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1.
Immunopharmacol Immunotoxicol ; 41(5): 549-557, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31530042

RESUMO

Objective: To investigate the role of miR-146a-5p in the effects of resveratrol (RSV) on inflammatory response in BV2 mouse microglial cells. Materials and methods: BV2 cells were pretreated by RSV and stimulated with lipopolysaccharide (LPS). Cell Viability was checked using a MTT assay. Real-Time PCR was performed to detect the levels of pro-inflammatory cytokines (tumor necrosisfactor-α-TNF-α, interleukin-1ß-IL-1ß and interleukin-6 - IL-6) and miR-146a-5p expression. Western blot was used to analyze the protein expression of TNF receptor associated factor 6 (TRAF6) and phospho-nuclear factor kappa B (pNF-κB). Gain-of-function and loss-of-function analysis of miR-146a-5p was performed using transfection of miR-146a-5p mimic and miR-146a-5p inhibitor, respectively. Results: Pretreatment with RSV significantly and dose dependently inhibited LPS-induced production of TNF-α, IL-1ß and IL-6 in BV2 cells. MiR-146a-5p was significantly upregulated after LPS treatment, and further increased in RSV and LPS-co-treated cells. MiR-146a-5p overexpression via miR-146a-5p mimic transfection downregulated the mRNA level of TNF-α, IL-1ß and IL-6, as well as abrogated the protein expression of TRAF6 and pNF-κB in BV2 cells exposed to LPS. More importantly, the reducion of TNF-α, IL-1ß and IL-6 level by RSV were reversed by miR-146a-5p silence via miR-146a-5p inhibitor transfection. Furthermore, silencing miR-146a-5p attenuated the inhibitory effect of RSV on the TRAF6/NF-κB pathway which was activated after induction with LPS. Conclusions: RSV can suppress LPS-induced inflammatory injury via modulating the miR-146a-5p/TRAF6/NF-κB axis in BV2 mouse microglial cells.


Assuntos
Anti-Inflamatórios/farmacologia , MicroRNAs/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Resveratrol/farmacologia , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Lipopolissacarídeos/imunologia , Camundongos , MicroRNAs/genética , Microglia/imunologia , Microglia/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Regulação para Cima
2.
Br J Pharmacol ; 180(14): 1803-1818, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36735592

RESUMO

BACKGROUND AND PURPOSE: Heparanase is the only confirmed endoglycosidase that cleaves heparan sulfate (HS), a ubiquitous glycosaminoglycan with various essential roles in multiple pathological processes. Thus, the development of heparanase inhibitors has become an attractive strategy for drug discovery, especially in tumour therapy, in which HS mimetics are the most promising compounds. The various biological effects of heparanase also suggest a role for HS mimetics in many non-cancer indications, such as type 1 diabetes. However, the potential benefits of HS mimetics in obesity-related type 2 diabetes have not been elucidated. EXPERIMENTAL APPROACH: In this study, we investigated muparfostat (PI-88), a developed HS mimetic currently enrolled in Phase III clinical trials, in obese mouse models and in vitro cultured murine hepatocytes. KEY RESULTS: Daily administration of muparfostat for 4 weeks caused hyperlipidaemia and aggravated hepatic steatosis in obese mice models, but not in lean animals. In cultured hepatocytes, muparfostat did not alter lipid accumulation. Acute tests suggested that muparfostat binds to lipoprotein lipase in competition with HS on vascular endothelial cell surfaces, thereby reducing the degradation of circulating triglycerides by lipoprotein lipase and subsequent uptake of fatty acids into vascular endothelial cells and causing hyperlipidaemia. This hyperlipidaemia aggravates hepatic steatosis and causes liver injury in muparfostat-treated obese mice. CONCLUSIONS AND IMPLICATIONS: The binding activity of HS mimetics to lipoprotein lipase should be investigated as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug-induced liver injury in obese individuals.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Animais , Camundongos , Células Endoteliais/metabolismo , Heparitina Sulfato , Lipase Lipoproteica/metabolismo , Camundongos Obesos
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