hypertension during pregnancy. We will close with a viewpoint on future research directions and implications for developing novel therapies.
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Affiliation(s)
- Shi Fang
- Department of Physiology, Cardiovascular Center (S.F., P.N., J.W., C.D.S.), Medical College of Wisconsin, Milwaukee.,Department of Neuroscience and Pharmacology, University of Iowa (S.F.)
| | - M Christine Livergood
- Department of Obstetrics and Gynecology (M.C.L.), Medical College of Wisconsin, Milwaukee
| | - Pablo Nakagawa
- Department of Physiology, Cardiovascular Center (S.F., P.N., J.W., C.D.S.), Medical College of Wisconsin, Milwaukee
| | - Jing Wu
- Department of Physiology, Cardiovascular Center (S.F., P.N., J.W., C.D.S.), Medical College of Wisconsin, Milwaukee
| | - Curt D Sigmund
- Department of Physiology, Cardiovascular Center (S.F., P.N., J.W., C.D.S.), Medical College of Wisconsin, Milwaukee
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33
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Lipocalin 2 serum levels correlate with age and bone turnover biomarkers in healthy subjects but not in postmenopausal osteoporotic women. Bone Rep 2021; 14:101059. [PMID: 34026950 PMCID: PMC8121999 DOI: 10.1016/j.bonr.2021.101059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 03/16/2021] [Accepted: 03/24/2021] [Indexed: 12/25/2022] Open
Abstract
Purpose Lipocalin 2 (LCN2) is an adipokine involved in many physiological functions, including bone metabolism. We previously demonstrated its implication in mouse models of mechanical unloading-induced osteoporosis and in a cohort of bed rest volunteers. We therefore aimed at studying its involvement in postmenopausal osteoporosis. Methods We measured serum LCN2 and correlated its levels to Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1), Tartrate Resistant Acid Phosphatase 5B (TRAcP5B), sclerostin, urinary N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX), parathyroid hormone and vitamin K by ELISA performed in a cohort of younger (50–65 years) and older (66–90 years) osteoporotic women in comparison to healthy subjects. A cohort of male healthy and osteoarthritic patients was also included. Sobel mediation analysis was used to test indirect associations among age, LCN2 and DKK1 or NTX. Results LCN2 levels were unchanged in osteoporotic and in osteoarthritis patients when compared to healthy subjects and did not correlate with BMD. However, serum LCN2 correlated with age in healthy women (R = 0.44; P = 0.003) and men (R = 0.5; P = 0.001) and serum concentrations of DKK1 (R = 0.47; P = 0.003) and urinary NTX (R = 0.34; P = 0.04). Sobel mediation analysis showed that LCN2 mediates an indirect relationship between age and DKK1 (P = 0.02), but not with NTX, in healthy subjects. Conclusions Taken together, the results suggest a hitherto unknown association between LCN2, DKK1 and age in healthy individuals, but not in postmenopausal osteoporotic women.
