Early Application of Sacubitril Valsartan Sodium After Acute Myocardial Infarction and its Influence on Ventricular Remodeling and TGF-ß1/Smad3 Signaling Pathway.

Objective: The objective of this study was to investigate the early application of sacubitril valsartan sodium (LCZ696) following acute myocardial infarction (AMI) and its impact on ventricular remodeling and the TGF-ß1/Smad3 signaling pathway in patients. Methods: The clinical data of 73 patients with AMI admitted to the hospital from June 2021 to September 2022 were retrospectively analyzed, and the patients were grouped according to the treatment methods, including 36 cases in the control group (conventional drug treatment) and 37 cases in the observation group (conventional drug + LCZ696 treatment). The clinical efficacy, cardiac function parameters [left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), stroke volume (SV)], cardiac function biochemical indicators [N-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin 3 (Gal-3), amino-terminal peptide of type III procollagen (PIIINP)], ventricular remodeling indicators [left ventricular posterior wall end-diastolic thickness (PWD), posterior wall end-systolic thickness (PWS), ventricular septal end-systolic thickness (IVSS)], ventricular hydrodynamic parameters [left ventricular flow rate in peak ejection (FRPE), flow reversal rate (FRR), flow reversal interval (FRI)], TGF-ß 1/Smad3 signaling pathway-related indicators (TGF-ß1, Smad3), quality of life score (SF-36 Quality of Life Scale) and occurrence of adverse reactions were compared between the two groups. Results: The main findings of the study are as follows: The observation group was significantly better than the control group in many aspects such as overall clinical effectiveness, cardiac function parameters, biochemical indicators, ventricular structure and function, TGF-ß1/Smad3 signaling pathway, and quality of life. Specifically, the observation group showed more significant positive effects in terms of improvement of cardiac function, adjustment of biochemical status, and adjustment of ventricular structure and fluid dynamics parameters. These results provide strong support for the application of new therapeutic approaches in the management of cardiovascular disease. After treatment, the total clinical effective rate in the observation group (89.19%) was significantly higher than that in the control group (69.44%) (P < .05). LVEF and SV in the two groups were significantly increased (P < .05), while LVEDD was significantly decreased (P < .05), and there were statistically significant differences in parameters between the two groups (P < .05). The levels of NT-proBNP, Gal-3 and PIIINP in both groups were significantly reduced (P < .05), and the levels in the observation group were significantly lower than those in the control group (P < .05). The PWD, PWS and IVSS in both groups significantly declined (P < .05), and the indicators in the observation group were significantly lower than those in the control group (P < .05). The FRPE and FRR in the two groups were significantly enhanced (P < .05), while the FRI was significantly reduced (P < .05), and the differences in the above parameters between the two groups were statistically significant (P < .05). The levels of TGF-ß1 and Smad3 in the two groups were significantly declined (P < .05), and the levels in the observation group were significantly lower than those in the control group (P < .05). During the period from before treatment to 6 months of treatment, the quality of life score in the two groups showed a significant downward trend (P < .05), and the score in the observation group after 3 months to 6 months of treatment was significantly lower than that in the control group (P < .05). During treatment, there was no statistical significance in the total incidence rate of adverse reactions between the two groups (P > .05). Conclusion: Early application of LCZ696 after AMI has a significant efficacy, and it can effectively improve the ventricular remodeling, regulate the expression levels of TGF-ß1 and Smad3, inhibit the TGF-ß1/Smad3 signaling pathway, promote the improvements of cardiac function and quality of life, and it has good safety and is worthy of clinical promotion and application. The study's key findings have important clinical implications for understanding and managing acute myocardial infarction (AMI). The observation group showed significant improvements in overall clinical efficacy, cardiac function, biochemical status, ventricular structure and function, etc., providing strong evidence for comprehensive treatment of AMI patients. This treatment method is expected to become an important part of the care and treatment strategy for AMI patients, help reduce cardiovascular risk, improve quality of life, and provide new research directions for future AMI treatment.

[IFN-alpha-induced gp96 upregulation negatively affects the anti-HBV efficiency of IFN-alpha].

