Metformin ameliorates ROS-p53-collagen axis of fibrosis and dyslipidemia in type 2 diabetes mellitus-induced left ventricular injury.

BACKGROUND: The link between oxidative stress (ROS), apoptosis (p53) and fibrosis (collagen) in type 2 diabetes mellitus (T2DM)-induced cardiac injury in the presence and absence of the antidiabetic drug, metformin has not been investigated before. MATERIAL AND METHODS: T2DM was induced in rats by a combination of high carbohydrate and fat diets (HCFD) and streptozotocin (50 mg/kg) injection. The protection group started metformin (200 mg/kg) treatment 14 days prior to the induction of diabetes and continued on metformin and HCFD until being sacrificed at week 12. RESULTS: Diabetes significantly induced blood levels of ROS and left ventricular p53 and collagen expression that was inhibited by metformin. Metformin also significantly reduced glycated haemoglobin and dyslipidemia induced by diabetes. In addition, a significant correlation between ROS-p53-collagen axis and glycaemia and hyperlipidaemia was observed. CONCLUSIONS: These findings show that metformin provides substantial protection against diabetic cardiomyopathy-induced ROS-p53 mediated fibrosis and dyslipidemia.

Association of resveratrol with the suppression of TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and systemic hypertension in thioacetamide-induced liver injury.

Chronic liver injury can lead to hepatic failure and the only available method of treatment would be liver transplantation. The link between inflammation (TNF-α), nuclear factor-kappa B (NF-kB), nitrosative stress (iNOS) and hypoxia-inducible factor-1α (HIF-1α) in thioacetamide (TAA) induced liver fibrosis, and hypertension with and without the incorporation of the anti-inflammatory and antioxidant resveratrol (RES) has not been investigated before. Consequently, we injected rats with either 200 mg/kg TAA for 8 weeks starting at week 2 (model group) or pretreated them before TAA injections with RES (20 mg/kg) for 2 weeks and continued them on RES and TAA until being culled at week 10 (protective group). In the model group, we documented the induction of hepatic fibrosis and upregulation of tumor necrosis factor-α (TNF-α), NF-kB, inducible nitric oxide synthase (iNOS), HIF-1α and the profibrotic biomarkers alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-9 (MMP-9) that was significantly (p ≤ 0.0014) ameliorated by RES. RES also significantly (p ≤ 0.0232) reduced triglycerides (TG), cholesterol (CHOL), very low-density lipoprotein (vLDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure, and heart rate (HR) induction by TAA. Also, a significant (p < 0.0001) positive correlation between TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and hypertension and liver injury biomarkers was observed. These findings suggest that in the hepatotoxic compound, TAA is associated with TNF-α/NF-kB/iNOS/HIF-1α-mediated fibrosis and hypertension, whilst being inhibited by RES.

Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone.

Acute restraint stress (ARS) is an unavoidable stress situation and may be encountered in different clinical situations. The aim of the current study was to investigate the effects of ARS on the hippocampus and cerebellum, assess the impact of these effects on the behavior and cognitive function, and determine whether pretreatment with ceftriaxone would attenuate the damages produced by ARS on the hippocampus and cerebellum. Four groups of male mice were included in this study: The control group, ARS group, ceftriaxone group, and ARS + ceftriaxone group. Tail suspension test, Y-maze task, and open field tests were used to assess depression, working spatial memory, and anxiety. The biochemical analyses included measurements of serum cortisol, tumor necrotic factor (TNF), interleukin-6, hippocampal expression of bone morphogenetic protein 9 (BMP9), lysosomal-associated membrane protein 1 (LAMP1), glutamate transporter 1 (GLT1), heat shock protein 90, cerebellar expression of S100 protein, glutamic acid decarboxylase (GAD), and carbon anhydrase. Histopathological examination of the brain sections was conducted on the hippocampus and cerebellum by hematoxylin and eosin stains in addition to ultrastructure evaluation using electron microscopy. Our results suggested that ceftriaxone had neuroprotective properties by attenuating the effects of ARS on the hippocampus and cerebellum in mice. This effect was demonstrated by the improvement in the cognitive and behavioral tests as well as by the preservation of the hippocampal and cerebellar architecture.