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Pan D, Sun Y, Zhang J, Zeng J, Yu S, Zhao D, Dong Z, Liu M, Liu S, Wang W, Wang S. An active protein from Dendrobium officinale residue: Protects the gastric mucosa and stabilized in the gastrointestinal tract. Int J Biol Macromol 2025; 294:139387. [PMID: 39753178 DOI: 10.1016/j.ijbiomac.2024.139387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/17/2024] [Accepted: 12/29/2024] [Indexed: 01/11/2025]
Abstract
A large number of by-products generated in the food industry is discarded as waste, especially the residue left after extracting plant resources, which is typically repurposed as fertilizer. In this study, we extracted and purified a new protein, DOP1, from the residue of Dendrobium officinale Kimura & Migo (D. officinale), and explored the protective effect of DOP1 on alcohol-induced gastric mucosal injury. Its amino acid composition and the stability of secondary structure were measured by amino acid analysis and various spectroscopic methods. The microscopic morphology of DOP1 was observed by electron microscopy and its particle distribution was determined to be in the range of 3.7-5.5 nm. In addition, DOP1 was found to exhibit excellent protective activity against alcohol-induced gastric mucosal injury, as well as anti-inflammatory and antioxidant activities by in vitro and in vivo activity assays, which may be related to the upregulation of TFF2 through the activation of PPARγ. Intriguingly, DOP1 does not degrade and remains active after being digested by the gastrointestinal tract. From an economic and sustainable perspective, the discovery of DOP1 will provide new opportunities for the enhanced utilization and sustainable development of D. officinale resources.
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Affiliation(s)
- Daian Pan
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China; Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun 130021, China
| | - Yanling Sun
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Jiayi Zhang
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Jing Zeng
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Shiting Yu
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Daqing Zhao
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Zhengqi Dong
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Medicinal Plant Development, Beijing 100193, China
| | - Meichen Liu
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Shichao Liu
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Weinan Wang
- Guangdong Provincial Key Laboratory of Natural Drugs Research and Development, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan 523808, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China.
| | - Siming Wang
- Changchun University of Chinese Medicine, Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China.
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Ortona S, Barisione C, Ferrari PF, Palombo D, Pratesi G. PCSK9 and Other Metabolic Targets to Counteract Ischemia/Reperfusion Injury in Acute Myocardial Infarction and Visceral Vascular Surgery. J Clin Med 2022; 11:jcm11133638. [PMID: 35806921 PMCID: PMC9267902 DOI: 10.3390/jcm11133638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 12/13/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury complicates both unpredictable events (myocardial infarction and stroke) as well as surgically-induced ones when transient clampage of major vessels is needed. Although the main cause of damage is attributed to mitochondrial dysfunction and oxidative stress, the use of antioxidant compounds for protection gave poor results when challenged in clinics. More recently, there is an assumption that, in humans, profound metabolic changes may prevail in driving I/R injury. In the present work, we narrowed the field of search to I/R injury in the heart/brain/kidney axis in acute myocardial infarction, major vascular surgery, and to the current practice of protection in both settings; then, to help the definition of novel strategies to be translated clinically, the most promising metabolic targets with their modulatory compounds—when available—and new preclinical strategies against I/R injury are described. The consideration arisen from the broad range of studies we have reviewed will help to define novel therapeutic approaches to ensure mitochondrial protection, when I/R events are predictable, and to cope with I/R injury, when it occurs unexpectedly.
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Affiliation(s)
- Silvia Ortona
- Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; (S.O.); (D.P.); (G.P.)
| | - Chiara Barisione
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
- Correspondence: ; Tel.: +39-010-555-7881
| | - Pier Francesco Ferrari
- Department of Civil, Chemical and Environmental Engineering, University of Genoa, Via Opera Pia, 15, 16145 Genoa, Italy;
| | - Domenico Palombo
- Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; (S.O.); (D.P.); (G.P.)
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
- Research Center for Biologically Inspired Engineering in Vascular Medicine and Longevity, University of Genoa, Via Montallegro, 1, 16145 Genoa, Italy
| | - Giovanni Pratesi
- Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; (S.O.); (D.P.); (G.P.)
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy
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Zou G, Zhou Z, Xi X, Huang R, Hu H. Pioglitazone Ameliorates Renal Ischemia-Reperfusion Injury via Inhibition of NF-κB Activation and Inflammation in Rats. Front Physiol 2021; 12:707344. [PMID: 34349671 PMCID: PMC8326914 DOI: 10.3389/fphys.2021.707344] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 06/25/2021] [Indexed: 11/15/2022] Open
Abstract
Renal ischemia-reperfusion injury (IRI) is considered as a major cause of acute kidney injury. In this study, we investigated the role of the NF-κB signaling pathway and inflammation in the amelioration of renal IRI using pioglitazone. Sprague–Dawley (SD) rats were subjected to bilateral renal artery clamping for 45 min followed by perfusion restoration for establishing a simulated renal IRI model. At 24 h post-operatively, we assessed the serum levels of creatinine and urea nitrogen, expression levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) and NF-κB-related (p-IKK-β and IκB-α) proteins, and mRNA expression levels of the inflammatory cytokines, including TNF-α and MCP-1, in the renal tissue of various study groups. The histopathological evaluation of renal tissue was also conducted. In rat renal tissue, pioglitazone treatment decreased the serum levels of post-renal IRI creatinine and urea nitrogen, as well as necrosis. Furthermore, it elevated the expression of PPAR-γ protein and decreased the expression of NF-κB-related proteins. Pioglitazone also decreased the mRNA expression of TNF-α and MCP-1 in the renal tissue. Thus, pioglitazone ameliorates renal IRI by inhibiting the NF-κB signaling pathway and inflammatory response in rats.
