NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression.

The key to preventing mCRPC progression is understanding how androgen-dependent PCa cells progress to independence and modify their transcriptional repertoire accordingly. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation, AR->TLK1B>NEK1>pYAP1-Y407, leading to CRPC adaptation. Phosphorylation of YAP1-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduce TEAD- and p73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and, if castrated, fail to progress to overt prostate carcinomas, even while displaying reduced E-Cadherin (E-Cad) expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen-independent growth with a mesenchymal morphology. Immunohistochemical examination of prostate cancer biopsies revealed that the pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, a pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus leading to degradation of YAP1, can suppress the transcriptional reprogramming of LNCaP cells to androgen-independent growth and EMT progression, even when YAP1-WT is overexpressed.

Diphenyl diselenide modulates antioxidant status, inflammatory and redox-sensitive genes in diesel exhaust particle-induced neurotoxicity.

This study seeks to determine the influence of diphenyl diselenide (DPDSe) on redox status, inflammatory and redox-sensitive genes in diesel exhaust particle (DEP)-induced neurotoxicity in male albino rats. Male Wistar albino rats were administered nasally with DEP (30 and 60 µg/kg) and treated with intraperitoneal administration of 10 mg/kg DPDSe. Non-enzymatic (lipid peroxidation and conjugated diene concentrations) and enzymatic (catalase, superoxide dismutase, glutathione peroxidase) antioxidant indices and activity of acetylcholinesterase enzyme were evaluated in brain tissues of the rats. Furthermore, the expression of genes linked to oxidative stress (HO-1, Nrf2), pro-inflammatory (NF-KB, IL-8, TNF-α) anti-inflammatory (IL-10) and brain-specific (GFAP, ENO-2) genes were also determined. The results indicated that DPDSe caused a notable reduction in the high levels of thiobarbituric acid reactive substances and conjugated diene observed in the brain of DEP-administered rats. DPDSe also reversed the observed reduction in catalase, superoxide dismutase and glutathione peroxidase enzyme activities in the brain of DEP-administered rats. Lastly, the downregulation of genes associated with redox homeostasis, anti-inflammatory and brain-specific genes and upregulation of pro-inflammatory genes observed in the DEP-treated groups were ameliorated by DPDSe. The immediate restoration of altered biochemical conditions and molecular expression in the brain of DEP-treated rats by DPDSe further validates its use as a promising therapeutic candidate for restoring neurotoxicity linked with DEP-induced oxidative stress.

Effect of citrus peels-supplemented diet on longevity, memory index, redox status, cholinergic and monoaminergic enzymes in Drosophila melanogaster model.

This study sought to determine the life span promoting effecof orange (Citrus sinensis), tangerine (Citrus maxima) and grapefruit (Citrus paradisi) peels in Drosophila melanogaster model. Flies (both gender, 3 to 5 days old) were divided into seven (7) groups (n = 5) containing 40 flies each; group I (control) flies were fed with basal diet, II-VII were flies were fed with basal diet containing 0.1 and 1.0% of tangerine peel (TP), orange peel (CP), and grapefruit peel (GP) respectively, for 14 days. Locomotor performance and memory index were assessed via negative geotaxis and aversive phototaxis suppression assays, respectively. Thereafter, the fly homogenates were assayed for activities of acetylcholinesterase (AChE), monoamine oxidase (MAO) and antioxidant enzymes as well as other indices of their redox. The results revealed that the citrus peels significantly improved longevity, locomotor performance, memory index, antioxidant status, and modulate cholinesterase and monoamine oxidase enzyme activities in treated flies when compared to the control. The results obtained suggest that the citrus peels offer potentials as dietary supplement with life span promoting properties in D. melanogaster model which could as well serve as a functional food additives. PRACTICAL APPLICATIONS: Citrus peels, although often considered agro-wastes, are used as food supplements and food ingredents especially in production of candies, jams and custards. This study suggests the use of orange (Citrus sinensis), tangerine (Citrus maxima), and grapefruit (Citrus paradisi) peels as dietary supplements which offers potential life span promoting properties.

Citrus spp. essential oils improve behavioral pattern, repressed cholinesterases and monoamine oxidase activities, and production of reactive species in fruit fly (Drosophila melanogaster) model of Alzheimer's Disease.

Much emphasis has been placed on the biological activities of citrus peel's essential oils (CPEOs) against human ailments. This study investigated the effect of Citrus limon and Citrus reticulata peel's essential oils (EOs) on behavioral and neurochemical imbalance in transgenic and Harwish (Wild) fruit flies. Flies were divided into seven groups comprising of the control and those that were fed with 0.1, 0.5, and 1.0 µg/ml of the dietary inclusions of study CPEOs for 7 days. Thereafter, behavioral profile was examined using lethality response and negative geotaxis assays. Effect of the EOs on cholinesterase and monoamine oxidase (MAO) activities, and antioxidative parameters were determined. The result showed a significant improvement of behavioral pattern and biochemical parameters of the flies fed with studied CPEOs inclusive diets. Conclusively, both EOs exert neuroprotective capability by reducing cholinesterases and monoamine activities, and also prevent oxidative stress, which are implicated in neuronal dysfunction in humans. PRACTICAL APPLICATIONS: With the growing increase in the search for safer alternatives, having no side effects, for the management of neurodegenerative diseases, a large proportion of the populace is beginning to find solace in the use of natural products. Also, the wide array of similarities between the humans and the dipteran insects, fruit flies is a perfect organism for the study of neurodegenerative diseases. Therefore, this study presents the neuroprotective potentials of lemon and tangerine peels-derived EOs, and the possibility of their exploration as neuroactive agents and alternative in the management of Alzheimer's disease (AD).