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The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species

A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

The interest in dietary polyphenols in recent years has greatly increased due to their antioxidant bioactivity with preventive properties against chronic diseases. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and are able to neutralize the effects of oxidative stress, inflammation, and apoptosis. Interestingly, all these mechanisms are involved in neurodegeneration. Although polyphenols display differences in their effectiveness due to interindividual variability, recent studies indicated that bioactive polyphenols in food and beverages promote health and prevent age-related cognitive decline. Polyphenols have a poor bioavailability and their digestion by gut microbiota produces active metabolites. In fact, dietary bioactive polyphenols need to be modified by microbiota present in the intestine before being absorbed, and to exert health preventive effects by interacting with cellular signalling pathways. This literature review includes an evaluation of the literature in English up to December 2019 in PubMed and Web of Science databases. A total of 307 studies, consisting of research reports, review articles and articles were examined and 146 were included. The review highlights the role of bioactive polyphenols in neurodegeneration, with a particular emphasis on the cellular and molecular mechanisms that are modulated by polyphenols involved in protection from oxidative stress and apoptosis prevention.

Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress&mdash, especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H2O2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H2O2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases.

Background The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. Method We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols - by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. Results Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. Conclusion This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance.

Ultraviolet (UV) radiations are responsible for skin photoaging inducing alteration of the molecular and cellular pathways resulting in dryness and reduction of skin elasticity. In this study, we investigated, in vitro, the antiaging and antioxidant effects of hyaluronan formulations based hydrogel. Skinkò E, an intradermic formulation composed of hyaluronic acid (HA), minerals, amino acids, and vitamins, was compared with the sole HA of the same size. For this purpose, HaCaT cells were subjected to UV-A radiations and H2O2 exposure and then treated with growth medium (CTR) combined with M-HA or Skinkò E to evaluate their protective ability against stressful conditions. Cells reparation was evaluated using a scratch in vitro model and Time-Lapse Video Microscopy. A significant protective effect for Skinkò E was shown with respect to M-HA. In addition, Skinkò E increased cell reparation. Therefore, NF-kB, SOD-2, and HO-1 were significantly reduced at the transcriptional and protein level. Interestingly, γ-H2AX and protein damage assay confirmed the protection by hyaluronans tested against oxidative stress. G6pdΔ ES cell line, highly susceptible to oxidative stress, was used as a further cellular model to assess the antioxidant effect of Skinkò E. Western blotting analyses showed that the treatment with this new formulation exerts marked antioxidant action in cells exposed to UV-A and H2O2. Thus, the protective and reparative properties of Skinkò E make it an interesting tool to treat skin aging.

The protective effects of ethanolic olive fruit extract (OFE) and purified oleuropein (Ole) have been evaluated against H2O2-induced oxidative damage and apoptosis in human embryonic kidney (HEK-293) cells. Olive compounds demonstrated a protective effect against H2O2-induced cell death resulting in total rescue of cell viability. This effect was accompanied by a marked decrease in intracellular reactive oxygen species (ROS) and lipid peroxidation as evidenced by malondialdehyde (MDA) production. Consequently, olive compounds reduced the apoptotic cell death. This was confirmed by flow cytometry analysis for multicaspases and by western blot and real-time PCR analyses for the expression of key effectors involved in the apoptotic process. Our data suggest that the anti-apoptotic effect could be due to the activation of the Erk/p38 signaling pathway and to the modulation of Bcl-2/Bax ratio. These findings provide new insight into the mechanisms underlying the protective effects of OFE and Ole against oxidative damage-induced apoptosis.