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Affiliation(s)
- Gaode Zou
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhiyu Zhou
- Department of Pathology, College of Basic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Xiaoqing Xi
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ruizhen Huang
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Honglin Hu
- Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Keshavarzi Z, Mohebbati R, Mohammadzadeh N, Alikhani V. THE PROTECTIVE ROLE OF ESTRADIOL & PROGESTERONE IN MALE RATS, FOLLOWING GASTRIC ISCHEMIA-REPERFUSION. ACTA ENDOCRINOLOGICA-BUCHAREST 2018; 14:30-35. [PMID: 31149233 DOI: 10.4183/aeb.2018.30] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background and Aim Ischemia-reperfusion (I/R) injury frequently occurs in different situations. Female sex hormones have a protective function. The purpose of this study was to determine the function of female sexual hormones on the gastric damage induced by I/R in male rats. Methods Forty (40) Wistar rats were randomized into five groups: intact, ischemia- reperfusion (IR), IR + estradiol (1mg/kg), IR + progesterone (16 mg / kg) and IR + combination of estradiol (1mg / kg) and progesterone (16 mg/ kg). Before the onset of ischemia and before reperfusion all treatments were done by intraperitoneal (IP) injection. After animal anesthesia and laparotomy, celiac artery was occluded for 30 minutes and then circulation was established for 24 hours. Results expressed as mean ± SEM and P <0.05 were considered statistically significant. Results The Glutathione (GSH) concentration significantly decreased after induction of gastric IR (P<0.001). Estradiol (P<0.001) and combined estradiol and progesterone (P<0.001) significantly increased GSH levels. The myeloperoxidase (MPO) concentration significantly increased after induction of gastric IR (P<0.001). Different treatments significantly reduced MPO levels (P<0.001). The gastric acid concentration significantly increased after induction of gastric IR (P<0.001). Treatment with estradiol, progesterone (P<0.05) and combined estradiol and progesterone (P<0.01) significantly reduced gastric acid levels. Superoxide dismutase (SOD) concentration decreased after induction of gastric IR. The SOD levels were not significant. Conclusion These data suggested that female sexual steroids have a therapeutic effect on gastrointestinal ischemic disorders by reduction of MPO and gastric acid, and increasing gastric GSH & SOD levels following gastric IR.
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Affiliation(s)
- Z Keshavarzi
- North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - R Mohebbati
- Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - V Alikhani
- Mashhad University of Medical Sciences, Mashhad, Iran
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El-Sayyad SM, Soubh AA, Awad AS, El-Abhar HS. Mangiferin protects against intestinal ischemia/reperfusion-induced liver injury: Involvement of PPAR-γ, GSK-3β and Wnt/β-catenin pathway. Eur J Pharmacol 2017; 809:80-86. [PMID: 28506911 DOI: 10.1016/j.ejphar.2017.05.021] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 05/05/2017] [Accepted: 05/10/2017] [Indexed: 12/13/2022]
Abstract
AIM Mangiferin (MF), a xanthonoid from Mangifera indica, possesses anti-inflammatory, immunomodulatory, and potent antioxidant effects; however, its protective effect against mesenteric ischemia/reperfusion (I/R)-induced liver injury has not been fully clarified. The study was designed to assess the possible mechanism of action of MF against mesenteric I/R model. MAIN METHODS Male Wister rats were treated with MF (20mg/kg, i.p) or the vehicle for 3 days before I/R, which was induced by clamping the superior mesenteric artery for 30min followed by declamping for 60min. KEY FINDINGS The mechanistic studies revealed that MF protected the 2 organs studied, viz., liver and intestine partly via increasing the content of β-catenin and PPAR-γ along with decreasing that of GSK-3β and the phosphorylated NF-қB-p65. MF antioxidant effect was evidenced by increasing contents of total antioxidant capacity and GST, besides normalizing that of MDA. Regarding the anti-inflammatory effect, MF reduced IL-1β and IL-6, effects that were mirrored on the tissue content of MPO. Moreover, MF possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of caspase-3. In the serum, intestinal I/R increased the activity of ALT, AST, and creatine kinase. SIGNIFICANCE The intimated protective mechanisms of MF against mesenteric I/R are mediated, partially, by modulation of oxidative stress, inflammation, and apoptosis possibly via the involvement of Wnt/β-catenin/NF-қβ/ PPAR-γ signaling pathways.
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Affiliation(s)
- Shorouk M El-Sayyad
- Department of Pharmacology & Toxicology, October 6 University,12585 Giza, Egypt
| | - Ayman A Soubh
- Department of Pharmacology & Toxicology, Ahram Canadian University, 12566 Giza, Egypt.
| | - Azza S Awad
- Department of Pharmacology & Toxicology, Ahram Canadian University, 12566 Giza, Egypt
| | - Hanan S El-Abhar
- Department of Pharmacology & Toxicology, Cairo University, 11562 Cairo, Egypt
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Abstract
Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.
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Affiliation(s)
- Eitaro Aihara
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Kristen A Engevik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Marshall H Montrose
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
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Saha L. Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences. World J Gastrointest Pharmacol Ther 2015; 6:120-126. [PMID: 26558146 PMCID: PMC4635152 DOI: 10.4292/wjgpt.v6.i4.120] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 07/11/2015] [Accepted: 10/12/2015] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identified so far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs (e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system (e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy. Finally, more studies are also needed to confirm the involvement of PPARs α and γ in gastric ulcer.
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Mahmoud-Awny M, Attia AS, Abd-Ellah MF, El-Abhar HS. Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways. PLoS One 2015. [PMID: 26196679 PMCID: PMC4509761 DOI: 10.1371/journal.pone.0132497] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mangiferin (MF), a xanthonoid from Mangifera indica, has been proved to have antisecretory and antioxidant gastroprotective effects against different gastric ulcer models; however, its molecular mechanism has not been previously elucidated. Therefore, the aim of this study was to test its modulatory effect on several signaling pathways using the ischemia/reperfusion model for the first time. Animals were treated with MF, omeprazole (OMP), and the vehicle. The mechanistic studies revealed that MF mediated its gastroprotective effect partly via inducing the expression of Nrf2, HO-1 and PPAR-γ along with downregulating that of NF-κB. Surprisingly, the effect of MF, especially the high dose, exceeded that mediated by OMP except for Nrf2. The molecular results were reflected on the biomarkers measured, where the antioxidant effect of MF was manifested by increasing total antioxidant capacity and glutathione, besides normalizing malondialdehyde level. Additionally, MF decreased the I/R-induced nitric oxide elevation, an effect that was better than that of OMP. In the serum, MF, dose dependently, enhanced endothelial nitric oxide synthase, while reduced the inducible isoform. Regarding the anti-inflammatory effect of MF, it reduced serum level of IL-1β and sE-selectin, effects that were mirrored on the tissue level of myeloperoxidase, the neutrophil infiltration marker. In addition, MF possessed an antiapoptotic character evidenced by elevating Bcl-2 level and reducing that of caspase-3 in a dose related order. As a conclusion, the intimated gastroprotective mechanisms of MF are mediated, partially, by modulation of oxidative stress, inflammation and apoptosis possibly via the Nrf2/HO-1, PPAR-γ/NF-κB signaling pathways.
