Kaempferol protects against streptozotocin-induced diabetic cardiomyopathy in rats by a hypoglycemic effect and upregulating SIRT1.

This study investigated if kaempferol could attenuate the oxidative, inflammatory, and fibrotic damage of the left ventricles (LVs) in streptozotocin (STZ)-diabetic rats by modulating silent mating type information regulation 2 homolog 1 (SIRT1) signaling. Adult male rats were divided into 5 groups (n = 12/each) as control, control + kaempferol, STZ-induced diabetes mellitus (STZ-DM), STZ-DM + kaempferol, and STZ-DM + kaempferol + EX-527, a sirtuin 1 (SIRT1) inhibitor. Administration of kaempferol to diabetic rats significantly preserved the systolic and diastolic functions of the LVs that was associated with a significant reduction in ventricular collagen deposition, infiltration of inflammatory cells, and protein expression of Bcl2-associated X protein (Bax), cleaved caspase-3, and cytochrome-C. In both the control and diabetic rats, kaempferol attenuated the loss in body weights, reduced fasting glucose levels, and increased fasting insulin levels and HOMA-ß. Besides, kaempferol lowered the levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), downregulated the transforming growth factor-ß1 (TGF-ß1) and reduced the nuclear levels of NF-κB p65. In concomitant, kaempferol increased the LV levels of manganese superoxide dismutase (MnSOD) and glutathione (GSH) and stimulated the total protein levels of Bcl2, the nuclear activity of SIRT1, and nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2). These events were associated with increased deacetylase activity and total levels of SIRT1 and a parallel decrease in the acetylation of Nrf2, NF-κB, smad2, and FOXO1. In conclusion: kaempferol attenuate diabetic cardiomyopathy in STZ-treated rats through its hypoglycaemic and insulin-releasing effects, as well as a cardiac independent mechanism that involves activation of SIRT1.

The impact of dehydroepiandrosterone on indomethacin-induced gastric lesions in rats.

UNLABELLED: Gastric ulcer is a common gastrointestinal disease. One suggested mechanism is increased oxidative stress. Puplished data showed that dehydroepiandrosterone (DHEA) may limit oxidative stress and lipid peroxidation. OBJECTIVE: To investigate the protective effect of DHEA on indomethacin-induced gastric ulcers in rats. METHODS: Forty male rats were randomly divided into four groups: l) CONTROL GROUP: receive the vehicle, 2) DHEA-treated group, 3) Indomethacin-induced ulcer group and 4) DHEA pretreated (prior to indomethacin) group. At the end of the experiment, rats were killed and the gastric contents were collected to determine the pH and acid concentration. Gastric mucosa was examined macroscopically and then parts of the tissues were collected for histopathological examination. Other parts of the gastric mucosa were homogenized to measure the levels of lipid peroxidation and oxidative stress parameters. RESULTS: Indomethacin-treated rats showed increased gastric acidity, acid concentration and ulcer index as compared to control rats. This is confirmed by histopathological studies. DHEA pre-treatment proir to indomethacin administration ameliorated all changes seen in the ulcered group. CONCLUSION: DHEA has a protective effect against indomethacin-induced gastric ulcers through decreasing acid secretion, prevention of lipid peroxidation and improving endogenous gastric antioxidant system.

Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats.

AIM: To investigate the effects of testosterone on myocardial contractility, oxidative stress status and expression of sodium channel protein (Nav1.5) and inward rectifying K channels (Kir 2.x) in normal and orchidectomized (ORX) rats. METHODS: One hundred four rats were randomly assigned into four groups (n = 26, each) as follows: (i) untreated controls, (ii) testosterone treated, (iii) orchidectomized rats and (iv) orchidectomized, testosterone-treated rats. Treatments with the vehicle or testosterone were carried out for 12 weeks, three times per week. At the end of treatment, surface ECG, isolated heart, tissue oxidative stress and lipid peroxidation experiments were carried out on the cardiac tissues. Also, immunohistochemical examination for Nav1.5 and PCR detection of mRNA of Kir2.1, Kir2.2 and Kir2.4 subunits of K channels were carried out. RESULTS: Orchidectomy impaired cardiac contractile function parameters left ventricular developed pressure (LVDP) and the peaks of the positive and negative pressure derivatives (dP/dtmax and -dP/dtmax respectively), increased heart rate and prolonged QT and QTc intervals, elevated pro-oxidant state in rat's hearts and decreased the expression of Kir 2.1 but not Kir2.2, Kir 2.4 and Nav1.5 channels. Exogenous testosterone administration to orchidectomized rats restored heart contractility and shortened QT and QTc intervals to their normal values, ameliorated the generated pro-oxidant state and improved the expression of Nav1.5 and Kir2.1, but not Kir2.2 or Kir2.4 channels. CONCLUSION: Testosterone improved cardiac contractility and shortened QT and QTc intervals in ORX rats. An effect that might be dependent of reduction in oxidative stress and enhancement of Kir2.1 channels but independent of Nav1.5 channel protein.

Single daily dose administration of cyclosporine in renal transplant recipients.

Cyclosporine (CsA) microemulsion has been the mainstay immunosuppressive agent for renal transplant recipients for years. A single daily dosing of cyclosporine (SD) is rarely used. The objective of this study was to evaluate the efficacy of SD versus twice daily dosing of CsA. Retrospective evaluation of SD use was conducted for 44 renal transplant recipients for 12 months (study group). Equal numbers of matched recipients were selected for age, sex, HLA mismatch, donor type, and immunosuppressive regimen (control group). We measured CsA trough (C0) and peak (C2) blood levels, 12-hour CsA profile, and the area under the concentration-time curve (AUC). There were significant differences in C0, C2, and calculated AUC after shifting to SD. In the study group, the mean AUC was 4619 ng/mL/h before versus 6567 ng/mL/h after shifting to SD (P=.004). This became more therapeutic and identical to the mean AUC in the control group, which was 6551 ng/mL/h. Total daily CsA dose was significantly lower in the study group compared with the control group (P<.0001). A significantly higher incidence of hepatitis was observed among the study group (P=.011). There were significantly fewer adverse effects in patients in the study group than the control group. There were no significant differences in graft and patient outcomes between the groups. We concluded that CsA dose should be individualized in renal transplant recipients especially if they have viral hepatitis. SD has the advantage of decreasing dosage and CsA-related adverse effects while maintaining optimal graft function.