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Protective effect and mechanism of resvera on adriamycin-induced cardiotoxicity in mice
Abstract
Aim: To observe the protective effect and mechanism of resvera on adriamycin-induced cardiotoxicity. Methods: The cardiotoxicity was induce by adriamycin (ADM) intraperitoneal injection (ip. 15 mg·kg-1). Then the protective effect of pretreatment of resvera on injured cardiomyocyes was observed. Results: Compared with the normal control group, ADM decreased the amplitude of ECG's QRS complex (P < 0.01), increased the incidence of arrhythmia (to 60%), injured myocardial ultrastructure, increased the activity of LDH, levels of NO and MDA in serum, decreased the activity of SOD, and increased the expression of p53 (P < 0.01). Compared with ADM group, 5, 10, 15 mg·kg-1 resvera decreased levels of LDH, NO and MDA, increased SOD activity, recovered the amplitude of QRS complex, decreased the incidence of arrhythmia and p53 expression (P < 0.01 or P < 0.05) in concentration-dependent manner, and lightened the myocardial ultrastructure injury. Resvera showed no significant change on normal mice except increasing the activity of SOD in serum. Conclusion: Resvera had protective effect on adriamycin-induced cardiotoxicity. The mechanism may be related to its enhancing myocardial SOD activity, inhibiting myocardial lipid peroxidation and apoptosis.
Aim: To observe the protective effect of resveratrol on doxorubicine (DOX)-induced injury in H9c2 cardiac cells and the underlying mechanism. Methods: H9c2 cells were treated with DOX to establish a model of cardiomyocyte injury. Resveratrol was applied before exposure to DOX to activate SIRT1, and SIRT1 siRNA was used to inhibit SIRT1. MTT was used to detect the viability of H9c2 cells. Flow cytometry was used to determine the apoptosis of H9c2 cells. The expression of SIRT1 was detected by Western blot. H9c2 cells transfected with GFP were observed under a fluorescence microscope, and the transfection efficiency was calculated in a randomly-selected view. Results: DOX decreased cell viability and induced apoptosis in time-and dose-dependent pattern. In contrast ,SIRT1 protein was significantly upregulated by RSV also in a time- and dose-dependent way. Pre-treatment with RSV effectively reduced injury of H9c2 cells induced by DOX. Pre-treatment with SIRT1 siRNA aggravated the injury of H9c2 cells induced by DOX, which could not be alleviated by RSV treatment. Conclusion: RSV can significantly protect H9c2 cells against DOX induced injury possibly by upregulating the expression of SIRT1 protein.
Aim: To observe the changes of diaphragm contractility and cytoskeletal proteins titin, nebulin and sarcoplasmic reticulum Ca2+-ATPase gene expressions in adriamycin-induced cytotoxicity in rats. Methods: The animal models of diaphragm damage were duplicated by injecting adriamycin into abdominal cavity one time. Forty male sprague-dawley rats were randomly divided into four groups (n = 10) : Three groups received adriamycin in low, middle and high dosage (10,20 and 40 mg · kg-1 ) respectively. Meanwhile, the normal saline was given to rats in control groups. Three days later, these rats were killed, and the diaphragm was removed by thoracotomy. The diaphragm contractility was assessed in isolated diaphragm strips perfusion by these paramemters including peak twitch tension (Pt), maximum tetanic tension (Po), time to peak contraction (CT), half relaxaion time (1/2RT), maximal rates of contraction (+dt/dtmax) and maximal rates of relaxation (-dt/dt max). The expressions of titin, nebulin and sarcoplasmic reticulum Ca2+-ATPase (SERCA) at mRNA level were detected by RT-PCR analysis. Results: In contrast to those in control group, Po, Pt, ± dt/dt max in the adriamycin group were lower (P < 0.01); CT, 1/2RT in the adriamycin group increased significantly (P <0.01). The levels of titin, nebulin and SERCA gene expressions in middle-dose group were lower than those in control group (P < 0.01 ). Conclusions: The mRNA levels of titin, nebulin and SERCA of diaphragm are down-regulated in adriamycin-induced cytotoxicity in rats. It may be associated with the decline of diaphragm contractility.
