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Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPAR? and Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

ABSTRACT: Gamma-glutamylcysteine ethyl ester (GCEE) is a precursor of glutathione (GSH) with promising hepatoprotective effects. This investigation aimed to evaluate the hepatoprotective effects of GCEE against cyclophosphamide- (CP-) induced toxicity, pointing to the possible role of peroxisome proliferator activated receptor gamma (PPAR?). Wistar rats were given GCEE two weeks prior to CP. Five days after CP administration, animals were sacrificed and samples were collected. Pretreatment with GCEE significantly alleviated CP-induced liver injury by reducing serum aminotransferases, increasing albumin, and preventing histopathological and hematological alterations. GCEE suppressed lipid peroxidation and nitric oxide production and restored GSH and enzymatic antioxidants in the liver, which were associated with downregulation of COX-2, iNOS, and NF-?B. In addition, CP administration significantly increased serum proinflammatory cytokines and the expression of liver caspase-3 and BAX, an effect that was reversed by GCEE. CP-induced rats showed significant downregulation of PPAR? which was markedly upregulated by GCEE treatment. These data demonstrated that pretreatment with GCEE protected against CP-induced hepatotoxicity, possibly by activating PPAR?, preventing GSH depletion, and attenuating oxidative stress, inflammation, and apoptosis. Our findings point to the role of PPAR? and suggest that GCEE might be a promising agent for the prevention of CP-induced liver injury.

SUBMITTER: Alqahtani S

PROVIDER: S-EPMC5198194 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPAR<i>γ</i> and Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

Alqahtani Sultan S Mahmoud Ayman M AM

Oxidative medicine and cellular longevity 20161215

Gamma-glutamylcysteine ethyl ester (GCEE) is a precursor of glutathione (GSH) with promising hepatoprotective effects. This investigation aimed to evaluate the hepatoprotective effects of GCEE against cyclophosphamide- (CP-) induced toxicity, pointing to the possible role of peroxisome proliferator activated receptor gamma (PPAR<i>γ</i>). Wistar rats were given GCEE two weeks prior to CP. Five days after CP administration, animals were sacrificed and samples were collected. Pretreatment with GCE ...[more]

PMID: 28074115

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Project description:BackgroundPersistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis.ObjectiveTo examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.Material and methodsThe effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied.ResultsCDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ.ConclusionsThe PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.

Dataset Information

Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPAR? and Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

Publications

Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPAR<i>γ</i> and Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

Similar Datasets

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