Echinacoside inhibited cardiomyocyte pyroptosis and improved heart function of HF rats induced by isoproterenol via suppressing NADPH/ROS/ER stress.

Prevalence of heart failure (HF) continues to rise over time and is a global difficult problem; new drug targets are urgently needed. In recent years, pyroptosis is confirmed to promote cardiac remodelling and HF. Echinacoside (ECH) is a natural phenylethanoid glycoside and is the major active component of traditional Chinese medicine Cistanches Herba, which is reported to possess powerful anti-oxidation and anti-inflammatory effects. In addition, we previously reported that ECH reversed cardiac remodelling and improved heart function, but the effect of ECH on pyroptosis has not been studied. So, we investigated the effects of ECH on cardiomyocyte pyroptosis and the underlying mechanisms. In vivo, we established HF rat models induced by isoproterenol (ISO) and pre-treated with ECH. Indexes of heart function, pyroptotic marker proteins, ROS levels, and the expressions of NOX2, NOX4 and ER stress were measured. In vitro, primary cardiomyocytes of neonatal rats were treated with ISO and ECH; ASC speckles and caspase-1 mediated pyroptosis in cardiomyocytes were detected. Hoechst/PI staining was also used to evaluate pyroptosis. ROS levels, pyroptotic marker proteins, NOX2, NOX4 and ER stress levels were all tested. In vivo, we found that ECH effectively inhibited pyroptosis, down-regulated NOX2 and NOX4, decreased ROS levels, suppressed ER stress and improved heart function. In vitro, ECH reduced cardiomyocyte pyroptosis and suppressed NADPH/ROS/ER stress. We concluded that ECH inhibited cardiomyocyte pyroptosis and improved heart function via suppressing NADPH/ROS/ER stress.

Echinacoside reverses myocardial remodeling and improves heart function via regulating SIRT1/FOXO3a/MnSOD axis in HF rats induced by isoproterenol.

Myocardial remodelling is important pathological basis of HF, mitochondrial oxidative stress is a promoter to myocardial hypertrophy, fibrosis and apoptosis. ECH is the major active component of a traditional Chinese medicine Cistanches Herba, plenty of studies indicate it possesses a strong antioxidant capacity in nerve cells and tumour, it inhibits mitochondrial oxidative stress, protects mitochondrial function, but the specific mechanism is unclear. SIRT1/FOXO3a/MnSOD is an important antioxidant axis, study finds that ECH binds covalently to SIRT1 as a ligand and up-regulates the expression of SIRT1 in brain cells. We hypothesizes that ECH may reverse myocardial remodelling and improve heart function of HF via regulating SIRT1/FOXO3a/MnSOD signalling axis and inhibit mitochondrial oxidative stress in cardiomyocytes. Here, we firstly induce cellular model of oxidative stress by ISO with AC-16 cells and pre-treat with ECH, the level of mitochondrial ROS, mtDNA oxidative injury, MMP, carbonylated protein, lipid peroxidation, intracellular ROS and apoptosis are detected, confirm the effect of ECH in mitochondrial oxidative stress and function in vitro. Then, we establish a HF rat model induced by ISO and pre-treat with ECH. Indexes of heart function, myocardial remodelling, mitochondrial oxidative stress and function, expression of SIRT1/FOXO3a/MnSOD signalling axis are measured, the data indicate that ECH improves heart function, inhibits myocardial hypertrophy, fibrosis and apoptosis, increases the expression of SIRT1/FOXO3a/MnSOD signalling axis, reduces the mitochondrial oxidative damages, protects mitochondrial function. We conclude that ECH reverses myocardial remodelling and improves cardiac function via up-regulating SIRT1/FOXO3a/MnSOD axis and inhibiting mitochondrial oxidative stress in HF rats.

Polyphyllin I attenuates pressure over-load induced cardiac hypertrophy via inhibition of Wnt/ß-catenin signaling pathway.