Aim: To explore the role of resveratrol (Res) on cardiomyocyte hypertrophy induced by isoproterenol (ISO) and the relationship with endoplasmic reticulum stress (ERS). Methods: Hypertrophic model of cardiomyocytes was induced by ISO. Hypertrophy status of cardiomyocytes was determined by measuring the cell surface area and the gene expression of ANP. The value of apoptosis was measured by flow cytometry, the content of LDH and MDA was measured in different groups, and the gene and protein expressions of GRP78 and CHOP were detected by real-time PCR and Western blot. Results: Res could attentuate ISO-induced cardiomyocyte hypertrophy and apoptosis by reducing the cell surface area, the gene expression of ANP and the value of apoptosis. Res could inhibit ERS by downregulating the gene and protein expression of GRP78 and CHOP. Meanwhile, the content of LDH and MDA was decreased. Conclusions: The results suggest that treatment of Res may protect cardiomyocyte hypertrophy, which is partially mediated by inhibiting the expression of ERS factors GRP78 and CHOP.
AIM: To study the effects of polydatin on free radical induced rat cortex mitochondria injury. METHODS: Fe2+ + VitC system was used to produce · OH. The mitochondria was isolated. Mitochondria membrane fluidity, swelling and contents of phospholipid were determined to measure the function of mitochondria membrane. The activities of ATPase and Cytochrome C oxidase were determined to measure the ability of mitochondria energy metabolism. The activity of superoxide dismutase (SOD) and content of malondial dehyde (MDA) were determined to measure the ability of anti oxygenation. RESULTS: · OH resulted in severe neuronal mitochondria injuries and the injuries and the injuries was alleviated by Polydatin (content of 100, 200, 400 mg · L-1). The swelling of mitochondria was ameliorated, the decomposability of mitochondrion membrane phospholipid was decreased, the membrane fluidity of mitochondria was increased. Polydatin also significantly inhibited the decrease in SOD, Cytochrome C oxidase and ATPase activity and the increase in MDA levels caused by free radical. CONCLUSION: Polydatin has a protective action against the rat neuronal mitochondria injuries induced by oxygen free radical. The mechanisms may be derived from scavenging free radicals, reducing lipid peroxides, and improving the energy metabolism.
AIM: To study the effect of fructose-1, 6-diphosphate (FDP) on adriamycin (ADM) induced cardiomyocyte apoptosis in rats. METHODS: Rats were treated ADM by intraperitoneal injection (2.50 mg·kg-1 body weight at six times every other day), and then the rats of ADM treated were intervened by FDP on different dosage by intraperitoneal injection (at twenty-one times every other day). TBA method, nitrate reductase method, DTNB method and pyrogallol autoxidation method were used to determine the content of lipid peroxide (LPO) and nitric oxide (NO), the activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in myocardium, respectively. The cardiomyocyte apoptosis was detected by transmission electron microscope and TUNEL method. The expression of inducible nitric oxide synthase (iNOS) mRNA of myocardium was detected by in situ hybridization. RESULTS: FDP (300, 600, 1200 mg·kg-1) could significantly reduced the content of LPO and NO in myocardium, significantly reduced the amount of cardiomyocyte apoptosis and expression level of iNOS mRNA in myocardium, and significantly increased the activity of SOD and GPx in myocardium, when rats were ADM treated. CONCLUSION: FDP can inhibit cardiomyocyte apoptosis induced by ADM, and reduce injury of cardiotoxicity induced by ADM. The mechanism FDP may be relate to protecting the activity of SOD and GPx in myocardium, to preventing lipid peroxidation, and reducing generation of NO.
In a comparison using age-matched Wistar-Kyoto rats (WKY), 16-week-old male spontaneously hypertensive rat (SHR) hearts were examined histologically and biochemically on the first and fourth day after administration of 20 mg/kg doxorubicin in order to examine whether membrane abnormalities in hypertrophied SHR myocardium are caused by lipid peroxidation. Morphological examination of the SHR revealed focal myocytolysis on the first day and severe cardiomyopathy involving diffuse myocytolysis and vacuolar degeneration in the left ventricle on the fourth day. The activity of a membrane-related enzyme, Na+/K(+)-ATPase, was already lower in control SHR than that of control WKY and was lower in both SHR and WKY than in the respective saline groups on the first day after administration, whereas the enzyme activity in the doxorubicin-treated SHR was not significantly different from that of the treated WKY. A thiobarbituric acid-reactant substance, a lipid peroxidation marker, was significantly higher in treated SHR than it was in the treated WKY on the first day. Furthermore, in comparison with WKY, alpha-tocopherol in the left ventricle in SHR was significantly lower on the fourth day after administration. These results show that a proneness to lipid peroxidation in the membrane system is closely associated with severity of doxorubicin-induced cardiomyopathy in SHR and suggests that membrane lipid peroxidation may cause a higher degree of vulnerability in hypertrophied SHR myocardium.