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Affiliation(s)
- Magdy Mahmoud-Awny
- Department of Pharmacology & Toxicology, October University, Cairo, Egypt
| | - Ahmed S. Attia
- Department of Microbiology & Immunologyology, Cairo University, Cairo, Egypt
| | | | - Hanan Salah El-Abhar
- Department of Pharmacology & Toxicology, Cairo University, Cairo, Egypt
- * E-mail:
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Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol 2014; 34:82-100. [PMID: 25340307 DOI: 10.3109/08830185.2014.969421] [Citation(s) in RCA: 302] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Macrophages are a functionally heterogeneous cell population that is mainly shaped by a variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce a classical activation of macrophages (M1), whereas IL-4 and IL-13 induce an alternative activation program in macrophages (M2). Reprogramming of intracellular metabolisms is required for the proper polarization and functions of activated macrophages. Similar to the Warburg effect observed in tumor cells, M1 macrophages increase glucose consumption and lactate release and decreased oxygen consumption rate. In comparison, M2 macrophages mainly employ oxidative glucose metabolism pathways. In addition, fatty acids, vitamins, and iron metabolisms are also related to macrophage polarization. However, detailed metabolic pathways involved in macrophages have remained elusive. Understanding the bidirectional interactions between cellular metabolism and macrophage functions in physiological and pathological situations and the regulatory pathways involved may offer novel therapies for macrophage-associated diseases.
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Affiliation(s)
- Linnan Zhu
- 1Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Wang Y, Chen H, Li H, Zhang J, Gao Y. Effect of angiopoietin-like protein 4 on rat pulmonary microvascular endothelial cells exposed to LPS. Int J Mol Med 2013; 32:568-76. [PMID: 23783408 PMCID: PMC3782553 DOI: 10.3892/ijmm.2013.1420] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 06/13/2013] [Indexed: 11/06/2022] Open
Abstract
Pulmonary microvascular endothelial cells (PMVECs) possess highly proliferative and angiogenic capacities and are localized at the critical interface between the blood and microvessel wall; they are the primary targets of inflammatory cytokines during lung inflammation. Angiopoietin-like protein 4 (Angptl4) is a circulating protein that has recently been im-plicated in the regulation of angiogenesis and metastasis. This study aimed to investigate the effect of Angptl4 on rat PMVECs (RPMVECs) exposed to lipopolysaccharide (LPS). The cell culture was stimulated with LPS. Total Angptl4 cDNA was obtained from Source BioScience. The PCR product was cloned into the pcDNA3.1-eGFP or the pcDNA3.1‑eGFP‑Angptl4 vector, which were then transfected into the RPMVECs using SuperFect transfection reagent. The Angptl4 mRNA levels, protein levels and cell morphology of the RPMVECs in the experimental groups were detected using real time-PCR, western blot analysis, MTT assay, ELISA and confocal microscopy methods, respective-ly. The Angptl4 expression vector, pcDNA3.1‑eGFP-Angptl4, was successfully constructed. The Angptl4 mRNA level in the LPS-pcDNA3.1-eGFP-transfected group (blank control) was slightly increased and was significantly higher in the experimental group compared with the empty vector and blank control group with significant differences. Pro-apoptotic caspase-8, -9 and Bax protein were inhibited, while p-AKT/AKT and p-Mek1/2 protein expression was also decreased. The rosiglitazone group had significantly decreased levels of the inflammatory cytokine, tumor necrosis factor (TNF)-α (P<0.01). The overexpression of Angptl4 inhibited the LPS-induced increase in the permeability of the RPMVECs, which was associated with the depolymerization of central F-actin in the RPMVECs. In conclusion, our study demonstrates that the overexpression of Angptl4 exerts protective, anti-inflammatory and anti-angiogenic effects. It re-presents a novel therapeutic target gene for the treatment of acute lung injury induced by LPS.
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Affiliation(s)
- Yuxi Wang
- Dalian Medical University, Dalian, Liaoning, P.R. China
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Mitochondrial dependent apoptosis: ameliorative effect of flunarizine on ischemia-reperfusion of celiac artery-induced gastric lesions in the rat. Dig Dis Sci 2011; 56:2244-51. [PMID: 21327706 DOI: 10.1007/s10620-011-1607-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Accepted: 01/29/2011] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Ischemia-reperfusion is a major event for induction of cellular apoptosis. Apoptosis is due to the activation of death receptor and/or mitochondrial pathways. Mitochondrial permeability transition pore opening is the cause of apoptosis. In our present study, we tried to evaluate the role of flunarizine in ischemia and reperfusion of celiac artery-induced gastric lesion in the rat. METHODS The therapeutic potential of flunarizine was assessed by measuring the changes in gastric lesion index, biomarker (i.e., thiobarbituric acid reactive substance, reduced glutathione, superoxide dismutase, myeloperoxidase, and total calcium and protein content), and mitochondrial damage (i.e., adenosine triphosphate and deoxyribonucleic acid fragmentation content) in ischemia and reperfusion-induced gastric lesion model. RESULTS Medium and higher doses of flunarizine produced a significant (P<0.05) ameliorative effect which was observed from the assessment of all the above-mentioned parameters (i.e., increase in reduced glutathione, superoxide dismutase and decrease in thiobarbituric acid reactive substance, myeloperoxidase, and total calcium content). Similar results were also obtained from omeprazole and cyclosporine. In the pre-treated group, deoxyribonucleic acid fragmentation pattern has also indicated that a mitochondria-associated anti-apoptotic effect of flunarizine was responsible to prevent the ischemia and reperfusion of celiac artery-induced gastric lesion. CONCLUSION The gastroprotective effect of flunarizine may be produced due to its inactivation potential of mitochondrial permeability transition pore opening associated with anti-oxidative, calcium regulation along with its anti-apoptotic effect.
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RAR/RXR and PPAR/RXR Signaling in Spinal Cord Injury. PPAR Res 2011; 2007:29275. [PMID: 18060014 PMCID: PMC1950239 DOI: 10.1155/2007/29275] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2006] [Accepted: 02/28/2007] [Indexed: 12/24/2022] Open
Abstract
The retinoid
acid receptors (RAR) and peroxisome proliferator-activated receptors (PPAR)
have been implicated in the regulation of inflammatory reactions. Both receptor families contain ligand-activated transcription factors which form heterodimers with retinoid X receptors (RXR). We review data that imply RAR/RXR and PPAR/RXR pathways in physiological reactions after spinal cord injury. Experiments show how RAR signaling may improve axonal regeneration and modulate reactions of glia cells. While anti-inflammatory properties of PPAR are well documented in the periphery, their possible roles in the central nervous system have only recently become evident. Due to its anti-inflammatory function this transcription factor family promises to be a useful target after spinal cord or brain lesions.
