Caprylic acid attenuates amyloid-ß proteotoxicity by supplying energy via ß-oxidation in an Alzheimer's disease model of the nematode Caenorhabditis elegans.

Computer-based analysis of motility was used as a measure of amyloid-ß (Aß) proteotoxicity in the transgenic strain GMC101, expressing human Aß1-42 in body wall muscle cells. Aß-aggregation was quantified to relate the effects of caprylic acid (CA) to the amount of the proteotoxic protein. Gene knockdowns were induced through RNA-interference (RNAi). Moreover, the estimation of adenosine triphosphate (ATP) levels, the mitochondrial membrane potential (MMP) and oxygen consumption served the evaluation of mitochondrial function. CA improved the motility of GMC101 nematodes and reduced Aß aggregation. Whereas RNAi for orthologues encoding key enzymes for α-lipoic acid and ketone bodies synthesis did not affect motility stimulation by CA, knockdown of orthologues involved in ß-oxidation of fatty acids diminished its effects. The efficient energy gain by application of CA was finally proven by the increase of ATP levels in association with increased oxygen consumption and MMP. In conclusion, CA attenuates Aß proteotoxicity by supplying energy via FAO. Since especially glucose oxidation is disturbed in Alzheimer´s disease, CA could potentially serve as an alternative energy fuel.

4-Phenylbutyric acid attenuates amyloid-ß proteotoxicity through activation of HSF-1 in an Alzheimer's disease model of the nematode Caenorhabditiselegans.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. The pathogenesis is a complex process, in which the proteotoxicity of amyloid-ß (Aß) was identified as a major factor. 4-Phenylbutyric acid (4-PBA) is an aromatic short-chain fatty acid that may attenuate Aß proteotoxicity through its already shown properties as a chemical chaperone or by inhibition of histone deacetylases (HDACs). In the present study, we investigated the molecular effects of 4-PBA on Aß proteotoxicity using the nematode Caenorhabditis elegans as a model. Computer-based analysis of motility was used as a measure of Aß proteotoxicity in the transgenic strain GMC101, expressing human Aß1-42 in body wall muscle cells. Aß aggregation was quantified using the fluorescent probe NIAD-4 to correlate the effects of 4-PBA on motility with the amount of the proteotoxic protein. Furthermore, these approaches were supplemented by gene regulation via RNA interference (RNAi) to identify molecular targets of 4-PBA. 4-PBA improved the motility of GMC101 nematodes and reduced Aß aggregation significantly. Knockdown of hsf-1, encoding an ortholog essential for the cytosolic heat shock response, prevented the increase in motility and decrease in Aß aggregation by 4-PBA incubation. RNAi for hda-1, encoding an ortholog of histone deacetylase 2, also increased motility. Double RNAi for hsf-1 and hda-1 revealed a dominant effect of hsf-1 RNAi. Moreover, 4-PBA failed to further increase motility under hda-1 RNAi. Accordingly, the results suggest that 4-PBA attenuates Aß proteotoxicity in an AD-model of C. elegans through activation of HSF-1 via inhibition of HDA-1.

MemophenolTM Prevents Amyloid-ß Deposition and Attenuates Inflammation and Oxidative Stress in the Brain of an Alzheimer's Disease Rat.

Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence rises with age. Inflammation and altered antioxidant systems play essential roles in the genesis of neurodegenerative diseases. In this work, we looked at the effects of MemophenolTM, a compound rich in polyphenols derived from French grape (Vitis vinifera L.) and wild North American blueberry (Vaccinium angustifolium A.) extracts, in a rat model of AD. Methods: For 60 days, the animals were administered with AlCl3 (100 mg/kg, orally) and D-galactose (60 mg/kg, intraperitoneally), while from day 30, MemophenolTM (15 mg/kg) was supplied orally for 30 consecutive days. AlCl3 accumulates mainly in the hippocampus, the main part of the brain involved in memory and learning. Behavioral tests were performed the day before the sacrifice when brains were collected for analysis. Results: MemophenolTM decreased behavioral alterations and hippocampus neuronal degeneration. It also lowered phosphorylated Tau (p-Tau) levels, amyloid precursor protein (APP) overexpression, and ß-amyloid (Aß) buildup. Furthermore, MemophenolTM reduced the pro-oxidative and pro-inflammatory hippocampus changes caused by AD. Our finding, relevant to AD pathogenesis and therapeutics, suggests that MemophenolTM, by modulating oxidative and inflammatory pathways and by regulating cellular brain stress response mechanisms, protects against the behavioral and histopathological changes associated with AD.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Amyloid-beta induced paralysis is reduced by cholecalciferol through inhibition of the steroid-signaling pathway in an Alzheimer model of Caenorhabditis elegans.

Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder resulting from the accumulation of toxic ß-amyloid (Aß) aggregates in the human brain. Epidemiological studies have shown that elevated cholesterol plasma levels are associated with the development of AD and we have previously shown that cholesterol restriction reduces the Aß-induced paralysis in an Alzheimer model of the nematode Caenorhabditis elegans. In the present study we investigated the effects of the cholesterol homolog cholecalciferol, i.e. vitamin D, on Aß-induced paralysis in C. elegans and its interference with the steroid-signaling pathway. Methods: Aß-induced paralysis was assessed in the C. elegans strain CL2006, expressing human Aß1-42 under control of a muscle-specific promoter. Knockdown of members of the steroid-signaling pathway was achieved by RNA interference (RNAi). Nuclear translocation of foxo transcription factor DAF-16 was visualized using the strain TJ356, carrying a daf-16::gfp transgene. Results: Cholecalciferol at a concentration of 1 µM reduced the Aß-induced paralysis in CL2006 significantly, which was reverted by increasing the cholesterol concentration in the medium. Knockdown of nhr-8, daf-36, daf-9 or daf-12, all reduced Aß-induced paralysis to the same extent as cholecalciferol with no additional or synergistic effects under co-application. Functional DAF-16 proved to be crucial for the effects of cholecalciferol and DAF-16 nuclear translocation was increased by cholecalciferol and also RNAi versus nhr-8, daf-36, daf-9 or daf-12 with no additive or synergistic effects. Conclusions: Our results suggest, that cholecalciferol inhibits Aß-induced paralysis in C. elegans through inhibition of steroid-signaling and the concomitant nuclear translocation of DAF-16.

The polyphenol quercetin protects from glucotoxicity depending on the aggresome in Caenorhabditis elegans.

PURPOSE: Impaired proteostasis, i.e., protein homeostasis, is considered as a consequence of high-glucose exposure and is associated with reduced survival. The previous studies demonstrated that the polyphenol quercetin can protect from glucotoxicity. The aim of the present study was to unravel the contribution of the aggresome, sequestering potentially cytotoxic aggregates and also acting as a staging center for eventual autophagic clearance from the cell. METHODS: Knockdown of the aggresome-relevant genes dnc-1 and ubql-1 was achieved in stress-sensitive mev-1 mutants of the nematode Caenorhabditis elegans by RNA interference (RNAi). Survival assay was conducted under heat stress at 37 °C, protein aggregation using ProteoStat® and chymotrypsin-like proteasomal activity according to the cleavage of a fluorogenic peptide substrate. RESULTS: Survival was reduced by knockdown of ubql-1 and even more by knockdown of dnc-1 which both were not further reduced by addition of glucose. The rescue of survival due to quercetin in glucose-exposed nematodes was completely prevented under RNAi versus ubql-1 or dnc-1. Both knockdowns caused an increase of aggregated protein and prevented the reduction of aggregated protein caused by quercetin in glucose-exposed animals. Finally, the knockdown of ubql-1 and dnc-1 blocked the increase of proteasomal activity achieved by quercetin in glucose-treated nematodes. CONCLUSIONS: The study provides evidence that quercetin protects C. elegans from glucotoxicity through the activation of the aggresome, thereby, quercetin prevents the aggregation and functional loss of proteins, which is typically caused by enhanced glucose concentrations.

Betaine-rich sugar beet molasses protects from homocysteine-induced reduction of survival in Caenorhabditis elegans.

