Publications by authors named "Vittorio Calabrese"

127 Publications

Protects SH-SY5YCells from DEHP-Induced Endoplasmic Reticulum Stress and Apoptosis.

Antioxidants (Basel) 2021 Mar 29;10(4). Epub 2021 Mar 29.

Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy.

(MO) is a medicinal plant that has been shown to possess antioxidant, anticarcinogenic and antibiotic activities. In a rat model, MO extract (MOe) has been shown to have a protective effect against brain damage and memory decline. As an extending study, here, we have examined the protective effect of MOe against oxidative stress and apoptosis caused in human neuroblastome (SH-SY5Y) cells by di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to induce neurotoxicity. Our data show that MOe prevents oxidative damage by lowering reactive oxygen species (ROS) formation, restoring mitochondrial respiratory chain complex activities, and, in addition, by modulating the expression of vitagenes, i.e., antioxidant proteins Nrf2 and HO-1. Moreover, MOe prevented neuronal damage by partly inhibiting endoplasmic reticulum (ER) stress response, as indicated by decreased expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and Glucose-regulated protein 78 (GRP78) proteins. MOe also protected SH-SY5Y cells from DEHP-induced apoptosis, preserving mitochondrial membrane permeability and caspase-3 activation. Our findings provide insight into understanding of molecular mechanisms involved in neuroprotective effects by MOe against DEHP damage.
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http://dx.doi.org/10.3390/antiox10040532DOI Listing
March 2021

Carbon Monoxide: from Poison to Clinical Trials.

Trends Pharmacol Sci 2021 Mar 26. Epub 2021 Mar 26.

Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA. Electronic address:

Every cell has a highly sophisticated system for regulating heme levels, which is particularly important with regard to turnover. Heme degradation generates CO and while CO has long been viewed as a metabolic waste product, and at higher concentrations cellularly lethal, we now know that CO is an indispensable gasotransmitter that participates in fundamental physiological processes necessary for survival. Irrefutable preclinical data have resulted in concerted efforts to develop CO as a safe and effective therapeutic agent, but against this notion lies dogma that CO is a poison, especially to the brain. The emergence of this debate is discussed here highlighting the neuroprotective properties of CO through its role on the central circadian clock and ongoing strategies being developed for CO administration for clinical use.
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http://dx.doi.org/10.1016/j.tips.2021.02.003DOI Listing
March 2021

Demonstrated hormetic mechanisms putatively subserve riluzole-induced effects in neuroprotection against amyotrophic lateral sclerosis (ALS): Implications for research and clinical practice.

Ageing Res Rev 2021 May 8;67:101273. Epub 2021 Feb 8.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC, 20057, USA. Electronic address:

This paper provides evidence to support that riluzole, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), like many neuroprotective agents, displays and exerts hormetic biphasic dose responses. These findings have important implications for the experimental study and clinical treatment of ALS.
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http://dx.doi.org/10.1016/j.arr.2021.101273DOI Listing
May 2021

Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis.

Antioxidants (Basel) 2020 Dec 18;9(12). Epub 2020 Dec 18.

Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69120 Heidelberg, Germany.

Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (HS) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The pathophysiological link of this crosstalk is represented by oxidative stress and inflammatory processes which contribute to the high prevalence of neuropsychiatric disorders, cognitive impairment, and dementia during the natural history of chronic kidney disease. Herein, we provide an overview of the main pathophysiological mechanisms related to high levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and neurotoxins, which play a critical role in the kidney-brain crosstalk. The present paper also explores the respective role of HS and carnosine in the modulation of oxidative stress and inflammation in the kidney-brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.
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http://dx.doi.org/10.3390/antiox9121303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767317PMC
December 2020

Putative hormetic mechanisms and effects of atypical antipsychotic agents: Implications for study design and clinical psychopharmacotherapeutics.

Chem Biol Interact 2021 Jan 23;333:109327. Epub 2020 Nov 23.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC, 20057, USA. Electronic address:

This paper addresses a novel putative mechanism by which atypical antipsychotic agents induce clinically significant neuroprotective effects that may be viable in the treatment of schizophrenia - and perhaps other neuropsychiatric disorders. Based upon experimental studies with multiple in vitro models (i.e., PC 12 cells, NSC-34 hybrid cells, SH-SY5Y cells, the immune cell line U-937) and several rodent in vivo models, six atypical antipsychotic drugs, within direct experimental comparisons and/or preconditioning protocol studies with six different stressor/toxic agents (i.e. rotenone, hydrogen peroxide, MPP+, serum withdrawal, beta-amyloid, and corticosterone) were demonstrated to induce neuroprotective effects with consistently hormetic dose response patterns. These findings suggest that some of the reported neuroprotective effects of atypical human antipsychotic agents are likely to be mediated by hormetic mechanisms. These findings may have important implications for both experimental study design and clinical therapeutics.
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http://dx.doi.org/10.1016/j.cbi.2020.109327DOI Listing
January 2021

Anti-inflammatory and Anti-oxidant Activity of Hidrox in Rotenone-Induced Parkinson's Disease in Mice.

