PMID: 

Oxid Med Cell Longev. 2019 ;2019:4750795. Epub 2019 Jun 17. PMID: 31316718

Abstract Title: 

Biotransformation of Cranberry Proanthocyanidins to Probiotic Metabolites byEnhances Their Anticancer Activity in HepG2 Cells.

Abstract: 

This study was designed to unravel the role ofin the bioconversion of cranberry proanthocyanidins and cytotoxicity of resulting metabolites to hepatocellular carcinoma HepG2 cells. Crude (CR) and flavonol+dihydrochalcone- (FL+DHC-), anthocyanin- (AN-), proanthocyanidin- (PR-), and phenolic acid+catechin- (PA+C-) rich fractions were subjected to fermentation withat 37°C for 12, 24, and 48 h under anaerobic conditions. The major metabolites produced by bioconversion of polyphenols were 4-hydroxyphenylacetic acid, 3-(4-hydroxyphenyl)propionic acid, hydrocinnamic acid, catechol, and pyrogallol. Furthermore, cytotoxicity of the biotransformed extracts was comparedto their parent extracts using human hepatocellular carcinoma HepG2 cells. The results showed that PR-biotransformed extract completely inhibited HepG2 cell proliferation in a dose- and time-dependent manner with ICvalues of 47.8 and 20.1g/mL at 24 and 48 h, respectively. An insight into the molecular mechanisms involved revealed that the cytotoxic effects of PR at 24 h incubation were mitochondria-controlled and not by proapoptotic caspase-3/7 dependent. The present findings suggest that the application of a bioconversion process using probiotic bacteria can enhance the pharmacological activities of cranberry proanthocyanidins by generating additional biologically active metabolites.

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PMID: 

J Food Biochem. 2019 Jul ;43(7):e12882. Epub 2019 May 1. PMID: 31353727

Abstract Title: 

Litchi (Litchi chinensis Sonn.) flower proanthocyanidin fraction exhibited protective efficacy to suppress nickel-induced expression for vascular endothelial growth factor in HepG2 cells.

Abstract: 

The protective efficacy of litchi (Litchi chinensis Sonn.) flower proanthocyanidin fraction (LFPF) composed of (-)-epicatechin and proanthocyanidin A2 against vascular endothelial growth factor (VEGF) generation induced by nickel (Ni) in hepatocellular carcinoma (Hep G2) cells was studied. VEGF is an angiogenic inducer, which promotes tumor angiogenesis, leading to rapid tumor growth and metastasis. VEGF could be substantially induced in the Ni-mediated Hep G2 cells. Through LFPF treatment, the Ni-induced VEGF generation could be suppressed significantly. The inhibition of HIF-1α expression by blocking phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways, and the suppression of Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT 3), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)/mitogen-activated protein kinase (MEK1/2)/extracellular-signal-regulated kinase (ERK1/2) pathways are important molecular mechanisms for the LFPF action. LFPF should probably reduce the risk of liver cancer in Ni-contaminated environments by inhibiting VEGF expression. PRACTICAL APPLICATIONS: LFPF mainly contained (-)-epicatechin and proanthocyanidin A2. Our results demonstrated that LFPF considerably suppressed the Ni-induced VEGF expression through inhibition of JAK2/STAT 3 and RAF1/MEK1/2/ERK1/2 pathways and prohibited HIF-1α expression through blocking PI3K/AKT/mTOR pathway. Litchi flowersmight have the potential to diminish the liver cancer risk in a Ni-contaminated environment through suitable treatment.

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PMID: 

Ann N Y Acad Sci. 2019 May 10. Epub 2019 May 10. PMID: 31074515

Abstract Title: 

Grape-derived polyphenols produce antidepressant effects via VGF- and BDNF-dependent mechanisms.

Abstract: 

Recent studies suggest that bioactive dietary polyphenol preparation (BDPP) and individual polyphenolic compounds ameliorate stress-induced depression-like behaviors, but the underlying molecular mechanisms are incompletely understood. VGF (non-acronymic) in the dorsal hippocampus (dHc) has been shown to play a role in depression-like behaviors and antidepressant efficacy, and the VGF-derived peptide TLQP-62 (named by the N-terminal 4 amino acids and length) infused into dHc has been shown to have antidepressant efficacy that is BDNF-TrkB dependent. Here, we investigated whether BDPP influences VGF expression in the dHc, and whether dHc VGF is required for BDPP antidepressant efficacy. We found that BDPP produced antidepressant-like effects in naive mice and reversed the depression-like behaviors induced by chronic variable stress. In addition, we found that BDPP had no detectable antidepressant efficacy in floxed mice with prior knockdown in the dHc of either VGF or BDNF, achieved by adeno-associated virus-Cre infusion. Our data indicate that dHc VGF and BDNF expression are required for the antidepressant actions of BDPP, and therefore suggest that a VGF(TLQP-62)-BDNF-TrkB autoregulatory feedback loop could play a role in the regulation of BDPP antidepressant efficacy, much as it has been suggested to function in the antidepressant efficacies of ketamine and TLQP-62.