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Qiao WL, Wang GM, Shi Y, Wu JX, Qi YJ, Zhang JF, Sun H, Yan CD. Differential expression of Bcl-2 and Bax during gastric ischemia-reperfusion of rats. World J Gastroenterol 2011; 17:1718-24. [PMID: 21483632 PMCID: PMC3072636 DOI: 10.3748/wjg.v17.i13.1718] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Revised: 12/21/2010] [Accepted: 12/28/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate expression of Bcl-2 and Bax in gastric ischemia-reperfusion (GI-R) and involvement of extracellular signal-regulated kinase (ERK) 1/2 activation.
METHODS: The GI-R model was established by ligature of the celiac artery for 30 min and reperfusion in Sprague-Dawley rats. Rats were assigned to groups in accordance with their evaluation period: control, 0, 0.5, 1, 3, 6, 24, 48, and 72 h. Expression and distribution of Bcl-2 and Bax proteins were analyzed by immunohistochemistry and western blotting in gastric tissue samples after sacrifice.
RESULTS: Compared with controls, the percentage of positive cells and protein levels of Bcl-2 decreased in the early phases of reperfusion, reached its minimum at 1 h (P < 0.05); it then increased, reaching its peak at 24 h of reperfusion (P < 0.05). The pattern of Bax expression was opposite to that of Bcl-2. Bax expression increased after reperfusion, with its peak at 1 h of reperfusion (P < 0.05), and then it decreased gradually to a minimum at 24 h after reperfusion (P < 0.05). On the other hand, inhibition of activation of ERK1/2 induced by PD98059, a specific upstream MEK inhibitor, had significant effects on Bcl-2 and Bax in GI-R. Compared with GI-R treatment only at 3 h of reperfusion, PD98059 reduced the number of Bcl-2 positive cells (0.58% of R3h group, P < 0.05) and Bcl-2 protein level (74% of R3h group, P < 0.05) but increased the number of Bax-positive cells (1.33-fold vs R3h group, P < 0.05) and Bax protein level (1.35-fold of R3h group, P < 0.05).
CONCLUSION: These results indicated that the Bcl-2 and Bax played a pivotal role in the gastric mucosal I-R injury and repair by activation of ERK1/2.
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Naito Y, Takagi T, Katada K, Tomatsuri N, Mizushima K, Handa O, Kokura S, Yagi N, Ichikawa H, Yoshikawa T. Gastric peroxisome proliferator activator receptor-γ expression and cytoprotective actions of its ligands against ischemia-reperfusion injury in rats. J Clin Biochem Nutr 2011; 48:170-7. [PMID: 21373272 PMCID: PMC3045692 DOI: 10.3164/jcbn.10-81] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 07/13/2010] [Indexed: 12/05/2022] Open
Abstract
The beneficial effects by peroxisome proliferator-activated receptor-γ (PPAR-γ) on gastric injury induced by ischemia-reperfusion have been confirmed, however, the precise mechanism of its cytoprotection is not elucidated thoroughly. The aim of the present study was to determine the gastric localization of PPAR-γ expression in the rat gastric mucosa, and to clarify the mechanism of its cytoprotective properties. The gastric expression of PPAR-γ was confirmed by RT-PCR and western blot, and localized on gastric epithelial cells. The protective effect of PPAR-γ ligands, pioglitazone or 15-deoxy-Δ12,14-prostaglandin J2, on gastric ischemia-reperfusion injury was reversed by the co-administration with PPAR-γ antagonist. The gastric expression of tumor necrosis factor-α and cytokine-induced neutrophil chemoattractant-1 increased significantly in rats treated ischemia-reperfusion, and these increases were significantly inhibited by treatment with pioglitazone. Among the 1,032 probes, 18 probes were up-regulated at least 1.5-fold, 17 were down-regulated at least 1.5-fold by pioglitazone. The network including calnexin, endoplasmic reticulum stress protein, heat shock proteins, and proteasome genes was induced by pioglitazone treatment. In conclusion, activation of gastric epithelial PPAR-γ receptor by its ligands may represent a novel therapeutic approach for gastric inflammation via up-regulation of heat shock proteins and endoplasmic reticulum-related proteins.
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Affiliation(s)
- Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
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15
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Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is known to play a central role in lipid metabolism and insulin sensitivity as well as inflammation and cell proliferation. According to the results obtained from studies on several animal models of gastrointestinal inflammation, PPARγ has been implicated in the regulation of the immune response, particularly inflammation control, and has gained importance as a potential therapeutic target in the management of gastrointestinal inflammation. In the present paper, we present the current knowledge on the role of PPARγ ligands in the gastrointestinal tract.
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Takaoka K, Sekiguchi F, Shigi H, Maeda Y, Nishikawa H, Kawabata A. Opposite effects of two thiazolidinediones, ciglitazone and troglitazone, on proteinase-activated receptor-1-triggered prostaglandin E(2) release. Toxicology 2009; 268:40-5. [PMID: 19954759 DOI: 10.1016/j.tox.2009.11.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2009] [Revised: 11/21/2009] [Accepted: 11/23/2009] [Indexed: 11/27/2022]
Abstract
Thiazolidinediones, known as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, may modify prostaglandin formation and exert gastroprotective effects. Since activation of proteinase-activated receptor-1 (PAR1) reveals endogenous prostanoid-dependent gastroprotection, we investigated if two thiazolidinediones, ciglitazone and troglitazone, modulate the prostaglandin E(2) (PGE(2)) release caused by activation of PAR1 in normal rat gastric mucosal epithelial RGM1 cells. Ciglitazone dramatically facilitated the PAR1-triggered PGE(2) production and cyclooxygenase-2 (COX-2) upregulation, although it had no effect by itself. In contrast, troglitazone suppressed the PAR1-triggered PGE(2) production and COX-2 upregulation. Either effect of ciglitazone and troglitazone was resistant to GW9662, a PPARgamma antagonist. The facilitation of the PGE(2) release by ciglitazone was blocked by inhibitors of MEK, p38 MAP kinase (p38MAPK) and PI3-kinase (PI3K), but not JNK. Nonetheless, ciglitazone failed to enhance the PAR1-triggered phosphorylation of ERK and p38MAPK. In conclusion, ciglitazone and troglitazone, exert opposite effects on the PAR1-triggered PGE(2) production and COX-2 upregulation by targeting molecules other than PPARgamma.
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Affiliation(s)
- Kaori Takaoka
- Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
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17
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Yanes LL, Sartori-Valinotti JC, Iliescu R, Romero DG, Racusen LC, Zhang H, Reckelhoff JF. Testosterone-dependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats. Am J Physiol Renal Physiol 2009; 296:F771-9. [PMID: 19211690 DOI: 10.1152/ajprenal.90389.2008] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system.
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Affiliation(s)
- Licy L Yanes
- Univ. of Mississippi Medical Center, Dept. of Physiology and Biophysics, 2500 N. State St., Jackson, MS 39216-4505, USA.
