Prophylactic supplementation of resveratrol is more effective than its therapeutic use against doxorubicin induced cardiotoxicity.

Resveratrol (RSV), a polyphenolic compound and naturally occurring phytoalexin, has been reported to exert cardio-protective effects in several animal studies. However, the outcome of initial clinical trials with RSV was less effective compared to pre-clinical studies. Therefore, RSV treatment protocols need to be optimized. In this study we evaluated prophylactic versus therapeutic effect of resveratrol (RSV) in mitigating doxorubicin (Dox)-induced cardiac toxicity in rats. To investigate prophylactic effects, RSV was supplemented for 2 weeks along with Dox administration. After 2 weeks, Dox treatment was stopped and RSV was continued for another 4 weeks. To study therapeutic effects, RSV treatment was initiated after 2 weeks of Dox administration and continued for 4 weeks. Both prophylactic and therapeutic use of RSV mitigated Dox induced deterioration of cardiac function as assessed by echocardiography. Also RSV treatment (prophylactic and therapeutic) prevented Dox induced myocardial damage as measured by cardiac enzymes (LDH and CK-MB) in serum. Which was associated with decrease in Dox induced myocardial apoptosis and fibrosis. Interestingly our study also reveals that prophylactic use of RSV was more effective than its therapeutic use in mitigating Dox induced apoptosis and fibrosis in the myocardium. Therefore, prophylactic use of resveratrol may be projected as a possible future adjuvant therapy to minimize cardiotoxic side effects of doxorubicin in cancer patients

Graphene Oxide-Gold Nanosheets Containing Chitosan Scaffold Improves Ventricular Contractility and Function After Implantation into Infarcted Heart

Abnormal conduction and improper electrical impulse propagation are common in heart after myocardial infarction (MI). The scar tissue is non-conductive therefore the electrical communication between adjacent cardiomyocytes is disrupted. In the current study, we synthesized and characterized a conductive biodegradable scaffold by incorporating graphene oxide gold nanosheets (GO-Au) into a clinically approved natural polymer chitosan (CS). Inclusion of GO-Au nanosheets in CS scaffold displayed two fold increase in electrical conductivity. The scaffold exhibited excellent porous architecture with desired swelling and controlled degradation properties. It also supported cell attachment and growth with no signs of discrete cytotoxicity. In a rat model of MI, in vivo as well as in isolated heart, the scaffold after 5 weeks of implantation showed a significant improvement in QRS interval which was associated with enhanced conduction velocity and contractility in the infarct zone by increasing connexin 43 levels. These results corroborate that implantation of novel conductive polymeric scaffold in the infarcted heart improved the cardiac contractility and restored ventricular function. Therefore, our approach may be useful in planning future strategies to construct clinically relevant conductive polymer patches for cardiac patients with conduction defects

Resveratrol treatment mitigates Dox induced cardiac fibrosis.

<p>(A) Masson’s trichrome staining: Photomicrographs of rat myocardial sections (X 200): Control group showed fine collagen fibers (arrows) among muscle fibers. Dox group showed dense collagen fibers (arrows) among thin muscle fibers. RSV-Dox group showed fine collagen fibers (arrows) among muscle fibers. In Dox-RSV group lesser amount of dense collagen fibers (arrows) among muscle fibers were detected. (B) Quantitative analysis (percent area) of collagen fibers. Data are mean ± SD. *<i>P</i> < 0.05, significantly different from respective control group, #<i>P</i> < 0.05, significantly different from respective Dox group, ^$<i>P</i> < 0.05, significantly different from respective Dox-RSV group.</p

Body weight (in grams) in different groups measured at baseline, after 2 and 6 weeks.

<p>Body weight (in grams) in different groups measured at baseline, after 2 and 6 weeks.</p

List of primers used for RT-PCR analysis.

<p>List of primers used for RT-PCR analysis.</p

Resveratrol treatment prevents Dox induced myocardial apoptosis.

<p>(A, B & C) Bax and Bcl-xl protein levels by Western blot. The protein levels of Bax increased and Bcl-xl decreased in Dox group compared to control animals. Treatment with RSV along with Dox or RSV treatment following Dox administration prevented Dox induced increase in Bax, and decrease in Bcl-xl levels. Histograms depict densitometric analysis (B and C). The results were normalized to ß-actin. (D & E) Caspase 3 expression by immunohistochemistry: Photomicrographs of rat myocardial sections (X 200). Control group showed –ve immunostaining among muscle fibers. Dox group showed caspase3 +ve areas (arrows) in myocardial sections. RSV-Dox group showed decreased expression of caspase 3 in myocardial sections. In Dox-RSV group also there was a decrease in caspase 3 +ve area. Data are mean ± SD. *<i>P</i> < 0.05, significantly different from respective control group, #<i>P</i> < 0.05, significantly different from respective Dox group, ^$<i>P</i> < 0.05, significantly different from respective DOX-RSV group.</p

Resveratrol treatment rescued Dox induced myocardial damage.

<p>(A). H & E staining: Photomicrographs of rat myocardial sections (x 200). Control group showed muscle fibers arranged in different directions (arrows), Dox group showing a wide area of widely spaced deeply acidophilic fibers including multiple disrupted (arrows), multiple thin attenuated (arrowheads) and multiple fibers exhibiting dark peripheral nuclei. RSV-Dox showed few congested blood vessels among muscle fibers, few deeply acidophilic (arrows) and few thin attenuated fibers (arrowheads) were present. In Dox-RSV group also sections showed some congested blood vessels among apparently normal muscle fibers, in addition to some deeply acidophilic fibers (arrows), some thin attenuated (arrowheads) and some fibers exhibiting dark peripheral nuclei were detected. (B). Quantitative analysis of (percent area) degenerated myocytes. (C&D). LDH and CK-MB levels in serum measured by commercial kits purchased from Stanbio Laboratory USA. Data are mean ± SD. *<i>P</i> < 0.05, significantly different from respective control group, #<i>P</i> < 0.05, significantly different from respective Dox group, ^$<i>P</i> < 0.05, significantly different from respective Dox-RSV group.</p

Effect of Dox, RSV-Dox and Dox-RSV on NFAT 3 and NFAT5 expression.

<p>(A&B) NFAT3 and NFAT5 expression was measured by RT-PCR. Dox treatment for 2 weeks significantly increased NFAT3 (A) and decreased NFAT5 (B), RSV supplementation along with Dox or after 2 weeks of Dox treatment prevented NFAT3 increase and NFAT5 decrease. ß-actin was used as internal control. Data are mean ± SD. *<i>P</i> < 0.05, significantly different from respective control group, #<i>P</i> < 0.05, significantly different from respective Dox group.</p