RESUMO
Activated microglia are divided into pro-inflammatory and anti-inflammatory functional states. In anti-inflammatory state, activated microglia contribute to phagocytosis, neural repair and anti-inflammation. Nrf2 as a major endogenous regulator in hematoma clearance after intracerebral hemorrhage (ICH) has received much attention. This study aims to investigate the mechanism underlying Nrf2-mediated regulation of microglial phenotype and phagocytosis in hematoma clearance after ICH. In vitro experiments, BV-2 cells were assigned to normal group and administration group (Nrf2-siRNA, Nrf2 agonists Monascin and Xuezhikang). In vivo experiments, mice were divided into 5 groups: sham, ICH + vehicle, ICH + Nrf2-/-, ICH + Monascin and ICH + Xuezhikang. In vitro and in vivo, 72 h after administration of Monascin and Xuezhikang, the expression of Nrf2, inflammatory-associated factors such as Trem1, TNF-α and CD80, anti-inflammatory, neural repair and phagocytic associated factors such as Trem2, CD206 and BDNF were analyzed by the Western blot method. In vitro, fluorescent latex beads or erythrocytes were uptaken by BV-2 cells in order to study microglial phagocytic ability. In vivo, hemoglobin levels reflect the hematoma volume. In this study, Nrf2 agonists (Monascin and Xuezhikang) upregulated the expression of Trem2, CD206 and BDNF while decreased the expression of Trem1, TNF-α and CD80 both in vivo and in vitro. At the same time, after Monascin and Xuezhikang treatment, the phagocytic capacity of microglia increased in vitro, neurological deficits improved and hematoma volume lessened in vivo. These results were reversed in the Nrf2-siRNA or the Nrf2-/- mice. All these results indicated that Nrf2 enhanced hematoma clearance and neural repair, improved neurological outcomes through enhancing microglial phagocytosis and alleviating neuroinflammation.
RESUMO
BACKGROUND AND AIMS: People with type 2 diabetes mellitus (T2DM) have increased morbidity and mortality due to coronavirus disease-19(COVID-19). It has been speculated that use of pioglitazone might increase such risk. The aim of our brief commentary is to review the safety of pioglitazone in people with T2DM and mild/moderate COVID-19. METHODS: We searched PubMed database using specific keywords related to our aims till May 15, 2020. Full text of relevant articles published in English language were retrieved and reviewed. RESULTS: Medications, including pioglitazone, that upregulate tissue expression of angiotensin converting enzyme 2 (ACE2), might have a dual role in COVID-19; on the one hand they might increase risk of infection as SARS-CoV2 uses ACE2 as a coreceptor to enter alveolar cells, but on the other hand, by reducing angiotensin II levels, they can protect against acute lung injury. There is no evidence to date that pioglitazone upregulates ACE2 in the alveolar cells; rather, there is evidence from animal studies of upregulation of ACE2 in insulin sensitive tissues, which might have a protective effect on lung injury. Moreover by moderating the exaggerated host proinflammatory response, pioglitazone can potentially reduce SARS-CoV-2 driven hyperinflammation. CONCLUSIONS: Pioglitazone has more potential for benefit than harm, and can be continued in people with T2DM and mild/moderate COVID-19, unless there are specific contraindications for its use. There is an urgent need to assess clinically relevant outcomes in people with diabetes and COVID-19 based upon baseline antidiabetes therapy, in particular pioglitazone.
Assuntos
Infecções por Coronavirus/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pioglitazona/uso terapêutico , Pneumonia Viral/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/virologia , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/virologia , Humanos , Inflamação/prevenção & controle , Inflamação/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pioglitazona/farmacologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Fatores de Risco , SARS-CoV-2RESUMO
The phenolic profile of the leaves of Beta vulgaris subspecies vulgaris variety rubra was investigated by high-performance liquid chromatography (HPLC) coupled to electrospray ionization high resolution mass spectrometric (ESI-HRMS-MS) detection. Mass spectrometry-based molecular networking was employed to dereplicate the known compounds. Twelve known compounds, seven of which are previously undescribed as constituents in the B. vulgaris leaves were dereplicated and assigned with various levels of identification confidence. The ameliorative effects of the aqueous methanolic extract of the leaves were assessed against alloxan induced diabetic rats. It was found that the extract significantly decreased (p < 0.001) serum glucose, lipid profile, ALT, AST, TNF-α, IL-1ß, IL-6, and hepatic MDA levels; and significantly increased (pâ¯<â¯0.001) hepatic TAO and GSH; and down-regulated the expression of hepatic NF-κB versus the untreated diabetic groups, in a dose-dependent manner. In molecular docking, all identified compounds exhibited good glide score against the PPAR-É£ target, confirming the in vivo observed activities. In conclusion, B. vulgaris has immunomodulatory / antioxidant effects that could be helpful in slowing the progression of diabetic complications.
Assuntos
Beta vulgaris/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Animais , Antioxidantes/metabolismo , Aterosclerose/sangue , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 1/sangue , Feminino , Glutationa/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Fenóis/análise , Compostos Fitoquímicos/análise , Fitoterapia , Extratos Vegetais/farmacologia , Ratos Wistar , Testes de Toxicidade AgudaRESUMO
The aim was to evaluate the effect of the ethanol extract of bacupari peel (EEB) on biometric measurements, hepatic lipogenesis and progression of non-alcoholic fatty liver disease (NAFLD) in obese Wistar rats. Chemical analysis of the bacupari peel extract identified 7-epiclusianone as the major constituent (140.02â¯mg/g) followed by morelloflavone (35.86â¯mg/g). Animals treated with high fat diet plus EEB (BHFD) reduced body mass index (BMI), liver weight and hepatosomatic index in relation to the obese control. The food intake was similar between hyperlipid group (HFD) groups with or without EEB. However, the normal control group (AIN-93â¯M) presented higher food intake and lower final weight compared to the obese control (HFD). The PPAR-α, CPT-1a and the ADIPOR2 genes expressions, and the concentration of the PPAR-α and the adiponectin protein level increased in the BHFD group in relation to the obese control. The EEB promoted reduction of the SREBP-1c gene expression and the percentage of hepatic fat and the degree of steatosis in relation to HFD. It was concluded that EEB showed a protective effect on NAFLD, as it promoted a reduction in BMI, induced lipid oxidation, reduced lipogenesis and hepatic steatosis. Moreover, our results suggest an interaction that can lead to an agonist activity of the EEB to the PPAR-α receptor.