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Key Words
- BALP, bone-specific alkaline phosphatase
- BMD, bone mineral density
- BMI, body mass index
- CTX, C-terminal telopeptide of type I collagen
- DKK1
- DKK1, Dickkopf WNT Signaling Pathway Inhibitor 1
- IL, interleukin
- LCN2, lipocalin 2
- Lipocalin-2
- NGAL
- NTX, N-terminal telopeptide of type I collagen
- NfκB, nuclear factor kappa-B
- Osteoarthritis
- Osteoporosis
- PTH, parathyroid hormone
- RANKL, receptor activator of nuclear factor kappa-B
- TNF, tumor necrosis factor
- TRAcP5B, tartrate-resistant acid phosphatase 5B
- Wnt
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Darwesh AM, Bassiouni W, Sosnowski DK, Seubert JM. Can N-3 polyunsaturated fatty acids be considered a potential adjuvant therapy for COVID-19-associated cardiovascular complications? Pharmacol Ther 2021; 219:107703. [PMID: 33031856 PMCID: PMC7534795 DOI: 10.1016/j.pharmthera.2020.107703] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has currently led to a global pandemic with millions of confirmed and increasing cases around the world. The novel SARS-CoV-2 not only affects the lungs causing severe acute respiratory dysfunction but also leads to significant dysfunction in multiple organs and physiological systems including the cardiovascular system. A plethora of studies have shown the viral infection triggers an exaggerated immune response, hypercoagulation and oxidative stress, which contribute significantly to poor cardiovascular outcomes observed in COVID-19 patients. To date, there are no approved vaccines or therapies for COVID-19. Accordingly, cardiovascular protective and supportive therapies are urgent and necessary to the overall prognosis of COVID-19 patients. Accumulating literature has demonstrated the beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFA) toward the cardiovascular system, which include ameliorating uncontrolled inflammatory reactions, reduced oxidative stress and mitigating coagulopathy. Moreover, it has been demonstrated the n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors to a group of potent bioactive lipid mediators, generated endogenously, which mediate many of the beneficial effects attributed to their parent compounds. Considering the favorable safety profile for n-3 PUFAs and their metabolites, it is reasonable to consider n-3 PUFAs as potential adjuvant therapies for the clinical management of COVID-19 patients. In this article, we provide an overview of the pathogenesis of cardiovascular complications secondary to COVID-19 and focus on the mechanisms that may contribute to the likely benefits of n-3 PUFAs and their metabolites.
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Affiliation(s)
- Ahmed M Darwesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Wesam Bassiouni
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Deanna K Sosnowski
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - John M Seubert
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
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Schillemans T, Shi L, Donat-Vargas C, Hanhineva K, Tornevi A, Johansson I, Koponen J, Kiviranta H, Rolandsson O, Bergdahl IA, Landberg R, Åkesson A, Brunius C. Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes - A nested case-control study. ENVIRONMENT INTERNATIONAL 2021; 146:106180. [PMID: 33113464 DOI: 10.1016/j.envint.2020.106180] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/30/2020] [Accepted: 10/01/2020] [Indexed: 06/11/2023]
Abstract
Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations. We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Västerbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D. PFAS levels correlated with 171 metabolite features (0.16 ≤ |r| ≤ 0.37, false discovery rate (FDR) adjusted p < 0.05). Out of these, 35 associated with T2D (p < 0.05), with 7 remaining after multiple testing adjustment (FDR < 0.05). PCA of the 35 PFAS- and T2D-related metabolite features revealed two patterns, dominated by glycerophospholipids and diacylglycerols, with opposite T2D associations. The glycerophospholipids correlated positively with PFAS and associated inversely with risk for T2D (Odds Ratio (OR) per 1 standard deviation (1-SD) increase in metabolite PCA pattern score = 0.2; 95% Confidence Interval (CI) = 0.1-0.4). The diacylglycerols also correlated positively with PFAS, but they associated with increased risk for T2D (OR per 1-SD = 1.9; 95% CI = 1.3-2.7). These results suggest that PFAS associate with two groups of lipid species with opposite relations to T2D risk.
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Affiliation(s)
- Tessa Schillemans
- Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Lin Shi
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; School of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, China
| | - Carolina Donat-Vargas
- Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, CEI UAM+CSIC, Madrid, Spain
| | - Kati Hanhineva
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Biochemistry, University of Turku, Turku, Finland
| | - Andreas Tornevi
- Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden
| | | | - Jani Koponen
- Department for Health Security, Environmental Health Unit, Finnish Institute for Health and Welfare, Kuopio, Finland
| | - Hannu Kiviranta
- Department for Health Security, Environmental Health Unit, Finnish Institute for Health and Welfare, Kuopio, Finland
| | - Olov Rolandsson
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
| | - Ingvar A Bergdahl
- Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden
| | - Rikard Landberg
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden
| | - Agneta Åkesson
- Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Carl Brunius
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
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Peroxisome proliferator-activated receptors in the pathogenesis and therapies of liver fibrosis. Pharmacol Ther 2020; 222:107791. [PMID: 33321113 DOI: 10.1016/j.pharmthera.2020.107791] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a dynamic wound-healing process associated with the deposition of extracellular matrix produced by myofibroblasts. HSCs activation, inflammation, oxidative stress, steatosis and aging play critical roles in the progression of liver fibrosis, which is correlated with the regulation of the peroxisome proliferator-activated receptor (PPAR) pathway. As nuclear receptors, PPARs reduce inflammatory response, regulate lipid metabolism, and inhibit fibrogenesis in the liver associated with aging. Thus, PPAR ligands have been investigated as possible therapeutic agents. Mounting evidence indicated that some PPAR agonists could reverse steatohepatitis and liver fibrosis. Consequently, targeting PPARs might be a promising and novel therapeutic option against liver fibrosis. This review summarizes recent studies on the role of PPARs on the pathogenesis and treatment of liver fibrosis.