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PMID: 

Indian J Clin Biochem. 2019 Apr ;34(2):213-218. Epub 2018 Feb 7. PMID: 31092996

Abstract Title: 

Grape Seed Extract Alleviates Dexamethasone-Induced Hyperlipidemia, Lipid Peroxidation, and Hematological Alteration in Rats.

Abstract: 

The ameliorative effects of dietary natural compounds have drawn increasing attention. Dietary antioxidant is considered a common practice adopted in traditional and alternative medicine. The current study was considered to assess the ameliorative effect of grape seed extract on dexamethasone-induced hepatotoxicity in rats. Rats were injected with dexamethasone, (0.1 mg/kg; i.m.), three times per week, for 30 days. The other groups; dexamethasone (0.1 mg/kg) and grape seed extract at a dose of 200 and 400 mg/kg were given orally to rats, respectively. Dexamethasone treatment resulted in a significant elevation in liver function markers activities, lipid profile, and hematological alterations; also, a remarkable increase in hepatic lipid peroxidation marker whereas decreased antioxidant activities in rats. However, administration of grape seed extract resulted in a reversal of dexamethasone-induced lipid peroxidation, antioxidant enzyme activities, liver function markers and lipid profile, and hematological alterations. Moreover, grape seed extract demonstrated preventive action against dexamethasone-induced histopathological changes in rat liver tissues. In conclusion, grape seed extract exhibited a protective effect in rats against oxidative stress, hyperlipidemia and hematological alterations induced by dexamethasone.

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PMID: 

Biomed Pharmacother. 2019 Jul ;115:108908. Epub 2019 May 17. PMID: 31108378

Abstract Title: 

Grape seeds proanthocyanidin extract ameliorates Ehrlich solid tumor induced renal tissue and DNA damage in mice.

Abstract: 

The current study was carried out to evaluate the protective effect of grape seed proanthocyanidins extract (GSPE) against Ehrlich solid tumor (EST) induced renal injury, with the respect to DNA fragmentation and P53 and PCNA proteins expression in renal tissue. A total of 50 female mice were randomly assigned into five groups. Control mice were injected with physiological saline solution. Mice of the 2group were administered with GSPE (50 mg/kg bw/every 2day/per OS) for 2 weeks and injected with physiological saline solution. Mice of the 3group were injected subcutaneously with 2.5 million cells of EAC/mouse. Mice of the 4group were injected with EAC as the 3group and administered with GSPE as the 2group simultaneously for 2 weeks. Mice of the 5group were injected with EAC as the 3group and left for 2 weeks (till development of solid tumor), then treated with GSPE for another 2 weeks. EST significantly increased serum levels of urea, creatinine, potassium and chloride. In addition, it induced renal tissue and DNA injuries and increased P53, PCNA and ki67 proteins expression in renal tissues. On the other hand, it decreased serum levels of sodium and calcium ions. However, treatment of EST bearing mice with GSPE normalized serum levels of the above-mentioned parameters and improved renal tissue structure and reduced renal tissue DNA damage and P53, PCNA and ki67 proteins expression. These results indicated that GSPE is a promising nephron protective agent against EST induced renal injury.

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PMID: 

Medicine (Baltimore). 2019 May ;98(21):e15515. PMID: 31124931

Abstract Title: 

Effect of grape seed proanthocyanidin extract on hard exudates in patients with non-proliferative diabetic retinopathy.

Abstract: 

PURPOSE: To evaluate the efficacy and safety of orally administered grape seed proanthocyanidin extract (GSPE) in patients with non-proliferative diabetic retinopathy (NPDR).METHODS: In this randomized (1:2:2), multicentre, double-blind trial, patients (n = 124; age: 40-78 years) were administered placebo, calcium dobesilate (CD; 750 mg/d), or GSPE (150 mg/d) orally for up to 12 months. All patients had retinal thickening with hard exudates (HEs) that met predefined criteria; the median best-corrected visual acuity was 0.8, as assessed usingthe Snellen visual acuity card. The main outcome measure was an improvement in HEs by at least 1 grade on a 10-grade severity scale. This was evaluated using fundus photography over 1 year.RESULTS: The rate of improvement in the HE severity was higher in the GSPE group than in the CD group. No statistically significant difference existed among the study groups in optical coherence tomography parameters, such as central subfield macular thickness and total macular volume (TMV). However, in the GSPE group, TMV after 9 months of treatment was significantly decreased compared with that at baseline. The GSPE group showed a significantly greater improvement in HE severity than did the placebo or CD group. Four cases in the GSPE group and 2 in the CD group were determined to have developed potential treatment-related adverse reactions, which were all gastrointestinal in nature.CONCLUSIONS: Oral GSPE therapy for 1 year improved HEs in patients with NPDR. The efficacy of GSPE for HEs was higher than that of oral CD in the study patients.

