Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10⁶ cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 ( CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities ( P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.

Selective cardiotoxicity of doxorubicin (DOX) remains a significant and dose-limiting clinical problem. The mechanisms implicated are not yet fully defined but may involve the production of reactive oxygen species or expression of cytokines. Although patients with advanced congestive heart failure express elevated circulating levels of tumour necrosis factor-α (TNFα), little is known about the prognostic importance and regulation of TNFα in the heart in cardiac disease states. Here we tested whether the expression of TNFα, along with oxidative stress, is associated with the development of DOX-induced cardiomyopathy (DOX-CM) and whether concurrent treatment with taurine (Taur), an antioxidant, or rolipram (Rolp), a TNFα inhibitor, offer a certain protection against DOX cardiotoxic properties. DOX (cumulative dose, 12 mg kg−1) was administered to rats in six equal (intraperitoneal) injections over a period of 6 weeks. Cardiomyopathy was evident by myocardial cell damage, which was characterized by a dense indented nucleus with peripheral heterochromatin condensation and distorted mitochondria, as well as significant increase in serum levels of creatine kinase and lactate dehydrogenase. DOX also induced an increment (P < 0.001) in serum TNFα and plasma nitric oxide levels. The extent of left ventricular (LV) superoxide anion, lipid peroxide measured as malondialdehyde, catalase and calcium content were markedly elevated, whereas superoxide dismutase, total and non-protein-bound thiol were dramatically decreased in DOX-treated rats. Exaggeration of DOX-CM was achieved by intraperitoneal injection of lipopolysaccharide (LPS) (1 mg kg−1) 18h before sampling and evaluated by highly significant increase in heart enzymes (P < 0.001), oxidative stress biomarkers and TNFα production. Pre- and co-treatment of DOX or DOX-LPS rats with Taur (1% daily supplemented in drinking water, 10 days before and concurrent with DOX) or Rolp (3 mg kg−1, intraperitoneally, one dose before DOX administration then every 2 weeks throughout the experimental period) ameliorated the deleterious effect of both DOX and LPS on the aforementioned parameters. Meanwhile, it is noteworthy that Rolp exhibited a more preferable effect on serum TNFα level. Taur and rolipram also restored the myocardial apoptosis induced by DOX. In conclusion, a cumulative dose of DOX affected free radical and TNFα production in the heart of an experimental cardiomyopathy animal model. The current results suggest that down-regulation of these radicals and cytokines could be maintained by using the free radical scavenger Taur or, more favourably, the TNFα inhibitor Rolp.

Diabetes and cerebral ischemic-reperfusion are among the most common causes of neurological complications in Egypt. The prevalence of diabetes in Egypt is high and it can be considered as a major clinical and public health problem. Blood glucose, lipid profile, oxidative stress makers (cerebral MDA & GSH), cerebral interleukin-4 (IL-4) level and cerebral cyclooxygenase-2 (COX-2) gene expression were measured in male albino rats weighing 200 ± 20 g. The rats were divided into five groups, normal control group, diabetic group (diabetes was induced by single dose of streptozotocin [STZ]), diabetic cerebral ischemic-reperfused group, two treated groups (diabetic and diabetic ischemic-reperfused), both groups treated with resveratrol. Histological study was done using H&E, AgNOR and cresyl violet stains. Immunohistochemistry for Bax and COX-2 was done with morphometric study. Diabetic and diabetic cerebral ischemic- reperfused rats showed significant increase in serum glucose level, serum TAG, serum LDL-C, atherogenic index, cerebral MDA and upregulation of COX-2 gene expression. These groups showed significant decrease in serum HDL, cerebral IL-4 and depletion of cerebral GSH when compared to normal control rats. Treating these groups with resveratrol resulted in significant decrease in serum glucose level, serum TAG, TC, serum LDL-C, atherogenic index, cerebral MDA and downregulation of COX-2 gene expression. The results of COX-2 gene expression were confirmed by COX-2 immunohistochemistry. Also, significant increase in serum HDL, cerebral IL-4 and cerebral GSH contents could be observed in these treated groups as compared to normal control group. Cerebral apoptotic index and optical density of Bax reaction revealed significant increase in diabetic and diabetic cerebral ischemic-reperfused rats while treatment of these groups with resveratrol resulted in significant decrease in cerebral apoptotic index and optical density of Bax reaction. These apoptotic results were confirmed with AgNOR and cresyl violet stains. The results of this research suggest that upregulation of cerebral COX-2 gene along with the decrease in cerebral IL-4 and enhanced cerebral apoptosis is critically involved in cerebral damage associated with diabetes and cerebral ischemic-reperfusion. Resveratrol can ameliorate these effects and has promising neuroprotective effect in diabetic-induced cerebral complications.

Background: Diabetes mellitus (DM) and hypertension (HTN) are accused of being responsible for the development of the cardiac fibrosis due to severe cardiomyopathy.Methods: Blood glucose (BG) test was carried out, lipid concentrations, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), matrix metalloproteinase (MMP-2), collagen-I and collagen-III were measured in maleAlbinorats weighing 179-219 g. The rats were divided into five groups, kept on either control diet or high fat diet (HFD), and simultaneously treated with rosiglitazone (PPAR-gamma) only for one group with 3 mg/kg/day via oral route for 30 days, and with rosiglitazone and felodipine combination for another group with 3 mg/kg/day and 5 mg/kg/day, respectively via oral route for 30 days.Results: Diabetic hypertensive (DH) rats which fed on a HFD, injected with streptozotocin (STZ) (i.p.) and obstruction for its right kidney was occurred develop hyperglycemia, hypertension, cardiac fibrosis, hypertriglyceridemia, hypercholesterolemia, increased TNF-α, increased TGF-β, decreased MMP-2, increased collagen-I and increased collagen-III, when compared to rats fed on control diet. Treating the DH rats with rosiglitazone only causes a significant decrease for BG levels by 52.79%, triglycerides (TGs) by 24.05%, total cholesterol (T-Chol) by 30.23%, low density lipoprotein cholesterol (LDL-C) by 40.53%, TNF-α by 20.81%, TGF-β by 46.54%, collagen-I by 48.11% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 272.73%. Moreover, Treating the DH rats with rosiglitazone and felodipine combination causes a significant decrease for BG levels by 61.08%, blood pressure (BP) by 16.78%, TGs by 23.80%, T-Chol by 33.27%, LDL-C by 45.18%, TNF-α by 22.82%, TGF-β by 49.31%, collagen-I by 64.15% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 290.91%. Rosiglitazone alone failed to decrease the BP in DH rats in the current dosage and duration.Conclusion: Our results indicate that the co-existence of diabetes and hypertension could induce cardiomyopathy which could further result in cardiac fibrosis, and that combination treatment with rosiglitazone and felodipine has a great protective role against the metabolic abnormalities, meanwhile, the treatment with rosiglitazone alone has a protective role with a minimal effect against these abnormalities and has no effect on decreasing BP in these cases which may lead to coronary artery diseases (CADs) in future.