Dopamine- and Grape-Seed-Extract-Loaded Solid Lipid Nanoparticles: Interaction Studies between Particles and Differentiated SH-SY5Y Neuronal Cell Model of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, primarily associated with dopaminergic neuron depletion in the Substantia Nigra. Current treatment focuses on compensating for dopamine (DA) deficiency, but the blood-brain barrier (BBB) poses challenges for effective drug delivery. Using differentiated SH-SY5Y cells, we investigated the co-administration of DA and the antioxidant Grape Seed Extract (GSE) to study the cytobiocompability, the cytoprotection against the neurotoxin Rotenone, and their antioxidant effects. For this purpose, two solid lipid nanoparticle (SLN) formulations, DA-co-GSE-SLNs and GSE-ads-DA-SLNs, were synthesized. Such SLNs showed mean particle sizes in the range of 187-297 nm, zeta potential values in the range of -4.1--9.7 mV, and DA association efficiencies ranging from 35 to 82%, according to the formulation examined. The results showed that DA/GSE-SLNs did not alter cell viability and had a cytoprotective effect against Rotenone-induced toxicity and oxidative stress. In addition, this study also focused on the evaluation of Alpha-synuclein (aS) levels; SLNs showed the potential to modulate the Rotenone-mediated increase in aS levels. In conclusion, our study investigated the potential of SLNs as a delivery system for addressing PD, also representing a promising approach for enhanced delivery of pharmaceutical and antioxidant molecules across the BBB.

Effects of dietary supplementation of grape seed extract in comparison with excessive level of vitamin E on growth performance and antioxidant function of broilers.

The present study was carried out to evaluate the effects of dietary vitamin E (VE) or grape seed extract (GSE) on the growth performance and antioxidant function of broilers. Two hundred sixteen broiler chicks were randomly assigned to 3 diets: diet supplemented with oxidized rice bran oil (CN group), CN group with 25 mg/kg VE or 100 mg/kg GSE. Dietary VE or GSE improved the growth performance, reverted the disturbed levels of liver antioxidant enzymes, and reduced liver damage of broilers fed oxidized rice bran oil. The mRNA data showed that supplementation of VE or GSE enhanced the antioxidant capacity of the broiler liver through activation of the Keap1-Nrf2/ARE signaling pathway. The results suggested that VE and GSE can increase weight gain, improve the oxidative status, and alleviate liver injury in broiler chicken fed oxidized rice bran oil.

Grape seed extract prevents chlorpyrifos-induced toxicity in rat liver through the modulation of phase I detoxification pathway.

Chlorpyrifos (CPF) poisoning is a public health problem for which there is not currently any effective prophylaxis. In this study, we investigated the protective effect of grape seed extract (GSE) against CPF-induced hepatotoxicity. Rats were daily treated either with CPF (2 mg/kg) or CPF and GSE (20 mg/kg) for 1 week, sacrificed, and their livers dissected for biochemical, molecular, and histopathological analyses. CPF generated liver dysfunction by altering carbohydrate, lipid, amino acid, ammonia and urea metabolism, and provoked mitochondrial impairment through disturbing tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and mitochondrial viability. CPF also induced cholinergic excitotoxicity along with oxidative stress and histopathological alterations. Interestingly, treatment with GSE prevented all the detrimental effects of CPF through the regulation of cytochrome P450 (CYP450) gene expression. Molecular docking analysis indicated that GSE-containing polyphenols acted as epigenetic modulators through inhibiting DNA (cytosine-5)-methyltransferase 1 (DNMT1), thus favoring the CYP2C6 detoxification pathway. Thereby, GSE might be a promising strategy in the protection of the liver against CPF toxicity.

Grape seed extract in combination with deferasirox ameliorates iron overload, oxidative stress, inflammation, and liver dysfunction in beta thalassemia children.

