Wogonin protects against bleomycin-induced mouse pulmonary fibrosis via the inhibition of CDK9/p53-mediated cell senescence.

Pulmonary fibrosis (PF) is a fatal interstitial lung disease associated with declining pulmonary function but currently with few effective drugs. Cellular senescence has been implicated in the pathogenesis of PF and could be a potential therapeutic target. Emerging evidence suggests wogonin, the bioactive compound isolated from Scutellaria baicalensis, owns the anti-senescence properties, however, the possible impact of wogonin on PF and the potential mechanisms remain unclear. In this study, a well-established mouse model of PF was utilized which mice were administrated with bleomycin (BLM). Strikingly, wogonin treatment significantly reduced fibrosis deposition in the lung induced by BLM. In vitro, wogonin also suppressed fibrotic markers of cultured epithelial cells stimulated by BLM or hydrogen peroxide. Mechanistic investigation revealed that wogonin attenuated the expressions of DNA damage marker γ-H2AX and senescence-related markers including phosphorylated p53, p21, retinoblastoma protein (pRB), and senescence-associated ß-galactosidase (SA-ß-gal). Moreover, wogonin, as a direct and selective inhibitor of cyclin-dependent kinase 9 (CDK9), exhibited anti-fibrotic capacity by inhibiting CDK9 and p53/p21 signalling. In conclusion, wogonin protects against BLM-induced PF in mice through the inhibition of cell senescence via the regulation of CDK9/p53 and DNA damage pathway. This is the first study to demonstrate the beneficial effect of wogonin on PF, and its implication as a novel candidate for PF therapy.

[Research progress on the role and mechanism of endothelial dysfunction in hyperhomocysteine-induced atherosclerosis].

Hyperhomocysteinemia (HHcy) is considered to be an independent risk factor for cardiovascular diseases, but the molecular mechanisms underlying its pathogenesis are not fully understood. Endothelial dysfunction is a key initiating factor in the pathogenesis of atherosclerosis, which is commonly observed in almost all HHcy-induced vascular diseases. HHcy promotes oxidative stress, inhibits nitric oxide production, suppresses hydrogen sulfide signaling pathway, promotes endothelial mesenchymal transition, activates coagulation pathways, and promotes protein N-homocysteination and cellular hypomethylation, all of which can cause endothelial dysfunction. This article reviews the specific links between HHcy and endothelial dysfunction, and highlights recent evidence that endothelial mesenchymal transition contributes to HHcy-induced vascular damage, with a hope to provide new ideas for the clinical treatment of HHcy-related vascular diseases.

Advances in the role of epigenetics in homocysteine-related diseases.

Homocysteine has a wide range of biological effects. However, the specific molecular mechanism of its pathogenicity is still unclear. The diseases induced by hyperhomocysteinemia (HHcy) are called homocysteine-related diseases. Clinical treatment of HHcy is mainly through folic acid and B-complex vitamins, which are not effective in reducing the associated end point events. Epigenetics is the alteration of heritable genes caused by DNA methylation, histone modification, noncoding RNAs and chromatin remodeling without altering the DNA sequence. In recent years the role of epigenetics in homocysteine-associated diseases has been gradually discovered. This article summarizes the latest evidence on the role of epigenetics in HHcy, providing new directions for its prevention and treatment.

Advances in the study of nicotinamide adenine dinucleotide phosphate oxidase in myocardial remodeling.

Myocardial remodeling is a key pathophysiological basis of heart failure, which seriously threatens human health and causes a severe economic burden worldwide. During chronic stress, the heart undergoes myocardial remodeling, mainly manifested by cardiomyocyte hypertrophy, apoptosis, interstitial fibrosis, chamber enlargement, and cardiac dysfunction. The NADPH oxidase family (NOXs) are multisubunit transmembrane enzyme complexes involved in the generation of redox signals. Studies have shown that NOXs are highly expressed in the heart and are involved in the pathological development process of myocardial remodeling, which influences the development of heart failure. This review summarizes the progress of research on the pathophysiological processes related to the regulation of myocardial remodeling by NOXs, suggesting that NOXs-dependent regulatory mechanisms of myocardial remodeling are promising new therapeutic targets for the treatment of heart failure.

Celastrol: A Promising Agent Fighting against Cardiovascular Diseases.

Cardiovascular diseases (CVD) are leading causes of morbidity and mortality worldwide; therefore, seeking effective therapeutics to reduce the global burden of CVD has become increasingly urgent. Celastrol, a bioactive compound isolated from the roots of the plant Tripterygium wilfordii (TW), has been attracting increasing research attention in recent years, as it exerts cardiovascular treatment benefits targeting both CVD and their associated risk factors. Substantial evidence has revealed a protective role of celastrol against a broad spectrum of CVD including obesity, diabetes, atherosclerosis, cerebrovascular injury, calcific aortic valve disease and heart failure through complicated and interlinked mechanisms such as direct protection against cardiomyocyte hypertrophy and death, and indirect action on oxidation and inflammation. This review will mainly summarize the beneficial effects of celastrol against CVD, largely based on in vitro and in vivo preclinical studies, and the potential underlying mechanisms. We will also briefly discuss celastrol's pharmacokinetic limitations, which hamper its further clinical applications, and prospective future directions.