Metabolic alterations in human pulmonary artery smooth muscle cells treated with PDGF-BB.

BACKGROUND: Metabolic abnormalities are considered to play a key regulatory role in vascular remodeling of pulmonary arterial hypertension. However, to date, there is a paucity of research documenting the changes in metabolome profiles within the supernatants of pulmonary artery smooth muscle cells (PASMC) during their transition from a contractile to a synthetic phenotype. METHODS: CCK-8 and Edu staining assays were used to evaluate the cell viability and proliferation of human PASMCs. IncuCyte ZOOM imaging system was used to continuously and automatically detect the migration of the PASMCs. A targeted metabolomics profiling was performed to quantitatively analyze 121 metabolites in the supernatant. Orthogonal partial least squares discriminant analysis was used to discriminate between PDGF-BB-induced PASMCs and controls. Metabolite set enrichment analysis was adapted to exploit the most disturbed metabolic pathways. RESULTS: Human PASMCs exhibited a transformation from contractile phenotype to synthetic phenotype after PDGF-BB induction, along with a significant increase in cell viability, proliferation, and migration. Metabolites in the supernatants of PASMCs treated with or without PDGF-BB were well profiled. Eleven metabolites were found to be significantly upregulated, whereas seven metabolites were downregulated in the supernatants of PASMCs induced by PDGF-BB compared to the vehicle-treated cells. Fourteen pathways were involved, and pyruvate metabolism pathway was ranked first with the highest enrichment impact followed by glycolysis/gluconeogenesis and pyrimidine metabolism. CONCLUSIONS: Significant and extensive metabolic abnormalities occurred during the phenotypic transformation of PASMCs. Disturbance of pyruvate metabolism pathway might contribute to pulmonary vascular remodeling.

RNA m6A methylation and regulatory proteins in pulmonary arterial hypertension.

m6A (N6­methyladenosine) is the most common and abundant apparent modification in mRNA of eukaryotes. The modification of m6A is regulated dynamically and reversibly by methyltransferase (writer), demethylase (eraser), and binding protein (reader). It plays a significant role in various processes of mRNA metabolism, including regulation of transcription, maturation, translation, degradation, and stability. Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary vascular disease characterized by abnormal proliferation of pulmonary artery smooth muscle cells. Despite the existence of several effective and targeted therapies, there is currently no cure for PAH and the prognosis remains poor. Recent studies have highlighted the crucial role of m6A modification in cardiovascular diseases. Investigating the role of RNA m6A methylation in PAH could provide valuable insights for drug development. This review aims to explore the mechanism and function of m6A in the pathogenesis of PAH and discuss the potential targeting of RNA m6A methylation modification as a treatment for PAH.

L-Carnitine Alleviates the Myocardial Infarction and Left Ventricular Remodeling through Bax/Bcl-2 Signal Pathway.

Purpose: L-carnitine (LC) is considered to have good therapeutic potential for myocardial infarction (MI), but its mechanism has not been clarified. The aim of the study is to elucidate the cardioprotective effects of LC in mice following MI and related mechanisms. Methods: ICR mice were treated with LC for 2 weeks after induction of MI with ligation of left anterior descending artery. Electrocardiographic (ECG) recording and echocardiography were used to evaluate cardiac function. H&E staining, TTC staining, and Masson staining were performed for morphological analysis and cardiac fibrosis. ELISA and immunofluorescence were utilized to detect biomarkers and inflammatory mediators. The key proteins in the Bax/Bcl-2 signaling pathway were also examined by Western blot. Results: Both echocardiography and histological measurement showed an improvement in cardiac function and morphology. Biomarkers such as LDH, NT-proBNP, cTnT, and AST, as well as the inflammatory cytokines IL-1ß, IL-6, and TNF-α, were decreased in plasma of mice receiving LC treatment after myocardial injury. In addition, the expression of α-SMA as well as the key proteins in the Bax/Bcl-2 signaling pathway in cardiac myocardium were much lower in mice with LC treatment compared to those without after MI. Conclusions: Our data suggest that LC can effectively ameliorate left ventricular (LV) remodeling after MI, and its beneficial effects on myocardial function and remodeling may be attributable at least in part to anti-inflammatory and inhibition of the Bax/Bcl-2 apoptotic signaling pathway.

Luteolin alleviates cognitive impairment in Alzheimer's disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation.

Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer's disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg-1 · d-1, ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL-1ß, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 µM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.