Antioxidants (Basel) 2020 Sep 3;9(9). Epub 2020 Sep 3.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy.

Background: In developed countries, the extension of human life is increasingly accompanied by a progressive increase in neurodegenerative diseases, most of which do not yet have effective therapy but only symptomatic treatments. In recent years, plant polyphenols have aroused considerable interest in the scientific community. The mechanisms currently hypothesized for the pathogenesis of Parkinson's disease (PD) are neuroinflammation, oxidative stress and apoptosis. Hydroxytyrosol (HT), the main component of Hidrox (HD), has been shown to have some of the highest free radical evacuation and anti-inflammatory activities. Here we wanted to study the role of HD on the neurobiological and behavioral alterations induced by rotenone.

Methods: A study was conducted in which mice received HD (10 mg/kg, i.p.) concomitantly with rotenone (5 mg/kg, o.s.) for 28 days.

Results: Locomotor activity, catalepsy, histological damage and several characteristic markers of the PD, such as the dopamine transporter (DAT) content, tyrosine hydroxylase (TH) and accumulation of α-synuclein, have been evaluated. Moreover, we observed the effects of HD on oxidative stress, neuroinflammation, apoptosis and inflammasomes. Taken together, the results obtained highlight HD's ability to reduce the loss of dopaminergic neurons and the damage associated with it by counteracting the three main mechanisms of PD pathogenesis.

Conclusion: HD is subject to fewer regulations than traditional drugs to improve patients' brain health and could represent a promising nutraceutical choice to prevent PD.
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http://dx.doi.org/10.3390/antiox9090824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576486PMC
September 2020

Hormesis: A potential strategic approach to the treatment of neurodegenerative disease.

Int Rev Neurobiol 2020 11;155:271-301. Epub 2020 Aug 11.

Departments of Neurology & Biochemistry, Georgetown University Medical Center, Washington, DC, United States.

This review describes neuroprotective effects mediated by pre- and post-conditioning-induced processes that act via the quantitative features of the hormetic dose response. These lead to the development of acquired resilience that can protect neuronal systems from endogenous and exogenous stresses and insult. Particular attention is directed to issues of dose optimization, inter-individual variation, and potential ways to further study and employ hormetic-based preconditioning approaches in medical and public health efforts to treat and prevent neurodegenerative disease.
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http://dx.doi.org/10.1016/bs.irn.2020.03.024DOI Listing
August 2020

Does Green Tea Induce Hormesis?

Dose Response 2020 Jul-Sep;18(3):1559325820936170. Epub 2020 Jul 15.

Department of Biomedical and Biotechnological Sciences, School of Medicine University of Catania, Catania, Italy.

Green tea, and its principal constituent (-)-epigallocatechin-3-gallate (EGCG), are commonly shown to induce biphasic concentration/dose responses in a broad range of cell types, including non-tumor cells, and tumor cell lines. The most active area of research dealt with an assessment of neural cells with application to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease cell models, often using preconditioning experimental protocols. The general findings demonstrate EGCG-induced hormetic effects resulting in an enhanced acquired resilience within an adaptive and temporally dependent homeodynamic framework. The biphasic dose responses displayed the typical quantitative features of the hormetic dose response with respect to the amplitude and width of the stimulatory response. These findings provide further evidence for the general occurrence of hormetic dose responses with such responses being independent of the biological model, end point, inducing agent, and mechanism. The biphasic nature of these responses has important implications since it suggests optimal dose ranges for end points of public health and therapeutic applications. These findings indicate the need to assess the entire dose-response continuum in order to better define the nature of the dose response, especially in the low-dose zone where such exposures are common in human populations.
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http://dx.doi.org/10.1177/1559325820936170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364811PMC
July 2020

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

Biomedicines 2020 Jun 26;8(6). Epub 2020 Jun 26.

