ABSTRACT
Sallylcysteine sulfoxide (alliin) is the main organosulfur component of garlic and its preparations. The present study aimed to examine the protective effect of alliin on cardiac function and the underlying mechanism in a mouse model of myocardial infarction (MI). Notably, alliin treatment preserved heart function, attenuated the area of infarction in the myocardium of mice and reduced lesions in the myocardium, including cardiomyocyte fibrosis and death. Further mechanistic experiments revealed that alliin inhibited necroptosis but promoted autophagy in vitro and in vivo. Cell viability assays showed that alliin dosedependently reduced the necroptotic index and inhibited the expression of necroptosisrelated receptorinteracting protein 1, receptorinteracting protein 3 and tumor necrosis factor receptorassociated factor 2, whereas the levels of Beclin 1 and microtubuleassociated protein 1 light chain 3, which are associated with autophagy, exhibited an opposite trend upon treatment with alliin. In addition, the level of peroxisome proliferatoractivated receptor γ was increased by alliin. Collectively, these findings demonstrate that alliin has the potential to protect cardiomyocytes from necroptosis following MI and that this protective effect occurs via the enhancement of autophagy.
Subject(s)
Autophagy/drug effects , Cysteine/analogs & derivatives , Myocardial Infarction/drug therapy , Myocytes, Cardiac/drug effects , Necroptosis/drug effects , Safrole/analogs & derivatives , Animals , Apoptosis/drug effects , Cell Survival/drug effects , Cysteine/pharmacology , Male , Mice , Mice, Inbred C57BL , Myocardial Infarction/metabolism , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Safrole/pharmacology , Signal Transduction/drug effectsABSTRACT
AIMS: The antihypertensive mechanism (s) of the epigallocatechin-3-gallate (EGCG), a major effective component in green tea, might associate with microRNAs (miRNAs). Here, we aimed to investigate which microRNA in aorta of spontaneously hypertensive rats (SHRs) were modulated by administration of EGCG and its mechanism. MAIN METHODS: The pharmacokinetic behaviors of EGCG and epigallocatechin (EGC) in Sprague-Dawley rats were analyzed by HPLC and DRUG AND STATISTICS software. Blood pressure of SHRs was monitored by the tail-cuff method, the miRNomes of aorta from SHRs was analyzed with deep sequencing, and expression of hypertension-associated miRNAs with significant change and their host genes and target genes were validated by real-time PCR and Western blot. KEY FINDINGS: The plasma deposition of EGCG and EGC best fitted a mono-compartmental model with maximum plasma concentration post-dose (Cmax, 6.65 vs 4.45⯵g/ml) and the corresponding time (Tmax, 15 vs 10â¯min). Systolic blood pressure (SBP) of SHRs decreased to the lowest point by 34.04â¯mmHg and recovered by 23.39â¯mmHg after 15 and 30â¯min of administration at dose of 300â¯mg/kg BW EGCG, respectively, and it decreased again at 60â¯min and recovered at time 2â¯h. Total 35 upregulated and 18 downregulated miRNAs were identified compared to the control group (pâ¯<â¯.01) after EGCG administration. Expression of hypertension-associated miRNA-126a-3p and miRNA-150-5p were further validated. In turn, their host gene and target genes were up-regulated and down-regulated, respectively. SIGNIFICANCE: Our results indicated that miRNA-150-5p might be involved in the antihypertensive effect of EGCG through SP1/AT1R pathway.
Subject(s)
Antihypertensive Agents/pharmacology , Aorta/metabolism , Catechin/analogs & derivatives , Gene Expression Regulation/drug effects , Hypertension/genetics , MicroRNAs/genetics , Tea/chemistry , Animals , Aorta/drug effects , Biomarkers/metabolism , Blood Pressure/drug effects , Catechin/pharmacology , Gene Expression Profiling , Hypertension/drug therapy , Hypertension/pathology , Male , Rats , Rats, Inbred SHR , Rats, Sprague-DawleyABSTRACT
Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).
