Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Mais filtros

Base de dados
Intervalo de ano de publicação
Biochem Pharmacol ; : 113856, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32061772


Cancer easily induces resistance to most chemotherapy drugs. In this study, we investigated the combination cytotoxic and antitumor effects of canagliflozin (CAN) and doxorubicin (DOX) in vitro and in vivo. CAN significantly increased the cytotoxicity of DOX in HepG2, HepG2-ADR (adriamycin or doxorubicin-resistant) and MCF7 cells. CAN significantly promoted the intracellular uptake of DOX in HepG2 cells. CAN also reduced the p-gp level in HepG2 cells. The function of p-gp required ATP, but CAN significantly reduced the intracellular ATP level. CAN might inhibit the function of p-gp, increase the intracellular DOX concentration and contribute to an enhanced cytotoxic activity. Autophagy plays a protective role in chemotherapy-induced cell survival. However, CAN significantly inhibited DOX-induced autophagy in HepG2 cells, and the mechanism appeared to be mediated by promoting ULK1 phosphorylation. The downregulation of P-glycoprotein (P-gp) may be associated with protein degradation but is independent of the autophagy pathway. Furthermore, in HepG2-xenograft BALB/c naked mice, CAN significantly increased the antitumor effect of DOX. This study is the first to report that a classical antidiabetic drug, CAN improved the sensitivity to the antitumor effect of DOX, and the potential molecular mechanisms of CAN may involve the inhibition of P-gp function and the autophagy pathway.

Am J Transl Res ; 11(9): 5634-5644, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632535


We aimed to investigate the role of long non-coding RNA (lncRNA) FOXD3 antisense RNA 1 (FOXD3-AS1) in myocardial Ischemia/reperfusion (I/R) injury. In our study, H9C2 cells were treated with oxygen-glucose deprivation and reoxygenation (OGD/R). RT-qPCR was performed to detect the expression level of lncRNA FOXD3-AS1 in OGD/R induced H9C2 cells. Then, pcDNA-lncRNA FOXD3-AS1 was transfected into H9C2 cells. The level of LC3 II was measured by immunofluorescence assay. And the expression of autophagy related genes were detected using western blot. In addition, 3-methyladenine (3 M), an autophagy inhibitor, was recruited to treat with H9C2 cells. The contents of creatine kinase (CK), CK isoenzymes (CK-MB), cardiac troponin I (cTnI), inflammation associated factors, reactive oxygen (ROS) and NO were evaluated by kits. Moreover, cell apoptosis was measured by a flow cytometry assay and the expression levels of apoptosis associated proteins were evaluated by western blot. Furthermore, the expression of NF-κB/iNOS/COX2 signaling were measured in our study. The results indicated that FOXD3-AS1 expression was increased in OGD/R-treated H9C2 cells and overexpression of FOXD3-AS1 upregulated the expression of LC3 II, Beclin1, ATG5 accompanied by a downregulated expression of p62. In addition, FOXD3-AS1 overexpression increased the levels of CK, CK-MB, cTnI, TNF-α, IL-1ß, IL-6, ROS and NO, whereas the increase of above factors were reversed following treatment with 3 M. Moreover, FOXD3-AS1 overexpression enhanced the rate of apoptosis cells coupled with a decrease of Bcl-2 expression and an increase of Bax and cleaved caspase 3 expression, which were reversed by 3 M. Furthermore, FOXD3-AS1 overexpression promoted the activation of NF-κB/iNOS/COX2 signaling, which was blocked following treatment with 3 M. These findings demonstrate that overexpression of lncRNA FOXD3-AS1 aggravates myocardial I/R injury through promoting autophagy, which was regulated by activating NF-κB/iNOS/COX2 signaling.