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18
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Michalik L, Wahli W. PPARs Mediate Lipid Signaling in Inflammation and Cancer. PPAR Res 2008; 2008:134059. [PMID: 19125181 PMCID: PMC2606065 DOI: 10.1155/2008/134059] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2008] [Accepted: 09/17/2008] [Indexed: 02/06/2023] Open
Abstract
Lipid mediators can trigger physiological responses by activating nuclear hormone receptors, such as the peroxisome proliferator-activated receptors (PPARs). PPARs, in turn, control the expression of networks of genes encoding proteins involved in all aspects of lipid metabolism. In addition, PPARs are tumor growth modifiers, via the regulation of cancer cell apoptosis, proliferation, and differentiation, and through their action on the tumor cell environment, namely, angiogenesis, inflammation, and immune cell functions. Epidemiological studies have established that tumor progression may be exacerbated by chronic inflammation. Here, we describe the production of the lipids that act as activators of PPARs, and we review the roles of these receptors in inflammation and cancer. Finally, we consider emerging strategies for therapeutic intervention.
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Affiliation(s)
- Liliane Michalik
- Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, 1015 Lausanne, Switzerland
| | - Walter Wahli
- Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, 1015 Lausanne, Switzerland
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19
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Significance of rosiglitazone inhibiting TLR4 expression in partial hepatic ischemia/reperfusion of mice. ACTA ACUST UNITED AC 2008; 28:564-7. [DOI: 10.1007/s11596-008-0516-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2008] [Indexed: 10/19/2022]
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20
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Zhang YM, Wei EQ, Li L, Qiao WL, Wang L, Zhang JF. Extracellular signal-regulated kinase pathways may mediate the protective effect of electrical stimulation of the paraventricular nucleus against ischaemia-reperfusion injury of the gastric mucosa. Clin Exp Pharmacol Physiol 2007; 34:742-52. [PMID: 17600551 DOI: 10.1111/j.1440-1681.2007.04652.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
1. The aim of the present study was to elucidate the role of the extracellular signal-regulated kinase (ERK) pathway in mediating the effects of electrical stimulation of the paraventricular nucleus (PVN) on apoptosis and proliferation induced by gastric ischaemia-reperfusion injury (GI/RI). 2. To investigate the effects of electrical stimulation of the hypothalamic PVN on gastric mucosal apoptosis and proliferation in response to ischaemia-reperfusion (I/R), we used a GI/RI model by clamping the coeliac artery for 30 min and then reperfusing the artery for 30 min or 1, 3 or 6 h. We used immunohistochemistry and western blotting to investigate the expression, activation and distribution of ERKs and the dynamic changes in their downstream cellular factors Bcl-2 and Bax at different times subsequent to electrical stimulation of the PVN in the I/R-injured gastric mucosa. 3. Electrical stimulation of the PVN markedly attenuated GI/RI at 30 min and 1 and 3 h after reperfusion. Electrical stimulation decreased gastric mucosal apoptosis, increased gastric mucosal proliferation and promoted the expression and activation of phosphorylated (p)-ERK1/2 30 min after reperfusion. Electrical stimulation increased the expression of Bcl-2 and decreased the expression of Bax at 30 min and 1 and 3 h after reperfusion. In contrast, inhibition of ERK1/2 activity by the specific upstream mitogen-activated protein kinase kinase inhibitor PD98059 produced similar effects at 1 h after reperfusion in rats subjected to I/R with or without electrical stimulation of the PVN. Administration of PD98059 aggravated gastric mucosal injury, increased apoptosis, decreased proliferation in gastric mucosal cells, decreased the expression and activity of p-ERK1/2 and Bcl-2 expression and increased Bax expression. 4. These results indicate that the PVN protects against GI/RI and that this protection is associated with the inhibition of cellular apoptosis and the promotion of proliferation in the gastric mucosa, probably by activating the ERK pathway.
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Affiliation(s)
- Yong-Mei Zhang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China
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21
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Role of mitogen-activated protein kinases in the regulation of paraventricular nucleus to gastric ischemia-reperfusion injuries. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200706020-00010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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22
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Di Paola R, Cuzzocrea S. Peroxisome proliferator-activated receptors ligands and ischemia-reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:157-75. [PMID: 17394034 DOI: 10.1007/s00210-007-0141-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2006] [Accepted: 01/28/2007] [Indexed: 12/19/2022]
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: alpha, beta/delta and gamma, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes like regulation of glucose and lipid redistribution. They also have anti-atherogenic, anti-inflammatory as well as antihypertensive functions. There is good evidence that ligands of PPARs reduce tissue injury associated with ischemia and reperfusion. The potential utility of PPAR ligands in ischemia and reperfusion will be discussed in this review.
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Affiliation(s)
- Rosanna Di Paola
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi, 98100 Messina, Italy
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23
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Sun J, Devish K, Langer WJ, Carmines PK, Lane PH. Testosterone treatment promotes tubular damage in experimental diabetes in prepubertal rats. Am J Physiol Renal Physiol 2007; 292:F1681-90. [PMID: 17311907 DOI: 10.1152/ajprenal.00482.2006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Puberty unmasks or accelerates progressive kidney diseases, including diabetes mellitus (DM), perhaps through effects of sex steroids. To test the hypothesis that rising androgen levels at puberty permit diabetic kidney damage, we studied four groups of male rats with and without streptozocin-induced DM: adult onset (A), adult onset after castration (AC), juvenile onset (J), and juvenile onset with testosterone treatment (JT). Profibrotic markers were measured after 6 wk with blood glucose levels 300-450 mg/dl. JT permitted increased expression of mRNA for two isoforms of transforming growth factor-beta and connective tissue growth factor compared with J animals with DM; prior castration did not provide protection in adult-onset DM. JT also permitted greater tubular staining for alpha-smooth muscle actin and fibroblast-specific protein, two markers of cell damage and potential epithelial mesenchymal transition. Once again, castration was not protective for these effects of DM in the AC group. These data indicate that puberty permits detrimental effects in the tubulointerstitium in the diabetic kidney, an effect mimicked by testosterone treatment of juvenile animals and partially blunted by castration of adults, but damage does not correlate with testosterone levels, suggesting a less direct mechanism.
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Affiliation(s)
- Jianhong Sun
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198-2169, USA
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24
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Li L, Zhang YM, Qiao WL, Wang L, Zhang JF. Effects of hypothalamic paraventricular nuclei on apoptosis and proliferation of gastric mucosal cells induced by ischemia/reperfusion in rats. World J Gastroenterol 2007; 13:874-81. [PMID: 17352016 PMCID: PMC4065922 DOI: 10.3748/wjg.v13.i6.874] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei (PVN) on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion (I/R) injury.
METHODS: For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals’ GI/R injury model was established by clamping the celiac artery for 30 min and allowing reperfusing the artery for 30 min, 1 h, 3 h or 6 h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times.
RESULTS: The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, 1 h and 3 h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation.
CONCLUSION: Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.
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Affiliation(s)
- Li Li
- Department of Pathophysiology, Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China
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25
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Qiao WL, Wang L, Zhang YM, Zhang JF, Wang GM. Extracellular signal-regulated kinase 1- and 2-mediated gastric mucosal injury and repair in gastric ischemia-reperfusion of rats. J Gastroenterol 2006; 41:1158-68. [PMID: 17287895 DOI: 10.1007/s00535-006-1902-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2006] [Accepted: 08/27/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND The current study was undertaken to investigate the time course of gastric ischemia-reperfusion (GI-R)-induced gastric mucosal injury and repair and whether extracellular signal-regulated kinase 1/2 (ERK1/2) were involved in GI-R-induced gastric mucosal injury and repair. METHODS Immunohistochemistry and Western blot analyses were used. RESULTS Gastric mucosal injury induced by ischemia alone was mild. However, the injury worsened after reperfusion, reaching a maximum at 1 h, and was accompanied by increased apoptotic cells and decreased proliferative cells. Then, the gastric mucosal cells began to repair the injury by enhanced proliferation, which peaked at 24 h after reperfusion, and by 72 h the damaged gastric mucosa was mostly repaired. The ERK1/2 (nonactivated ERK1/2) protein expression level and distribution profile showed no significant changes during the entire reperfusion phase, but the p-ERK1/2 (activated ERK1/2) level changed dramatically. The p-ERK1/2 protein level was decreased at 0.5 h after reperfusion began, and then gradually increased, peaking after 3 h of reperfusion; these changes in p-ERK1/2 occurred simultaneously in the cytoplasm and nucleus. On the other hand, inhibition of the activation of ERK1/2, induced by PD98059, a specific ERK1/2 upstream inhibitor, aggravated the gastric mucosal injury, and apoptosis was increased and proliferation was reduced in the gastric mucosal cells after the same duration of reperfusion. CONCLUSIONS Serious gastric mucosal damage involving apoptotic cells occurred rapidly at an early stage of reperfusion and was closely related to the suppression of ERK1/2 activation. The activated ERK1/2 signaling transduction pathway played an important role. Activated ERK1/2 participated in the regulation of gastric mucosal injury and repair induced by GI-R, and might be mediated by the inhibition of apoptosis and the promotion of proliferation in gastric mucosal cells.
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Affiliation(s)
- Wei-Li Qiao
- Department of Physiology and Neurobiology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, Jiangsu, China
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26
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Shimada T, Fujii Y, Koike T, Tabei K, Namatame T, Yamagata M, Tajima A, Yoneda M, Terano A, Hiraishi H. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates trefoil factor family 2 (TFF2) expression in gastric epithelial cells. Int J Biochem Cell Biol 2006; 39:626-37. [PMID: 17118693 DOI: 10.1016/j.biocel.2006.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2006] [Revised: 10/17/2006] [Accepted: 10/19/2006] [Indexed: 12/28/2022]
Abstract
Although trefoil factor family 2 (TFF2) plays a critical role in the defense and repair of gastric mucosa, the regulatory mechanism of TFF2 expression is not fully understood. In this study, we investigated the regulation of TFF2 expression by peroxisome proliferator-activated receptor gamma (PPARgamma) in gastric epithelial cells. MKN45 gastric cells were used. TFF2 mRNA expression was analyzed by real-time quantitative RT-PCR. The promoter sequence of the human TFF2 gene was cloned into pGL3-basic vector for reporter gene assays. Ciglitazone was mainly used as a specific PPARgamma ligand. MKN45 cells expressed functional PPARgamma proteins. Endogenous TFF2 mRNA expression and TFF2 reporter gene transcription was significantly up-regulated by ciglitazone in a dose-dependent manner. Reporter gene assays showed that two distinct cis-elements are involved in the response to PAPRgamma activation. Within one of these element (nucleotides -558 to -507), we identified a functional peroxisome proliferator responsive element (PPRE) at -522 (5'-GGGACAAAGGGCA-3'). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay confirmed the binding of PPARgamma to this sequence. Another element (nucleotides -407 to -358) appeared to be a composite enhancer element indirectly regulated by PPARgamma and a combination of these two cis-elements was required for the full response of the human TFF2 gene expression to PPARgamma. These data demonstrate that human TFF2 gene is a direct target of PPARgamma in gastric epithelial cells. Since TFF2 is a critical gastroprotective agent, PPARgamma may be involved in the gastric mucosal defense through regulating TFF2 expression in humans.
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Affiliation(s)
- Tadahito Shimada
- Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan.
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27
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Ojeda NB, Grigore D, Yanes LL, Iliescu R, Robertson EB, Zhang H, Alexander BT. Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring. Am J Physiol Regul Integr Comp Physiol 2006; 292:R758-63. [PMID: 16917022 DOI: 10.1152/ajpregu.00311.2006] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to examine the developmental origins of adult disease. In this model only male IUGR offspring remain hypertensive in adulthood, revealing sex-specific differences. The purpose of this study was to determine whether testosterone with participation of the renin-angiotensin system (RAS) contributes to hypertension in adult male IUGR offspring. At 16 wk of age a significant increase in testosterone (346 +/- 34 vs. 189 +/- 12 ng/dl, P < 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 +/- 1 vs. 125 +/- 1 mmHg, P < 0.05, IUGR vs. control, respectively). Gonadectomy (CTX) at 10 wk of age significantly reduced MAP by 16 wk of age in IUGR offspring (124 +/- 2 mmHg, P < 0.05 vs. intact IUGR) but had no effect in control (125 +/- 2 mmHg). A significant decrease in MAP in intact IUGR (111 +/- 3 mmHg, P < 0.05 vs. untreated intact IUGR) and castrated IUGR (110 +/- 4 mmHg, P < 0.05 vs. untreated CTX IUGR) after treatment with enalapril for 2 wk suggests a role for RAS involvement. However, the decrease in blood pressure in response to enalapril was greater in intact IUGR (Delta36 +/- 1 mmHg, P < 0.05) compared with CTX IUGR (Delta15 +/- 2 mmHg), indicating an enhanced response to RAS blockade in the presence of testosterone. Thus these results suggest that testosterone plays a role in modulating hypertension in adult male IUGR offspring with participation of the RAS.
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Affiliation(s)
- Norma B Ojeda
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA
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28
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Iliescu R, Cucchiarelli VE, Yanes LL, Iles JW, Reckelhoff JF. Impact of androgen-induced oxidative stress on hypertension in male SHR. Am J Physiol Regul Integr Comp Physiol 2006; 292:R731-5. [PMID: 16971373 DOI: 10.1152/ajpregu.00353.2006] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Men have higher blood pressure than women, and androgens and oxidative stress have been implicated as playing roles in this sexual dimorphism. The spontaneously hypertensive rat (SHR) is an animal model of both androgen- and oxidative stress-mediated hypertension. Therefore, the present studies were performed to test the hypothesis that androgens cause hypertension in SHR in part by stimulating superoxide production via NADPH oxidase. Castration of male SHR reduced blood pressure by 15% and attenuated both basal and NADPH-stimulated superoxide production in kidney cortical homogenates. Expression of p47(phox) and gp91(phox) but not p22(phox) subunits of NADPH oxidase were significantly lower in kidney cortex from castrated males compared with intact males. Moreover, inhibition of NADPH oxidase with apocynin caused approximately 15 mmHg reduction in blood pressure and reduced basal and NADPH-stimulated superoxide production in intact male SHR, but had no effect on blood pressure or superoxide production in castrated males. These data support the hypothesis that androgens cause oxidative stress and thereby increase blood pressure in male SHR via an NADPH oxidase-dependent mechanism.
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Affiliation(s)
- Radu Iliescu
- Department of Physiology and Biophysics, The Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216-4505, USA
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Vasudevan H, Nagareddy PR, McNeill JH. Gonadectomy prevents endothelial dysfunction in fructose-fed male rats, a factor contributing to the development of hypertension. Am J Physiol Heart Circ Physiol 2006; 291:H3058-64. [PMID: 16815981 DOI: 10.1152/ajpheart.00598.2005] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Insulin resistance has been shown to be associated with increased blood pressure (BP). The sex hormones estrogen and testosterone have opposing effects in the development of increased BP. Since testosterone has been implicated in increased BP following insulin resistance, we have tried to dissect out the effects of insulin resistance on endothelium-dependent vasorelaxation in the presence and absence of testosterone. Both gonadectomized and sham-operated male Wistar rats fed with a high-fructose diet developed insulin resistance, but BP increased only in the sham-operated rats. Reintroduction of testosterone in vivo restored the increase in BP, thereby abolishing the protective effects of gonadectomy. Fructose feeding did not affect plasma testosterone levels. Insulin resistance induced endothelial dysfunction in the mesenteric arteries of sham-operated rats, which was prevented by gonadectomy, thus suggesting a key role for testosterone in the pathogenesis of secondary vascular complications. Subsequent to blocking the actions of endothelium-dependent hyperpolarizing factor (EDHF), relaxation to acetylcholine (ACh) was lower in sham-operated fructose-fed rats compared with other groups, suggesting the involvement of nitric oxide (NO) in vasorelaxation. Inhibition of NO synthesis nearly abolished the ACh-evoked relaxation in both fructose-fed groups, thus suggesting a testosterone-independent impairment of EDHF-mediated relaxation. The improvement in endothelial function following gonadectomy could be ascribed to a NO component, although plasma nitrite and nitrate levels were unchanged. In summary, testosterone is essential in vivo for the development of endothelial dysfunction and hypertension secondary to insulin resistance, suggesting a facilitatory role for testosterone in increasing BP in fructose-fed male rats.
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Affiliation(s)
- Harish Vasudevan
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada
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Song J, Kost CK, Martin DS. Androgens augment renal vascular responses to ANG II in New Zealand genetically hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2006; 290:R1608-15. [PMID: 16469840 DOI: 10.1152/ajpregu.00364.2005] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Males develop higher blood pressure than do females. This study tested the hypothesis that androgens enhance responsiveness to ANG II during the development of hypertension in New Zealand genetically hypertensive (NZGH) rats. Male NZGH rats were obtained at 5 wk of age and subjected to sham operation (Sham) or castration (Cas) then studied at three age groups: 6–7, 11–12, and 16–17 wk. Mean arterial blood pressure (MAP), heart rate (HR), and renal blood flow (RBF) measurements were recorded under Inactin anesthesia. These variables were measured after enalapril (1 mg/kg) treatment and during intravenous ANG II infusion (20, 40, and 80 ng/kg/min). Plasma testosterone was measured by ELISA. Angiotensin type 1 (AT1) receptor expression was assessed by Western blot analysis and RT-PCR. ANG II-induced MAP responses were significantly attenuated in Cas NZGH rats. At the highest ANG II dose, MAP increased by 40 ± 4% in Sham vs. 22 ± 1% in Cas NZGH rats of 16–17 wk of age. Similarly, renal vascular resistance (RVR) responses to ANG II were reduced by castration (209 ± 20% in Sham vs. 168 ± 10% in Cas NZGH rats at 16–17 wk of age). Castration also reduced MAP recorded in conscious NZGH rats of this age group. Testosterone replacement restored baseline MAP and the pressor and RVR responses to ANG II. Castration reduced testosterone concentrations markedly. Testosterone treatment restored these concentrations. Neither castration nor castration+testosterone treatment affected AT1 receptor mRNA or protein expression. Collectively, these data suggest that androgens modulate renal and systemic vascular responsiveness to ANG II, which may contribute to androgen-induced facilitation of NZGH rat hypertension.
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Affiliation(s)
- Jin Song
- Basic Biomedical Sciences, University of South Dakota, Vermillion SD 57069, USA
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Michalik L, Wahli W. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Invest 2006; 116:598-606. [PMID: 16511592 PMCID: PMC1386118 DOI: 10.1172/jci27958] [Citation(s) in RCA: 172] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Tissue damage resulting from chemical, mechanical, and biological injury, or from interrupted blood flow and reperfusion, is often life threatening. The subsequent tissue response involves an intricate series of events including inflammation, oxidative stress, immune cell recruitment, and cell survival, proliferation, migration, and differentiation. In addition, fibrotic repair characterized by myofibroblast transdifferentiation and the deposition of ECM proteins is activated. Failure to initiate, maintain, or stop this repair program has dramatic consequences, such as cell death and associated tissue necrosis or carcinogenesis. In this sense, inflammation and oxidative stress, which are beneficial defense processes, can become harmful if they do not resolve in time. This repair program is largely based on rapid and specific changes in gene expression controlled by transcription factors that sense injury. PPARs are such factors and are activated by lipid mediators produced after wounding. Here we highlight advances in our understanding of PPAR action during tissue repair and discuss the potential for these nuclear receptors as therapeutic targets for tissue injury.
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Affiliation(s)
- Liliane Michalik
- Center for Integrative Genomics, National Research Centre Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland.
