Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Icariside II alleviates lipopolysaccharide-induced acute lung injury by inhibiting lung epithelial inflammatory and immune responses mediated by neutrophil extracellular traps.

AIMS: Acute lung injury (ALI) is a life-threatening lung disease characterized by inflammatory cell infiltration and lung epithelial injury. Icariside II (ICS II), one of the main active ingredients of Herba Epimedii, exhibits anti-inflammatory and immunomodulatory effects. However, the effect and mechanism of ICS II in ALI remain unclear. The purpose of the current study was to investigate the pharmacological effect and underlying mechanism of ICS II in ALI. MAIN METHODS: Models of neutrophil-like cells, human peripheral blood neutrophils, and lipopolysaccharide (LPS)-induced ALI mouse model were utilized. RT-qPCR and Western blotting determined the gene and protein expression levels. Protein distribution and quantification were analyzed by immunofluorescence. KEY FINDINGS: ICS II significantly reduced lung histopathological damage, edema, and inflammatory cell infiltration, and it reduced pro-inflammatory cytokines in ALI. There is an excessive activation of neutrophils leading to a significant production of NETs in ALI mice, a process mitigated by the administration of ICS II. In vivo and in vitro studies found that ICS II could decrease NET formation by targeting neutrophil C-X-C chemokine receptor type 4 (CXCR4). Further data showed that ICS II reduces the overproduction of dsDNA, a NETs-related component, thereby suppressing cGAS/STING/NF-κB signalling pathway activation and inflammatory mediators release in lung epithelial cells. SIGNIFICANCE: This study suggested that ICS II may alleviate LPS-induced ALI by modulating the inflammatory response, indicating its potential as a therapeutic agent for ALI treatment.