AIMS: Cardiac hypertrophy is one of most important risk factors for cardiovascular mortality. Activation of Wnt/ß-catenin signaling pathway is acknowledged to be an important mechanism for pathogenesis of cardiac hypertrophy. Polyphyllin I (PPI), a component in the traditional Chinese medicinal herb, has shown anticancer effect partially via interruption of Wnt/ß-catenin signaling pathway. Our aim was to test whether PPI attenuates cardiac hypertrophy. MATERIALS AND METHODS: Adult male C57BL/6J mice were subjected to either pressure overload generated by transverse aortic constriction (TAC) or sham surgery (control group). Angiotensin-II (Ang-II) was used to induce cardiomyocyte hypertrophy in vitro. PPI was intraperitoneally administrated daily for 4 weeks after TAC surgery and then cardiac function was determined by echocardiography and histological analysis was performed. KEY FINDINGS: PPI significantly ameliorated cardiac dysfunction of mice subjected to TAC. Meanwhile, PPI attenuated TAC induced cardiac hypertrophy indicated by blunted increase in heart mass, cross section area of cardiomyocyte, cardiac fibrosis and expression of hypertrophic biomarkers ANP, BNP and ß-MHC. In addition, PPI also ameliorated Ang-II induced cardiomyocyte hypertrophy in vitro. Importantly, PPI decreased protein expression of active ß-catenin/total ß-catenin, phosphorylation of GSK3ß and Wnt target genes c-myc, c-jun, c-fos and cyclin D1 and its anti-hypertrophic effect was blunted by supplementation of Wnt 3a. SIGNIFICANCE: Our results suggest that PPI attenuates cardiac dysfunction and attenuate development of pressure over-load induced cardiac hypertrophic via suppressing Wnt/ß-catenin signaling pathway. PPI might be a candidate drug for treatment of cardiac hypertrophy.

Bioactive gentixanthone and gentichromone from the whole plants of Gentianella acuta (Michx.) Hulten.

Five new compounds, gentixanthones A1 (1), A2 (2), and gentichromones A1-A3 (3-5), together with thirteen known xanthones (6-18) were obtained from the whole plants of Gentianella acuta (Michx.) Hulten. Their structures were elucidated by chemical and spectroscopic methods. Among them, compounds 6, 8, 13, 14, and 17 were obtained from Gentianella genus firstly, and 7, 12, 15, 16, and 18 were isolated from this plant for the first time. Meanwhile, inhibitory effects of 1-18 on motility of mouse isolated intestine tissue were determined. As results, xanthones 1, 2, 6, 7, 9, 10 and 14 were found to have significant reduce effect on intestine contraction tension, and structure-activity relationship was discussed.

Protective effects of Weilikang decoction on gastric ulcers and possible mechanisms.

Although Weilikang decoction (WLK) has been used for gastric ulcer (GU) therapy in a clinical setting with good curative effect for >20 years, the mechanism remains unclear. Several GU animal models, induced by ethanol, hydrochloric acid, aspirin, pylorus ligation, acetic acid and indomethacin, were used to investigate the gastroprotective effects of WLK decoction. Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), indomethacin, and N-ethylmaleimide (NEM) were pretreated, respectively, to investigate the action mechanism. Real-time polymerase chain reaction and Western blot analysis methods were used to determine the effects of WLK on indomethacin-induced GUs. The WLK-administered groups (2.5, 1.25 and 0.625 g/kg) significantly reduced the GU areas induced by ethanol, hydrochloric acid and aspirin. Furthermore, the effects could be quenched by L-NAME and NEM, but not by indomethacin. The 2.5 and 1.25 g/kg WLK groups showed significantly decreased effects on GU areas induced by pylorus ligation and acetic acid. WLK treatment significantly decreased mRNA expression on cyclooxygenase (COX)-1, COX-2, interleukin-6, tumor necrosis factor α and inducible nitric oxide synthase (iNOS) mRNA, but showed no effect on endothelial nitric oxide synthase mRNA expression. Western blot analysis result showed that WLK-treated groups markedly downregulated COX-2 protein expression. The anti-ulcer potential of WLK can be primarily attributed to its regulatory effects on nitric oxide, sulfhydryl compounds, and reduction effect on mucosal expression of proinflammatory cytokines.