The emerging role of sacubitril/valsartan in pulmonary hypertension with heart failure.

Pulmonary hypertension due to left heart disease (PH-LHD) represents approximately 65%-80% of all patients with PH. The progression, prognosis, and mortality of individuals with left heart failure (LHF) are significantly influenced by PH and right ventricular (RV) dysfunction. Consequently, cardiologists should devote ample attention to the interplay between HF and PH. Patients with PH and HF may not receive optimal benefits from the therapeutic effects of prostaglandins, endothelin receptor antagonists, or phosphodiesterase inhibitors, which are specific drugs for pulmonary arterial hypertension (PAH). Sacubitril/valsartan, the angiotensin receptor II blocker-neprilysin inhibitor (ARNI), was recommended as the first-line therapy for patients with heart failure with reduced ejection fraction (HFrEF) by the 2021 European Society of Cardiology Guidelines. Although ARNI is effective in treating left ventricular (LV) enlargement and lower ejection fraction, its efficacy in treating individuals with PH and HF remains underexplored. Considering its vasodilatory effect at the pre-capillary level and a natriuretic drainage role at the post-capillary level, ARNI is believed to have a broad range of potential applications in treating PH-LHD. This review discusses the fundamental pathophysiological connections between PH and HF, emphasizing the latest research and potential benefits of ARNI in PH with various types of LHF and RV dysfunction.

Glutathione S-Transferase Alpha 4 Promotes Proliferation and Chemoresistance in Colorectal Cancer Cells.

Glutathione S-transferase alpha 4 (GSTA4) is a phase II detoxifying enzyme that is overexpressed in colorectal cancer (CRC) and regulated by the oncogenic transcription factor AP-1. However, the role of GSTA4 in these CRC cells remains unclear. In this study, we investigated the roles of GSTA4 in the CRC cells by inactivating GSTA4 in HCT116 human CRC cells (Defined as HCT116ΔGSTA4) using the CRISPR/Cas9 gene editing. Cell proliferation, clonogenicity, and susceptibility to chemotherapeutic drugs were analyzed in vitro and in a xenograft model. The results showed that loss of GSTA4 significantly decreased cell proliferation and clonogenicity, whereas it increased intracellular reactive oxygen species and cell susceptibility to 5-fluorouracil (5-FU) and oxaliplatin. Additionally, exposure of HCT116ΔGSTA4 cells to 5-FU increased the expression of γH2AX, a hallmark of double-stranded DNA breaks. In contrast, no remarkably increased γH2AX was noted in oxaliplatin-treated HCT116ΔGSTA4 cells compared with HCT116 cells. Moreover, loss of GSTA4 blocked the AKT and p38 MAPK pathways, leading to proliferative suppression. Finally, the xenograft model showed decreased tumor size for HCT116ΔGSTA4 cells compared with HCT116 cells, confirming in vitro findings. These findings suggest that GSTA4 is capable of promoting proliferation, tumorigenesis, and chemoresistance and is a potential target for CRC therapy.

A Signature for Smoking Status of Coronary Heart Disease Patients through Weighted Gene Coexpression Network Analysis.

BACKGROUND: Smoking is one of the risk factors of coronary heart disease (CHD), while its underlying mechanism is less well defined. PURPOSE: To identify and testify 6 key genes of CHD related to smoking through weighted gene coexpression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and pathway analysis. METHODS: CHD patients' samples were first downloaded from Gene Expression Omnibus (GEO). Then, genes of interest were obtained after analysis of variance (ANOVA). Thereafter, 23 coexpressed modules that were determined after genes with similar expression were incorporated via WGCNA. The biological functions of genes in the modules were researched by enrichment analysis. Pearson correlation analysis and PPI network analysis were used to screen core genes related to smoking in CHD. RESULTS: The violet module was the most significantly associated with smoking (r = -0.28, p = 0.006). Genes in this module mainly participated in biological functions related to the heart. Altogether, 6 smoking-related core genes were identified through bioinformatics analyses. Their expressions in animal models were detected through the animal experiment. CONCLUSION: This study identified 6 core genes to serve as underlying biomarkers for monitoring and predicting smoker's CHD risk.

Construction of a Support Vector Machine-Based Classifier for Pulmonary Arterial Hypertension Patients.

Pulmonary arterial hypertension (PAH) is a disease leading to right heart failure and death due to increased pulmonary arterial tension and vascular resistance. So far, PAH has not been fully understood, and current treatments are much limited. Gene expression profiles of healthy people and PAH patients in GSE33463 dataset were analyzed in this study. Then 110 differentially expressed genes (DEGs) were obtained. Afterward, the PPI network based on DEGs was constructed, followed by the analysis of functional modules, whose results showed that the genes in the major function modules significantly enriched in immune-related functions. Moreover, four optimal feature genes were screened from the DEGs by support vector machine-recursive feature elimination (SVM-RFE) algorithm (EPB42, IFIT2, FOSB, and SNF1LK). The receiver operating characteristic curve showed that the SVM classifier based on optimal feature genes could effectively distinguish healthy people from PAH patients. Last, the expression of optimal feature genes was analyzed in the GSE33463 dataset and clinical samples. It was found that EPB42 and IFIT2 were highly expressed in PAH patients, while FOSB and SNF1LK were lowly expressed. In conclusion, the four optimal feature genes screened here are potential biomarkers for PAH and are expected to be used in early diagnosis for PAH.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.

Besides being powerhouses of the cell, mitochondria released into extracellular space act as intercellular signaling. Mitochondria and their components mediate cell-to-cell communication in free form or embedded in a carrier. The pathogenesis of cardiovascular disease is complex, which shows close relationship with inflammation and metabolic abnormalities. Since mitochondria sustain optimal function of the heart, extracellular mitochondria are emerging as a key regulator in the development of cardiovascular disease. In this review, we provide recent findings in the presence and forms of mitochondria transfer between cells, as well as the effects of these mitochondria on vascular inflammation and ischemic myocardium. Mitochondrial transplantation is a novel treatment paradigm for patients suffering from acute cardiovascular accident and challenges the traditional methods of mitochondria isolation.

Optimization of Ring Laser Gyroscope Bias Compensation Algorithm in Variable Temperature Environment.

In a high accuracy strapdown inertial navigation system (SINS), the ring laser gyroscope's (RLG) bias changes and the performance decreases due to factors in the RLG's self-heating and changes in ambient temperature. Therefore, it is important to study the bias temperature drift characteristics of RLGs in high, low, and variable temperature environments. In this paper, a composite temperature calibration scheme is proposed. The composite temperature model introduces the derivative term and the temperature derivative cross-multiplier on the basis of the static model and sets the overlap regions for the piecewise least squares fitting. The results show that the composite temperature model can compensate the bias trend term well at ambient temperature, improve the fitting accuracy, and smooth the output curve. The compensation method has a small amount of calculations and flexible parameter design. The precision of the laser gyros in one SINS is improved by about 64.9%, 15.7%, and 3.6%, respectively, which has certain engineering application value.