BACKGROUND AND PURPOSE: Iron overload in the body is associated with serious and irreversible tissue damage. This study aimed to investigate the iron-chelating, antioxidant, anti-inflammatory, and hepatoprotective activities of grape seed extract (GSE) supplement as well as its safety in ß-thalassemia major (ß-TM) pediatric patients receiving deferasirox as a standard iron-chelation therapy. MATERIALS AND METHODS: The children were randomly allocated to either GSE group (n = 30) or control group (n = 30) to receive GSE (100 mg/day) or placebo capsules, respectively, for 4 weeks. The serum levels of iron, ferritin, total iron-binding capacity (TIBC), alanine transaminase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and glutathione (GSH) as well as superoxide dismutase (SOD) activity and hemoglobin (Hb) concentration were measured pre-and post-intervention. RESULTS: GSE supplement significantly attenuated the serum levels of iron (p = 0.030), ferritin (p = 0.017), ALT (p = 0.000), AST (p = 0.000), TNF-α (p = 0.000), and hs-CRP (p = 0.001). The TIBC level (p = 0.020) significantly enhanced in the GSE group compared with the placebo group. Moreover, GSE supplement remarkably improved the oxidative stress markers, MDA (p = 0.000) and GSH (p = 0.001). The changes in the SOD activity (p = 0.590) and Hb concentration (p = 0.670) were not statistically different between the groups. CONCLUSION: GSE supplement possesses several health beneficial influences on children with ß-TM by alleviating iron burden, oxidative stress, inflammation, and liver dysfunction.

Administration time effect of dietary proanthocyanidins on the metabolome of Fischer 344 rats is sex- and diet-dependent.

Proanthocyanidins (PAs) are one of the most commonly ingested polyphenols in the human diet, with a wide range of beneficial health effects. Remarkably, PAs have been reported to influence core and peripheral clock genes expression, and their effects may change in a time-of-day dependent manner. Therefore, the aim of this study was to investigate whether the capacity of PAs to modulate the metabolome is conditioned by the time-of-day in which these compounds are consumed in a diet- and sex-dependent manner. To do this, a grape seed proanthocyanidin extract (GSPE) was administered to female and male Fischer 344 rats at ZT0 (in the morning) and ZT12 (at night) and the GSPE administration time effect was evaluated on clock genes expression, melatonin hormone and serum metabolite levels in a healthy and obesogenic context. The results showed an administration time effect of GSPE on the metabolome in a sex and diet-dependent manner. Specifically, there was an effect on amino acid, lipid and cholate metabolite levels that correlated with the central clock genes expression. Therefore, this study shows a strong influence of sex and diet on the PAs effects on the metabolome, modulated in turn by the time-of-day.

Dietary effect of grape (Vitis vinifera) seed extract mitigates hepatic disorders caused by oxidized fish oil in rainbow trout (Oncorhynchus mykiss).

The major goal of this study was to determine the effect of grape seed extract (GSE) on liver damage in rainbow trout (Oncorhynchus mykiss) that was caused by the consumption of dietary oxidized fish oil (OFO). Rainbow trout were fed six different experimental diets coded OX-GSE 0 (OFO diet), OX-GSE 1 (OFO and 0.1% GSE), OX-GSE 3 (OFO and 0.3% GSE), GSE 0 (fresh fish oil and 0.0% GSE), GSE 1 (fresh fish oil and 0.1% GSE), and GSE 3 (fresh fish oil and 0.3% GSE) for 30 days. The lowest % hepatosomatic index (HSI) result was calculated in fish fed with OX-GSE 0 and the highest HSI was determined in fish fed with GSE 1 diets (p < 0.05). Histopathologically, hydropic degeneration in hepatocytes significantly increased OX-GSE 0 and GSE 3 compared to GSE 1 diets (p < 0.05). Deposition of lipid droplets in hepatocytes was significantly increased in OX-GSE 0 and OX-GSE 3 groups than others (p < 0.05). Liver biochemistry parameters such as superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) were significantly affected by OX and GSE treatments (p < 0.05). There were significant differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) among the liver enzymes analyzed in serum in OX and GSE (p < 0.05), meanwhile no difference was observed in lactate dehydrogenase (LDH) values between groups (p > 0.05). In conclusion, liver biochemistry and histopathology of rainbow trout consuming diets containing oxidized fish oil were negatively affected. However, it was determined that the supplementation of 0.1% GSE to the diet had a significant ameliorative role in these adverse effects.

