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.

Modulator effects of OCT on glucose and immune system play important roles in renal cell fate decision and chronic kidney disease progression.

Wnt/β‐catenin signaling pathway plays a crucial role in diabetic cardiomyopathy (DCM), thus we aimed at investigating the effect of one therapeutic approach with resveratrol (RSV) given systemically and combined treatment of RSV with mesenchymal stem cells (MSCs) that was either RSV‐preconditioned or not on Wnt/β‐catenin signaling pathway in streptozotocin‐induced DCM, and to evaluate effects of RSV preconditioning on MSCs therapeutic potential. The rats were divided into control (C, n = 8), diabetic (DM, n = 8), diabetic treated with systemic RSV (DM‐RSV, n = 8), diabetic treated with RSV and nonconditioned MSCs (DM‐RSV‐MSCs, n = 8), diabetic treated with RSV and RSV‐incubated with MSCs (DM‐RSV‐MSCc, n = 8) and diabetic treated with RSV‐conditioned MSCs (DM‐MSCc, n = 8). Echocardiography (Echo) showed significant improvement of cardiac functions in all groups treated with RSV either systemic or added in culture media. Data of ejection fraction (EF%) of DM‐RSV‐MSCc (81.50; interquartile range [IQR], 80.00–83.00) was comparable to both DM‐RSV‐MSCs (77.50; IQR, 71.50–79.00), and DM‐MSCc (71.50; IQR, 70.00–74.50). Histological examination of the left ventricles was performed for all groups. DM group revealed significant myocardial hypertrophy, apoptosis, interstitial fibrosis, and microvascular affection. All treated groups were associated, in variable degrees, with attenuation of cardiac hypertrophy and fibrosis, decreased area% for cardiac immunostaining of secreted frizzled‐related protein (sFRP2) and Wnt/β‐catenin and improvement of the microvasculature. In conclusion, MSCs pretreated with resveratrol for 7 days showed increased 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, and combined use of RSV (systemically and in culture media) significantly could improve cardiac remodeling capacity of MSCs via attenuation of sFRP2‐mediated fibrosis and the downstream Wnt/β‐catenin pathway.

Bone marrow derived mesenchymal stem cells (BM-MSCs) have demonstrated potential in treating diabetic cardiomyopathy. However, diabetic patients are on multiple drugs and there is lack of understanding on how transplanted stem cells would respond in presence of such drugs. Metformin is an AMP Kinase (AMPK) activator, the widest used anti-diabetic drug. In this study, we investigated the effect of metformin on the efficacy of stem cell therapy in a diabetic cardiomyopathy animal model using streptozotocin (STZ) in male Wistar rats. To comprehend the effect of metformin on the efficacy of BM-MSCs, we transplanted BM-MSCs (1 million cells/rat) with or without metformin. Our data demonstrate that transplantation of BM-MSCs prevented cardiac fibrosis and promoted angiogenesis in diabetic hearts. However, metformin supplementation downregulated BM-MSCs mediated cardioprotection. Interestingly, both BM-MSCs and metformin treatment individually, improved cardiac function with no synergistic effect of metformin supplementation along with BM-MSCs. Investigating the mechanisms of loss of efficacy of BM-MSCs in the presence of metformin, we found that metformin treatment impairs homing of implanted BM-MSCs in the heart and leads to poor survival of transplanted cells. Furthermore, our data demonstrate that metformin mediated activation of AMPK is responsible for poor homing and survival of BM-MSCs in the diabetic heart. Hence, current study confirms that a conflict arises between metformin and BM-MSCs for treating diabetic cardiomyopathy. Approximately 10% of the world population is diabetic to which metformin is prescribed very commonly. Hence, future cell replacement therapies in combination with AMPK inhibitors may be more effective for diabetic patients.

Ischemia-reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia), and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases (AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min), and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion, single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation procedures.

Apelin and its receptor (APJ) are involved in the regulation of a variety of pathophysiological processes. We studied the effect of apelin treatment on obesity-induced type 2 diabetes mellitus (T2DM) and possible interaction between apelin/APJ system and renin-angiotensin system (RAS). Forty eight male albino rats were divided into two groups: control group and diabetic group. Diabetic group was subdivided into: control diabetic, apelin-treated, apelin + losartan-treated, apelin + l-NAME-treated and losartan-treated diabetic subgroup. Administration of apelin-13 yielded an improvement of IR, dyslipidaemia, inflammation, oxidative stress with significant decrease in AT1R gene expression and significant increase in ACE2 gene expression in adipose tissues. Losartan + apelin yielded a further significant decrease in ATR1 gene expression, glycaemic indices, serum TGs and TPA versus Apelin only. Adding l-NAME in subgroup (2D) reversed the effect of apelin. We suggested that the beneficial effect of Apelin is mainly mediated by NO-activated pathway and/or ACE2/Ang (1-7) dependent pathway.

Ischaemia-reperfusion (I-R) injury is a serious pathology that is often encountered with thrombotic events, during surgery when blood vessels are cross-clamped, and in organs for transplantation. Increased oxidative stress is the main pathology in I-R injury, as assessed in studies on the heart, kidney, and brain with little data available on gastric I-R (GI-R). Liraglutide is a GLP-1 receptor agonist that has insulinotropic and weight reducing actions, and melatonin that has been much studied as a chronotropic hormone; have also studied as being anti-oxidative stress agents. Herein, we aimed to explore the effects of liraglutide and melatonin on GI-R injury with high-fat/sucrose diet. Rats were divided into six groups; two diet-control, two melatonin- and two liraglutide-pretreated groups. All rats were subjected to 30 minutes of gastric ischaemia followed by 1 hour of reperfusion. Gastric tissues were assessed for the percentage of DNA fragmentation, myeloperoxidase activity, total oxidant status, total antioxidant capacity, oxidative stress index, BMI and histopathological examination. We showed that high-fat feeding for four weeks prior to GI-R significantly increased BMI, oxidative stress indices and decreased total antioxidant capacity, with a neutral effect on apoptosis compared to controls. Pretreatment with either melatonin (10 mg/kg per day orally) or liraglutide (25 μg/kg per day ip) reverses these effects. Furthermore, both drugs reduced weight only in HFS-fed rats. Both liraglutide and melatonin have nearly similar protective effects on gastric I-R injury through decreasing the oxidative stress and apoptosis.

These results demonstrate that treatment with OCT has a renoprotective effect in ischemic AKI, possibly by suppressing cell loss. Changes in the expression of IFN-g and NHE-1 could partially link OCT to the cell survival-promoted effects.