Centre for Pediatric and Adolescent Medicine, University of Heidelberg, 69117 Heidelberg, Germany.

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 < 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 < 0.001). The glucose-induced increase in 4-hydroxy--2-nonenal (HNE) and protein carbonylation was reduced dose-dependently by carnosine by more than 50% ( < 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; < 0.001), but not Hsp70, Sirt-1 and HO-1 proteins ( 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.
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http://dx.doi.org/10.3390/biomedicines8060177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344982PMC
June 2020

Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney.

Cell Stress Chaperones 2020 11 4;25(6):919-928. Epub 2020 Jun 4.

Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, LR01SE1, Rue Avicenne, 5000, Monastir, Tunisia.

Environmental toxicants such as phthalate have been involved in multiple health disorders including renal diseases. Oxidative damage is implicated in many alterations caused by phthalate especially the di(2-ethylhexyl) phthalate (DEHP), which is the most useful phthalate. However, information regarding its mechanism of renal damage is lacking. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene expression implicated in free radical scavenging and cytoprotection including the antioxidant glutathione (GSH) pathway. The aim of this study was to assess whether DEHP affects the Nrf2 pathway and the GSH concentration. Mice were divided into four groups: a control group and three groups treated with DEHP at different concentrations (5, 50, and 200 mg/kg body weight) for 30 days. Our results showed that DEHP altered the normal levels of serum biochemical parameters creatinine (CREA), urea, and lactate dehydrogenase (LDH). This phthalate caused oxidative damage through the induction of lipid peroxidation and protein oxidation as marked by increase of protein carbonyl (PC) and loss of protein-bound sulfhydryls (PSH). Simultaneously, DEHP treatment decreased the protein level of Nrf-2, HO-1, and GCLC (responsible of GSH synthesis) and decreased the GSH level. Inhibition of the Nrf2 pathway is related to the activation of the mitochondrial pathway of apoptosis. This apoptotic process is evidenced by an upregulation of p53 and Bax protein levels in addition to a downregulation of Bcl-2. Collectively, our data demonstrated that depletion of Nrf2 and GSH was associated with the elevation of oxidative stress and the activation of intrinsic apoptosis in mouse kidney treated with DEHP.
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http://dx.doi.org/10.1007/s12192-020-01127-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591664PMC
November 2020

Healthspan Enhancement by Olive Polyphenols in Wild Type and Parkinson's Models.

Int J Mol Sci 2020 May 29;21(11). Epub 2020 May 29.

Faculty of Life Sciences, Institute of Biology, Molecular Genetics Group, Humboldt University of Berlin, Philippstr. 13, House 22, 10115 Berlin, Germany.

Parkinson's disease (PD) is the second most prevalent late-age onset neurodegenerative disorder, affecting 1% of the population after the age of about 60 years old and 4% of those over 80 years old, causing motor impairments and cognitive dysfunction. Increasing evidence indicates that Mediterranean diet (MD) exerts beneficial effects in maintaining health, especially during ageing and by the prevention of neurodegenerative disorders. In this regard, olive oil and its biophenolic constituents like hydroxytyrosol (HT) have received growing attention in the past years. Thus, in the current study we test the health-promoting effects of two hydroxytyrosol preparations, pure HT and Hidrox (HD), which is hydroxytyrosol in its "natural" environment, in the established invertebrate model organism . HD exposure led to much stronger beneficial locomotion effects in wild type worms compared to HT in the same concentration. Consistent to this finding, in OW13 worms, a PD-model characterized by α-synuclein expression in muscles, HD exhibited a significant higher effect on α-synuclein accumulation and swim performance than HT, an effect partly confirmed also in swim assays with the UA44 strain, which features α-synuclein expression in DA-neurons. Interestingly, beneficial effects of HD and HT treatment with similar strength were detected in the lifespan and autofluorescence of wild-type nematodes, in the neuronal health of UA44 worms as well as in the locomotion of rotenone-induced PD-model. Thus, the hypothesis that HD features higher healthspan-promoting abilities than HT was at least partly confirmed. Our study demonstrates that HD polyphenolic extract treatment has the potential to partly prevent or even treat ageing-related neurodegenerative diseases and ageing itself. Future investigations including mammalian models and human clinical trials are needed to uncover the full potential of these olive compounds.
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http://dx.doi.org/10.3390/ijms21113893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312680PMC
May 2020

Nutrition and the ageing brain: Moving towards clinical applications.

Ageing Res Rev 2020 09 24;62:101079. Epub 2020 May 24.

