Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy.

Encephalopathy is a frequent and lethal consequence of sepsis. Recently, a growing body of evidence has provided important insights into the role of iron dyshomeostasis in the context of inflammation. The molecular mechanisms underlying iron dyshomeostasis and its relationship with macrophage phenotypes are largely unknown. Here, we aimed to characterize the changes in iron-transporter and storage proteins and the microglia phenotype that occur during the course of sepsis, as well as their relationship with sepsis-induced encephalopathy. We used a cecal ligation and puncture (CLP) murine model that closely resembles sepsis-induced encephalopathy. Rats were subjected to CLP or sham laparotomy, then were neurologically assessed at 6 h, 24 h, and 3 days after sepsis induction. The serum and brain were collected for subsequent biochemical, histological, and immunohistochemical assessment. Here, an iron excess was observed at time points that followed the pro-inflammatory macrophage polarization in CLP-induced encephalopathy. Our results revealed that the upregulation of non-transferrin-bound iron uptake (NTBI) and ferritin reduction appeared to be partially responsible for the excess free iron detected within the brain tissues. We further demonstrated that the microglia were shifted toward the pro-inflammatory phenotype, leading to persistent neuro-inflammation and neuronal damage after CLP. Taken together, these findings led us to conclude that sepsis increased the susceptibility of the brain to the iron burden via the upregulation of NTBI and the reduction of ferritin, which was concomitantly and correlatively associated with dominance of pro-inflammatory microglia and could explain the neurological dysfunction observed during sepsis.

Neuroprotective effect of Crocus sativus against cerebral ischemia in rats.

The present study aimed to investigate the role of vascular endothelial growth factor (VEGF) in the neuroprotective effect of Crocus sativus (saffron) against cerebral ischemia/reperfusion injury (I/R) in rats. Four groups of a total forty I/R rats with 60-min occlusion followed by 48 h reperfusion or sham surgery were used. The sham and left-brain I/R control groups where treated with normal saline. The rats of the other two groups received saffron extract (100 or 200 mg/kg, ip, respectively) for 3 successive weeks prior to left-brain I/R. Other four doses of saffron extract were received by the rats of the last 2 groups 60 min prior to operation, during the surgery, and on days 1 and 2 following reperfusion. I/R group showed marked neurobehavioral, neurochemical and histopathological alterations. The results revealed a significant reduction in neurological deficit scores in the saffron-treated rats at both doses. Saffron significantly attenuated lipid peroxidation, decreased NO and brain natriuretic peptide (BNP) contents in I/R-brain tissue. On the other hand, saffron reversed the depletion of GSH in the injured brain. Moreover, saffron treatment evidently reduced apoptosis as revealed by a decrease in caspase-3 and Bax protein expression with a marked decrease in the apoptotic neuronal cells compared to I/R group. In addition, saffron administration effectively upregulated the expression of VEGF in I/R-brain tissue. In conclusion, saffron treatment offers significant neuroprotection against I/R damage possibly through diminishing oxidative stress and apoptosis and enhancement of VEGF.

Antihypertensive Effects of Roselle-Olive Combination in L-NAME-Induced Hypertensive Rats.

This study aimed to evaluate the antihypertensive efficacy of a new combination therapy of Hibiscus sabdariffa and Olea europaea extracts (2 : 1; Roselle-Olive), using N(G)-nitro-L-arginine-methyl ester- (L-NAME-) induced hypertensive model. Rats received L-NAME (50 mg/kg/day, orally) for 4 weeks. Concurrent treatment with Roselle-Olive (500, 250, and 125 mg/kg/day for 4 weeks) resulted in a dose-dependent decrease in both systolic and diastolic blood pressure, reversed the L-NAME-induced suppression in serum nitric oxide (NO), and improved liver and kidney markers, lipid profile, and oxidative status. Furthermore, Roselle-Olive significantly lowered the elevated angiotensin-converting enzyme activity (ACE) and showed a marked genoprotective effect against oxidative DNA damage in hypertensive rats. Roselle-Olive ameliorated kidney and heart lesions and reduced aortic media thickness. Real-time PCR and immunohistochemistry showed an enhanced endothelial nitric oxide synthase (eNOS) gene and protein expression in both heart and kidney of Roselle-Olive-treated rats. To conclude, our data revealed that Roselle-Olive is an effective combination in which H. sabdariffa and O. europaea synergistically act to control hypertension. These effects are likely to be mediated by antioxidant and genoprotective actions, ACE inhibition, and eNOS upregulation by Roselle-Olive constituents. These findings provide evidences that Roselle-Olive combination affords efficient antihypertensive effect with a broad end-organ protective influence.

Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats.

Statins are the first line treatment for the management of hyperlipidemia. However, the primary adverse effect limiting their use is myopathy. This study examines the efficacy and safety of red yeast rice (RYR), a source of natural statins, as compared with atorvastatin, which is the most widely used synthetic statin. Statin interference with the endogenous synthesis of coenzyme Q10 (CoQ10) prompted the hypothesis that its deficiency may be implicated in the pathogenesis of statin-associated myopathy. Hence, the effects of combination of CoQ10 with either statin have been evaluated. Rats were rendered hyperlipidemic through feeding them a high-fat diet for 90 days, during the last 30 days of the diet they were treated daily with either atorvastatin, RYR, CoQ10, or combined regimens. Lipid profile, liver function tests, and creatine kinase were monitored after 15 and 30 days of drug treatments. Heart contents of CoQ9 and CoQ10 were assessed and histopathological examination of the liver and aortic wall was performed. RYR and CoQ10 had the advantage over atorvastatin in that they lower cholesterol without elevating creatine kinase, a hallmark of myopathy. RYR maintained normal levels of heart ubiquinones, which are essential components for energy production in muscles. In conclusion, RYR and CoQ10 may offer alternatives to overcome atorvastatin-associated myopathy.