Redox modulation by plant polyphenols targeting vitagenes for chemoprevention and therapy: Relevance to novel anti-cancer interventions and mini-brain organoid technology

The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression. Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects depending on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression, by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role, representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages, and thus inhibit its progression. Lastly, we discuss innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis, from basic cancer research to clinical practice, as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain, as well as test drug toxicity and drive personalized and precision medicine in brain cancer

Sleep, anxiety and psychiatric symptoms in children with Tourette syndrome and tic disorders

Objective: The current study evaluated the relationship between tic, sleep disorders and specific psychiatric symptoms (anxiety, depression, obsessive compulsive symptoms). Methods: Assessment of 36 consecutive children and adolescents with tic disorders included: the Yale Global Tic Severity Scale (YGTSS) to assess the severity of tic symptoms; the Self-administered scale for children and adolescents (SAFA) to evaluate the psychopathological profile; a specific sleep questionnaire consisting of 45 items to assess the presence of sleep disorders. An age and sex-matched control group was used for comparisons. Results: Sleep was significantly more disturbed in patients with tic disorders than in controls. Difficulties in initiating sleep and increased motor activity during sleep were the most frequent sleep disturbances found in our sample. Patients showed also symptoms of anxiety (SAFA A), depressed mood (SAFA D) and doubteindecision (SAFA O). Additionally, difficulties in initiating sleep resulted associated with other SAFA subscales relative to obsessiveecompulsive symptoms and depression symptoms. Furthermore, anxiety symptoms (SAFA A) resulted associated with increased motor activity during sleep. Conclusions: Findings confirm literature studies reporting high frequency of sleep problems, anxiety and other psychopathological symptoms in patients with tic disorders, and support the hypothesis that intrusive thoughts and other emotional disturbances might disrupt the sleep onset of these patients. These results suggest the importance of a thorough assessment of sleep and psychiatric disturbances in patients with tic disorders

La programmazione e la realizzazione delle grandi opere pubbliche

La programmazione e la realizzazione delle grandi opere pubblich

Repeated anabolic androgenic steroid treatment causes antidepressant-reversible alterations of the hypothalamic - pituitary - adrenal axis, BDNF levels and behavior

Abuse of anabolic androgenic steroids (AASs) is frequently associated with changes in mood, including depression. However, the nature of this association is still largely unexplored. As a model of AAS abuse, we used male adult rats injected for 4 weeks with either nandrolone or stanozolol at daily doses (5 mg/kg, s.c.) that are considered equivalent to those abused by humans on a milligram per kilogram of body weight basis. AAS treatment reduced levels of brain-derived neurotrophic factor in the hippocampus and prefrontal cortex, reduced the expression of low-affinity glucocorticoid receptors in the hippocampus, and increased morning trough basal plasma corticosterone levels. All these changes have been related to the pathophysiology of major depressive disorder. Accordingly, rats treated with nandrolone or stanozolol showed an increased immobility time in the forced swim test, which is widely used for the screening of antidepressant drugs. All effects produced by AASs were prevented by co-administration with the classical antidepressant, chlorimipramine. The evidence that supraphysiological doses of AASs induce changes indicative of a depressive state in normal rats, raises the concern that AAS abuse in humans may cause depression regardless of exposure to stress or other risk factors. (C) 2010 Elsevier Ltd. All rights reserved

Prenatal Methylmercury Exposure: Effects on Stress Response During Active Learning

The long-term impact of prenatal methylmercury (MeHg) exposure on the stress response during active learning was investigated. Pregnant rats were gavage fed MeHg (8 mg/kg) on gestational day 15. Ninety-day-old rats born to both MeHg- and saline-treated dams were subjected to an active avoidance test. The active avoidance-experienced rats (AAERs) with prenatal exposure to MeHg showed significant impairment in learning ability and exhibited higher levels of corticosterone than the untreated AAERs. The present findings suggest that the abnormal increase in plasma corticosterone levels could contribute to the poor performance of MeHg-treated AAERs in this learning task

Social isolation selectively reduces hippocampal brain-derived neurotrophic factor without altering plasma corticosterone

It is well known that housing conditions may alter several physiological and behavioral parameters. In this study, we have investigated whether a prolonged period of partial social isolation can modify central brain-derived neurotrophic (BDNF) concentrations. Male Sprague-Dawley rats were singly housed for 8 weeks before hippocampi, prefrontal cortices and striata were collected for BDNF determination. Compared to rats housed two per cage, isolated rats showed a significant reduction on BDNF protein concentrations in the hippocampus while no changes were observed in the other brain regions examined. Moreover, housing condition had no effect on basal plasma corticosterone. On the basis of the proposed etiological participation of reduced central BDNF concentrations in affective disorders, our results would candidate social isolation as a model for the study of antidepressant treatments. (c) 2006 Elsevier B.V. All rights reserved