PURPOSE: Homocysteine (Hcy) in humans represents a blood-borne biomarker which predicts the risk of age-related diseases and mortality. Using the nematode Caenorhabditis elegans, we tested whether feeding betaine-rich sugar beet molasses affects the survival under heat stress in the presence of Hcy, in spite of a gene loss in betaine-homocysteine methyltransferase. METHODS: Knockdown of the genes relevant for remethylation or transsulfuration of Hcy was achieved by RNA interference (RNAi). Survival assay was conducted under heat stress at 37 °C and Hcy levels were determined by enzyme-linked immunosorbent assay. RESULTS: Addition of 500 mg/l betaine-rich sugar beet molasses (SBM) prevented the survival reduction that was caused by exposure to Hcy at 37 °C. Although SBM was no longer capable of reducing Hcy levels under RNAi versus homologues for 5, 10-methylenetetrahydrofolate reductase or cystathionine-ß-synthase, it still enabled the survival extension by SBM under exposure to Hcy. In contrast, RNAi for the small heat shock protein hsp-16.2 or the foxo transcription factor daf-16 both prevented the extension of survival by betaine-rich molasses in the presence of Hcy. CONCLUSIONS: Our studies demonstrate that betaine-rich SBM is able to prevent survival reduction caused by Hcy in C. elegans in dependence on hsp-16.2 and daf-16 but independent of the remethylation pathway.

Ginseng Extract Ameliorates the Negative Physiological Effects of Heat Stress by Supporting Heat Shock Response and Improving Intestinal Barrier Integrity: Evidence from Studies with Heat-Stressed Caco-2 Cells, C. elegans and Growing Broilers.

Climatic changes and heat stress have become a great challenge in the livestock industry, negatively affecting, in particular, poultry feed intake and intestinal barrier malfunction. Recently, phytogenic feed additives were applied to reduce heat stress effects on animal farming. Here, we investigated the effects of ginseng extract using various in vitro and in vivo experiments. Quantitative real-time PCR, transepithelial electrical resistance measurements and survival assays under heat stress conditions were carried out in various model systems, including Caco-2 cells, Caenorhabditis elegans and jejunum samples of broilers. Under heat stress conditions, ginseng treatment lowered the expression of HSPA1A (Caco-2) and the heat shock protein genes hsp-1 and hsp-16.2 (both in C. elegans), while all three of the tested genes encoding tight junction proteins, CLDN3, OCLN and CLDN1 (Caco-2), were upregulated. In addition, we observed prolonged survival under heat stress in Caenorhabditis elegans, and a better performance of growing ginseng-fed broilers by the increased gene expression of selected heat shock and tight junction proteins. The presence of ginseng extract resulted in a reduced decrease in transepithelial resistance under heat shock conditions. Finally, LC-MS analysis was performed to quantitate the most prominent ginsenosides in the extract used for this study, being Re, Rg1, Rc, Rb2 and Rd. In conclusion, ginseng extract was found to be a suitable feed additive in animal nutrition to reduce the negative physiological effects caused by heat stress.

Inhibition of mitophagy decreases survival of Caenorhabditis elegans by increasing protein aggregation.

Autophagy of mitochondria, i.e., mitophagy, plays a crucial role in coping with stressors in the aging process, metabolic disturbances, and neurological disorders. Impairments of the process might consequently lead to enhanced accumulation of aged and aggregated proteins and reduced cellular integrity in response to stress. In the present study, we used the stress-sensitive mutant mev-1 of Caenorhabditis elegans to assess the effects of the knockdown of mitophagy relevant genes on survival under heat stress, the amount of autophagosomes, and on protein aggregation. RNA interference for dct-1, drp-1, eat-3, fis-1, fzo1, glb-1, pink-1, and pgam-5 all resulted in a significant reduction of survival time at 37 °C. These effects were associated with a decrease in autophagosomal flux of proteins, as indicated by increased accumulation of GFP-tagged SQST-1, and a reduced amount of lysosomes demonstrating that autophagy was hampered. Moreover, the gene knockdowns led to increased levels of reactive oxygen species in mitochondria and an enhanced protein aggregation. In conclusion, our studies show that mitophagy is of central importance to keep mitochondria functional in order to prevent production of excess reactive oxygen species and protein aggregation and finally a reduction of survival under heat stress.