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Abstract
Ischemic preconditioning, the most powerful protection against infarction, activates PI3Kinase (PI3K)/AKT and P42/44MAPK. Pioglitazone, a thiazolidinedione and PPARgamma receptor agonist used in Type II diabetes treatment, has been shown to activate these kinase cascades. We therefore hypothesized that pioglitazone could protect the myocardium when given prior to myocardial ischemia/reperfusion injury. Langendorff perfused rat hearts underwent 40 minutes of stabilization then 35 minutes of regional ischemia and 120 minutes of reperfusion (control) or Pioglitazone (1, 2, 5, and 10 microM)-given before ischemia. Additional groups underwent the same protocol but with either PI3K inhibitors (15 microM LY294002 or 100 nM wortmannin) or P42/44MAPK inhibitors (10 microM U0126 or 10 microM PD98059) given either during stabilization or at reperfusion. Infarct size was determined as a percentage of risk zone (I/R%). Pioglitazone (2 microM) significantly reduced I/R% compared with control (25.4 +/- 3.1 versus 47.3 +/- 3.4; P < 0.05). This protection was abolished by PI3K inhibitors (pioglitazone+LY294002 46.5 +/- 5.0, pioglitazone + wortmannin 48.8 +/- 4.6 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05) but not by P42/44MAPK inhibitors (pioglitazone+U0126 30.7 +/- 5.7, pioglitazone + PD98059 28.5 +/- 6.3 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05) given in stabilization. However when the inhibitors were given at reperfusion, the protection was abrogated by blocking either pathway (pioglitazone+LY294002 49.8 +/- 3.1, pioglitazone+U0126 48.7 +/- 3.7 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05). In conclusion pioglitazone induced significant protection against ischemia/reperfusion injury when administered prior to ischemia. This protection appears to involve PI3K and P42/44MAPK.
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Affiliation(s)
- Abigail M Wynne
- The Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, London, United Kingdom
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Reckelhoff JF, Yanes LL, Iliescu R, Fortepiani LA, Granger JP. Testosterone supplementation in aging men and women: possible impact on cardiovascular-renal disease. Am J Physiol Renal Physiol 2005; 289:F941-8. [PMID: 16210452 DOI: 10.1152/ajprenal.00034.2005] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Treatment of aging men and women with testosterone supplements is increasing. The supplements are given to postmenopausal women mainly to improve their libido and to aging men to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, such as sildenafil, to treat erectile dysfunction. The increased use of testosterone supplements in aging individuals has occurred despite the fact that there have been no rigorous clinical trials examining the effects of chronic testosterone on the cardiovascular-renal disease risk. Studies in humans and animals have suggested that androgens can increase blood pressure and compromise renal function. Androgens have been shown to increase tubular sodium and water reabsorption and activate various vasoconstrictor systems in the kidney, such as the renin-angiotensin system and endothelin. There is also evidence that androgens may increase oxidative stress. Furthermore, the kidney contains the enzymes necessary to produce androgens de novo. This review presents an overview of the data from human and animal studies in which the role of androgens in promoting renal and cardiovascular diseases has been investigated.
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Affiliation(s)
- Jane F Reckelhoff
- Dept. of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
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Collino M, Patel NSA, Lawrence KM, Collin M, Latchman DS, Yaqoob MM, Thiemermann C. The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion. Kidney Int 2005; 68:529-36. [PMID: 16014029 DOI: 10.1111/j.1523-1755.2005.00430.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND We have recently reported that pretreatment of rats with endotoxin (lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPARgamma, rather than an up-regulation of PPARgamma expression. METHODS Rats were pretreated with LPS (1 mg/kg, IP, 24 hours prior to ischemia) in the absence (control) or presence of the selective PPARgamma antagonist GW9662 (1 mg/kg, IP, 24 and 12 hours prior to ischemia). Twenty-four hours after injection of LPS, rats were subjected to 60 minutes of bilateral renal ischemia, followed by 6 hours of reperfusion. Serum and urinary indicators of renal injury and dysfunction were measured, specifically serum creatinine, aspartate aminotransferase, and gamma-glutamyl-transferase, creatinine clearance, urine flow, and fractional excretion of sodium. Kidney PPARgamma1 mRNA levels were determined by reverse transcriptase-polymerase chain reaction. RESULTS Pretreatment with LPS significantly attenuated all markers of renal injury and dysfunction caused by I/R. Most notably, GW9662 abolished the protective effects of LPS. Additionally, I/R caused an up-regulation of kidney PPARgamma1 mRNA levels compared to sham animals, which were unchanged in rats pretreated with LPS. CONCLUSION We document here for the first time that endogenous ligands of PPARgamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.
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Affiliation(s)
- Massimo Collino
- Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary-University of London, London, UK
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Lu J, Imamura K, Nomura S, Mafune KI, Nakajima A, Kadowaki T, Kubota N, Terauchi Y, Ishii G, Ochiai A, Esumi H, Kaminishi M. Chemopreventive Effect of Peroxisome Proliferator–Activated Receptor γ on Gastric Carcinogenesis in Mice. Cancer Res 2005; 65:4769-74. [PMID: 15930296 DOI: 10.1158/0008-5472.can-04-2293] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) is known to be expressed in several cancers, and the treatment of these cancer cells with PPARgamma ligands often induces cell differentiation and apoptosis. Recently, the chemopreventive potential of PPARgamma ligands on colon carcinogenesis was reported, although the effect of PPARgamma on colon carcinogenesis and the mechanism of the effect remain controversial. In this study, we attempted to elucidate the role of PPARgamma in gastric carcinogenesis and explored the possible use of PPARgamma ligand as a chemopreventive agent for gastric cancer. N-methyl-N-nitrosourea (MNU, 240 ppm) was given in drinking water for 10 weeks to induce gastric cancer in PPARgamma wild-type (+/+) and heterozygous-deficient (+/-) mice, followed by treatment with PPARgamma ligand [troglitazone, 0.15% (w/w) in powder food] or the vehicle alone for 42 weeks. At the end of the experiment, PPARgamma (+/-) mice were more susceptible to MNU-induced gastric cancer than wild-type (+/+) mice (89.5%/55.5%), and troglitazone significantly reduced the incidence of gastric cancer in PPARgamma (+/+) mice (treatment 55.5%/vehicle 9%) but not in PPARgamma (+/-) mice. The present study showed that (a) PPARgamma suppresses gastric carcinogenesis, (b) the PPARgamma ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and (c) troglitazone's chemopreventive effect is dependent on PPARgamma.
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Affiliation(s)
- Jie Lu
- Department of Gastrointestinal Surgery, Faculty of Medicine, University of Tokyo, Japan.
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