Kaempferol Protects Against Cadmium Chloride-Induced Memory Loss and Hippocampal Apoptosis by Increased Intracellular Glutathione Stores and Activation of PTEN/AMPK Induced Inhibition of Akt/mTOR Signaling.

This study investigated the protective effect of Kaempferol against CdCl2-induced hippocampal damage and memory deficit in rats and investigated if such effects involve modulating the activity of AMPK/PTEN/Akt/mTOR axis. Adult male rats (n = 12/group) were divided into control or CdCl2-treated rats received the vehicle of Kaempferol for consecutive 6 weeks. Also, hippocampal cells were treated with CdCl2 in the presence or absence of Kaempferol for 24 h with or without 1 h pre-incubation with compound C, an AMPK inhibitor or with bpV a PTEN inhibitor. Kaempferol improved the behavioral of CdCl2-treated rats, preserved hippocampus structure and reduced hippocampal levels of ROS and protein levels of Bax and cleaved caspase-3. In both control and CdCl2-treated rats, Kaempferol significantly increased hippocampal levels of GSH levels and protein levels of Nfr2, Bcl2 and synaptic proteins (SNAP-25, PSD-25, and synapsin). Concomitantly, it increased the activity of PTEN and AMPK and subsequently, decreased the activity of Akt and mTOR. In cultured cells, individual pharmacological inhibition of PTEN by bpv or AMPK of compound C (CC) partially prevented the stimulatory effect of Kaempferol on Akt/mTOR and its inhibitory effect on cell death whereas a combination of both inhibitors completely prevented this. Also, inhibition of PTEN alone completely abolished the inhibitory effect of Kaempferol by synaptic proteins, whereas inhibition of AMPK completely abolished its stimulatory effect of Nfr2. In conclusion, Kaempferol protects against CdCl2-induced memory deficits and hippocampal apoptosis by its antioxidant potential and inhibition of Akt/mTOR axis and requires the activation of PTEN and AMPK.

Exendin-4 protects the hearts of rats from ischaemia/reperfusion injury by boosting antioxidant levels and inhibition of JNK/p66 Shc/NADPH axis.

Exendin-4, a glucagon-like peptide-1 receptor agonist, was shown to protect against cardiac ischaemia/reperfusion (I/R) injury by suppressing oxidative stress. p66 Shc, a pro-oxidant and an apoptotic protein, is activated in the infarcted left ventricles (LVs) after induction of I/R. This study investigated if the cardiac protective effect of Exendin-4 against I/R injury in rats involves inhibition of p66 Shc and to determine the underlying mechanisms behind this. Adult male rats (n = 12/group) were divided into four groups as a sham, a sham + Exendin-4, an I/R, and an I/R + Exendin-4. Exendin-4 was administered to rats 7 days before the induction of I/R. Ischaemia was induced by ligating the left anterior descending (LAD) coronary artery for 40 minutes followed by reperfusion for 10 minutes. The infarct myocardium was used for further analysis. Exendin-4 significantly reduced infarct area (by 62%), preserved LV function and lowered serum levels of LDH and CK-MB in I/R-induced rats. Also, it significantly reduced LV levels of ROS and MDA and protein levels of cytochrome-c and cleaved caspase-3 but significantly increased levels of glutathione (GSH) and manganese superoxide dismutase (MnSOD) in LVs of I/R rats indicating antioxidant and anti-apoptotic effects. Furthermore, it inhibited JNK and p66 Shc activation and downregulated protein levels of p66 Shc and NADPH oxidase with no effect on protein levels/activity of p53 and PKCßII. Of note, Exendin-4 also increased GSH and MnSOD in LVs of control rats. In conclusion, Exendin-4 cardioprotective effect in I/R hearts is mediated mainly by antioxidant effect and inhibition of JNK/P66 Shc/NADPH oxidase.

Chronic consumption of a high-fat diet rich in corn oil activates intrinsic cell death pathway and induces several ultrastructural changes in the atria of healthy and type 1 diabetic rat.

This study investigates the effect of chronic consumption of a high-fat diet rich in corn oil (CO-HFD) on atrial cells ultrastructure, antioxidant levels and markers of intrinsic cell death of both control and type 1 diabetes mellitus (T1DM)-induced rats. Adult male rats (10 rats/group) were divided into four groups: control fed standard diet (STD) (3.82 kcal/g, 9.4% fat), CO-HFD (5.4 kcal/g, 40% fat), T1DM fed STD, and T1DM + CO-HFD. CO-HFD and T1DM alone or in combination impaired systolic and diastolic functions of rats and significantly reduced levels of GSH and the activity of SOD, enhanced lipid peroxidation, increased protein levels of P53, Bax, cleaved caspase-3, and ANF and decreased levels of Bcl-2 in their atria. Concomitantly, atrial cells exhibited fragmentation of the myofibrils, disorganized mitochondria, decreased number of atrionatriuretic factor (ANF) granules, and loss of gap junctions accompanied by changes in capillary walls. Among all treatments, the severity of all these findings was more severe in T1DM and most profound in the atria of T1DM + CO-HFD. In conclusion, chronic consumption of CO-HFD by T1DM-induced rats elicits significant biochemical and ultrastructural damage to rat atrial cells accompanied by elevated oxidative stress and mitochondria-mediated cell death.