Inhibition of chaperone-mediated autophagy prevents glucotoxicity in the Caenorhabditis elegans mev-1 mutant by activation of the proteasome.

Chronic hyperglycemia is a hallmark of diabetes mellitus and the main cause of diabetes-associated complications. Increased intracellular glucose levels lead to damaged proteins and in consequence disturb cellular proteostasis. As an important contributor to the maintenance and restoration of proteostasis, autophagy mediates the lysosomal degradation of damaged proteins or entire cellular organelles. In the present study we used the stress-sensitive mev-1 mutant of the nematode Caenorhabditis elegans in order to assess the role of lmp-2, a homologue of the lysosome associated membrane protein type 2A, in the context of glucotoxicity, which was achieved by feeding glucose in a liquid medium. Knockdown of lmp-2 by RNA interference completely prevented the survival reduction caused by glucose under heat stress. Those effects were associated with the prevention of (1) increased lysosome formation and (2) reduction of proteasomal activity, which were observed under glucose feeding. Finally, the survival reduction due to knockdown of ubiquitin remained unaffected by the additional lmp-2 knockdown in the absence or presence of glucose. In conclusion, our study provides evidence that lmp-2, a key player in chaperone-mediated autophagy, is functional in C. elegans, too. Inhibition of lmp-2 prevents the reduction of proteasomal activity by glucose and thereby prevents also glucotoxicity.

PEK-1 is crucial for hormesis induced by inhibition of the IRE-1/XBP-1 pathway in the Caenorhabditis elegans mev-1 mutant.

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes an imbalance of proteostasis and is related to many pathological conditions. In answer to this ER stress cells activate a network of three integrated signaling pathways consolidated as the unfolded protein response of the ER (UPR(ER)), which is also present in the stress-sensitive Caenorhabditis elegans mutant mev-1. Whereas inhibition of one of those pathways by RNA-interference (RNAi) versus xbp-1 results in reduced survival of mev-1 nematodes under heat stress, additional knockdown of the xbp-1 splicing activator ire-1 results in a PEK-1-dependent hormetic response. In contrast, increased survival under ire-1/xbp-1 double RNAi was found to be independent of the presence of HSP-4, an UPR(ER)-specific chaperone, as evidenced under ire-1/xbp-1/hsp-4 triple knockdown conditions. Moreover, ire-1/xbp-1 double-RNAi significantly increased chymotrypsin-like proteasomal activity, which was completely blocked under additional RNAi versus pek-1. In conclusion, we identified PEK-1 as a mediator of hormesis in the mev-1 mutant of C. elegans which is induced by simultaneous inhibition of XBP-1 and its splicing activator IRE-1 and mediated through activation of the proteasome.

Resveratrol reduces amyloid-beta (Aß1₋42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans.

PURPOSE: Resveratrol is a polyphenol present in red wine for which the capability of directly interfering with the hallmark of Alzheimer's disease (AD), i.e. toxic ß-amyloid protein (Aß) aggregation, has been shown recently. Since the stimulation of proteostasis could explain reduced Aß-aggregation, we searched for proteostasis targets of resveratrol. METHODS: The transgenic Caenorhabditis elegans strain CL2006, expressing Aß1-42 under control of a muscle-specific promoter and responding to Aß-toxicity with paralysis, was used as a model. Target identification was accomplished through specific knockdowns of proteostasis genes by RNA interference. Effects of resveratrol on protein aggregation were identified using ProteoStat(®) Detection Reagent, and activation of proteasomal degradation by resveratrol was finally proven using a specific fluorogenic peptide substrate. RESULTS: Resveratrol at a concentration of 100 µM caused a 40 % decrease in paralysis. UBL-5 involved in unfolded protein response (UPR) in mitochondria proved to be necessary for the prevention of Aß-toxicity by resveratrol. Also XBP-1, which represents an endoplasmic reticulum-resident factor involved in UPR, was identified to be necessary for the effects of resveratrol. Regarding protein degradation pathways, the inhibition of macroautophagy and chaperone-mediated autophagy prevented resveratrol from reducing paralysis as did the inhibition of proteasomal degradation. Finally, resveratrol reduced the amount of lysosomes, suggesting increased flux of proteins through the autophagy pathways and activated proteasomal degradation. CONCLUSIONS: Resveratrol reduces the Aß-induced toxicity in a C. elegans model of AD by targeting specific proteins involved in proteostasis and thereby reduces the amount of aggregated Aß.

Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12.

Besides its function in transport of fatty acids into mitochondria in order to provide substrates for ß-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 µM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors.

Hormesis is induced in the red flour beetle Tribolium castaneum through ingestion of charred toast.

PURPOSE: Charred foods are generally suspected to exert health threats by providing toxicants, such as acrylamide or polycyclic aromatic hydrocarbons. Using the red flour beetle Tribolium castaneum as a model organism, we tested its survival under heat stress in response to feeding charred toast. METHODS: Survival of beetles was measured at 42 °C after a pre-feeding phase with flour enriched with increasing concentrations of charred toast. In order to assess the influence of key transcription factors for phase-I and phase-II xenobiotic metabolism, gene homologs for ahr and nrf-2, respectively, were knocked down by the use of RNA interference (RNAi). RESULTS: Beetles fed only charred toast died off much earlier than control beetles fed on flour, whereas beetles fed flour enriched with 5% charred toast survived significantly longer than the control. Both, ahr and nrf-2 proved essential in order to enable the increase in survival by the feeding of 5% charred toast. Moreover, functional loss of ahr and nrf-2 made the beetles hypersensitive versus the feeding of 100% charred toast. Finally, at the transcriptional level, it was shown that RNAi for ahr blocked the inducing activities of charred toast on nrf-2. CONCLUSIONS: Our studies suggest a hormetic response of the red flour beetle to feeding of charred toast that causes an increased stress resistance through the activation of ahr and nrf-2. Those adaptations, however, are saturable and accordingly the hormetic effects at increasing concentrations of the toxicants become expended.

Impairment of the proteasome is crucial for glucose-induced lifespan reduction in the mev-1 mutant of Caenorhabditis elegans.

Hyperglycemia is a hallmark of diabetes that is associated with diabetic complications and a reduction of lifespan. Using the mev-1 mutant of the nematode Caenorhabditis elegans we here tried to identify molecular mechanisms underlying the lifespan reducing effects of glucose. The lowest glucose concentration tested (10mM) caused a significant lifespan reduction at 37°C and was used to assess effects on mitochondrial efficiency, formation of protein carbonyls and levels of methylglyoxal, a precursor of advanced glycation end products (AGEs). RNA-interference (RNAi) served the identification of targets for glucose-induced damage. Levels of protein carbonyls and AGEs remained unaffected by 10mM glucose. Levels of reactive oxygen species inside mitochondria were increased but their scavenging by ascorbic acid did not influence lifespan reduction by glucose. Mitochondrial efficiency was reduced by glucose as concluded from a lowered P/O-ratio. A reduced lifespan of mev-1 that was unaffected by the addition of glucose resulted from RNAi of key players of mitochondrial unfolded protein response. Besides increased accumulation of misfolded proteins, reduced proteasomal degradation caused the same phenotype as was evidenced by RNAi for UBQ-1 or UBA-1. Accumulation of functionally impaired proteins, e.g. in mitochondria, underlies the lifespan reducing effects of glucose. Our study provides evidence for a crucial importance of the proteostasis network for lifespan regulation which is impaired by glucose.

Effects of plant extracts on the reversal of glucose-induced impairment of stress-resistance in Caenorhabditis elegans.

Enhanced blood glucose levels are a hallmark of diabetes and are associated with diabetic complications and a reduction of lifespan. In order to search for plant extracts that display preventive activities in such a scenario, we tested 16 extracts used in human nutrition for their survival enhancing activities in the nematode Caenorhabditis elegans. Nematodes were exposed for 48 h to 10 mM glucose in the absence or presence of 0.1% extract. Thereafter, survival was measured at 37 °C. Extracts made from coffee, kola, rooibos and cinnamon, did not influence the glucose-induced reduction of survival. Those made from ginseng, camomile, lime blossom, paraguay tea, balm, rhodiola, black tea, or knotgrass all extended the lifespan of the glucose-treated nematodes significantly but did not rescue survival completely. Extracts from the leaves of blackberries, from hibiscus, elderberries, or jiaogulan completely countered the glucose-induced survival reduction. A potent activation of the proteasome was shown for the most preventive extracts suggesting a more efficient degradation of proteins impaired by glucose. In conclusion, we present a simple animal model to screen for plant extracts with potency to reverse glucose toxicity. Extracts from blackberry leaves, hibiscus, elderberries, and jiaogulan were identified as very potent in this regard whose exact mechanisms of action appear worthwile to investigate at the molecular level.

Investigating hormesis, aging, and neurodegeneration: From bench to clinics.

Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.

Frankincense: A neuronutrient to approach Parkinson's disease treatment.

Parkinson's disease (PD), characterized by tremor, slowness of movement, stiffness, and poor balance, is due to a significant loss of dopaminergic neurons in the substantia nigra pars compacta and dopaminergic nerve terminals in the striatum with deficit of dopamine. To date the mechanisms sustaining PD pathogenesis are under investigation; however, a solid body of experimental evidence involves neuroinflammation, mitochondrial dysfunction, oxidative stress, and apoptotic cell death as the crucial factors operating in the pathogenesis of PD. Nutrition is known to modulate neuroinflammatory processes implicated in the pathogenesis and progression of this neurodegenerative disorder. Consistent with this notion, the Burseraceae family, which includes the genera Boswellia and Commiphora, are attracting emerging interest in the treatment of a wide range of pathological conditions, including neuroinflammation and cognitive decline. Bioactive components present in these species have been shown to improve cognitive function and to protect neurons from degeneration in in vitro, animal, as well as clinical research. These effects are mediated through the anti-inflammatory, antiamyloidogenic, anti-apoptotic, and antioxidative properties of bioactive components. Although many studies have exploited possible therapeutic approaches, data from human studies are lacking and their neuroprotective potential makes them a promising option for preventing and treating major neurodegenerative disorders.

Transgenerational hormesis in healthy aging and antiaging medicine from bench to clinics: Role of food components.

Neurodegenerative diseases have multifactorial pathogenesis, mainly involving neuroinflammatory processes. Finding drugs able to treat these diseases, expecially because for most of these diseases there are no effective drugs, and the current drugs cause undesired side effects, represent a crucial point. Most in vivo and in vitro studies have been concentrated on various aspects related to neurons (e.g. neuroprotection), however, there has not been focus on the prevention of early stages involving glial cell activation and neuroinflammation. Recently, it has been demonstrated that nutritional phytochemicals including polyphenols, the main active constituents of the Mediterranean diet, maintain redox balance and neuroprotection through the activation of hormetic vitagene pathway. Recent lipidomics data from our laboratory indicate mushrooms as strong nutritional neuronutrients with strongly activity against neuroinflammation in Meniere' diseaseas, a model of cochleovestibular neural degeneration, as well as in animal model of traumatic brain injury, or rotenone induced parkinson's disease. Moreover, Hidrox®, an aqueous extract of olive containing hydroxytyrosol, and Boswellia, acting as Nrf2 activators, promote resilience by enhancing the redox potential, and thus, regulate through hormetic mechanisms, cellular stress response mechanisms., Thus, modulation of cellular stress pathways, in particular vitagenes system, may be an innovative approach for therapeutic intervention in neurodegenerative disorders.

RNA-interference in the nematode Caenorhabditis elegans is effective using paraformaldehyde-inactivated E. coli HT115 bacteria as a food source.

The nematode Caenorhabditis elegans is a widely used research model for the investigation of metabolism, aging and age-associated diseases. However, when investigating the impact of natural compounds or drugs on those topics, a major confounder is the metabolism of these test substances by live E. coli bacteria, the standard food source of C. elegans. Using paraformaldehyde instead of heat to inactivate E. coli, which allows for high-throughput technologies and better food availability, it is shown here that RNA-interference works equally well, thus demonstrating the absence of considerable interfering modifications of paraformaldehyde with nucleic acids.