Metabotropic glutamate 2/3 receptors and epigenetic modifications in psychotic disorders: a review

Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as "major psychosis"; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group developed an epigenetic model of schizophrenia originated by Prenatal Restraint Stress (PRS) paradigm in mice. PRS mice developed some behavioral alterations observed in schizophrenic patients and classic animal models of schizophrenia, i.e. deficits in social interaction, locomotor activity and prepulse inhibition. They also showed specific changes in promoter DNA methylation activity of genes related to schizophrenia such as reelin, BDNF and GAD67, and altered expression and function of mGlu2/3 receptors in the frontal cortex. Interestingly, behavioral and molecular alterations were reversed by treatment with mGlu2/3 agonists. Based on these findings, we speculate that pharmacological modulation of these receptors could have a great impact on early phase treatment of psychosis together with the possibility to modulate specific epigenetic key protein involved in the development of psychosis. In this review, we will discuss in more details the specific features of the PRS mice as a suitable epigenetic model for major psychosis. We will then focus on key proteins of chromatin remodeling machinery as potential target for new pharmacological treatment through the activation of metabotropic glutamate receptors

Postharvest dehydration and defoliation

Background and Aims: Sfursat is an Italian wine produced with partially dehydrated Nebbiolo grapes in the Valtellina region which is located at high altitude. The research aims to understand the influence of fruit exposure on the rate of water loss by harvested fruit and the influence of exposure and dehydration on the content of phenolic substances and anthocyanins in the wine. Methods and Results: Clusters of Nebbiolo grapes from control vines (ND) and from vines that were defoliated at fruitset (DFS) or post-veraison (DPV) were harvested at a sugar concentration of about 230 g/L (there was no significant difference among the treatments), and dehydrated at 10, 20 or 30°C and at 60% relative humidity (RH), and air flow. Fruit were sampled at 10 and 20% weight loss (WL). Leaf removal had little effect on the physical characteristics of bunches and on the anthocyanins content and profile of harvested Nebbiolo grapes but affected dehydration. At 10 and 20°C, DFS fruit lost mass more slowly than DPV and ND fruit. In ND fruit, 20% WL reduced anthocyanins from 554 mg/kg fresh mass (FM) at harvest to 458, 432 and 396 mg/kg FM at 10, 20 and 30°C, respectively. In DFS and DPV berries, anthocyanins increased during dehydration at 10°C. At harvest, ND berries had a lower content of total stilbenes than those from defoliated vines. Dehydration (10°C, 20% WL) increased stilbene concentration in ND and DPV fruit. Dehydration at 10°C induced a rise in the flavonol concentration in fruit from defoliated vines. Catechin concentration was 106.5 mg/kg DM (dry mass), the highest value in ND berries at harvest. Wine was produced only from grapes dehydrated at 10°C. Wine from DFS fruit had a higher content of phenolic substances (2704.8 mg/L) and anthocyanins (104 mg/L) than that from DPV (2454.9 and 96.2 mg/L, respectively) and ND (2301.9 and 100.5 mg/L, respectively) fruit. Conclusions: Postharvest dehydration was slower where vines had been defoliated and resulted in changes in the ratios among groups of phenolic substances as well as among single phenolic components. Significance of the Study: In Nebbiolo grapes for Sfurzat wine production, defoliation at fruit set enables fruit to reach phenolic maturity at a lower sugar concentration allowing dehydration to increase sugar concentration without producing excessively alcoholic wines

Antioxidant and anti-inflammatory properties of tomato fruits synthesizing different amounts of stilbenes.

Resveratrol, a plant phenolic compound, is found in grapes and red wine, but is not widely distributed in other common food sources. The pathway for resveratrol biosynthesis is well characterized. Metabolic engineering of this compound has been achieved in tomato plants (Lycopersicon esculentum Mill.) in order to improve their nutritional value. Tomato plants synthesizing resveratrol were obtained via the heterologous expression of a grape (Vitis vinifera L.) cDNA encoding for the enzyme stilbene synthase (StSy), under the control of the fruit-specific promoter TomLoxB. The resulting LoxS transgenic plants accumulated trans-resveratrol and trans-piceid, in particular in the skin of the mature fruits. Quantitative analyses carried out on LoxS fruits were compared with those of a tomato line constitutively expressing the stsy gene (35SS). The LoxS fruits contained levels of trans-resveratrol that were 20-fold lower than those previously reported for the 35SS line. The total antioxidant capability and ascorbate content in transformed fruits were also evaluated, and a significant increase in both was found in the LoxS and 35SS lines. These results could explain the higher capability of transgenic fruits to counteract the pro-inflammatory effects of phorbol ester in monocyte-macrophages via the inhibition of induced cyclo-oxygenase-2 enzyme

Nutraceutical characterization of anthocyanin-rich fruits produced by «Sun Black» tomato line