Department of Nutrition and Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, UK. Electronic address:

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3 Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required.
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http://dx.doi.org/10.1016/j.arr.2020.101079DOI Listing
September 2020

Healthspan Maintenance and Prevention of Parkinson's-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in .

Int J Mol Sci 2020 Apr 8;21(7). Epub 2020 Apr 8.

Humboldt University of Berlin, Faculty of Life Sciences, Institute of Biology, Molecular Genetics Group, Philippstr. 13, House 22, 10115 Berlin, Germany.

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer's and Parkinson's disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.
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http://dx.doi.org/10.3390/ijms21072588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178172PMC
April 2020

Prevents DEHP-Induced Mitochondrial Dysfunction and Apoptosis in PC12 Cells.

Int J Mol Sci 2020 Mar 20;21(6). Epub 2020 Mar 20.

Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia n. 97, 95125 Catania, Italy.

(HE) is a medicinal plant known to possess anticarcinogenic, antibiotic, and antioxidant activities. It has been shown to have a protective effect against ischemia-injury-induced neuronal cell death in rats. As an extending study, here we examined in pheochromocytoma 12 (PC12) cells, whether HE could exert a protective effect against oxidative stress and apoptosis induced by di(2-ethylhexyl)phthalate (DEHP), a plasticizer known to cause neurotoxicity. We demonstrated that pretreatment with HE significantly attenuated DEHP induced cell death. This protective effect may be attributed to its ability to reduce intracellular reactive oxygen species levels, preserving the activity of respiratory complexes and stabilizing the mitochondrial membrane potential. Additionally, HE pretreatment significantly modulated Nrf2 and Nrf2-dependent vitagenes expression, preventing the increase of pro-apoptotic and the decrease of anti-apoptotic markers. Collectively, our data provide evidence of new preventive nutritional strategy using HE against DEHP-induced apoptosis in PC12 cells.
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http://dx.doi.org/10.3390/ijms21062138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139838PMC
March 2020

Healthy Effects of Plant Polyphenols: Molecular Mechanisms.

Int J Mol Sci 2020 Feb 13;21(4). Epub 2020 Feb 13.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy.

The increasing extension in life expectancy of human beings in developed countries is accompanied by a progressively greater rate of degenerative diseases associated with lifestyle and aging, most of which are still waiting for effective, not merely symptomatic, therapies. Accordingly, at present, the recommendations aimed at reducing the prevalence of these conditions in the population are limited to a safer lifestyle including physical/mental exercise, a reduced caloric intake, and a proper diet in a convivial environment. The claimed health benefits of the Mediterranean and Asian diets have been confirmed in many clinical trials and epidemiological surveys. These diets are characterized by several features, including low meat consumption, the intake of oils instead of fats as lipid sources, moderate amounts of red wine, and significant amounts of fresh fruit and vegetables. In particular, the latter have attracted popular and scientific attention for their content, though in reduced amounts, of a number of molecules increasingly investigated for their healthy properties. Among the latter, plant polyphenols have raised remarkable interest in the scientific community; in fact, several clinical trials have confirmed that many health benefits of the Mediterranean/Asian diets can be traced back to the presence of significant amounts of these molecules, even though, in some cases, contradictory results have been reported, which highlights the need for further investigation. In light of the results of these trials, recent research has sought to provide information on the biochemical, molecular, epigenetic, and cell biology modifications by plant polyphenols in cell, organismal, animal, and human models of cancer, metabolic, and neurodegenerative pathologies, notably Alzheimer's and Parkinson disease. The findings reported in the last decade are starting to help to decipher the complex relations between plant polyphenols and cell homeostatic systems including metabolic and redox equilibrium, proteostasis, and the inflammatory response, establishing an increasingly solid molecular basis for the healthy effects of these molecules. Taken together, the data currently available, though still incomplete, are providing a rationale for the possible use of natural polyphenols, or their molecular scaffolds, as nutraceuticals to contrast aging and to combat many associated pathologies.
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http://dx.doi.org/10.3390/ijms21041250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072974PMC
February 2020

Hormesis and Ginkgo biloba (GB): Numerous biological effects of GB are mediated via hormesis.

Ageing Res Rev 2020 12 10;64:101019. Epub 2020 Jan 10.