Background A major limitation in the treatment for malignant mesothelioma is related to serious side effects caused by chemotherapeutics and to the development of cancer-resistance. Advances in cancer therapies have been reached thanks to the introduction of alternative approaches, such as the use of phytochemicals. Curcumin-C3complex®/Bioperine® is a commercially standardized extract containing a ratio-defined mixture of three curcuminoids and piperine that greatly increase its bioavailability. Interestingly, the anticancer effect of this formulation has been described in different studies and several clinical trials have been started, but to our knowledge none refers to human mesothelioma. Methods Curcumin-C3complex®/Bioperine® anticancer effect was evaluated in vitro in different human mesothelioma cell lines analysing cell proliferation, colony-forming assay, wound healing assays, invasion assay and FACS analysis. In vivo anticancer properties were analysed in a mesothelioma xenograft mouse model in CD1 Nude mice. Results Curcumin-C3complex®/Bioperine® in vitro induced growth inhibition in all mesothelioma cell lines analysed in a dose- and time-depended manner and reduced self-renewal cell migration and cell invasive ability. Cell death was due to apoptosis. The analysis of the molecular signalling pathway suggested that intrinsic apoptotic pathway is activated by this treatment. This treatment in vivo delayed the growth of the ectopic tumours in a mesothelioma xenograft mouse model. Conclusions Curcumin-C3complex®/Bioperine® treatment strongly reduces in vitro tumorigenic properties of mesothelioma cells by impairing cellular self-renewal ability, proliferative cell rate and cell migration and delays tumor growth in xenograft mouse model by reducing angiogenesis and increasing apoptosis. Considering that curcumin in vivo synergizes drug effects, its administration to treatment regimen may help to enhance drug therapeutic efficacy in mesothelioma. Our results suggest that implementation of standard pharmacological therapies with novel compounds may pave the way to develop alternative approaches to mesothelioma. Electronic supplementary material The online version of this article (10.1186/s13046-019-1368-8) contains supplementary material, which is available to authorized users.

Huntington’s disease (HD) has traditionally been described as a disorder purely of the brain, however evidence indicates that peripheral abnormalities are also commonly seen. Among others, severe unintended body weight loss represents a prevalent and often debilitating feature of HD pathology, with no therapies available. It correlates with disease progression and significantly affects the quality of life of HD patients. Curcumin, a naturally occurring polyphenol with multiple therapeutic properties, has been validated to exert important beneficial effects under health conditions as well as in different pathological settings, including neurodegenerative and gastrointestinal (GI) disorders. Here, we investigated the potential therapeutic action that curcumin-supplemented diet may exert on central and peripheral dysfunctions in R6/2 mice, a well-characterized HD animal model which recapitulates some features of human pathology. Maintenance of normal motor function, protection from neuropathology and from GI dysfunction, preservation of GI emptying, and conserved intestinal contractility, proved the beneficial role of life-long dietary curcumin in HD and corroborated the potential of the compound to be exploited to alleviate very debilitating symptoms associated with the disease.

Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methylCpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50 kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5. (C) 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Background Huntington Disease (HD) has traditionally been described as a disorder purely of the brain, however emerging evidence indicates that peripheral abnormalities are also commonly seen. Among others, unintended body weight loss represents a hallmark of peripheral HD pathology. It correlates with disease progression and significantly affects the quality of life of HD patients. Although the underlying molecular mechanism is still unknown, evidence suggests that body weight loss seems not to be secondary to inadequate nutrition or to chorea, but rather attributable to changes in the metabolism and defective nutrients absorption along the intestinal tract. Curcumin, a naturally occurring polyphenol, has been validated to exert important beneficial effects in a multitude of gastrointestinal dysfunction and neurodegenerative processes similar to those occurring in HD. Although its therapeutic effect in HD is still questionable, recent evidence indicates that curcumin significantly improves neuropathology as well neurochemical and neurobehavioral defects in a mouse model of the disease, however whether it may be suited to be developed to treat gastrointestinal dysfunction in the disease is not clear yet. Aim In this study, we aimed to investigate the potential beneficial effects that the chronic administration of curcumin may have on gastrointestinal dysfunction commonly occurring in R6/2 mice as the disease progresses. Method Curcumin along with bioperine (bioavailability enhancing-agent) was orally administered to females 10 days before pregnancy and during the entire gestation period up to the end of lactation. Starting from the third week of age, pups were daily treated with 40 mg/kg curcumin for 7 weeks. KCl-induced contraction was evaluated in isolated intestinal tract from both curcumin and vehicle-treated mice. Results Our preliminary data demonstrate that chronic administration of curcumin is safe and well tolerated in R6/2 mice. It prevents the gradual weight loss despite no changes in food intake were observed. From the functional point of view, curcumin considerably ameliorates the intestinal phenotype and restores the normal intestinal reactivity compared to untreated R6/2 mice.