Tomato (Solanum lycopersicum L.) is one of the most cultivated vegetable in the world and it represents a large source of bioactive compounds, including carotenoids and polyphenols (phenolic acids and flavonoids). However, the concentration of flavonoids in tomato is considered sub-optimal, particularly because anthocyanins are not generally present. Therefore, this crop has been the object of an intense metabolic engineering in order to obtain anthocyanin-enriched tomatoes by using either breeding or transgenic strategies. Some wild tomato species, such as S. chilense and S. cheesmaniae, biosynthesize anthocyanins in the fruit sub-epidermal tissue, and some alleles from those genotypes have been introgressed into a new developed purple tomato line, called “Sun Black” (SB). It is a tomato line with a purple skin color, both in green and in red fruit stages, due to the biosynthesis of anthocyanins in the peel, and a normal red color pulp, with a taste just like a traditional tomato. SB is the result of a breeding programme and it is not a genetically modified (GM) product. We report the chemical characterization and structure elucidation of the attractive anthocyanins found in the peel of SB tomato, as well as other bioactive compounds (carotenoids, polyphenols, vitamin C) of the whole fruit. Using one- and two-dimensional NMR experiments, the two main anthocyanins were identified to be petunidin 3-O-[6″-O-(4‴-O-E-p-coumaroyl-α-rhamnopyranosyl) -β-glucopyranoside]-5-O-β-glucopyranoside (petanin) and malvidin 3-O-[6″-O-(4‴-O-E-p-coumaroyl-α-rhamnopyranosyl)-β-glucopyranoside]-5-O-β-glucopyranoside (negretein). The total anthocyanins in the whole ripe fruit was 1.2 mg/g dry weight (DW); 7.1 mg/100 g fresh weight (FW). Chlorogenic acid (the most abundant phenolic acid) was 0.6 mg/g DW; 3.7 mg/100 g FW. The main flavonol, rutin was 0.8 mg/g DW; 5 mg/100 g FW. The total carotenoid content was 211.3 μg/g DW; 1,268 μg/100 g FW. The total phenolic content was 8.6 mg/g DW; 52.2 mg/100 g FW. The vitamin C content was 37.3 mg/100 g FW. The antioxidant activities as measured by the TEAC and ORAC assays were 31.6 and 140.3 μmol TE/g DW, respectively (193 and 855.8 μmol TE/100 g FW, respectively). The results show the unique features of this new tomato genotype with nutraceutical properties.publishedVersio

Opsonin-deficient nucleoproteic corona endows unPEGylated liposomes with stealth properties in vivo

For several decades, surface grafted polyethylene glycol (PEG) has been a go-to strategy for preserving the synthetic identity of liposomes in physiological milieu and preventing clearance by immune cells. However, the limited clinical translation of PEGylated liposomes is mainly due to the protein corona formation and the subsequent modification of liposomes’ synthetic identity, which affects their interactions with immune cells and blood residency. Here we exploit the electric charge of DNA to generate unPEGylated liposome/DNA complexes that, upon exposure to human plasma, gets covered with an opsonin-deficient protein corona. The final product of the synthetic process is a biomimetic nanoparticle type covered by a proteonucleotidic corona, or “proteoDNAsome”, which maintains its synthetic identity in vivo and is able to slip past the immune system more efficiently than PEGylated liposomes. Accumulation of proteoDNAsomes in the spleen and the liver was lower than that of PEGylated systems. Our work highlights the importance of generating stable biomolecular coronas in the development of stealth unPEGylated particles, thus providing a connection between the biological behavior of particles in vivo and their synthetic identity

Notch3 contributes to T-cell leukemia growth via regulation of the unfolded protein response

Unfolded protein response (UPR) is a conserved adaptive response that tries to restore protein homeostasis after endoplasmic reticulum (ER) stress. Recent studies highlighted the role of UPR in acute leukemias and UPR targeting has been suggested as a therapeutic approach. Aberrant Notch signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), as downregulation of Notch activity negatively affects T-ALL cell survival, leading to the employment of Notch inhibitors in T-ALL therapy. Here we demonstrate that Notch3 is able to sustain UPR in T-ALL cells, as Notch3 silencing favored a Bip-dependent IRE1α inactivation under ER stress conditions, leading to increased apoptosis via upregulation of the ER stress cell death mediator CHOP. By using Juglone, a naturally occurring naphthoquinone acting as an anticancer agent, to decrease Notch3 expression and induce ER stress, we observed an increased ER stress-associated apoptosis. Altogether our results suggest that Notch3 inhibition may prevent leukemia cells from engaging a functional UPR needed to compensate the Juglone-mediated ER proteotoxic stress. Notably, in vivo administration of Juglone to human T-ALL xenotransplant models significantly reduced tumor growth, finally fostering the exploitation of Juglone-dependent Notch3 inhibition to perturb the ER stress/UPR signaling in Notch3-dependent T-ALL subsets

RESEARCH ARTICLE Sour Cherry (Prunus cerasus L) Anthocyanins as Ingredients for Functional Foods

In the recent years many studies on anthocyanins have revealed their strong antioxidant activity and their possible use as chemotherapeutics. The finding that sour cherries (Prunus cerasus L) (also called tart cherries) contain high levels of anthocyanins that possess strong antioxidant and anti-inflammatory properties has attracted much attention to this species. Here we report the preliminary results of the induction of anthocyanin biosynthesis in sour cherry callus cell cultures. The evaluation and characterization of the in vitro produced pigments are compared to those of the anthocyanins found in vivo in fruits of several sour cherry cultivars. Interestingly, the anthocyanin profiles found in whole fruit extracts were similar in all tested genotypes but were different with respect to the callus extract. The evaluation of antioxidant activity, performed by ORAC and TEAC assays, revealed a relatively high antioxidant capacity for the fruit extracts (from 1145 to 2592 µmol TE/100 g FW) and a lower one for the callus extract (688 µmol TE/100 g FW)