Departments of Neurology and Biochemistry, Georgetown University Medical Center, 4000 Reservoir Road, Washington DC, USA. Electronic address:

Ginkgo biloba (GB) extracts have been shown to commonly induce biphasic dose responses in a range of cell types and endpoints (e.g., cochlea neural stem cells, cell viability, cell proliferation). The magnitude and width of the low dose stimulation of these biphasic dose responses are similar to those reported for hormetic dose responses. These hormetic dose responses occur within direct stimulatory responses as well as in preconditioning experimental protocols, displaying acquired resistance within an adaptive homeodynamic and temporal framework and repeated measurement protocols. The demonstrated GB dose responses further reflect the general occurrence of hormetic dose responses that consistently appear to be independent of the biological model, endpoint, inducing agent, and/or mechanism. These findings have important implications for consideration(s) of study designs involving dose selection, dose spacing, sample size, and statistical power. This illustrates and strengthens the need to characterize the low dose stimulatory response range and optimal dose in order to explore potential public health and clinical applications of plant-derived agents, such as GB.
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http://dx.doi.org/10.1016/j.arr.2020.101019DOI Listing
December 2020

Nutritional Mushroom Treatment in Meniere's Disease with : A Rationale for Therapeutic Intervention in Neuroinflammation and Antineurodegeneration.

Int J Mol Sci 2019 Dec 31;21(1). Epub 2019 Dec 31.

Department of Medical and Surgery Sciences, University of Catania, Via Santa Sofia 78, 95123 Catania, Italy.

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 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 . 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 -treated group. This was paralleled by a significant ( < 0.01) induction, after treatment, of vitagenes such as HO-1, Hsp70, Trx, sirtuin-1, and γ-GC liase in lymphocyte and by a significant ( < 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.
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http://dx.doi.org/10.3390/ijms21010284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981469PMC
December 2019

Curcumin, Hormesis and the Nervous System.

Nutrients 2019 Oct 10;11(10). Epub 2019 Oct 10.

Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia, 97-95125 Catania, Italy.

Curcumin is a polyphenol compound extracted from the rhizome of (family ) commonly used as a spice to color and flavor food. Several preclinical studies have suggested beneficial roles for curcumin as an adjuvant therapy in free radical-based diseases, mainly neurodegenerative disorders. Indeed, curcumin belongs to the family of hormetins and the enhancement of the cell stress response, mainly the heme oxygenase-1 system, is actually considered the common denominator for this dual response. However, evidence-based medicine has clearly demonstrated the lack of any therapeutic effect of curcumin to contrast the onset or progression of neurodegeneration and related diseases. Finally, the curcumin safety profile imposes a careful analysis of the risk/benefit balance prior to proposing chronic supplementation with curcumin.
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http://dx.doi.org/10.3390/nu11102417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835324PMC
October 2019

Di (2-ethylhexyl) phthalate targets the thioredoxin system and the oxidative branch of the pentose phosphate pathway in liver of Balb/c mice.

Environ Toxicol 2020 Jan 5;35(1):78-86. Epub 2019 Sep 5.

Faculty of Dental Medicine, Laboratory for Research on Biologically Compatible Compounds, University of Monastir, Monastir, Tunisia.

Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that gives flexibility to various polyvinyl chloride products. It is a pollutant easily released into the environment and can cause many adverse effects to living organisms including hepatotoxicity. The thioredoxin system is a determining factor in the redox balance maintaining in the liver, which is a vulnerable tissue of reactive oxygen species overproduction because of its high energy needs. In order to determine if the thioredoxin system is a target in the development of DEHP hepatotoxicity, Balb/c mice were administered with DEHP intraperitoneally daily for 30 days. Results demonstrated that after DEHP exposure, biochemical profile changes were observed. This phthalate causes oxidative damage through the induction of lipid peroxydation as well as the increase of superoxide dismutase and catalase activities. As new evidence provided in this study, we demonstrated that the DEHP affected the thioredoxin system by altering the expression and the activity of thioredoxin (Trx) and thioredoxin Reductase (TrxR1). The two enzyme activities of the oxidative phase of the pentose phosphate pathway: Glucose-6-phosphate dehydrogenase and 6-Phosphogluconate dehydrogenase were also affected by this phthalate. This leads to a decrease in the level of nicotinamide adenine dinucleotide phosphate used by the TrxR1 to maintain the regeneration of the reduced Trx. We also demonstrated that such effects can be responsible of DEHP-induced DNA damage.
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http://dx.doi.org/10.1002/tox.22844DOI Listing
January 2020

Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies.

Pharmacol Res 2019 12 12;150:104371. Epub 2019 Aug 12.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA. Electronic address:

This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic.
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http://dx.doi.org/10.1016/j.phrs.2019.104371DOI Listing
December 2019

Environment and Male Fertility: Effects of Benzo-α-Pyrene and Resveratrol on Human Sperm Function In Vitro.

J Clin Med 2019 Apr 25;8(4). Epub 2019 Apr 25.

Department of Clinical and Experimental Medicine, 95123 Catania, Italy.

Lifestyle, cigarette smoking and environmental pollution have a negative impact on male fertility. Therefore, the aim of this study was to evaluate the in-vitro effects of benzo-α-pyrene (BaP) and aryl hydrocarbon receptor (AHR) agonists on motility and bio-functional sperm parameters. We further assessed whether resveratrol (RES), an AHR antagonist and antioxidant molecule, had any protective effect. To accomplish this, 30 normozoospermic, healthy, non-smoker men not exposed to BaP were enrolled. Spermatozoa of 15 men were incubated with increasing concentrations of BaP to evaluate its effect and to establish its dose response. Then, spermatozoa of the 15 other men were incubated with BaP (15 µM/mL), chosen according to the dose-response and/or RES to evaluate its antagonistic effects. The effects of both substances were evaluated after 3 h of incubation on total and progressive sperm motility and on the following bio-functional sperm parameters evaluated by flow cytometry: Degree of chromatin compactness, viability, phosphatidylserine externalization (PS), late apoptosis, mitochondrial membrane potential (MMP), DNA fragmentation, degree of lipoperoxidation (LP), and concentrations of mitochondrial superoxide anion. Benzo-α-pyrene decreased total and progressive sperm motility, impaired chromatin compactness, and increased sperm lipoperoxidation and mitochondrial superoxide anion levels. All these effects were statistically significant at the lowest concentration tested (15 µM/mL) and they were confirmed at the concentration of 45 µM/mL. In turn, RES was able to counteract the detrimental effects of BaP on sperm motility, abnormal chromatin compactness, lipid peroxidation, and mitochondrial superoxide. This study showed that BaP alters sperm motility and bio-functional sperm parameters and that RES exerts a protective effect on BaP-induced sperm damage.
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http://dx.doi.org/10.3390/jcm8040561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518055PMC
April 2019

GABA-containing compound gammapyrone protects against brain impairments in Alzheimer's disease model male rats and prevents mitochondrial dysfunction in cell culture.

J Neurosci Res 2019 06 11;97(6):708-726. Epub 2019 Feb 11.

Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.

Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer's disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma-aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: "free" moiety attached to the position 4 of the 1,4-dihydropyridine (DHP) ring, and two "crypto" moieties as part of the DHP scaffold. The "free" and "crypto" GABA moieties are linked by a peptide bond (-CONH-), resulting in a peptide-mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di-2-ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA-A and GABA-B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide-like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti-dementia drugs.
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http://dx.doi.org/10.1002/jnr.24396DOI Listing
June 2019

Clinical Trials on Diabetic Nephropathy: A Cross-Sectional Analysis.

Diabetes Ther 2019 Feb 7;10(1):229-243. Epub 2019 Jan 7.

Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Introduction: Treatment options and decisions are often based on the results of clinical trials. We have evaluated the public availability of results from completed, registered phase III clinical trials on diabetic nephropathy and current treatment options.

Methods: This was a cross-sectional analysis in which STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. In June 2017, 34 completed phase III clinical trials on diabetic nephropathy in the ClinicalTrials. gov registry were identified and matched to publications in the ClinicalTrials.gov registry and to those in the PubMed and Google Scholar databases. If no publication was identified, the principal investigator was contacted. The ratio of published and non-published studies was calculated. Various parameters, including study design, drugs, and comparators provided, were analyzed.

Results: Drugs/supplements belonged to 26 different categories of medications, with the main ones being angiotensin-converting enzyme inhibitors, angiotensin-II receptors blockers, and dipeptidyl-peptidase-4-inhibitors. Among the trials completed before 2016 (n = 32), 22 (69%) were published, and ten (31%) remained unpublished. Thus, data on 11 different interventions and more than 1000 patients remained undisclosed. Mean time to publication was 26.5 months, which is longer than the time constrictions imposed by the U.S. Food and Drug Administration Amendments Act. Most trials only showed weak effects on micro- and macroalbuminuria, with an absolute risk reduction of 1.0 and 0.3%, respectively, and the number needed to treat varied between 91 and 333, without any relevant effect on end-stage-renal disease by intensive glucose-lowering treatment. Comparison of the results, however, was difficult since study design, interventions, and the renal outcome parameters vary greatly between the studies.

