RESUMO
BACKGROUND: Previous studies have reported that puerarin possesses cardioprotective, vasodilatory, anti-inflammatory, anti-apoptotic, and hypoglycemic properties. However, the impact of puerarin on sepsis-associated encephalopathy (SAE) remains unexplored. In this study, we explored whether puerarin can modulate microglia-mediated neuroinflammation for the treatment of SAE and delved into the underlying mechanisms. METHODS: We established a murine model of SAE through intraperitoneal injection of lipopolysaccharide (LPS). The puerarin treatment group received pretreatment with puerarin. For in vitro experiments, BV2 cells were pre-incubated with puerarin for 2 h before LPS exposure. We employed network pharmacology, the Morris Water Maze (MWM) test, Novel Object Recognition (NOR) test, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), Western blotting, and quantitative real-time PCR (qRT-PCR) to elucidate the molecular mechanism of underlying puerarin's effects in SAE treatment. RESULTS: Our findings demonstrate that puerarin significantly reduced the production of inflammatory cytokines (TNF-α and IL-6) in the peripheral blood of LPS-treated mice. Moreover, puerarin treatment markedly ameliorated sepsis-associated cognitive impairment. Puerarin also exhibited inhibitory effects on the release of TNF-α and IL-6 from microglia, thereby preventing hippocampal neuronal cell death. Network pharmacology analysis identified AKT1 as a potential therapeutic target for puerarin in SAE treatment. Subsequently, we validated these results in both in vitro and in vitro experiments. Our study conclusively demonstrated that puerarin reduced LPS-induced phosphorylation of AKT1, with the AKT activator SC79 reversing puerarin's anti-inflammatory effects through the activation of the AKT1 signaling pathway. CONCLUSION: Puerarin exerts an anti-neuroinflammatory effect against SAE by modulating the AKT1 pathway in microglia.
Assuntos
Encefalopatia Associada a Sepse , Camundongos , Animais , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Microglia , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismoRESUMO
OBJECTIVE: To select a suitable combination of classic angiogenic and vascular stabilization factors to improve the proliferation and maturity of neovascularization of lung tissue in a rat pulmonary arterial hypertension (PAH) model. METHODS: PAH rat model was established by intraperitoneal injection of monocrotaline. Proangiogenic factors hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), as well as vascular stabilization factors angiopoietin-1 (Ang-1), platelet-derived growth factor, and transforming growth factor-beta were transfected by pairs into the lung tissue of rats with PAH through lentivirus. Four weeks later, pulmonary artery angiography and hemodynamic parameters were determined to testify the remission of PAH. Immunofluorescence staining and Western blot were performed to investigate the structure and function of neovascularization. RESULTS: The pulmonary artery pressure and weight index of the right ventricle in HGF+Ang-1 and VEGF+Ang-1 groups were significantly decreased compared with vehicle group. The contrast medium filling time and right pulmonary artery root diameter were also significantly decreased. In addition, the maturity and perfusion of neovascularization in HGF+Ang-1 and VEGF+Ang-1 groups were promoted compared to vehicle group, and vascular leakage was reduced. Finally, the adherens junction integrity of vascular endothelial cells in HGF+Ang-1 and VEGF+Ang-1 combinations was upregulated compared with other combinations. CONCLUSIONS: HGF+Ang-1 transfection and VEGF+Ang-1 transfection alleviate PAH by promoting maturation and stability of new blood vessels, which may be potential candidates for PAH treatment.
Assuntos
Hipertensão Pulmonar/fisiopatologia , Pulmão , Neovascularização Fisiológica/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Animais , Fator de Crescimento de Hepatócito/farmacologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Masculino , Monocrotalina , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Recent studies demonstrated that FoxO3 circular RNA (circFoxO3) plays an important regulatory role in tumourigenesis and cardiomyopathy. However, the role of circFoxO3 in neurodegenerative diseases remains unknown. The aim of this study was to examine the possible role of circFoxO3 in neurodegenerative diseases and the underlying mechanisms. To model human neurodegenerative conditions, hippocampus-derived neurons were treated with glutamate. Using molecular and cellular biology approaches, we found that circFoxO3 expression was significantly higher in the glutamate treatment group than that in the control group. Furthermore, silencing of circFoxO3 protected HT22 cells from glutamate-induced oxidative injury through the inhibition of the mitochondrial apoptotic pathway. Collectively, our study demonstrates that endogenous circFoxO3 plays a key role in inducing apoptosis and neuronal cell death and may act as a novel therapeutic target for neurodegenerative diseases.