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Meng T, Qin W, Liu B. SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication. Front Endocrinol (Lausanne) 2020; 11:568861. [PMID: 33304318 PMCID: PMC7701141 DOI: 10.3389/fendo.2020.568861] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/21/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetic mellitus (DM) is a significant public health concern worldwide with an increased incidence of morbidity and mortality, which is particularly due to the diabetic vascular complications. Several pivotal underlying mechanisms are associated with vascular complications, including hyperglycemia, mitochondrial dysfunction, inflammation, and most importantly, oxidative stress. Oxidative stress triggers defective angiogenesis, activates pro-inflammatory pathways and causes long-lasting epigenetic changes to facilitate the development of vascular complications. Therefore, therapeutic interventions targeting oxidative stress are promising to manage diabetic vascular complications. Sirtuin1 (SIRT1), a class III histone deacetylase belonging to the sirtuin family, plays critical roles in regulating metabolism and ageing-related pathological conditions, such as vascular diseases. Growing evidence has indicated that SIRT1 acts as a sensing regulator in response to oxidative stress and attenuates vascular dysfunction via cooperating with adenosine-monophosphate-activated protein kinase (AMPK) to activate antioxidant signals through various downstream effectors, including peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α), forkhead transcription factors (FOXOs), and peroxisome proliferative-activated receptor α (PPARα). In addition, SIRT1 interacts with hydrogen sulfide (H2S), regulates NADPH oxidase, endothelial NO synthase, and mechanistic target of rapamycin (mTOR) to suppress oxidative stress. Furthermore, mRNA expression of sirt1 is affected by microRNAs in DM. In the current review, we summarize recent advances illustrating the importance of SIRT1 in antagonizing oxidative stress. We also discuss whether modulation of SIRT1 can serve as a therapeutic strategy to treat diabetic vascular complications.
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Affiliation(s)
- Teng Meng
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shenzhen University, Shenzhen, China
| | - Weifeng Qin
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
| | - Baohua Liu
- Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
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Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm. Nutrients 2020; 12:nu12113476. [PMID: 33198317 PMCID: PMC7696073 DOI: 10.3390/nu12113476] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
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Wang Y, Cui X, Lin Q, Cai J, Tang L, Liang Y. Active Peptide KF-8 from Rice Bran Attenuates Oxidative Stress in a Mouse Model of Aging Induced by d-Galactose. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:12271-12283. [PMID: 32942847 DOI: 10.1021/acs.jafc.0c04358] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
This study investigated the effects of a physiologically active peptide derived from rice bran (KF-8) on oxidative stress in d-galactose (d-gal)-induced aging mice and the underlying molecular mechanisms. The aging model was developed by subcutaneously injecting Institute of Cancer Research mice with 250 mg/kg d-gal daily for 12 weeks and simultaneously treating them with 30 mg/kg KF-8. The relative expression levels of Nrf2 and NF-κB in the liver were determined by the western blot. The regulation of Nrf2 and NF-κBp65 by KF-8 was further validated in NIH/3T3 cells. Compared with the control mice, the aging mice had significantly decreased body weights as well as superoxide dismutase and GSH-Px levels (p < 0.05); however, they had increased serum reactive oxygen species and malondialdehyde and 8-hydroxydeoxyguanosine levels accompanied by aortic and brain injuries. They also had elevated RAGE, TLR4, IκB, Bax, and caspase-8 expressions and NF-κB/p65 phosphorylation but reduced BcL-2 expression in the liver. Moreover, in vitro experiments demonstrated that the pretreatment of H2O2-treated NIH/3T3 cells with KF-8 significantly mitigated the NF-κB signaling and attenuated the Nrf2 nuclear transport (both p < 0.05). In conclusion, KF-8 treatment inhibited aging-induced oxidative stress-related organ injury in mice by attenuating NF-κB/p38 signaling and preserving Nrf2 activity.
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Affiliation(s)
- Yuqian Wang
- Molecular Nutrition Branch, National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Xiaoji Cui
- Molecular Nutrition Branch, National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Qinlu Lin
- Molecular Nutrition Branch, National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Jie Cai
- Molecular Nutrition Branch, National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Liuhuan Tang
- Molecular Nutrition Branch, National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
| | - Ying Liang
- Molecular Nutrition Branch, National Engineering Laboratory for Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China
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Xu L, Brown EE, Santiago CP, Keuthan CJ, Lobanova E, Ash JD. Retinal homeostasis and metformin-induced protection are not affected by retina-specific Pparδ knockout. Redox Biol 2020; 37:101700. [PMID: 32863184 PMCID: PMC7767733 DOI: 10.1016/j.redox.2020.101700] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/08/2020] [Accepted: 08/19/2020] [Indexed: 11/25/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of three nuclear hormone receptors (PPARα, PPARδ, and PPARγ) that are known to regulate expression of lipid metabolism and oxidative stress genes. Given their role in reducing oxidative stress in a variety of tissues, these genes are likely important for retinal homeostasis. This hypothesis has been further supported by recent studies suggesting that PPAR-activating drugs are protective against retinal degenerations. The objective of the present study was to determine the role of PPARδ in the neuroretina. RNA-seq data show that Pparα and Pparδ are both expressed in the retina, but that Pparδ is expressed at 4-fold higher levels. Single-cell RNAseq data show that Pparδ is broadly expressed in all retinal cell types. To determine the importance of Pparδ to the retina, we generated retina-specific Pparδ knockout mice. We found that deletion of Pparδ had a minimal effect on retinal function or morphology out to 12 months of age and did not increase retinal sensitivity to oxidative stress induced by exposure to bright light. While data show that PPARδ levels were increased by the drug metformin, PPARδ was not necessary for metformin-induced protection from light damage. These data suggest that Pparδ either has a redundant function with Pparα or is not essential for normal neuroretina function or resistance to oxidative stress.
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Affiliation(s)
- Lei Xu
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Emily E Brown
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Clayton P Santiago
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Casey J Keuthan
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Ekaterina Lobanova
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA; Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, 32610, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA
| | - John D Ash
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL, USA.
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Xu Y, Li X, Han Y, Wang Z, Han C, Ruan N, Li J, Yu X, Xia Q, Wu G. A New Prognostic Risk Model Based on PPAR Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma. PPAR Res 2020; 2020:6937475. [PMID: 33029112 PMCID: PMC7527891 DOI: 10.1155/2020/6937475] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVE This study is aimed at using genes related to the peroxisome proliferator-activated receptor (PPAR) pathway to establish a prognostic risk model in kidney renal clear cell carcinoma (KIRC). METHODS For this study, we first found the PPAR pathway-related genes on the gene set enrichment analysis (GSEA) website and found the KIRC mRNA expression data and clinical data through TCGA database. Subsequently, we used R language and multiple R language expansion packages to analyze the expression, hazard ratio analysis, and coexpression analysis of PPAR pathway-related genes in KIRC. Afterward, using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website, we established the protein-protein interaction (PPI) network of genes related to the PPAR pathway. After that, we used LASSO regression curve analysis to establish a prognostic survival model in KIRC. Finally, based on the model, we conducted correlation analysis of the clinicopathological characteristics, univariate analysis, and multivariate analysis. RESULTS We found that most of the genes related to the PPAR pathway had different degrees of expression differences in KIRC. Among them, the high expression of 27 genes is related to low survival rate of KIRC patients, and the high expression of 13 other genes is related to their high survival rate. Most importantly, we used 13 of these genes successfully to establish a risk model that could accurately predict patients' prognosis. There is a clear correlation between this model and metastasis, tumor, stage, grade, and fustat. CONCLUSIONS To the best of our knowledge, this is the first study to analyze the entire PPAR pathway in KIRC in detail and successfully establish a risk model for patient prognosis. We believe that our research can provide valuable data for future researchers and clinicians.