Conclusion: Despite the financial and human resources involved and the relevance for therapeutic guidelines and clinical decisions, about one-third of phase III clinical trials on diabetic nephropathy remain unpublished. Interventions used in published trials showed a low efficacy on renal outcome.

Funding: Deutsche Forschungsgemeinschaft (DFG): SFB 1118.
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http://dx.doi.org/10.1007/s13300-018-0551-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349284PMC
February 2019

Sm. Polyphenols Modulate Interferon Gamma/Histamine-Induced Inflammation in Human NCTC 2544 Keratinocytes.

Molecules 2018 Oct 2;23(10). Epub 2018 Oct 2.

Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via Santa Sofia, 97-95123 Catania, Italy.

, known as the prickly-leaf tea tree, contains a variety of bioactive compounds. The purposes of this study were to characterize the polyphenols extracted from leaves and assess their potential antioxidant and anti-inflammatory effects. The polyphenol extracts were prepared by maceration with solvents of increasing polarity. The LC/MS-MS technique was used to identify and quantify the phenolic compounds. An assessment of the radical scavenging activity of all extracts was performed using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) (ABTS⁺), and ferric reducing antioxidant power (FRAP) assays. The anti-inflammatory activity was determined on interferon gamma (IFN-γ)/histamine (H)-stimulated human NCTC 2544 keratinocytes by Western blot and RT-PCR. Compared to other solvents, methanolic extract presented the highest level of phenolic contents. The most frequent phenolic compounds were quercetin, followed by gallic acid and ellagic acid. DPPH, ABTS⁺, and FRAP assays showed that methanolic extract exhibits strong concentration-dependent antioxidant activity. IFN-γ/H treatment of human NCTC 2544 keratinocytes induced the secretion of high levels of the pro-inflammatory mediator inter-cellular adhesion molecule-1 (ICAM-1), nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB), which were inhibited by extract. In conclusion, the extract of leaves is rich in flavonoids, and presents antioxidant and anti-inflammatory proprieties. It can be proposed as a useful compound to treat inflammatory skin diseases.
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http://dx.doi.org/10.3390/molecules23102526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222365PMC
October 2018

biomass increases dendritic arborization of newly-generated neurons in mouse hippocampal dentate gyrus.

Oncotarget 2018 Aug 31;9(68):32929-32942. Epub 2018 Aug 31.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.
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http://dx.doi.org/10.18632/oncotarget.25978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152478PMC
August 2018

Protective Actions of Anserine Under Diabetic Conditions.

Int J Mol Sci 2018 Sep 13;19(9). Epub 2018 Sep 13.

Centre for Paediatric and Adolescent Medicine, University Hospital of Heidelberg, 69120 Heidelberg, Germany.

Background/aims: In rodents, carnosine treatment improves diabetic nephropathy, whereas little is known about the role and function of anserine, the methylated form of carnosine.

Methods: Antioxidant activity was measured by oxygen radical absorbance capacity and oxygen stress response in human renal tubular cells (HK-2) by RT-PCR and Western-Immunoblotting. In wildtype (WT) and diabetic mice (db/db), the effect of short-term anserine treatment on blood glucose, proteinuria and vascular permeability was measured.

Results: Anserine has a higher antioxidant capacity compared to carnosine ( < 0.001). In tubular cells (HK-2) stressed with 25 mM glucose or 20⁻100 µM hydrogen peroxide, anserine but not carnosine, increased intracellular heat shock protein (Hsp70) mRNA and protein levels. In HK-2 cells stressed with glucose, co-incubation with anserine also increased hemeoxygenase (HO-1) protein and reduced total protein carbonylation, but had no effect on cellular sirtuin-1 and thioredoxin protein concentrations. Three intravenous anserine injections every 48 h in 12-week-old db/db mice, improved blood glucose by one fifth, vascular permeability by one third, and halved proteinuria (all < 0.05).

Conclusion: Anserine is a potent antioxidant and activates the intracellular Hsp70/HO-1 defense system under oxidative and glycative stress. Short-term anserine treatment in diabetic mice improves glucose homeostasis and nephropathy.
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http://dx.doi.org/10.3390/ijms19092751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164239PMC
September 2018

Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities.

J Neurosci Res 2018 10 11;96(10):1641-1662. Epub 2018 Aug 11.

Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts, USA.