Effects of grape seed extract on the properties of pullulan polysaccharide/xanthan gum active films for apple preservation.

Grape seed extract (GSE) was added to pullulan polysaccharide (PP)/xanthan gum (XG) as composite film (PP/XG/GSE or PXG). The observed composite morphology indicated their biocompatibility. Sample PXG100 (contain 100 mg/L GSE) demonstrated the best mechanical properties, with tensile strength of 16.62 ± 1.27 MPa, and the elongation at break of (22.60 ± 0.48)%. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging activity of PXG150 were the highest at (81.52 ± 1.57)% and (90.85 ± 1.54)%, respectively. PXG films also demonstrated inhibitory effects on Staphylococcus aureus, Escherichia coli, and Bacillus subtilis. The PXG films could also prolong the shelf life of fresh-cut apples because it could decrease the rate of weight loss and retain more vitamin C and total polyphenol even on the 5th day. The weight loss rate of PXG150 was decreased from (8.58 ± 0.6)% (control) to (4.15 ± 0.19)%. It was able to achieve vitamin C and total polyphenol retention rate of 91 % and 72 %, respectively, which was significantly higher that the control sample. Therefore, GSE had contributed in enhancing the antibacterial, antioxidant properties, mechanical strength, UV protection and water resistance in PXG composite films. This effectively extend the shelf life of fresh-cut apples, which it will be an excellent food packaging material.

Combinations of grape seed procyanidin extract and milk thistle silymarin extract against lung cancer - The role of MiR-663a and FHIT.

AIMS: Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) contain structurally distinct polyphenols, and each agent has been shown to exert antineoplastic effects against lung cancer. We hypothesize that combinations of GSE and MTE will additively enhance their anticancer effects against lung cancer. MATERIALS AND METHODS: The anti-proliferative effects of GSE, MTE and combinations were evaluated in lung neoplastic cell lines. A dose range finding (DRF) study to determine safety, bioavailability and bioactivity, followed by human lung cancer xenograft efficacy studies were conducted in female nude mice with once daily gavage of leucoselect phytosome (LP), a standardized GSE, and/or siliphos, a standardized MTE. The roles of tumor suppressors miR-663a and its predicted target FHIT in mediating the additive, anti-proliferative effecs of GSE/MTE were also assessed. KEY FINDINGS: GSE with MTE additively inhibited lung preneoplastic and cancer cell proliferations. Mice tolerated all dosing regimens in the DRF study without signs of clinical toxicity nor histologic abnormalities in the lungs, livers and kidneys. Eight weeks of LP and siliphos additively inhibited lung tumor xenograft growth. Plasma GSE/metabolites and MTE/metabolites showed that the combinations did not decrease systemic bioavailabilities of each agent. GSE and MTE additively upregulated miR-663a and FHIT in lung cancer cell lines; transfection of antisense-miR-663a significantly abrogated the anti-proliferative effects of GSE/MTE, upregulation of FHIT mRNA and protein. LP and siliphos also additively increased miR-663a and FHIT protein in lung tumor xenografts. SIGNIFICANCE: Our findings support clinical translations of combinations of GSE and MTE against lung cancer.

Gut Microbiota Influences the Photoperiod Effects on Proanthocyanidins Bioavailability in Diet-Induced Obese Rats.

