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1.
Biomed Pharmacother ; 123: 109732, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31945695

RESUMO

Hyperglycemia/oxidative stress has been implicated in the initiation and progression of diabetic complications while the components of Keap1/Nrf2/ARE signaling are being exploited as therapeutic targets for the treatment/management of these pathologies. Antioxidant agents like drugs, nutraceuticals and pure compounds that target the proteins of this pathway and their downstream genes hold the therapeutic strength to put the progression of this disease at bay. Here, we elucidate how the modulation of Keap1/Nrf2/ARE had been exploited for the treatment/management of end-stage diabetic kidney complication (diabetic nephropathy) by looking into (1) Nrf2 nuclear translocation and phosphorylation by some protein kinases at specific amino acid sequences and (2) Keap1 downregulation/Keap1-Nrf2 protein-protein inhibition (PPI) as potential therapeutic mechanisms exploited by Nrf2 activators for the modulation of diabetic nephropathy biomarkers (Collagen IV, Laminin, TGF-ß1 and Fibronectin) that ultimately lead to the amelioration of this disease progression. Furthermore, we brought to limelight the relationship between diabetic nephropathy and Keap1/Nrf2/ARE and finally elucidate how the modulation of this signaling pathway could be further explored to create novel therapeutic milestones.

2.
Biomed Pharmacother ; 117: 109097, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31212128

RESUMO

An overdose of the most popular analgesic, acetaminophen (APAP), is one of the leading causes of acute liver failure. It is well established that glutathione is exhausted by APAP-reactive intermediate N­acetyl­p­benzoquinone-imine (NAPQI). This leads to elevated phosphorylated-c-Jun N-terminal kinase (p-JNK), which further activates reactive oxygen species (ROS), initiates an inflammatory response, and finally leads to severe hepatic injury. The present study was conducted to investigate the protective role of mangiferin (MAN), a naturally occurring xanthone and anti-oxidant, on APAP-induced hepatotoxicity. C57BL/6 mice were pretreated with or without MAN at 1 h prior to APAP challenge. MAN was administered at a dose of 12.5-50 mg/kg along with APAP at a dose of 400 mg/kg. According to the ALT/AST ratio, 25 mg/kg MAN was the most potent dose for further experiments. Serum ALT and AST depletion were observed in APAP + MAN (25 mg/kg)-treated mice at 6, 12, and 24 h. Early (1 h after APAP treatment) GSH depletion by APAP overdose was restored by MAN treatment, which reduced APAP-Cys adduct formation and promoted protection. p-JNK downregulation and AMPK activation were observed in MAN-treated mice, which could mechanistically reduce oxidative stress and inflammation. MAN up-regulated liver GSH and SOD and reduced lipid peroxidation. HO-1 protein and p47 phox mRNA expression indicated that MAN regulated oxidative stress along with JNK deactivation. The expression of inflammatory response genes TNF-α, IL-6, MCP-1, CXCL-1, and CXCL-2 reached the basal levels after MAN treatment. mRNA, protein, and serum levels of IL-1ß were reduced, and NF-κB expression was similar to that of the MAN-treated APAP mice. MAN post-treatment (1 h after APAP treatment) also protected the mice from hepatotoxicity. In conclusion, MAN had a protective and therapeutic role in APAP-induced hepatotoxicity by improving the metabolism of acetaminophen and APAP-Cys adduct formation followed by JNK-mediated oxidative stress and inflammation.


Assuntos
Acetaminofen/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Xantonas/farmacologia , Animais , Antioxidantes/farmacologia , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
3.
J Neurosci Res ; 96(1): 138-150, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28609588

RESUMO

Diabetic encephalopathy (DE), one of the most prevalent chronic complications of diabetes mellitus, is short of effective prevention and formidable therapeutic strategies. The aim of the present study is to reveal the imbalance of tryptophan (Trp) and its metabolites in streptozotocin (STZ)-induced experimental DE rats to underscore their critical values in clinical diagnosis of the disease. For this purpose, we first developed an accurate and appropriate simultaneous method for measuring Trp and its metabolites using liquid chromatography-tandem mass spectrometry, which was in accordance with the requirements of biological sample analysis. Secondly, a single STZ intraperitoneal injection was administered to male Sprague-Dawley rats, and their cognitive function was detected by Morris water maze tests. Cerebrospinal fluid (CSF), serum, and brain tissue were then collected for the determination of Trp and its metabolites. Compared with age-matched control rats, the levels of neuroprotective serotonin decreased significantly in the samples of cortices, hippocampi, striatum, CSF, and serums in the STZ-induced DE rats, while the levels of neurotoxic 3-hydroxykynurenine increased significantly. Moreover, analogous changes of both compounds were found in the central nervous system and peripheral blood of the STZ-induced DE rats. In conclusion, we established a quantitative method for the simultaneous detection of Trp and its metabolites, and we also present a critical elucidation of the nervous system dysfunction in DE.


Assuntos
Encefalopatias/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Neurotransmissores/metabolismo , Triptofano/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/patologia , Encefalopatias/patologia , Diabetes Mellitus Experimental/patologia , Masculino , Neurotransmissores/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos , Triptofano/análise
4.
Sci Rep ; 6: 37293, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27857189

RESUMO

Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy. The current study was designed to investigate the impact of KCNQ1 genetic polymorphism on the efficacy of repaglinide and furthermore to identify the potential mechanism of action in patients with type 2 diabetes. A total of 305 patients and 200 healthy subjects were genotyped for the KCNQ1 rs2237892 polymorphism, and 82 patients with T2DM were randomized for the oral administration of repaglinide for 8 weeks. HepG2 cells were incubated with repaglinide in the absence or presence of a KCNQ1 inhibitor or the pcDNA3.1-hKCNQ1 plasmid, after which the levels of Akt, IRS-2 and PI(3)K were determined. Our data showed that repaglinide significantly decreased HOMA-IR in patients with T2DM. Furthermore, the level of HOMA-IR was significantly reduced in those patients with CT or TT genotypes than CC homozygotes. The KCNQ1 inhibitor enhanced repaglinide efficacy on insulin resistance, with IRS-2/PI(3)K/Akt signaling being up-regulated markedly. As in our clinical experiment, these data strongly suggest that KCNQ1 genetic polymorphism influences repaglinide response due to the pivotal role of KCNQ1 in regulating insulin resistance through the IRS-2/PI(3)K/Akt signaling pathway. This study was registered in the Chinese Clinical Trial Register on May 14, 2013. (No. ChiCTR-CCC13003536).


Assuntos
Carbamatos/administração & dosagem , Diabetes Mellitus Tipo 2 , Resistência à Insulina/genética , Canal de Potássio KCNQ1/genética , Piperidinas/administração & dosagem , Polimorfismo Genético , Transdução de Sinais , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Células Hep G2 , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Canal de Potássio KCNQ1/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
5.
Acta Biochim Pol ; 60(4): 579-83, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24273760

RESUMO

INTRODUCTION: The statin-induced effects on high density lipoprotein (HDL) are relatively small compared with those of low density lipoprotein (LDL) and, as a result, most clinical trials of statins are underpowered with respect to HDL parameters. This study experimentally investigated, the effects of statin on serum lipids, atherogenic index and examined the possibility of a relationship amongst serum concentrations of HDL-C, atherogenic index and activity of lecithin:cholesterol acyl transferase. METHOD: Thirty albino rats equally divided into 2 groups were used for the study. Group 1 was given 0.05mg/g of statin daily for 28 days, while group 2 served as control. HDL concentration was determined as a measure of HDL-C. Total cholesterol (TC), triglyceride (TG) and HDL-C were determined spectrophotometrically while LDL-C was calculated using the Frieldwald formula. Effect on the activity of lecithin:cholesterol acyl transferase was determined by the difference between the amount of free cholesterol converted to cholesteryl ester in the two experimental groups. Effects on body and relative organs weights were also determined. RESULTS: The administration of statin caused a significant increase in serum concentration of HDL-C, while levels of LDL-C, triglyceride and total cholesterol were reduced. Simvastatin caused a significant reduction in the atherogenic index (TC/HDL-C; LDLC/HDL-C). The administration of statin significantly induced the activity of lecithin:cholesterol acyl transferase (LCAT) as evident by reduced serum concentration of free cholesterol when compared with control. The administration of statin caused reduced body and relative organs weights. CONCLUSION: The study showed that serum antihyperlipidemic and antiatherogenic activity of statin may involve the induction of LCAT.


Assuntos
Aterosclerose/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fosfatidilcolina-Esterol O-Aciltransferase/sangue , Sinvastatina/administração & dosagem , Animais , Aterosclerose/sangue , Regulação Enzimológica da Expressão Gênica/genética , Humanos , Hipolipemiantes/administração & dosagem , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Ratos
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