RESUMO
Macrophage-mediated inflammation plays an important role in hypertensive cardiac remodeling, whereas effective pharmacological treatments targeting cardiac inflammation remain unclear. Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to vascular inflammation-related diseases by mediating macrophage migration and activation. Darapladib, the most advanced Lp-PLA2 inhibitor, has been evaluated in phase III trials in atherosclerosis patients. However, the role of darapladib in inhibiting hypertensive cardiac fibrosis remains unknown. Using a murine angiotensin II (Ang II) infusion-induced hypertension model, we found that Pla2g7 (the gene of Lp-PLA2) was the only upregulated PLA2 gene detected in hypertensive cardiac tissue, and it was primarily localized in heart-infiltrating macrophages. As expected, darapladib significantly prevented Ang II-induced cardiac fibrosis, ventricular hypertrophy, and cardiac dysfunction, with potent abatement of macrophage infiltration and inflammatory response. RNA sequencing revealed that darapladib strongly downregulated the expression of genes and signaling pathways related to inflammation, extracellular matrix, and proliferation. Moreover, darapladib substantially reduced the Ang II infusion-induced expression of nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) and interleukin (IL)-1ß and markedly attenuated caspase-1 activation in cardiac tissues. Furthermore, darapladib ameliorated Ang II-stimulated macrophage migration and IL-1ß secretion in macrophages by blocking NLRP3 inflammasome activation. Darapladib also effectively blocked macrophage-mediated transformation of fibroblasts into myofibroblasts by inhibiting the activation of the NLRP3 inflammasome in macrophages. Overall, our study identifies a novel anti-inflammatory and anti-cardiac fibrosis role of darapladib in Lp-PLA2 inhibition, elucidating the protective effects of suppressing NLRP3 inflammasome activation. Lp-PLA2 inhibition by darapladib represents a novel therapeutic strategy for hypertensive cardiac damage treatment.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Benzaldeídos/uso terapêutico , Cardiotônicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Fibrose/prevenção & controle , Inflamação/prevenção & controle , Oximas/uso terapêutico , Angiotensina II , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Benzaldeídos/farmacologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/prevenção & controle , Cardiotônicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fibrose/induzido quimicamente , Fibrose/metabolismo , Coração/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oximas/farmacologiaRESUMO
Purpose: To explore the effectiveness of the model based on non-negative matrix factorization (NMF), analyze the tumor microenvironment and immune microenvironment for evaluating the prognosis of lung adenocarcinoma, establish a risk model, and screen independent prognostic factors. Methods: Downloading the transcription data files and clinical information files of lung adenocarcinoma from TCGA database and GO database, the R software was used to establish the NMF cluster model, and then the survival analysis between groups, tumor microenvironment analysis, and immune microenvironment analysis was performed according to the NMF cluster result. R software was used to construct prognostic models and calculate risk scores. Survival analysis was used to compare survival differences between different risk score groups. Results: Two ICD subgroups were established according to the NMF model. The survival of the ICD low-expression subgroup was better than that of the ICD high-expression subgroup. Univariate COX analysis screened out HSP90AA1, IL1, and NT5E as prognostic genes, and the prognostic model established on this basis has clinical guiding significance. Conclusion: The model based on NMF has the prognostic ability for lung adenocarcinoma, and the prognostic model of ICD-related genes has a certain guiding significance for survival.
RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) with inferior vena cava and right atrium thrombus is rare, accounting for approximately 1.4%-4.9% of cases. These patients are rarely reported, but the condition is being increasingly discovered with advances in imaging techniques, and their prognosis is extremely pessimistic with no current effective treatment. This condition is further associated with unexpected sudden death by cardiac arrest and acute large area pulmonary embolism. CASE SUMMARY: A 34-year-old man with advanced HCC with a hepatic vein thrombus extending into the right atrium had a long-term, disease-free survival following 5-mo sequential treatment combined with transcatheter arterial chemoembolization and curative liver resection. No severe adverse effects were encountered, such as massive hemorrhage or pulmonary embolism. The proper selection of operative method is an important factor. CONCLUSION: HCC with a tumor thrombus extending into the right atrium has a significant impact on the survival of patients. Thrombectomy combined with adjuvant therapy may be beneficial for these patients.