Assuntos
Apoptose/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Hipocampo/metabolismo , Mitocôndrias/metabolismo , RNA Circular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Ácido Glutâmico/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Targeted increase in glucose uptake of ischemic myocardium is a potential therapeutic strategy for myocardial ischemia. PEDF presents a profound moderating effect on glucose metabolism of cells, but its role is still controversial. Here, we try to demonstrate the direct effect of PEDF on glucose uptake in ischemic myocyte and to elucidate its underlying mechanism. METHODS AND RESULTS: Lentivirus vectors carrying PEDF gene were delivered into the myocardium to locally overexpress PEDF in a myocardial ischemia/reperfusion rat model. PET imaging showed that PEDF local overexpression increased [18F]-FDG uptake of ischemic myocardium. In vitro, PEDF directly increased the glucose uptake in hypoxic cardiomyocytes. The expression of glucose transporter 4 (GLUT4) on plasma membrane of hypoxic cardiomyocytes was significantly upregulated by PEDF, but its total amount was not changed. The increased glucose uptake and cardioprotective effects induced by PEDF were blocked by the GLUT4 inhibitor indinavir. PEDF-mediated GLUT4 translocation and glucose uptake increase in hypoxic cardiomyocytes were prevented by phosphatidyl-inositol-3 kinase (PI3K) inhibitor or AKT inhibitor. The PEDF-mediated glucose uptake was also diminished when PEDF receptor (PEDFR) was downregulated or potent phospholipase A2 enzymatic activity was inhibited. CONCLUSIONS: PEDF can increase glucose uptake in ischemic myocardium through a PEDFR-dependent mechanism, involving PI3K/AKT signaling and GLUT4 translocation.
Assuntos
Proteínas do Olho/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Isquemia Miocárdica/genética , Miocárdio/metabolismo , Fatores de Crescimento Neural/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serpinas/genética , Animais , Transporte Biológico , Western Blotting , DNA/genética , Modelos Animais de Doenças , Proteínas do Olho/biossíntese , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fatores de Crescimento Neural/biossíntese , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ratos Sprague-Dawley , Serpinas/biossíntese , Transdução de SinaisRESUMO
The aim of this article was to study the influence of immunity function of advanced malignant obstructive jaundice (MOJ) treated by percutaneous transhepatic biliary external and internal drainage. Ninety-six cases of MOJ were divided into two groups according to the different ways of biliary drainage. Fifty-two external drainage tubes were placed in 41 cases of percutaneous transhepatic biliary external drainage group and 66 metal stents were placed in 55 cases of percutaneous transhepatic biliary internal drainage group. Liver function, serum TNF-α and cellular function were examined one day before operation and one week after operation and liver function was re-examined two weeks after operation, in order to observe the change and analyze the association among them and compare with the control group. All patients' conditions were improved after operation. In the percutaneous transhepatic biliary external and internal drainage groups, the total level of bilirubin decreased from (343.54±105.56) µmol/L and (321.19±110.50) µmol/L to (290.56±103.46) µmol/L and (283.72±104.95) µmol/L after operation respectively, which were significantly lower than pre-operation (P<0.05), but there was no significant difference between the two groups (P>0.05). Serum alanine aminotransferase (ALT) of all patients one week after operation was significantly lower than that before operation. TNF-α in percutaneous transhepatic biliary external and internal groups decreased from (108.58±19.95) pg/mL, (109.98±16.24) pg/mL of pre-operation to (104.32±19.59) pg/mL, (83.92±13.43) pg/mL of post-operation respectively, there was notable improvement (P<0.01) in internal drainage group after operation. Patients' serum CD4, CD3 and CD4/CD8 were notably increased, but CD8 was notably decreased (P<0.05). There was no difference in external drainage group (P>0.05). There was a significant difference between the two groups. Serum TNF-α and ALT had positive correlation. Percutaneous transhepatic biliary internal or external drainage was an effective and important method to treat MOJ. Patients' immune function was weak when they suffered MOJ, but body's cellular immune function can be notably improved after internal biliary drainage.