Nutritional Mushroom Treatment in Meniere’s Disease with Coriolus versicolor: A Rationale for Therapeutic Intervention in Neuroinflammation and Antineurodegeneration

Meniere’s disease (MD) represents a clinical syndrome characterized by episodes of spontaneous vertigo, associated with fluctuating, low to medium frequencies sensorineural hearing loss (SNHL), tinnitus, and aural fullness affecting one or both ears. To date, the cause of MD remains substantially unknown, despite increasing evidence suggesting that oxidative stress and neuroinflammation may be central to the development of endolymphatic hydrops and consequent otholitic degeneration and displacement in the reuniting duct, thus originating the otolithic crisis from vestibular otolithic organs utricle or saccule. As a starting point to withstand pathological consequences, cellular pathways conferring protection against oxidative stress, such as vitagenes, are also induced, but at a level not sufficient to prevent full neuroprotection, which can be reinforced by exogenous nutritional approaches. One emerging strategy is supplementation with mushrooms. Mushroom preparations, used in traditional medicine for thousands of years, are endowed with various biological actions, including antioxidant, immunostimulatory, hepatoprotective, anticancer, as well as antiviral effects. For example, therapeutic polysaccharopeptides obtained from Coriolus versicolor are commercially well established. In this study, we examined the hypothesis that neurotoxic insult represents a critical primary mediator operating in MD pathogenesis, reflected by quantitative increases of markers of oxidative stress and cellular stress response in the peripheral blood of MD patients. We evaluated systemic oxidative stress and cellular stress response in MD patients in the absence and in the presence of treatment with a biomass preparation from Coriolus. Systemic oxidative stress was estimated by measuring, in plasma, protein carbonyls, hydroxynonenals (HNE), and ultraweak luminescence, as well as by lipidomics analysis of active biolipids, such as lipoxin A4 and F2-isoprostanes, whereas in lymphocytes we determined heat shock proteins 70 (Hsp72), heme oxygenase-1 (HO-1), thioredoxin (Trx), and γ-GC liase to evaluate the systemic cellular stress response. Increased levels of carbonyls, HNE, luminescence, and F2-isoprostanes were found in MD patients with respect to the MD plus Coriolus-treated group. This was paralleled by a significant (p < 0.01) induction, after Coriolus treatment, of vitagenes such as HO-1, Hsp70, Trx, sirtuin-1, and γ-GC liase in lymphocyte and by a significant (p < 0.05) increase in the plasma ratio-reduced glutathione (GSH) vs. oxidized glutathione (GSSG). In conclusion, patients affected by MD are under conditions of systemic oxidative stress, and the induction of vitagenes after mushroom supplementation indicates a maintained response to counteract intracellular pro-oxidant status. The present study also highlights the importance of investigating MD as a convenient model of cochlear neurodegenerative disease. Thus, searching innovative and more potent inducers of the vitagene system can allow the development of pharmacological strategies capable of enhancing the intrinsic reserve of vulnerable neurons, such as ganglion cells to maximize antidegenerative stress responses and thus providing neuroprotection

Carnosine Activates Cellular Stress Response in Podocytes and Reduces Glycative and Lipoperoxidative Stress

Carnosine improves diabetic complications, including diabetic nephropathy, in in vivo models. To further understand the underlying mechanism of nephroprotection, we studied the effect of carnosine under glucose-induced stress on cellular stress response proteins in murine immortalized podocytes, essential for glomerular function. High-glucose stress initiated stress response by increasing intracellular heat shock protein 70 (Hsp70), sirtuin-1 (Sirt-1), thioredoxin (Trx), glutamate-cysteine ligase (gamma-glutamyl cysteine synthetase; γ-GCS) and heme oxygenase-1 (HO-1) in podocytes by 30–50% compared to untreated cells. Carnosine (1 mM) also induced a corresponding upregulation of these intracellular stress markers, which was even more prominent compared to glucose for Hsp70 (21%), γ-GCS and HO-1 (13% and 20%, respectively; all p < 0.001). Co-incubation of carnosine (1 mM) and glucose (25 mM) induced further upregulation of Hsp70 (84%), Sirt-1 (52%), Trx (35%), γ-GCS (90%) and HO-1 (73%) concentrations compared to untreated cells (all p < 0.001). The glucose-induced increase in 4-hydroxy-trans-2-nonenal (HNE) and protein carbonylation was reduced dose-dependently by carnosine by more than 50% (p < 0.001). Although podocytes tolerated high carnosine concentrations (10 mM), high carnosine levels only slightly increased Trx and γ-GCS (10% and 19%, respectively, compared to controls; p < 0.001), but not Hsp70, Sirt-1 and HO-1 proteins (p not significant), and did not modify the glucose-induced oxidative stress response. In podocytes, carnosine induced cellular stress tolerance and resilience pathways and was highly effective in reducing high-glucose-induced glycative and lipoperoxidative stress. Carnosine in moderate concentrations exerted a direct podocyte molecular protective action