RESUMO
OBJECTIVE: To investigate the effects of erythropoietin (EPO) on the expression of aquaporin 2 (AQP(2)) after renal ischemia/reperfusion (IR). METHODS: Twenty-four Wistar rats were randomly divided into 3 equal groups: IR group undergoing resection of the right kidney, closuring of the left renal artery, vein, and ureter, and un-closuring 40 min later; IR + EPO group undergoing the above mentioned procedures and then intraperitoneal injection of EPO 3000 U/kg on days 1 and 2 after the treatment; and control group undergoing resection of the right kidney only without IR of the left kidney. Urine volume and urine osmotic pressure were measured. Blood samples were collected to detect the serum blood urea nitrogen (BUN) and creatinine (Cr). Three days after the treatment the kidneys were taken out. RT-PCR and Western blotting were used to detect the mRNA and protein expression of AQP(2). RESULTS: The urine volume of the IR + EPO group was (26.0 +/- 2.3) microl .min(-1).kg(-1), significantly lower than that of the IR group [(59.1 +/- 1.3) microl .min(-1) . kg(-1), P < 0.01]. The urine osmotic pressure of the IR + EPO group was (1508 +/- 121) mOsm/kg H(2)O, significantly higher than that of the IR group [(235 +/- 99) mOsm/kg H(2)O, P < 0.01]. The serum BUN and Cr levels of the IR + EPO group were (12.3 +/- 6.0) mmol/L and (51 +/- 5) micromol/L respectively, both significantly lower than those of the IR group [(29.9 +/- 3.7) mmol/L and (141 +/- 5) micromol/L respectively, both P < 0.01]. The mRNA and protein expression of AQP(2) were highly positive in the control group. The protein expression levels of AQP(2) of the IR + EPO group were not significantly different from those of the control group (both P > 0.05), and the protein expression levels of AQP(2) of the IR group were significantly lower than those of the control group (both P < 0.01). CONCLUSION: EPO can inhibit the down-regulation of AQP(2) in response to IR and this may take part in the EPO protective mechanism of renal ischemia/reperfusion injury.
Assuntos
Aquaporina 2/biossíntese , Eritropoetina/farmacologia , Nefropatias/metabolismo , Rim/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos , Ratos WistarRESUMO
The purpose of this study was to investigate the association of tumor tissue and plasma miR-146a/b expressions with the clinicopathological properties and overall survival (OS) in surgical patients with intrahepatic cholangiocarcinomas (ICC).Eighty-seven patients with ICC were enrolled. Tumor tissue and plasma sample were collected and miR-146a/b expressions were assessed by quantitative polymerase chain reaction (qPCR). The median follow-up duration was 31 months, and the last follow-up date was January 2017.miR-146a (Pâ<â.001) and miR-146b (Pâ=â.006) expressions in tumor tissue were positively associated with that in plasma. Tissue miR-146a was negatively correlated with age (Pâ=â.036), poor differentiation (Pâ=â.020), N stage (Pâ=â.020), and TNM stage (Pâ=â.007), as well as ECOG performance (Pâ=â.008), whereas plasma miR-146a was inversely associated with N stage (Pâ=â.003), TNM stage (Pâ=â.003), and ECOG performance (Pâ=â.011). Moreover, tissue miR-146b was negatively correlated with gender (Pâ=â.043) and T stage (Pâ=â.047). Kaplan-Meier curves suggested that high expression of tissue miR-146a (Pâ<â.001) and plasma miR-146a (Pâ=â.029) were correlated with prolonged OS. Nevertheless, no association of miR-146b expression in tumor tissue (Pâ=â.187) and plasma (Pâ=â.336) with OS was discovered. Univariate analysis indicated that both tissue miR-146a (Pâ<â.001) and plasma miR-146a (Pâ=â.035) could predict better OS, whereas multivariate analysis revealed that only tissue miR-146a (Pâ=â.001) high expression was an independent factor for prolonged OS.Both plasma and tissue miR-146a expression correlated with favorable OS, whereas only tissue miR-146a was an independent prognostic biomarker in surgical patients with ICC.