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Affiliation(s)
- Yingkun Xu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Xiunan Li
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Yuqing Han
- Department of Radiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Zilong Wang
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Chenglin Han
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Ningke Ruan
- The Nursing College of Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jianyi Li
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Xiao Yu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Qinghua Xia
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
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Xu Y, Li X, Han Y, Wang Z, Han C, Ruan N, Li J, Yu X, Xia Q, Wu G. A New Prognostic Risk Model Based on PPAR Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma. PPAR Res 2020; 2020:6937475. [PMID: 33029112 PMCID: PMC7527891 DOI: 10.1155/2020/6937475;] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 10/11/2024] Open
Abstract
Objective This study is aimed at using genes related to the peroxisome proliferator-activated receptor (PPAR) pathway to establish a prognostic risk model in kidney renal clear cell carcinoma (KIRC). Methods For this study, we first found the PPAR pathway-related genes on the gene set enrichment analysis (GSEA) website and found the KIRC mRNA expression data and clinical data through TCGA database. Subsequently, we used R language and multiple R language expansion packages to analyze the expression, hazard ratio analysis, and coexpression analysis of PPAR pathway-related genes in KIRC. Afterward, using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website, we established the protein-protein interaction (PPI) network of genes related to the PPAR pathway. After that, we used LASSO regression curve analysis to establish a prognostic survival model in KIRC. Finally, based on the model, we conducted correlation analysis of the clinicopathological characteristics, univariate analysis, and multivariate analysis. Results We found that most of the genes related to the PPAR pathway had different degrees of expression differences in KIRC. Among them, the high expression of 27 genes is related to low survival rate of KIRC patients, and the high expression of 13 other genes is related to their high survival rate. Most importantly, we used 13 of these genes successfully to establish a risk model that could accurately predict patients' prognosis. There is a clear correlation between this model and metastasis, tumor, stage, grade, and fustat. Conclusions To the best of our knowledge, this is the first study to analyze the entire PPAR pathway in KIRC in detail and successfully establish a risk model for patient prognosis. We believe that our research can provide valuable data for future researchers and clinicians.
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Affiliation(s)
- Yingkun Xu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Xiunan Li
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Yuqing Han
- Department of Radiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Zilong Wang
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Chenglin Han
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Ningke Ruan
- The Nursing College of Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jianyi Li
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Xiao Yu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Qinghua Xia
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
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Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity. Cells 2020; 9:cells9071708. [PMID: 32708786 PMCID: PMC7407644 DOI: 10.3390/cells9071708] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
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Zhang M, Sunaba T, Sun Y, Shibata T, Sasaki K, Isoda H, Kigoshi H, Kita M. Acyl-CoA dehydrogenase long chain (ACADL) is a target protein of stylissatin A, an anti-inflammatory cyclic heptapeptide. J Antibiot (Tokyo) 2020; 73:589-592. [PMID: 32439989 DOI: 10.1038/s41429-020-0322-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/27/2020] [Accepted: 05/01/2020] [Indexed: 01/10/2023]
Abstract
Stylissatin A (SA) is a cyclic heptapeptide isolated from the marine sponge Stylissa massa. SA shows anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cells, but the detailed mechanism of action remains unclear. Here we report that D-Tyr1-tBuSA, a more potent SA derivative, inhibited production of the proinflammatory cytokines Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in LPS-stimulated RAW264.7 cells (EC50 = 1.4 and 5.9 μM, respectively). This compound also inhibited the LPS-stimulated expression of inducible nitric oxide synthase (iNOS) at 20 μM. Using a biotin derivative of SA, acyl-CoA dehydrogenase long chain (ACADL) was identified as a target protein of SA and its derivatives. It is proposed that SA and its derivatives might suppress the β-oxidation of fatty acids by ACADL, and the accumulation of fatty acids on macrophages would inhibit the nuclear factor-kappa B (NF-κB) signaling pathway and iNOS expression to show anti-inflammatory activity. Our research might provide a new mechanism of inflammation in macrophages, and contribute to the development of treatments for inflammatory diseases.