Blood-brain barrier (BBB) breakdown, due to the concomitant disruption of the tight junctions (TJs), normally required for the maintenance of BBB function, and to the altered transport of molecules between blood and brain and vice-versa, has been suggested to significantly contribute to the development and progression of different brain disorders including Huntington’s disease (HD). Although the detrimental consequence the BBB breakdown may have in the clinical settings, the timing of its alteration remains elusive for many neurodegenerative diseases. In this study we demonstrate for the first time that BBB disruption in HD is not confined to established symptoms, but occurs early in the disease progression. Despite the obvious signs of impaired BBB permeability were only detectable in concomitance with the onset of the disease, signs of deranged TJs integrity occur precociously in the disease and precede the onset of overt symptoms. To our perspective this finding may add a new dimension to the horizons of pathological mechanisms underlying this devastating disease, however much remains to be elucidated for understanding how specific BBB drug targets can be approached in the future.

Rett syndrome (RTT, MIM 312750) is a rare and orphan progressive neurodevelopmental disorder affecting girls almost exclusively, with a frequency of 1/15,000 live births of girls. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulate gene expression. Despite almost two decades of research into the functions and role of MeCP2, little is known about the mechanisms leading from MECP2 mutation to the disease. Oxidative stress (OS) is involved in the pathogenic mechanisms of several neurodevelopmental and neurodegenerative disorders, although in many cases it is not clear whether OS is a cause or a consequence of the pathology. Fairly recently, the presence of a systemic OS has been demonstrated in RTT patients with a strong correlation with the patients' clinical status. The link between MECP2 mutation and the redox imbalance found in RTT is not clear. Animal studies have suggested a possible direct correlation between Mecp2 mutation and increased OS levels. In addition, the restoration of Mecp2 function in astrocytes significantly improves the developmental outcome of Mecp2-null mice and reexpression of Mecp2 gene in the brain of null mice restored oxidative damage, suggesting that Mecp2 loss of function can be involved in oxidative brain damage. Starting from the evidence that oxidative damage in the brain of Mecp2-null mice precedes the onset of symptoms, we evaluated whether, based on the current literature, the dysfunctions described in RTT could be a consequence or, in contrast, could be caused by OS. We also analyzed whether therapies that at least partially treated some RTT symptoms can play a role in defense against OS. At this stage we can propose that OS could be one of the main causes of the dysfunctions observed in RTT. In addition, the major part of the therapies recommended to alleviate RTT symptoms have been shown to interfere with oxidative homeostasis, suggesting that MeCP2 could somehow be involved in the protection of the brain from OS.

Background Curcumin, the active ingredient in turmeric, has been validated to harbour important beneficial effects for a multitude of inflammatory-based diseases and also for neurodegenerative processes similar to those occurring in HD. To this regard, it has been recently described that curcumin significantly improves neuropathology and positively affects some of the neurochemical and neurobehavioral disease-related defects in a mouse model of HD. Although the mechanism of its neuroprotective action is still not completely understood, it has been hypothesised to act majorly through anti-inflammatory and anti-oxidative activities. Aim Here, our purpose is to investigate whether such specific properties of curcumin may potentially play a role in the control of the gradual body weight loss and in the accumulation of redox metals commonly observed in HD. We also want to examine whether the described beneficial effect of curcumin in HD is a shared mechanism across multiple HD models and not confined only to a single or few systems. Methods Curcumin along with bioperine (bioavailability enhancing-agent) was orally administered to females 10 days before pregnancy and during the entire gestation period up to the end of lactation. Starting from the third week of age, pups were daily treated with 40 mg/kg curcumin for 7 weeks. Results In line with other studies, so far, our preliminary data confirmed that curcumin has an outstanding safety profile with no adverse effect also in R6/2 mice. Evaluation of any potential beneficial effects of the treatment is in progress. Conclusion Curcumin is well tolerated also in R6/2 HD mice and, based on its therapeutic properties, it could conceivably represent an attractive possibility to develop a valuable dietary supplement in neurodegenerative diseases such as HD.