Mitochondrial oxidative stress has been suggested as a major etiological factor in cardiovascular diseases. Manganese superoxide dismutase (MnSOD) is an essential antioxidant mitochondrial enzyme. Although polyphenols can induce MnSOD expression, their mechanism of action remains unclear. We examined the effect of bavachalcone, a bioactive compound isolated from Psoralea corylifolia, on MnSOD protein expression and explored whether this effect is mediated through the AMP-activated protein kinase (AMPK) signaling pathway. Our data showed that bavachalcone enhanced the luciferase activity of the MnSOD promoter and increased MnSOD mRNA and protein expressions. Moreover, bavachalcone suppressed the mitochondrial superoxide production in endothelial cells. Conversely, bavachalcone stimulated liver kinase B1 and AMPKα phosphorylation. mRNA interference by using short hairpin RNA (shRNA) of AMPK inhibited bavachalcone-induced MnSOD expression. A-769662, an AMPK activator, also stimulated AMPK activity and increased MnSOD expression. Furthermore, AMPK knockdown by shRNA-AMPK reversed the inhibitory effects of bavachalcone on mitochondrial superoxide production in endothelial cells. These findings indicate that bavachalcone can protect the endothelial function by increasing AMPK activity and MnSOD expression and reducing mitochondrial oxidative stress.
The circadian clock regulates many aspects of (patho)physiology in the central nervous system and in the peripheral tissues. RAR-related orphan receptor α (RORα), an orphan nuclear receptor, is involved in circadian rhythm regulation, including regulation of cardiovascular function. Bavachalcone, a prenylchalcone, is a major bioactive chalcone isolated from Psoralea corylifolia. This natural ingredient activated RORα1 luciferase reporter activity on drug screening. In addition, bavachalcone induced RORα1 expression in mRNA and protein levels in a dose-dependent manner and enhanced the circadian amplitude of Bmal1 mRNA expression after serum shock. Moreover, bavachalcone suppressed senescence in human endothelial cells and mRNA expression of p16ink4a (a marker of replicative senescence) and IL-1α (a proinflammatory cytokine of the senescence-associated secretory phenotype). These inhibitory effects were partially reversed by the RORα inhibitor VPR-66. Our results demonstrate that bavachalcone, as a natural medicine ingredient, has a pharmacological function in regulating RORα1.
The longevity gene klotho has numerous physiological functions, such as regulating calcium and phosphorus levels, delaying senescence, improving cognition, reducing oxidative stress, and protecting vascular endothelial cells. This study tested whether 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a small molecule with antiaging effects, regulates the expression and physiological effects of klotho. Our results showed that THSG dose-dependently increased the luciferase reporter activity of the klotho gene, reversed the decrease in mRNA and protein expression of klotho which was induced by angiotensin II in NRK-52E renal tubular epithelial cells, and increased klotho mRNA expression in the cerebral cortex, hippocampus, testis, and kidney medulla of spontaneously hypertensive rats. THSG also reduced the number of senescent cells induced by angiotensin II and improved the antioxidant capacity and enhanced the bone strength in vivo. Based on klotho's role in promoting cognition, regulating bone metabolism, and improving renal function, the effect of THSG on klotho expression will be beneficial to the functional improvement or enhancement of the expressed organs or tissues.
Hypertension is a common health problem that substantially increases the risk of cardiovascular disease. The condition increases blood pressure, which causes alterations in vascular structure and leads to the development of vascular pathologies. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a resveratrol analogue extracted from a Chinese medicinal plant, has been proven to have numerous vascular protection functions. This study investigated whether THSG can improve vascular remodeling, which has thus far remained unclear. Orally administering THSG to spontaneously hypertensive rats (SHRs) aged 12 weeks for 14 weeks significantly inhibited intima-media thickness in the lower parts of the aortic arch, increased the vascular diastolic rate in response to acetylcholine, and reduced remodelling-related mRNA expression, such as that of ACTA2, CCL3, COL1A2, COL3A1, TIMP1 WISP2, IGFBP1, ECE1, KLF5, MYL1 BMP4, FN1, and PAI-1. Immunofluorescence staining also showed an inhibitory effect similar to that of THSG on PAI-1 protein expression in rat aortas. Results from immunoprecipitation and a Western blot assay showed that THSG inhibited the acetylation of Smad3. A chromatin immunoprecipitation assay showed that THSG prevented Smad3 binding to the PAI-1 proximal promoter in SHR aortas. In conclusion, our results demonstrated that the inhibitory effect of THSG on aortic remodelling involved the deacetylating role of Smad3 with increasing blood flow and with constant blood pressure.
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