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

The impact of chronic fentanyl administration on the cerebral cortex in mice: Molecular and histological effects

Purpose: Fentanyl, a fully synthetic opioid, is widely used for severe pain management and has a huge abuse potential for its psychostimulant effects. Unlike other opioids, the neurotoxic effects of chronic fentanyl administration are still unclear. In particular, little is known about its effect on the cerebral cortex. The current study aims to test the chronic toxicity of fentanyl in the mice model. Methods: Adult male Balb/c mice were chronically treated with low (0.05 mg/kg, i.p) and high (0.1 mg/kg, i.p) doses of fentanyl for 5 consecutive weeks, and various neurotoxic parameters, including apoptosis, oxidative stress, and neuroinflammatory response were assessed in the cortex. Potential histological as well as neurochemical changes were also evaluated. Results: The results of this study show that chronic fentanyl administration induced intense levels of apoptosis, oxidative stress, and neuroinflammation in the cerebral cortex. These findings were found to be correlated with histopathological characteristics of neural degeneration and white matter injury. Moreover, fentanyl administration was found to reduce the expression of both NMDA receptor subunits and dopamine receptors and elevate the level of epidermal growth factor (EGF). Conclusion: Fentanyl administration induced neurotoxic effects in the mouse cerebral cortex that could be primarily mediated by the evoked oxidative-inflammatory response. The altered expression of NMDA receptors, dopamine receptors, and EGF suggests the pernicious effects of fentanyl addiction that may end in the development of toxic psychosis.This study is funded by a grant from the Deanship of Scientific Research, Yarmouk University , Jordan (Grant # 29/2021 ). Open access of this article is generously funded by Qatar National Library (QNL).Scopu

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 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

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

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