Biochem Pharmacol ; 152: 45-59, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29551587


Canagliflozin (CAN) regulates intracellular glucose metabolism by targeting sodium-glucose co-transporter 2 (SGLT2) and intracellular glucose metabolism affects inflammation. In this study, we hypothesized that CAN might exert anti-inflammatory effects. The anti-inflammatory effects and action mechanisms of CAN were assayed in lipopolysaccharide (LPS)-induced RAW264.7 and THP-1 cells and NIH mice. Results showed that CAN significantly inhibited the production and release of interleukin (IL)-1, IL-6, or tumor necrosis factor-α (TNF-α) in the LPS-induced RAW264.7 and THP-1 cells, and mice. CAN also significantly inhibited intracellular glucose metabolism and 6-phosphofructo-2-kinase (PFK2) expression. CAN increased the levels of sequestosome-1 (SQSTM1/p62), upregulated the ratios of microtubule-associated protein 1A/1B-light chain 3 (LC3) II to I, promoted the formation of LC3 puncta, and enhanced the activities of lysosome. The inhibition of autophagy by 3-methyladenine (3-MA) reversed the effects of CAN on IL-1α levels. Increased autophagy might be associated with increased AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, p62 demonstrated good co-localization with IL-1α and possibly mediated IL-1α degradation. CAN-induced increase in p62 was dependent on the nuclear factor kappa B (NFκB) signaling pathway. These results indicated that CAN might exert anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy. Attenuated glucose metabolism by PFK2, increased autophagy flow by AMPK, and increased p62 levels by NFκB might be responsible for the molecular mechanisms of CAN. This drug might serve as a new promising anti-inflammatory drug for acute or chronic inflammatory diseases via independent hypoglycemic mechanisms. This drug might also be used as an important reference for similar drug research and development by targeting intracellular glucose metabolism and autophagy in immune cells.

Autofagia/efeitos dos fármacos , Canagliflozina/farmacologia , Glucose/metabolismo , Inflamação/induzido quimicamente , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Canagliflozina/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio , Células THP-1
Sci Total Environ ; 628-629: 366-374, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29448021


This study aims to assess the effects and the mechanisms of silica nanoparticles (SiNPs) on hepatotoxicity in both normal and metabolic syndrome mouse models induced by fructose. Here, we found that SiNPs exposure lead to improved insulin resistance in metabolic syndrome mice, but markedly worsened hepatic ballooning, inflammation infiltration, and fibrosis. Moreover, SiNPs exposure aggravated liver injury in metabolic syndrome mice by causing serious DNA damage. Following SiNPs exposure, liver superoxide dismutase and catalase activities in metabolic syndrome mice were stimulated, which is accompanied by significantly increased malondialdehyde and 8-hydroxy-2-deoxyguanosine levels as compared to normal mice. Scanning electron microscope (SEM) revealed that SiNPs were more readily deposited in the liver mitochondria of metabolic syndrome mice, resulting in more severe mitochondrial injury as compared to normal mice. We speculated that SiNPs-induced mitochondrial injury might be the cause of hepatic oxidative stress, which further lead to a series of liver lesions as observed in mice following SiNPs exposure. Based on these results, it is likely that SiNPs will increase the risk and severity of liver disease in individuals with metabolic syndrome. Therefore, SiNPs should be used cautiously in food additives and clinical settings.

Frutose/metabolismo , Síndrome Metabólica/metabolismo , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Animais , Fígado , Síndrome Metabólica/induzido quimicamente , Camundongos , Estresse Oxidativo , Medição de Risco
Sci Rep ; 7(1): 5270, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28706254


Diabetes is an inflammatory disease. Inflammation plays an important role in islet functions. However, the exact mechanisms by which inflammation affects islet functions remain unclear. In this study, we investigated the regulatory effects of miR-30a on inflammation and islet functions. The results indicate that miR-30a serves as an inflammation-resolving buffer factor by targeting interleukin 1a (IL-1α) in immune cells and in islet cells, which might play an important role in inflammation homeostasis. miR-30a ameliorates islet functions in an inflammatory micro-environment by targeting the IL-1α/nuclear factor kappa B (NFKB) p65 subunit (p65)/p62 (SQSTM1)/insulin axis, which can be developed into a novel antidiabetic approach. miR-30a serves as a promising inflammation-response biomarker in inflammatory diseases and is possibly activated by the toll-like receptor 4 (TLR4)/IL-1α/NFKB pathways. However, the exact molecular mechanisms by which miR-30a regulates inflammation and islet functions as well as the potential applications in transitional medicine require further elucidation.

Diabetes Mellitus Experimental/fisiopatologia , Inflamação/patologia , Células Secretoras de Insulina/patologia , Interleucina-1alfa/metabolismo , Macrófagos/patologia , MicroRNAs/genética , Animais , Células Cultivadas , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Interleucina-1alfa/genética , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais