Ranolazine ameliorates T1DM-induced testicular dysfunction in rats; role of NF-κB/TXNIP/GSDMD-N/IL-18/Beclin-1 signaling pathway.

Approximately 90% of diabetic males have varying degrees of testicular dysfunction. The current study investigates the possible beneficial consequences of ranolazine against T1DM-induced testicular dysfunction in rats. Thirty-two male Sprague Dawley rats were assorted into 4 groups; normal, diabetic (single 50 mg/kg STZ, I.P.) and ranolazine (40 and 80 mg/kg, orally). The present investigation revealed that the hypoglycemic impact of ranolazine significantly improved the testicular weight and body weight of the final rats, as well as the concentration of blood testosterone, sperm count, and viability, all of which were associated with STZ-induced testicular dysfunction. Furthermore, as demonstrated by elevated reduced glutathione (GSH) activity and lowered malondialdehyde (MDA) levels, diabetic rats administered ranolazine showed a noteworthy improvement in the oxidant/antioxidant ratio. Furthermore, a substantial rise in beclin-1 concentration was seen in conjunction with a significant decrease in thioredoxin-interacting protein (TXNIP) and interleukin-18 (IL-18) concentrations when ranolazine was administered. Although ranolazine exhibited a reduction in inflammation as seen by lower expression of nuclear factor-κB (NF-κB) and cluster of differentiation (CD68) in the testicles, these biochemical findings were validated by improvements in the morphological and histopathological outcomes of both the pancreatic and testicular tissues. In conclusion, daily oral administration of ranolazine (40 and 80 mg/kg) for 8 weeks could be a promising therapy for T1DM-induced testicular dysfunction through its dose-dependent anti-oxidant and anti-inflammatory effects.

Ameliorative effect of Metformin / alpha-lipoic acid combination on diabetic nephropathy via modulation of YAP/ miR-29a/PTEN/p-AKT axis.

Diabetic nephropathy (DN) is the most frequent and serious complication of type 2 diabetes (T2DM). Lack of a precise remedy and socio-economic burden of DN patients implements searching about alternative therapies. This study aims to evaluate the possible beneficial effect of alpha-lipoic acid (α-LA) alone or in combination with metformin (Met) in ameliorating STZ/High fat diet (HFD)-induced DN. T2DM was induced via HFD administration for 15 weeks and single ip injection of STZ (35 mg/kg) at week 7. Male Sprague-Dawley rats were randomly grouped as follows: control group, STZ/HFD-induced DN, Met/T; daily treated with 150 mg/kg Met, α-LA/T group; daily treated with 100 mg/kg α-LA, and Met/T + α-LA/T group; daily treated with Met and α-LA at same doses. Administration of Met and α-LA succeeded in attenuating STZ/HFD-induced DN as manifested by significant decrease in kidney weight as well as renal and cardiac hypertrophy index. Moreover, Met and α-LA improved glycemic control, kidney functions and lipid profile as well as restored redox balance. Additionally, Met and α-LA administration significantly upregulated PTEN level accompanied by significant downregulation in renal p-AKT and miR-29a levels. Histopathologically, Met and α-LA administration mitigated STZ/HFD-induced histopathological alterations in kidney and heart. Moreover, immunohistochemical examination revealed a significant decrease in renal YAP, collagen I and Ki-67. Taken together, these observations revealed that Met and α-LA administration could protect against STZ/HFD-induced DN.

Diacerein mitigates adenine-induced chronic kidney disease in rats: Focus on TLR4/MYD88/TRAF6/NF-κB pathway.

Chronic kidney disease (CKD) is a serious problem which negatively affects human health. AIMS: The purpose of this investigation was to explore the possible beneficial impacts of diacerein on adenine-induced CKD in rats. MAIN METHODS: 32 male Sprague Dawley rats were allocated into 4 groups; normal, diseased (200 mg/kg adenine, orally) and diacerein (25 and 50 mg/kg, orally). KEY FINDINGS: Adenine produced marked reduction in rats' body weights and a substantial increase in kidney/body weight index. Additionally, adenine significantly increased serum creatinine and BUN levels besides proteinuria levels, and also reduced creatinine clearance. Adenine induced oxidative stress as evidenced by increased MDA content and diminished GSH concentration in renal tissues. These biochemical measurements were confirmed by the morphological and histopathological results. Moreover, adenine revealed substantial elevation in renal level and expression of MYD88, TRAF6 and TNF-α, and renal level of IL-1ß in addition to increased expression of TLR4, NF-κB p65 and p-NF-κB p65 while reduced the expression of IκB-α. Diacerein in a dose-dependent manner effectively ameliorated adenine-induced alterations. SIGNIFICANCE: Diacerein could be used as a therapeutic agent to attenuate CKD after further clinical studies.