SCOPE: Polyphenols health effects on obesity are mainly attributed to their metabolites generated after their gastrointestinal digestion, in which gut microbiota plays an important role. Moreover, gut microbiota composition and polyphenols bioavailability are influenced by differences in day light length (photoperiod). Thus, this study evaluates if a grape seed proanthocyanidins (GSPEs) extract bioavailability is influenced by different photoperiod exposure via gut microbiota modulation in an obesogenic context. METHODS AND RESULTS: Cafeteria diet-induced obese Fischer 344 rats are housed under different photoperiod conditions (6, 12, or 18 h of light per day) during 9 weeks and administered with GSPE (25 mg kg-1 ) or GSPE and an antibiotic cocktail (ABX) for the last 4 weeks. Serum GSPE-derived metabolites are quantified by HPLC-MS/MS. CONCLUSION: A higher bioavailability is observed under 6 h light/18 h darkness (L6) compared to 18 h light/6 h darkness (L18). Individual metabolites, especially those from the gut microbiota, are affected by photoperiods. ABX treatment alters these photoperiod-mediated changes. Therefore, these results suggest that gut microbiota plays a key role in the photoperiod effects on GSPE bioavailability in obese rats.

Grape Seed Extract Attenuates Demyelination in Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Inflammatory Response of Immune Cells.

OBJECTIVE: To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action. METHODS: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor- α (TNF- α), interleukin-1 ß (IL-1 ß), IL-6, IL-12, IL-17 and interferon-γ (IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively. RESULTS: GSE reduced the secretion of TNF-α, IL-1 ß and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P<0.01), inhibited the secretion of TNF-α, IL-1 ß, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days (P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors (P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4 (TLR4) and Rho-associated kinase (ROCKII, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors (P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+ and CD45+CD4+ cells, and weakened the differentiation of Th1 and Th17 (P<0.05). Moreover, it reduced the secretion of inflammatory factors (P<0.01), and prevented the activation of microglia (P<0.05). CONCLUSION: GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.

Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways.

Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.

Grape Seed Components as Protectors of Inflammation, DNA Damage, and Cancer.

PURPOSE OF REVIEW: Oxidative stress is related to the pathogenesis of several chronic diseases, including inflammatory processes. Free radicals excess increase not only oxidative stress but also genomic instability. Polyphenols are non-enzymatic antioxidants that act as a defense barrier against free radicals and non-radical oxidants. The purpose of this article was to review published articles relating dietary polyphenols contained in grape seed proanthocyanidin extracts with its potential for reversing DNA damage. RECENT FINDINGS: Proanthocyanidin components exert pleiotropic actions having several biological, biochemical, and significant pharmacological effects and showed the ability to reduce cytotoxicity and genotoxicity. Grape seed proanthocyanidin extracts showed the ability to reduce cytotoxicity and genotoxicity through the comet assay and the micronucleus technique.

Grape seed extract proanthocyanidin antagonizes aristolochic acid I-induced liver injury in rats by activating PI3K-AKT pathway.

Aristolochic acid is internationally recognized as a carcinogen. It has been shown that the main toxic mechanism of aristolochic acid on the liver and kidney is the induction of ROS-induced oxidative stress damage. To investigate whether proanthocyanidins (GSPE), a natural antioxidant product from grape seed extract, could antagonize AA-I-induced liver injury. Thirty-two SD rats were selected and divided into aristolochic acid exposure group (AA-I), normal control group, GSPE group and GSPE intervention group. The protective effects of GSPE on AA-I liver injury were evaluated by examining the body weight, liver index, liver function and liver pathological sections of rats. The results of body weight, liver index, liver function and liver pathological sections of rats showed that GSPE had antagonistic effects on AA-I-induced liver injury. antioxidant enzyme activity in the GSPE intervention group was significantly higher than that in the aristolochic acid group, apoptotic cells were significantly lower than that in the aristolochic acid group, protein and mRNA expression of PI3K-AKT and BCL-2 were significantly higher than that in the aristolochic acid group, BAX, The protein and mRNA expression of BAX, CASPAES-3, CASPAES-9 were significantly lower than those of the aristolochic acid group. GSPE can antagonize aristolochic acid-induced hepatotoxicity, and its mechanism of action is to antagonize aristolochic acid I-induced liver injury by inhibiting PI3K-AKT pathway-mediated hepatocyte apoptosis.

