Flavonoid Extract from Propolis Provides Cardioprotection following Myocardial Infarction by Activating PPAR-γ.

We have previously reported that flavonoid extract from propolis (FP) can improve cardiac function in rats following myocardial infarction (MI). However, the mechanisms responsible for the cardioprotective effects of FP have not been fully elucidated. In the current study, we explored whether FP can reduce inflammatory cytokines and attenuate sympathetic nerve system activity and antiendoplasmic reticulum (ER) stress and whether the cardioprotective effects are related to peroxisome proliferator-activated receptor gamma (PPAR-γ) activation. Sprague Dawley rats were randomly divided into six groups: Sham group received the surgical procedure but no artery was ligated; MI group received ligation of the left anterior descending (LAD) branch of the coronary artery; MI + FP group received FP (12.5 mg/kg/d, intragastrically) seven days prior to LAD ligation; FP group (Sham group + 12.5 mg/kg/d, intragastrically); MI + FP + GW9662 group received FP prior to LAD ligation with the addition of a specific PPAR-γ inhibitor (GW9662), 1 mg/kg/d, orally); and MI + GW9662 group received the PPAR-γ inhibitor and LAD ligation. The results demonstrated that the following inflammatory markers were significantly elevated following MI as compared with expression in sham animals: IL-1ß, TNF-α, CRP; markers of sympathetic activation: plasma norepinephrine, epinephrine and GAP43, nerve growth factor, thyroid hormone; and ER stress response markers GRP78 and CHOP. Notably, the above changes were attenuated by FP, and GW9662 was able to alleviate the effect of FP. In conclusion, FP induces a cardioprotective effect following myocardial infarction by activating PPAR-γ, leading to less inflammation, cardiac sympathetic activity, and ER stress.

Ghrelin Ameliorates Angiotensin II-Induced Myocardial Fibrosis by Upregulating Peroxisome Proliferator-Activated Receptor Gamma in Young Male Rats.

Angiotensin (Ang) II contributes to the formation and development of myocardial fibrosis. Ghrelin, a gut peptide, has demonstrated beneficial effects against cardiovascular disease. In the present study, we explored the effect and related mechanism of Ghrelin on myocardial fibrosis in Ang II-infused rats. Adult Sprague-Dawley (SD) rats were divided into 6 groups: Control, Ang II (200ng/kg/min, microinfusion), Ang II+Ghrelin (100 µg/kg, subcutaneously twice daily), Ang II+Ghrelin+GW9662 (a specific PPAR-γ inhibitor, 1 mg/kg/d, orally), Ang II+GW9662, and Ghrelin for 4 wks. In vitro, adult rat cardiac fibroblasts (CFs) were pretreated with or without Ghrelin, Ghrelin+GW9662, or anti-Transforming growth factor (TGF)-ß1 antibody and then stimulated with or without Ang II (100 nmol/L) for 24 h. Ang II infusion significantly increased myocardial fibrosis, expression of collagen I, collagen III, and TGF-ß1, as well as TGF-ß1 downstream proteins p-Smad2, p-Smad3, TRAF6, and p-TAK1 (all p<0.05). Ghrelin attenuated these effects. Similar results were seen in Ang II-stimulated rat cardiac fibroblasts in vitro. In addition, Ghrelin upregulated PPAR-γ expression in vivo and in vitro, and treatment with GW9662 counteracted the effects of Ghrelin. In conclusion, Ghrelin ameliorated Ang II-induced myocardial fibrosis by upregulating PPAR-γ and in turn inhibiting TGF-ß1signaling.

Flavonoid Extract from Propolis Inhibits Cardiac Fibrosis Triggered by Myocardial Infarction through Upregulation of SIRT1.

