Role of SIRT1 in sepsis-induced encephalopathy: Molecular targets for future therapies.

Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction, and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioural deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioural impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+ -dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO), which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.

Aescin Protects against Experimental Benign Prostatic Hyperplasia and Preserves Prostate Histomorphology in Rats via Suppression of Inflammatory Cytokines and COX-2.

BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common urogenital condition in aging males, while inflammation and tissue proliferation constitute the main pathophysiological factors. The adverse effects of currently available BPH medications limit patient compliance. We tested the protective effect of aescin against the development of BPH in rats. METHODS: A total of 18 male Wistar rats were divided into 3 groups: control (sesame oil 1 mL/kg, s.c.); BPH (testosterone oenanthate 3 mg/kg, s.c., in sesame oil), and BPH-aescin rats (testosterone oenanthate 3 mg/kg, s.c. + aescin 10 mg/kg/day, p.o.). All treatments continued for 4 weeks. Serum and prostatic samples were harvested for biochemical and histopathological examination. RESULTS: Induction of BPH by testosterone increased the prostate weight and prostate weight index, serum testosterone, prostate expression of inflammatory (IL-1ß, TNF-α, and COX-2), and proliferative markers (PCNA and TGF-ß1). Concurrent treatment with aescin decreased the testosterone-induced increase in prostatic IL-1ß, TNF-α, and COX-2 expression by 47.9%, 71.2%, and 64.4%, respectively. Moreover, aescin reduced the prostatic proliferation markers TGF-ß1 and PCNA by 58.3% and 71.9%, respectively, and normalized the prostate weight. CONCLUSION: The results of this study showed, for the first time, that aescin protected against the development of experimental BPH in rats via its anti-inflammatory and antiproliferative effects. These findings warrant further studies to clinically repurpose aescin in the management of BPH.

Antidepressant potential of Mesembryanthemum cordifolium roots assisted by metabolomic analysis and virtual screening.

Depression is a common mental disturbance that can be categorized as mild, moderate or severe. Mesemberine alkaloids, the main recognized phytoconstituents of some plants belonging to family Mesembryanthemaceae, are well-known as serotonin reuptake inhibitors. Therefore, the objective of this study is to evaluate the antidepressant activity of the alkaloidal fraction of Mesembryanthemum cordifolium L.f. (Aptenia cordifolia) roots, family Mesembryanthemaceae using forced swimming test, assisted by metabolomic analysis and in silico ligand-based and structure-based screening. Results showed that the alkaloidal fraction displayed an antidepressant activity superior to imipramine hydrochloride, a standard antidepressant agent. Nine alkaloids were annotated from the metabolomic analysis. Interestingly, among the dereplicated constituents, mesembrane (5) displayed strong binding affinity to SERT protein, which is slightly higher than the antidepressant drug venlafaxine. In conclusion, the alkaloidal fraction of the M. cordifolium (A. cordifolia) root exhibits an antidepressant activity which can be attributed in part to mesembrane (5).

The impact of single and combined PPAR-α and PPAR-γ activation on the neurological outcomes following cerebral ischemia reperfusion.

AIM: The neuronal damage and accompanied functional deficits induced by cerebral ischemia are among the most common causes of disabilities in adults. Activation of subtypes of peroxisome proliferator-activated receptors (PPARs); PPAR-α and PPAR-γ have shown neuroprotective effects in different neurodegenerative diseases including stroke. Thus, this study aimed to compare the effects of two different agonists: PPAR-α (fenofibrate) and PPAR-γ (pioglitazone) as well as the effect of their combination in ameliorating post-ischemia behavioral deficits. METHODS: Male Wistar rats were either pretreated with vehicle, fenofibrate (100 mg/kg/day p.o), pioglitazone (10 mg/kg/day p.o) or their combination for 14 days prior to bilateral common carotid artery occlusion followed by reperfusion for 24 hoursh. The sensory motor functions of rats were assessed, then rats were sacrificed to determine infarct volume and histopathological changes as well as oxidative stress, inflammatory and apoptotic markers in the brain tissue. KEY FINDINGS: Pre-treatment with fenofibrate and pioglitazone in addition to their combination improved neurobehavioral dysfunction, reduced cerebral infarct volume, attenuated inflammatory and apoptotic markers and ameliorated histopathological changes in I/R injured rats. The effect of pioglitazone in cerebral cortex was higher than its corresponding effect in fenofibrate while the combined administration of both drugs had additive neuroprotective effect and normalized inflammatory and apoptotic mediators in ischemic rats. SIGNIFICANCE: The study compared the neuroprotective effects of PPAR-α and PPAR-γ agonists, and tested the impact of their combination. We concluded that no additional benefits on the functional outcomes might be gained upon their combination.