Co-treatment with grape seed extract and mesenchymal stem cells in vivo regenerated beta cells of islets of Langerhans in pancreas of type I-induced diabetic rats.

BACKGROUND: Nowadays, diabetes mellitus is known as a silent killer because individual is not aware that he has the disease till the development of its complications. Many researchers have studied the use of stem cells in treatment of both types of diabetes. Mesenchymal stem cells (MSCs) hold a lot of potential for regenerative therapy. MSCs migrate and home at the damaged site, where they can aid in the repair of damaged tissues and restoring their function. Oxidative stress and inflammation represent a huge obstacle during MSCs transplantation. Therefore, the present study aimed to evaluate the role of grape seed extract (GSE) administration during MSCs transplantation in streptozotocin (STZ)-induced type I diabetes. Furthermore, testing some of GSE components [procyanidins(P)-B1 and P-C1] in conjunction with MSCs, in vivo, was performed to determine if one of them was more effective in relieving the measured attributes of diabetes more than the whole GSE. METHODS: Firstly, GSE was prepared from the seeds of Muscat of Alexandria grapes and characterized to identify its phytochemical components. Experimental design was composed of control group I, untreated diabetic group II, GSE (300 mg/kg)-treated diabetic group III, MSCs (2 × 106 cells/rat)-treated diabetic group IV and GSE (300 mg/kg)/MSCs (2 × 106 cells/rat)-treated diabetic group V. Type I diabetes was induced in rats by intravenous injection with 65 mg/kg of STZ. Treatment started when fasting blood glucose (FBG) level was more than 200 mg/dl; GSE oral administration started in the same day after MSCs intravenous injection and continued daily for 30 consecutive days. RESULTS: The results showed that GSE/MSCs therapy in type I-induced diabetic rats has dramatically managed homeostasis of glucose and insulin secretion; together with, improvement in levels of inflammatory markers and oxidative stress. CONCLUSION: Co-treatment with GSE and MSCs in vivo regenerates beta cells in type I-induced diabetic rats.

Synergistic effect between plant extracts and fluoride to protect against enamel erosion: An in vitro study.

Polyphenol-rich solutions, such as plant extracts and teas, can modify the salivary pellicle and improve the protection against dental erosion. In this study, we further explored how these polyphenol-rich plant extracts solutions behave in the presence of fluoride. We distributed enamel specimens into 9 groups (n = 15): Control_No_F- (Deionized water); Control_F- (500 ppm F-), Grape_Seed_No_F- (Grape seed extract), Grape_Seed_F- (Grape seed extract + 500 ppm F-), Grapefruit_Seed_No_F- (Grapefruit seed extract), Grapefruit_Seed_F- (Grapefruit seed extract + 500 ppm F-), Blueberry_No_F- (Blueberry extract), Blueberry_F- (Blueberry extract + 500 ppm F-), and Sn2+/F-_Rinse (commercial solution containing 800 ppm Sn2+ and 500 ppm F-). The specimens were submitted to 5 cycles (1 cycle per day), and each cycle consisted of: salivary pellicle formation (human saliva, 30 min, 37°C), modification of the pellicle (2 min, 25°C), pellicle formation (60 min, 37°C), and an erosive challenge (1 min, citric acid). Between cycles, the specimens were kept in a humid chamber. Relative surface hardness (rSH), relative surface reflection intensity (rSRI) and calcium released to the acid were analysed, using general linear models, and Kruskal-Wallis with post-hoc Dunn's tests. We observed that the presence of fluoride in synergy with the extract solutions provided better protection than the groups containing extract or fluoride only. For rSH, we observed a significant main effect of extracts (F(4,117) = 9.20; p<0.001) and fluoride (F(1,117) = 511.55; p<0.001), with a significant interaction (F(3,117) = 6.71; p<0.001). Grape_Seed_F- showed the best protection, better than fluoride, and Sn2+/F-_Rinse. Calcium results also showed greater protection for the groups containing fluoride, whereas for rSRI, despite a significant interaction between extract and fluoride (F(3,117) = 226.05; p<0.001), the differences between the groups were not as clearly observed. We conclude that polyphenols from plant extracts, when combined with fluoride, improve the protective effect of salivary pellicles against enamel erosion.

