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Food Chem Toxicol ; 123: 349-362, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30423402


Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.

Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/administração & dosagem , Citocromo P-450 CYP2E1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Curcumina/análogos & derivados , Curcumina/química , Curcumina/metabolismo , Citocromo P-450 CYP2E1/genética , Humanos , Hidrogenação , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
Front Pharmacol ; 9: 615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962947


Bleomycin (BLM) is a broad spectrum anti-tumor drug and inducing pulmonary fibrosis. As an anti-tumor drug without immunosuppression, it is urgent to find a drug that reduces the side effects of BLM. Scutellarin (SCU), a flavone extracted from Erigeron breviscapus (Vant.) Hand-Mazz, has anti-inflammatory activity and ability to inhibit tumor cell growth, migration, and invasion. However, the combined role of SCU and BLM treatment in tumor is unclear. This study aimed to investigate the possible effect and related mechanisms of BLM combined with SCU in the treatment of tumor through in vivo and in vitro experiments. In vivo experiments showed that BLM combined with SCU in the treatment of mice bearing H22 ascites tumor prolonged the survival time, alleviated BLM-induced pulmonary fibrosis, reduced the production of TNF-α; IL-6, and the levels of MDA and MPO. BLM combined with SCU increased the apoptotic rate of H22 ascites cells and the levels of cleaved-caspases-3 and -8. Furthermore, BLM combined with SCU increased the protein expression of p53 and gene expression of miR-29b, and decreased the expression of TGF-ß1. In vitro experiment results showed that BLM combined with SCU inhibited the viability of H22 cells and MRC-5 cells, promoted H22 cell apoptosis, up-regulated the protein expression of p53 and down-regulated the protein expression of α-SMA and collagen-I in MRC-5 cells. These experimental results suggested that SCU could enhance the anti-tumor effect of BLM and reduce BLM-induced pulmonary fibrosis, indicating SCU as a potential adjuvant for BLM in the future.

Int Immunopharmacol ; 62: 15-22, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29966943


Pogostone (PO), a major component of Pogostemon cablin, displays potent protective effects against lipopolysaccharide-induced acute lung injury (ALI) in mice. This study aimed to investigate the protective effect of PO on TNF-α-induced cell injury in human alveolar epithelial cells in vitro and its underlying mechanism. The cell viability was measured using the MTS method. The cell apoptosis was determined using flow cytometry. The activities of reactive oxygen species (ROS) were detected using a fluorescence microscope. The pro-inflammatory cytokines and antioxidant genes were assessed using reverse transcription-polymerase chain reaction. The protein expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα), and nuclear factor-kappa B (NF-κB) p65 was analyzed using the Western blot analysis. PO alleviated cell apoptosis and inhibited ROS production. It alleviated TNF-α-induced cell injury, suppressed the levels of inflammatory cytokines [interleukin (IL)-6, IL-1ß, and IL-8], and enhanced the expression of antioxidant genes (quinine oxidoreductase 1, glutamate cysteine ligase catalytic subunit, heme oxygenase-1). It increased the expression of Keap1 and promoted the activation of Nrf2. However, the phosphorylation of IκBα and the nuclear expression of NF-κB p65 decreased. The anti-inflammatory and antioxidant effects of PO were abrogated following Nrf2 and NF-κB p65 knockdown. The results indicated a protective effect of PO against TNF-α-induced cell injury in A549 cells by modulating the balance between Nrf2 and NF-κB p65 signaling pathways. They verified PO as a promising anti-inflammatory adjuvant drug for treating ALI.

Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , Óleos Voláteis/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
Phytomedicine ; 39: 111-118, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29433672


BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are most widely used as effective anti-inflammatory agents. However, their clinical application brings about inevasible gastrointestinal side effects. Pogostemon cablin is a traditional herbal medicine used for the treatment of gastrointestinal diseases in China. One of its representative components, the tricyclic triterpenoid ß-patchoulone (ß-PAE) has demonstrated great anti-inflammatory activity and gastroprotective effect against ethanol-induced gastric injury, but its protective effect against gastric ulcer induced by indomethacin is still unknown. PURPOSE: To assess the protective effect of ß-PAE against ulcer produced by indomethacin and reveal the underlying pharmacological mechanism. STUDY DESIGN: We used an indomethacin-induced gastric ulcer model of rats in vivo. METHODS: Gastroprotective activity of ß-PAE (10, 20, 40 mg/kg, i.g.) was estimated via indomethacin-induced gastric ulcer model in rats. Histopathological and histochemical assessment of ulcerated tissues were performed. Protein and mRNA expression were determined by Elisa, Western blotting and qRT-PCR. RESULTS: ß-PAE could inhibit ulcer formation. Histopathological and histochemical assessment macroscopically demonstrated that ß-PAE alleviates indomethacin-induced gastric ulceration in dose-dependent manner. After administration of ß-PAE, elevated tumor necrosis factor -α level was significantly decreased and the phosphorylation of JNK and IκB was markedly inhibited. ß-PAE suppressed the levels of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule and monocyte chemoattractant protein 1, as well as myeloperoxidase. Meanwhile, ß-PAE increased cyclooxygenase enzyme activities (COX-1 and COX-2) to enhance the production of prostaglandin E2. Proangiogenic protein, vascular endothelial growth factor and its receptor fms-like tyrosine kinase-1 mRNA expression were promoted while anti-angiogenic protein, endostatin-1 and its receptor ETAR mRNA expression were decreased. CONCLUSION: ß-PAE may provide gastroprotection in indomethacin-induced gastric ulcer in rats by reducing inflammatory response and improving angiogenesis.

Indometacina/efeitos adversos , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/farmacologia , Dinoprostona/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Masculino , Pogostemon/química , Ratos Sprague-Dawley , Sesquiterpenos de Guaiano , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/metabolismo