Age-related changes in the brain reflect a dynamic interaction of genetic, epigenetic, phenotypic, and environmental factors that can be temporally restricted or more longitudinally present throughout the lifespan. Fundamental to these mechanisms is the capacity for physiological adaptation through modulation of diverse molecular and biochemical signaling occurring from the intracellular to the network-systemic level throughout the brain. A number of agents that affect the onset and progression of Parkinson's disease (PD)-like effects in experimental models exhibit temporal features, and mechanisms of hormetic dose responses. These findings have particular significance since the hormetic dose response describes the amplitude and range of potential therapeutic effects, thereby affecting the design and conduct of studies of interventions against PD (and other neurodegenerative diseases), and may also be important to a broader consideration of hormetic processes in resilient adaptive responses that might afford protection against the onset and/or progression of PD and related disorders.
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http://dx.doi.org/10.1002/jnr.24244DOI Listing
October 2018

Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer's disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms.

Immun Ageing 2018 14;15. Epub 2018 Feb 14.

1Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy.

Human life develops and expands not only in time and space, but also in the retrograde permanent recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered or lost under pathological conditions such as Alzheimer's disease, including recently associated oxidant pathologies, such as ocular neural degeneration occurring in glaucoma or neurosensorial degeneration occurring in Menière's disease. Oxidative stress and altered antioxidant systems have been suggested to play a role in the aetiology of major neurodegenerative disorders, and altered expression of genes sensing oxidative stress, as well as decreased cellular stress response mechanisms could synergistically contribute to the course of these oxidant disorders. Thus, the theory that low levels of stress can produce protective responses against the pathogenic processes is a frontier area of neurobiological research focal to understanding and developing therapeutic approaches to neurodegenerative disorders. Herein, we discuss cellular mechanisms underlying AD neuroinflammatory pathogenesis that are contributory to Alzheimer's disease. We describe endogenous cellular defence mechanism modulation and neurohormesis as a potentially innovative approach to therapeutics for AD and other neurodegenerative conditions that are associated with mitochondrial dysfunction and neuroinflammation. Particularly, we consider the emerging role of the inflammasome as an important component of the neuroprotective network, as well as the importance of and nutritional mushrooms in redox stress responsive mechanisms and neuroprotection.
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http://dx.doi.org/10.1186/s12979-017-0108-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813410PMC
February 2018

Elemental mercury neurotoxicity and clinical recovery of function: A review of findings, and implications for occupational health.

Environ Res 2018 05 22;163:134-148. Epub 2018 Feb 22.

Department of Neurology and Biochemistry, and Neuroethics Studies Program-Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center, Washington, D.C. 20057, USA. Electronic address:

This paper assessed approximately 30 studies, mostly involving occupationally exposed subjects, concerning the extent to which those who developed elemental mercury (Hg)-induced central and/or peripheral neurotoxicities from chronic or acute exposures recover functionality and/or performance. While some recovery occurred in the vast majority of cases, the extent of such recoveries varied considerably by individual and endpoint. Factors accounting for the extensive inter-individual variation in toxicity and recovery were not specifically assessed such as age, gender, diet, environmental enrichment, chelation strategies and dose-rate. While the data indicate that psychomotor endpoints often show substantial and relatively rapid (i.e., 2-6 months) recovery and that neuropsychological endpoints display slower and less complete recovery, generalizations are difficult due to highly variable study designs, use of different endpoints measured between studies, different Hg exposures based on blood/urine concentrations and Hg dose-rates, the poor capacity for replicating findings due to the unpredictable/episodic nature of harmful exposures to elemental Hg, and the inconsistency of the initiation of studies after induced toxicities and the differing periods of follow up during recovery periods. Finally, there is strikingly limited animal model literature on the topic of recovery/reversibility of elemental Hg toxicity, a factor which significantly contributes to the overall marked uncertainties for predicting the rate and magnitude of recovery and the factors that affect it.
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http://dx.doi.org/10.1016/j.envres.2018.01.021DOI Listing
May 2018

Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions.

Ageing Res Rev 2018 Mar 15;42:40-55. Epub 2017 Dec 15.

International Life Sciences Institute, Europe (ILSI Europe), Av E. Mounier 83, Box 6, 1200 Brussels, Belgium. Electronic address:

Background: Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated.

Objectives: This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop 'Nutrition for the Ageing Brain: Functional Aspects and Mechanisms' in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe).

Conclusion: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age.
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http://dx.doi.org/10.1016/j.arr.2017.12.004DOI Listing
March 2018