An optimized machine learning method for predicting wogonin therapy for the treatment of pulmonary hypertension.

Human health is at risk from pulmonary hypertension (PH), characterized by decreased pulmonary vascular resistance and constriction of the pulmonary vessels, resulting in right heart failure and dysfunction. Thus, preventing PH and monitoring its progression before treating it is vital. Wogonin, derived from the leaves of Scutellaria baicalensis Georgi, exhibits remarkable pharmacological activity. In this study, we examined the effectiveness of wogonin in mitigating the progression of PH in mice using right heart catheterization and hematoxylin-eosin (HE) staining. As an alternative to minimize the possibility of harming small animals, we present a scientifically effective feature selection method (BSCDWOA-KELM) that will allow us to develop a novel simpler noninvasive prediction method for wogonin in treating PH. In this method, we use the proposed enhanced whale optimizer (SCDWOA) in conjunction with the kernel extreme learning machine (KELM). Initially, we let SCDWOA perform global optimization experiments on the IEEE CEC2014 benchmark function set to verify its core advantages. Lastly, 12 public and PH datasets are examined for feature selection experiments using BSCDWOA-KELM. As shown in the experimental results for global optimization, the proposed SCDWOA has better convergence performance. Meanwhile, the proposed binary SCDWOA (BSCDWOA) significantly improves the ability of KELM to classify data. By utilizing the BSCDWOA-KELM, key indicators such as the Red blood cell (RBC), the Haemoglobin (HGB), the Lymphocyte percentage (LYM%), the Hematocrit (HCT), and the Red blood cell distribution width-size distribution (RDW-SD) can be efficiently screened in the Pulmonary hypertension dataset, and one of its most essential points is its accuracy of greater than 0.98. Consequently, the BSCDWOA-KELM introduced in this study can be used to predict wogonin therapy for treating pulmonary hypertension in a simple and noninvasive manner.

Elucidation of the Mechanisms and Molecular Targets of Qishen Yiqi Formula for the Treatment of Pulmonary Arterial Hypertension using a Bioinformatics/Network Topology-based Strategy.

BACKGROUND AND OBJECTIVE: Qishen Yiqi formula (QSYQ) is used to treat cardiovascular disease in the clinical practice of traditional Chinese medicine. However, few studies have explored whether QSYQ affects pulmonary arterial hypertension (PAH), and the mechanisms of action and molecular targets of QSYQ for the treatment of PAH are unclear. A bioinformatics/network topology-based strategy was used to identify the bioactive ingredients, putative targets, and molecular mechanisms of QSYQ in PAH. METHODS: A network pharmacology-based strategy was employed by integrating active component gathering, target prediction, PAH gene collection, network topology, and gene enrichment analysis to systematically explore the multicomponent synergistic mechanisms. RESULTS: In total, 107 bioactive ingredients of QSYQ and 228 ingredient targets were identified. Moreover, 234 PAH-related differentially expressed genes with a |fold change| >2 and an adjusted P value < 0.005 were identified between the PAH patient and control groups, and 266 therapeutic targets were identified. The pathway enrichment analysis indicated that 85 pathways, including the PI3K-Akt, MAPK, and HIF-1 signaling pathways, were significantly enriched. TP53 was the core target gene, and 7 other top genes (MAPK1, RELA, NFKB1, CDKN1A, AKT1, MYC, and MDM2) were the key genes in the gene-pathway network based on the effects of QSYQ on PAH. CONCLUSION: An integrative investigation based on network pharmacology may elucidate the multicomponent synergistic mechanisms of QSYQ in PAH and lay a foundation for further animal experiments, human clinical trials and rational clinical applications of QSYQ.

Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling.

BACKGROUND: Baicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A2A receptor (A2AR) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo. METHODS: We established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A2AR knockout (A2AR-/-) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A2AR agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A2AR expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured. RESULTS: Compared with WT mice, A2AR-/- mice exhibited increased right ventricular systolic pressure (RVSP), right ventricle-to-left ventricle plus septum [RV/(LV + S)] ratio, RV weight-to-body weight (RV/BW) ratio, and lung wet weight-to-body weight (Lung/BW) ratio in the absence of an altered mean carotid arterial pressure (mCAP). These changes were accompanied by increases in pulmonary artery wall area and thickness and reductions in arterial oxygen pressure (PaO2) and hydrogen ion concentration (pH). In the HPH model, A2AR-/- mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A2AR-/- HPH mice with baicalin or CGS21680 attenuated the hypoxia-induced increases in RVSP, RV/(LV + S) and Lung/BW, as well as pulmonary arterial remodeling. Additionally, baicalin or CGS21680 alone could reverse the hypoxia-induced increases in CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression. Moreover, baicalin improved the hypoxemia induced by 4 weeks of hypoxia. Finally, we found that A2AR levels in WT lung tissue were enhanced by hypoxia and that baicalin up-regulated A2AR expression in WT hypoxic mice. CONCLUSIONS: Baicalin exerts protective effects against clinical HPH, which are partly mediated through enhanced A2AR activity and down-regulated SDF-1/CXCR4-induced PI3K/AKT signaling. Therefore, the A2AR may be a promising target for baicalin in treating HPH.

The potential of asiaticoside for TGF-ß1/Smad signaling inhibition in prevention and progression of hypoxia-induced pulmonary hypertension.

AIMS: Asiaticoside (AS) is a saponin monomer extracted from the medicinal plant Centella asiatica, which has a variety of biological effects. We intended to investigate the effects of asiaticoside on a hypoxia-induced pulmonary hypertension (HPH) rat model and examine the possible effects of asiaticoside on TGF-ß1/Smad signaling in vivo and in vitro. MAIN METHODS: The rat HPH model was established by hypoxic exposure and asiaticoside was administered for four weeks. Parameters including the mean pulmonary artery pressure (mPAP), the right ventricular hypertrophy (RVH) and the percentage of medial wall thickness were used to evaluate the development of HPH. TGF-ß1, TGF-ß receptor, Smad2/3 and phospho-Smad2/3 expressions were detected and the proliferation, migration and apoptosis of pulmonary arterial smooth muscle cells (PASMCs) adjusted by asiaticoside under the hypoxic condition were evaluated. KEY FINDINGS: Our data indicate that asiaticoside attenuated pulmonary hypertension, pulmonary vascular remodeling and RV hypertrophy in HPH rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-ß1/Smad2/3 signaling and inhibiting the proliferation by inducing apoptosis of the PASMCs. SIGNIFICANCE: Given the preventative potential in animal models and in vitro, we propose asiaticoside as a promising protective treatment in HPH.