Effects of Grape Seed Extract Supplementation on Endothelial Function and Endurance Performance in Basketball Players.

While dietary polyphenols supplements can improve endothelial function and blood flow to exercise, the effects of chronic supplementation with grape seed extract (GSE) containing a high dose of polyphenols on endurance performance are not known. Accordingly, in 12 elite athletes, we compared the effects of both GSE and placebo (PL) on submaximal VO2, time to exhaustion performance, and endothelial function during progressive cycling exercise for 14 days. Endothelial function was evaluated from the brachial artery via flow-mediated dilation (FMD). Compared to PL, GSE decreased submaximal VO2 at 80% and 120% of VO2peak and increased the time to exhaustion (p < 0.05). GSE also resulted in FMD-induced increase in brachial artery diameter (14.4 ± 5.2% vs. 17.6 ± 4.5%, p = 0.035). We demonstrated that chronic supplementation with GSE improved endurance performance and these effects may partially be due to vasodilation in active skeletal muscle mediated by enhanced endothelial function. Thus, our results suggest that GSE appears to be an ergogenic nutraceutical that can improve exercise performance in elite athletes.

Grape Seed Proanthocyanidins Modulate the Hepatic Molecular Clock via MicroRNAs.

SCOPE: Circadian rhythm is an endogenous and self-sustained timing system, responsible for the coordination of daily processes in 24-h timescale. It is regulated by an endogenous molecular clock, which is sensitive to external cues as light and food. This study has previously shown that grape seed proanthocyanidins extract (GSPE) regulates the hepatic molecular clock. Moreover, GSPE is known to interact with some microRNAs (miRNAs). Therefore, the aim of this study is to evaluate if the activity of GSPE as modulator of hepatic clock genes can be mediated by miRNAs. METHODS AND RESULTS: 250 mg kg-1 of GSPE is administered to Wistar rats before a 6-h jet lag and sacrificed at different time points. GSPE modulated both expression of Bmal1 and miR-27b-3p in the liver. Cosinor-based analysis reveals that both Bmal1 and miR-27b-3p expression follow a circadian rhythm, a negative interaction between them, and the role of GSPE adjusting the hepatic peripheral clock via miRNA. Additionally, in vitro studies show that Bmal1 is sensitive to GSPE (25 mg L-1 ). However, this effect is independent of miR-27b-3p. CONCLUSION: miRNA regulation of peripheral clocks via GSPE may be part of a complex mechanism that involves the crosstalk with the central system rather than a direct effect.

Antioxidant effect of grape seed extract corrects experimental autoimmune encephalomyelitis behavioral dysfunctions, demyelination, and glial activation.

Background and purpose: Multiple sclerosis (MS), a multifactorial autoimmune disease of the central nervous system (CNS), is characterized by demyelination and chronic inflammation, as well as axonal and neuronal loss. There is no cure for MS, and despite a significant improvement in the therapeutic management of patients during the last 20 years, some symptoms are still resistant to treatment, and the evolution of the disease to progressive form seems still ineluctable. The etiology of MS is complex and still not fully understood. However, inflammation is a major driver of physiopathology and oxidative stress contributes to CNS lesions and promotes existing inflammatory response. Plant polyphenols are endowed with many therapeutic benefits through alleviating oxidative stress and inflammation, thus providing neuroprotection in MS. We presently evaluated the curative effect of grape seed extract (GSE) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Experimental approach: Six-week-old C57Bl/6J females were subjected to the EAE paradigm (using myelin oligodendrocyte glycoprotein peptide fragment (35-55), complete Freund's adjuvant, and pertussis toxin) and then chronically treated with GSE from day 10 to day 30 post-induction. Clinical score and body weight were monitored daily, while evaluation of sensitive, motor, cognitive, and anxiety-related behaviors was performed weekly. Then, the GSE effect was evaluated on whole brain and spinal cord samples through the evaluation of oxidative stress damage, antioxidant capacities, myelin alteration, astroglial and microglial proliferation, and sirtuin expression. Key results: Grape seed extract curative chronic treatment corrected the clinical course of EAE, as well as the mechanical hypersensitivity, and avoided the development of EAE mouse thermal cold allodynia. The neuropathological evaluation showed that GSE reduced oxidative stress in the brain and spinal cord by decreasing the lipid and protein oxidation through correction of the three main antioxidant enzyme activities, namely, superoxide dismutase, catalase, and glutathione peroxidase, as well as restoring normal myelin protein expression and correcting microglial and astroglial protein overexpression and sirtuin downregulation. Conclusion and implications: These data strongly support GSE as an effective therapeutic approach in MS treatment.