The flavonoid extract from propolis (FP) has been shown to protect against heart injury induced by isoproterenol. However, the effect of FP on cardiac fibrosis after myocardial infarction (MI) as well as the underlying mechanisms is not known. In the present study, we used biochemical and histological approaches to examine the effects of FP on MI-induced cardiac fibrosis and the related mechanisms in a rat MI model and in angiotensin II- (Ang II-) treated rat cardiac fibroblasts (CFs). In vivo, MI was generated by ligation of the left anterior descending coronary artery of rats, which remained for 4 weeks. Rats were randomly divided into the sham, MI, FP (12.5 mg/kg/d), and MI+FP groups. We found that FP treatment improved heart function, reduced cardiac fibrosis, and downregulated the expression of fibrosis-related factors including collagen I, collagen III, matrix metalloproteinase-2 (MMP-2), MMP-9, transforming growth factor-ß1 (TGF-ß1), and p-Smad2/3, which coincided with the upregulated expression of silent information regulator 1 (SIRT1) in the hearts of MI rats. Our in vitro experiments showed that FP inhibited the proliferation and migration of primary cultured rat CFs and downregulated the expression of the above-mentioned fibrosis-related factors in Ang II-stimulated CFs. In addition, FP can decrease ROS production induced by MI and Ang II in vivo and vitro. Notably, silencing SIRT1 counteracted the FP-induced effects on CFs treated with Ang II. We conclude that FP inhibits MI-induced cardiac fibrosis through SIRT1 activation and that FP represents a potential promising drug for the treatment of MI patients in the clinic.

Flavonoids Extraction from Propolis Attenuates Pathological Cardiac Hypertrophy through PI3K/AKT Signaling Pathway.

Propolis, a traditional medicine, has been widely used for a thousand years as an anti-inflammatory and antioxidant drug. The flavonoid fraction is the main active component of propolis, which possesses a wide range of biological activities, including activities related to heart disease. However, the role of the flavonoids extraction from propolis (FP) in heart disease remains unknown. This study shows that FP could attenuate ISO-induced pathological cardiac hypertrophy (PCH) and heart failure in mice. The effect of the two fetal cardiac genes, atrial natriuretic factor (ANF) and ß-myosin heavy chain (ß-MHC), on PCH was reversed by FP. Echocardiography analysis revealed cardiac ventricular dilation and contractile dysfunction in ISO-treated mice. This finding is consistent with the increased heart weight and cardiac ANF protein levels, massive replacement fibrosis, and myocardial apoptosis. However, pretreatment of mice with FP could attenuate cardiac dysfunction and hypertrophy in vivo. Furthermore, the cardiac protection of FP was suppressed by the pan-PI3K inhibitor wortmannin. FP is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorder, such as fibrosis. The effects may be closely correlated with PI3K/AKT signaling. FP may be clinically used to inhibit PCH progression and heart failure.

[Study on hypoglycemic effect and mechanism of total flavonoids of Propolis in STZ diabetic rats].

OBJECTIVE: To study hypoglycemic effect and mechanism of the total flavonoids of Propolis (TFP) in the STZ diabetic rats. METHODS: The model of type 2 diabetic rats was induced by high-fat diet feeding for 4 weeks combined with intraperitoneal injection of streptozotocin (STZ). Then the rats without above-mentioned treatment were selected as the normal control group,the diabetic rats were randomly divided into four groups by blood glucose, the model control group, high doses (240 mg/kg), medium doses (120 mg/kg) and low doses (60 mg/kg) TFP groups. The TFP preparation was intragastric administration given to rats in TFP groups. The model control rats were treated intragastric administration with 0.5% sodium carboxymethyl cellulose (CMC-Na) for 4 weeks. The rats were fed with high fat diet during treatment. 12 hours after the last administration, glucose (GLU), total cholesterol (TC), triglyceride (TG), high density lipoprotein( HDL-C), low density lipoprotein LDL-C), glycated hemoglobin (GHb), serum insulin INS), C-peptide (C-P), superoxide dismutase( SOD), malondialdehyde (MDA), glutathione (GSH), tumor necrosis factor-alpha (TNF-alpha), free fatty acid (FFA), nitric oxide (NO), and hepatic glycogen were determined. RESULTS: Compared with the normal group, the levels of GLU, TC, TG, HDL-C, FFA, TNF-alpha, NO, MDA and GHb in serum were increased significantly in the model control group (P < 0.05-P < 0.001), the levels of HDL-C, INS, C-P, SOD and GSH in serum and hepatic glycogen in hepatic tissue were decreased significantly (P < 0.01 or P < 0.001). The levels of all above indexes of high and medium doses groups were improved significantly compared with the model control group (P < 0.05-P < 0.01). CONCLUSION: TFP can significantly decrease the level of blood glucose,improve the glucose and lipid metabolism and inhibit insulin resistance in STZ diabetic rats.