Impact of protocatechuic acid on high fat diet-induced metabolic syndrome sequelae in rats.

The study aimed to assess the possible protective impact of protocatechuic acid (PCA) on high fat diet (HFD)-induced metabolic syndrome (Mets) sequelae in rats. Forty-two male Sprague-Dawley (SD) rats were randomly grouped as follows: CTR group; PCA group; HFD group; HFD-PCA group and HFD-MET group. Rats were fed on standard diet or HFD for 14 weeks. HFD-fed rats exhibited significant decreases in food intake and adiponectin (ADP) level; yet, body weight and anthropometrical parameters were significantly increased. Moreover, insulin sensitivity was impaired as indicated by significant elevation in glucose AUC during oral glucose tolerance test (OGTT), fasting serum glucose, fasting serum insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index. Furthermore, chronic HFD feeding elicited significant increases in serum lipid profile and free fatty acids (FFAs) with concomitant hepatic steatosis. Additionally, serum C-reactive protein (CRP), interleukin 1b (Il-1b) and monocyte chemoattractant protein 1(MCP-1) levels were increased. Also, HFD-fed rats exhibited an increase in MDA level, while superoxide dismutase (SOD) and glutathione (GSH) activities were decreased. Moreover, the insulin-signaling pathway was markedly impaired in soleus muscles as indicated by a decrease in insulin-induced AKT phosphorylation. Histopathologically, adipose tissues showed significant increase in adipocyte size. Also, flow cytometry analysis of adipose tissue confirmed a significant increase in the percentage of number of CD68+ cells. PCA administration succeeded to attenuate HFD-induced obesity, insulin resistance, oxidative stress and inflammation. In conclusion, PCA administration could protect against HFD-induced Mets, possibly via its hypoglycemic, insulin-sensitizing, anti-oxidant and anti-inflammatory effects.

Cinnamaldehyde exerts vasculoprotective effects in hypercholestrolemic rabbits.

The effects of cinnamaldehyde (CIN), a commonly consumed food flavor, against high-cholesterol diet (HCD)-induced vascular damage in rabbits were evaluated. Male New Zealand rabbits (n = 24) were allocated to four groups at random: control, fed with standard rabbit chow; CIN, fed with standard diet and administered CIN; HCD, fed with 1% cholesterol-enriched diet; and HCD-CIN, fed with HCD and treated with CIN. CIN was orally given at a dose of (10 mg/kg/day) concomitantly with each diet type from day 1 until the termination of the experimental protocol (4 weeks). HCD elicited significant elevations in serum levels of total cholesterol (TC), triglycerides (TGs), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) compared with control rabbits. Moreover, aortic levels of nitric oxide metabolites (NOx) and antioxidant enzyme activities were significantly lower, while aortic levels of malondialdehyde (MDA) and myeloperoxidase (MPO) activity were significantly higher, in HCD-fed rabbits relative to control animals. CIN administration mitigated or completely reversed HCD-induced metabolic alterations, vascular oxidative stress, and inflammation. Moreover, CIN ameliorated HCD-induced vascular functional and structural irregularities. Aortic rings from HCD-CIN group showed improved relaxation to acetylcholine compared to aortas from HCD group. Moreover, CIN decreased atherosclerotic lipid deposition and intima/media (I/M) ratio of HCD aortas. CIN-mediated effects might be related to its ability to attenuate the elevated aortic mRNA expression of cholesteryl ester transfer protein (CETP) and MPO in HCD group. Interestingly, the vasculoprotective effects of CIN treatment in the current study do not seem to be mediated via Nrf2-dependent mechanisms. In conclusion, CIN may mitigate the development of atherosclerosis in hypercholestrolemic rabbits via cholesterol-lowering, antiinflammatory and antioxidant activities.