The effects of grape seed proanthocyanidins in cafeteria diet-induced obese Fischer 344 rats are influenced by faecal microbiota in a photoperiod dependent manner.

Polyphenols are of high interest due to their beneficial health effects, including anti-obesity properties. The gut microbiota may play an important role in polyphenol-mediated effects as these bacteria are significantly involved in the metabolism of polyphenols. Moreover, seasonal rhythms have been demonstrated to influence both the gut microbiota composition and polyphenol bioavailability. Thus, the goal of this study was to evaluate the impact of photoperiods and microbiota on polyphenol functionality in an obesogenic context. Towards this aim, cafeteria diet-fed Fischer 344 rats were housed under three different photoperiod conditions (L6: 6 h of light, L12: 12 h of light and L18: 18 h of light) for 9 weeks. During the last 4 weeks of the experiment, rats were daily administered with an oral dose of a grape seed proanthocyanidin extract (GSPE) (25 mg per kg body weight). Additionally, rats treated with GSPE and an antibiotic cocktail (ABX) in their drinking water were included for a better understanding of the gut microbiota role in GSPE functionality. Vehicle and non-ABX treated rats were included as controls. GSPE decreased body weight gain and fat depots only under L18 conditions. Interestingly, the gut microbiota composition was strongly altered in this photoperiod. GSPE + ABX-treated rats gained significantly less body weight compared to the rats of the rest of the treatments under L18 conditions. These results suggest that GSPE functionality is modulated by the gut microbiota in a photoperiod dependent manner. These novel findings corroborate seasonal rhythms as key factors that must be taken into account when investigating the effects of polyphenols in the treatment or prevention of chronic diseases.

Pellicle modification with natural bioproducts: Influence on tooth color under erosive conditions.

Salivary pellicle was modified with bioproducts and we assessed the change in tooth color and the protection of enamel to erosion. Human enamel specimens were assigned to one of three solutions: grape seed extract or black tea (bioproducts), or deionized water (negative control); after which one half the specimens underwent erosive challenges. The specimens underwent 15 cycles involving salivary pellicle formation (10 min, 37°C), incubation in solution (2 min, 25°C), subsequent pellicle formation (90 min, 37°C). Half of the specimens was kept in a humid chamber and the other half was submitted to erosion (2 min, 1% citric acid). After 15 such cycles, the pellicle was removed. Tooth color and the surface reflection intensity were assessed after every five cycles and after pellicle removal. For non-eroded specimens, the exposure to bioproducts promoted significantly greater color change than the deionized water, with increases in yellow appearance. After pellicle removal, the color was similar in all non-eroded specimens. The bioproducts increased the surface reflection intensity over cycles. For the erosion-exposed specimens, erosion itself resulted in color change. Black tea and deionized water resulted in increased yellow appearance. Exposure to the bioproducts resulted in higher relative surface reflection intensity values over time, but only grape seed extract resulted in higher relative surface reflection intensity value at the time of pellicle removal. The bioproducts caused transient staining effect, which was reduced after pellicle removal. For enamel submitted to erosion, grape seed extract resulted in less color change and better protection of enamel against erosion than black tea or water.