RESUMEN
BACKGROUND: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Abnormal activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome plays a vital role in the pathogenesis of sepsis. Matrine is proved to show good anti-inflammatory properties, whereas its effect and the underlying molecular machinery on sepsis remains unclear. PURPOSE: The aim of this study is to evaluate the effect and mechanism of Matrine on sepsis. STUDY DESIGN: THP-1 cells and J774A.1 cells were stimulated by lipopolysaccharide (LPS) with nigericin or adenosine triphosphate (ATP) to establish an in vitro model. Cecal ligation and puncture (CLP)-induced sepsis mouse model was used. Matrine was given by gavage. METHODS: To investigate the NLRP3 inflammasome activation, phorbol myristate acetate (PMA)-induced THP-1 cells were first primed with LPS and then stimulated by matrine, followed by treatment with nigericin or ATP. The concentration of interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) in the cell culture supernatant was detected. The mechanism was explored by cell death assay, immunoblots and immunofluorescence in vitro. C57BL/6 mice were intragastrically administered with matrine for 5 days before CLP. The therapeutic effect of matrine was evaluated by symptoms, pathological analysis, ELISA and RT-qPCR. RESULTS: Our results revealed that matrine inhibited IL-1ß and IL-18 secretion, suppressed caspase-1 activation, reduced cell death, and blocked ASC speck formation upon NLRP3 inflammasome activation. Furthermore, matrine restrains NLRP3 inflammasome activation as well as pyroptosis through regulating the protein tyrosine phosphatase non-receptor type 2 (PTPN2)/JNK/SREBP2 signaling. Matrine also prominently improved the symptoms and pathological changes with reduced levels of TNF-α, IL-1ß, and IL-6 in the lung tissues and serum in a dose-dependent manner. CONCLUSION: Matrine effectively alleviates the symptoms of CLP-induced sepsis in mice, restrains NLRP3 inflammasome activation by regulating PTPN2/JNK/SREBP2 signaling pathway, and may become a promising therapeutic agent for sepsis treatment.
Asunto(s)
Inflamasomas , Sepsis , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18 , Matrinas , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Lipopolisacáridos/farmacología , Nigericina , Ratones Endogámicos C57BL , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Adenosina Trifosfato , Interleucina-1beta/metabolismoRESUMEN
Limb ischemia reperfusion (LIR) can activate endogenous cytoprotective mechanisms by generating specific proteins against reperfusion injury in remote organs. The present study investigated the roles of heme oxygenase-1 (HO-1) pathway and the molecular mechanisms underlying the regulation of this pathway on lung injury following LIR. LIR was induced by ischemia for 4 hours followed by reperfusion for 6 hours (LIR 6 hours) or 16 hours (LIR 16 hours) in male Sprague-Dawley rats. HO-1 inducer cobalt protoporphyrin (Copp) or HO-1 inhibitor zinc protoporphyrin (Znpp) was intravenously injected 24 hours before ischemia. The animals were randomly divided into nine groups, including normal control, LIR 6 hours, LIR 16 hours, Copp, Copp + LIR 6 hours, Copp + LIR 16 hours, and Znpp, Znpp+ LIR 6 hours, and Znpp + LIR 16 hours groups (each group included four samples). Lung injury was examined through histopathology. Quantitative real-time PCR, immunohistochemistry and Western blot were applied to detect the mRNA and protein levels of HO-1, Nrf2, and Bach1. Our study showed that LIR induced Nrf2 upregulation but Bach1 downregulation to promote HO-1 expression in lung tissues. Activation of HO-1 pathway by Copp potentially enhanced Nrf2 expression but inhibition of the pathway by Znpp promoted Bach1 expression. Inducer of HO-1 pathway, Copp injection improved the lung injury. Nevertheless, Znpp injection aggravated the lung injury following LIR. Our findings suggested that activated HO-1 pathway might exert protective effects on the lung injury following LIR.
Asunto(s)
Hemo Oxigenasa (Desciclizante)/genética , Lesión Pulmonar/genética , Daño por Reperfusión/genética , Transducción de Señal/genética , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Activadores de Enzimas/farmacología , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/efectos de los fármacos , Miembro Posterior/enzimología , Pulmón , Lesión Pulmonar/etiología , Lesión Pulmonar/patología , Lesión Pulmonar/prevención & control , Masculino , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Protoporfirinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/complicaciones , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & controlRESUMEN
Essential hypertension is a leading global public health issue, billions of people suffered from it every year. Recently, multiple evidence suggests that DNA methylation play an important role in regulating blood pressure. Here, we tested the risk for essential hypertension conferred by single nucleotide polymorphisms (SNPs) within DNA methyltransferase 1 (DNMT1). Three loci (rs2228611, rs2228612, and rs16999593) were selected to be analyzed in 3410 cases and 1307 normal controls in southern Chinese aged 60 or above. No significant association with essential hypertension was observed for rs2228612 and rs16999593. A higher risk of essential hypertension was found in the minor A allele of rs2228611 in the codominant and recessive model (P < 0.05). After stratified by sex, this association was found in male but not female. Furthermore, this difference was abolished after BMI adjustment in the whole population and reduced in male. In addition, the mutation rate of rs2228611 was higher in the obesity group compared with the normal weight group of male. Intriguingly, rs2228611 was also a risk factor of essential hypertension in normal weight male. These findings indicated that rs2228611 might contribute to male hypertension via BMI-dependent mechanisms in obesity male and BMI-independent mechanisms in normal weight male.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1/genética , Hipertensión Esencial/genética , Predisposición Genética a la Enfermedad/genética , Anciano , Alelos , Pueblo Asiatico/genética , Presión Sanguínea , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Factores SexualesRESUMEN
Essential hypertension (EH) is a worldwide problem. Acetaldehyde dehydrogenase 2 (ALDH2) gene has been suggested to be correlated with EH. However, the results are inconsistent. This study aimed to investigate the associations of ALDH2 rs671 polymorphism with EH in a Chinese Han population in Shanghai. Genotype of ALDH2 rs671 was analyzed in 1923 EH patients and 1115 control subjects. We found no association between ALDH2 rs671 and EH risk or EH-related quantitative blood chemistry values. Furthermore, a meta-analysis was performed and the summary results from 11220 patients and 8339 control subjects were consistent with our findings. These results indicated that rs671 of ALDH2 may not associate with the risk of EH.