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Affiliation(s)
- Menghua Zhang
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8571, Japan.,PhD Program in Human Biology, School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba, 305-8577, Japan
| | - Taiki Sunaba
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8571, Japan
| | - Yiting Sun
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan
| | - Takahiro Shibata
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan
| | - Kazunori Sasaki
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8571, Japan.,Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology, Tsukuba, 305-8565, Japan
| | - Hiroko Isoda
- Graduate School of Life and Environmental Sciences, and Alliance for Research on North Africa (ARENA), University of Tsukuba, Tsukuba, 305-8577, Japan
| | - Hideo Kigoshi
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, 305-8571, Japan.
| | - Masaki Kita
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
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Neurovascular protection by peroxisome proliferator-activated receptor α in ischemic stroke. Exp Neurol 2020; 331:113323. [PMID: 32320699 DOI: 10.1016/j.expneurol.2020.113323] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/14/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. Currently, the only pharmacological therapy for ischemic stroke is thrombolysis with tissue plasminogen activator that has a narrow therapeutic window and increases the risk of intracerebral hemorrhage. New pharmacological treatments for ischemic stroke are desperately needed, but no neuroprotective drugs have successfully made it through clinical trials. Beneficial effects of peroxisome proliferator-activated receptor alpha (PPARα) activation on vascular integrity and function have been reported, and PPARα agonists have clinically been used for many years to manage cardiovascular disease. Thus, PPARα has gained interest in recent years as a target for neurovascular disease such as ischemic stroke. Accumulating preclinical evidence suggests that PPARα activation modulates several pathophysiological hallmarks of stroke such as oxidative stress, blood-brain barrier (BBB) dysfunction, and neuroinflammation to improve functional recovery. Therefore, this review summarizes the various actions PPARα exerts in neurovascular health and disease and the potential of employing exogenous PPARα agonists for future pharmacological treatment of ischemic stroke.
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Bahrami A, Bo S, Jamialahmadi T, Sahebkar A. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ageing: Molecular mechanisms. Ageing Res Rev 2020; 58:101024. [PMID: 32006687 DOI: 10.1016/j.arr.2020.101024] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 12/11/2019] [Accepted: 01/27/2020] [Indexed: 12/15/2022]
Abstract
Human ageing is determined by degenerative alterations and processes with different manifestations such as gradual organ dysfunction, tissue function loss, increased population of aged (senescent) cells, incapability of maintaining homeostasis and reduced repair capacity, which collectively lead to an increased risk of diseases and death. The inhibitors of HMG-CoA reductase (statins) are the most widely used lipid-lowering agents, which can reduce cardiovascular morbidity and mortality. Accumulating evidence has documented several pleiotropic effects of statins in addition to their lipid-lowering properties. Recently, several studies have highlighted that statins may have the potential to delay the ageing process and inhibit the onset of senescence. In this review, we focused on the anti-ageing mechanisms of statin drugs and their effects on cardiovascular and non-cardiovascular diseases.
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Impact of Donor Human Milk in the Preterm Very Low Birth Weight Gut Transcriptome Profile by Use of Exfoliated Intestinal Cells. Nutrients 2019; 11:nu11112677. [PMID: 31694290 PMCID: PMC6893464 DOI: 10.3390/nu11112677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open
Abstract
Background: Own mother’s milk (OMM) is the optimal nutrition for preterm infants. However, pasteurized donor human milk (DHM) is a valid alternative. We explored the differences of the transcriptome in exfoliated epithelial intestinal cells (EEIC) of preterm infants receiving full feed with OMM or DHM. Methods: The prospective observational study included preterm infants ≤ 32 weeks’ gestation and/or ≤1500 g birthweight. Total RNA from EEIC were processed for genome-wide expression analysis. Results: Principal component analysis and unsupervised hierarchical clustering analysis revealed two clustered groups corresponding to the OMM and DHM groups that showed differences in the gene expression profile in 1629 transcripts. The OMM group overexpressed lactalbumin alpha gene (LALBA), Cytochrome C oxidase subunit I gene (COX1) and caseins kappa gene (CSN3), beta gene (CSN2) and alpha gene (CSN1S1) and underexpressed Neutrophil Cytosolic Factor 1 gene (NCF1) compared to the DHM group. Conclusions: The transcriptomic analysis of EEIC showed that OMM induced a differential expression of specific genes that may contribute to a more efficient response to a pro-oxidant challenge early in the postnatal period when preterm infants are at a higher risk of oxidative stress. The use of OMM should be strongly promoted in preterm infants.
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Pan CH, Chen CJ, Shih CM, Wang MF, Wang JY, Wu CH. Oxidative stress-induced cellular senescence desensitizes cell growth and migration of vascular smooth muscle cells through down-regulation of platelet-derived growth factor receptor-beta. Aging (Albany NY) 2019; 11:8085-8102. [PMID: 31584878 PMCID: PMC6814625 DOI: 10.18632/aging.102270] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 09/05/2019] [Indexed: 01/08/2023]
Abstract
The relationship between aging and restenosis are unclear. The purposes of this study were to investigate the possible pathological role and mechanism of aging on formation of restenosis. Our data indicated that cell proliferation and migration of the oxidative stress-induced senescent vascular smooth muscle cells were obviously desensitized to stimulation by platelet-derived growth factor (PDGF)-BB, which may have been caused by suppression of promoter activity, transcription, translation, and activation levels of PDGF receptor (PDGFR)-β. The analyzed data obtained from the binding array of transcription factors (TFs) showed that binding levels of eighteen TFs on the PDGFR-β promoter region (-523 to -1) were significantly lower in senescent cells compared to those of non-senescent cells. Among these TFs, the bioinformatics prediction suggested that the putative binding sites of ten TFs were found in this promoter region. Of these, transcriptional levels of seven TFs were markedly reduced in senescent cells. The clinical data showed that the proportion of restenosis was relatively lower in the older group than that in the younger group. Our study results suggested that a PDGFR-β-mediated pathway was suppressed in aging cells, and our clinical data showed that age and the vascular status were slightly negatively correlated in overall participants.
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Affiliation(s)
- Chun-Hsu Pan
- School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
| | - Chang-Jui Chen
- Department of Pharmacy, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Chun-Ming Shih
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Ming-Fu Wang
- Department of Food and Nutrition, Providence University, Taichung 433, Taiwan
| | - Jie-Yu Wang
- School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
| | - Chieh-Hsi Wu
- School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
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Darwesh AM, Sosnowski DK, Lee TYT, Keshavarz-Bahaghighat H, Seubert JM. Insights into the cardioprotective properties of n-3 PUFAs against ischemic heart disease via modulation of the innate immune system. Chem Biol Interact 2019; 308:20-44. [DOI: 10.1016/j.cbi.2019.04.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/17/2019] [Accepted: 04/30/2019] [Indexed: 12/19/2022]
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50
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Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism. Molecules 2019; 24:molecules24142545. [PMID: 31336903 PMCID: PMC6680900 DOI: 10.3390/molecules24142545] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/08/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.
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Affiliation(s)
- Fan Hong
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Shijia Pan
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yuan Guo
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Yonggong Zhai
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
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