OBJECTIVE: To investigate the effect of the Interferon-alpha-induced gp96 upregulation on the anti-HBV efficiency of Interferon-alpha (IFN-alpha). METHODS: The effect of IFN-alpha on the transcription and expression of heat shock protein gp96 was determined by real-time PCR, luciferase reporter assay and Western blot. The effect of over-expression or knock-down of gp96 by transfection or RNA interference, and treatment with IFN-alpha on HBV expression and replication was examined by ELISA and RT-PCR. RESULTS: IFN-alpha treatment led to increased gp96 expression in a time- and dose-dependent manner. The overexpression of gp96 enhanced HBV expression and replication, whereas downregulation of gp96 resulted in decreased HBV replication. Finally, we verified that blocking IFN-alpha-induced upregulation of gp96 significantly enhanced IFN-alpha-mediated HBV inhibitory effects. CONCLUSION: IFN-alpha-induced upregulation of gp96 may negatively affect the anti-HBV function of IFN-alpha. These data provide valuable insight for enhancing the antiviral efficacy of IFN-alpha by simultaneous inhibition of gp96.

miR­21/PTEN pathway mediates the cardioprotection of geniposide against oxidized low­density lipoprotein­induced endothelial injury via suppressing oxidative stress and inflammatory response.

Oxidized low­density lipoprotein (ox­LDL)­induced vascular endothelial damage, oxidative stress and inflammation play a vital role in the pathophysiology of atherosclerosis. Geniposide is the primary active ingredient from Gardenia jasminoides Ellis associated with anti­oxidative properties and cardioprotective action. However, the therapeutic mechanism of geniposide in atherosclerosis remains unclear. Hence, the present study aimed to elucidate the underlying mechanisms of geniposide in oxidative stress and inflammatory response during ox­LDL injury in human umbilical vein endothelial cells (HUVECs), focusing particularly on the microRNA (miR)­21/PTEN pathway. The results demonstrated that geniposide pretreatment significantly increased cell viability, decreased lactate dehydrogenase release, increased miR­21 level and decreased PTEN expression under ox­LDL condition. Subsequently, transfection with miR­21 mimic enhanced the protection of geniposide on ox­LDL­induced cytotoxicity and apoptosis (mediated by the upregulation of apoptotic rate and caspase­3 activity), whereas miR­21 inhibitor reversed these effects of geniposide. In addition, geniposide resulted in an anti­oxidant effect as evidenced by the decrease in reactive oxygen species generation, malondialdehyde content and NADPH oxidase 2 expression, and the increase in superoxide dismutase, glutathione peroxidase and catalase activities in ox­LDL­treated HUVECs, which were exacerbated by miR­21 mimic and reversed by miR­21 inhibitor. Furthermore, geniposide mitigated the ox­LDL­induced inflammatory response, demonstrated by a downregulation of pro­inflammatory cytokine (IL­1ß, IL­6, and TNF­α) levels and an upregulation of anti­inflammatory cytokine (IL­10) level. However, miR­21 mimic enhanced, whereas miR­21 inhibitor attenuated, these effects of geniposide. In conclusion, the present results indicated that geniposide protects HUVECs from ox­LDL injury by inhibiting oxidative stress and inflammation, and that these effects are partly due to the enhancement of the miR­21/PTEN pathway.

Increased expression of Gp96 by HBx-induced NF-κB activation feedback enhances hepatitis B virus production.

Elevated expression of heat shock protein gp96 in hepatitis B virus (HBV)-infected patients is positively correlated with the progress of HBV-induced diseases, but little is known regarding the molecular mechanism of virus-induced gp96 expression and its impact on HBV infection. In this study, up-regulation of gp96 by HBV replication was confirmed both in vitro and in vivo. Among HBV components, HBV x protein (HBx) was found to increase gp96 promoter activity and enhance gp96 expression by using a luciferase reporter system, and western blot analysis. Further, we found that HBx-mediated regulation of gp96 expression requires a NF-κB cis-regulatory element on the gp96 promoter, and chromatin immunoprecipitation results demonstrated that HBx promotes the binding of NF-κB to the gp96 promoter. Significantly, both gain- and loss-of-function studies showed that gp96 enhances HBV production in HBV-transfected cells and a mouse model based on hydrodynamic transfection. Moreover, up-regulated gp96 expression was observed in HBV-infected patients, and gp96 levels were correlated with serum viral loads. Thus, our work demonstrates a positive feedback regulatory pathway involving gp96 and HBV, which may contribute to persistent HBV infection. Our data also indicate that modulation of gp96 function may represent a novel strategy for the intervention of HBV infection.