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PMID: 

Nutr Neurosci. 2019 May 25:1-15. Epub 2019 May 25. PMID: 31131731

Abstract Title: 

Neuroprotective benefits of grape seed and skin extract in a mouse model of Parkinson's disease.

Abstract: 

Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta, and it involves oxidative stress. Our goal was to evaluate the neuroprotective effect ofred grape seed and skin extract (GSSE) in a model of Parkinson's disease. GSSE is very rich in phenolic compounds, such as flavonoids, anthocyanins, catechins and stilbenes, which are present in the pulp, seeds, and leaves of the fruit. GSSE is known for its antioxidant properties and has shown beneficial effects against oxidative injury in different organs, such as the kidneys, liver, heart and brain. In this study, we revealed the neuroprotective effect of GSSE on midbrain dopaminergic neurons bothand. We used the neurotoxin 6-hydroxydopamine (6-OHDA), which induces oxidative damage and mimics the degeneration of dopaminergic neurons observed in Parkinson's disease. We found that GSSE was effective in protecting dopamine neurons from 6-OHDA toxicity by reducing apoptosis, the level of reactive oxygen species (ROS) and inflammation. Furthermore, we found that GSSE treatment efficiently protected against neuronal loss and improved motor function in an6-OHDA model of Parkinson's disease (PD). Altogether, our results show that GSSE acts at multiple levels to protect dopamine neurons from degeneration in a model of PD.

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PMID: 

Cancer Prev Res (Phila). 2019 Aug ;12(8):557-566. Epub 2019 May 28. PMID: 31138523

Abstract Title: 

A Pilot Study of a Grape Seed Procyanidin Extract for Lung Cancer Chemoprevention.

Abstract: 

Grape seed procyanidin extract (GSE) had been reported to exert antineoplastic properties in preclinical studies. A modified phase I, open-label, dose-escalation clinical study was conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome (LP), a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Eight subjects ages 46-68 years were enrolled into the study and treated with escalating oral doses of LP for 3 months. Bronchoscopies with bronchoalveolar lavage and bronchial biopsies were performed before and after 3 months of LP treatment. Hematoxylin and eosin stain for histopathology grading and IHC examination for Ki-67 proliferative labeling index (Ki-67 LI) were carried out on serially matched bronchial biopsy samples from each subject to determine responses to treatment. Two subjects were withdrawn due to issues unrelated to the study medication, and a total of 6 subjects completed the full study course. In general, 3 months of LP, reaching the highest dose per study protocol was well tolerated and no dosing adjustment was necessary. Such a treatment regimen significantly decreased bronchial Ki-67 LI by an average of 55% (= 0.041), with concomitant decreases in serum miR-19a, -19b, and -106b, which were oncomirs previously reported to be downregulated by GSE, including LP, in preclinical studies. In spite of not reaching the original enrollment goal of 20, our findings nonetheless support the continued clinical translation of GSE as an antineoplastic and chemopreventive agent against lung cancer.

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PMID: 

J Cancer Res Ther. 2019 Jul-Sep;15(3):512-516. PMID: 31169212

Abstract Title: 

Radioprotective effect of grape seed extract against gamma irradiation in mouse bone marrow cells.

Abstract: 

Introduction: Ionizing radiations produce free radicals which are often responsible for DNA damage or cell death. Grape seed extract (GSE) is a natural compound having an antioxidant that protects DNA, lipids, and proteins from free radical damages. In this study, radioprotective effect of the GSE has been investigated in mouse bone marrow cells using micronucleus test.Materials and Methods: Four groups of mice were investigated in this study: Mice in Group 1 were subjected to injection of distilled water with no irradiation. Mice in Group 2 were exposed to 3 Gy gamma radiation after the injection of distillated water. Mice in Group 3 were injected with 200 mg/kg of the GSE without any irradiation. In another group, mice were exposed to three gray gamma irradiation after the injection of GSE. Animals were killed, and slides were prepared from the bone marrow cells 24 h after irradiation. The slides were stained with May Grunwald-Giemsa method and analyzed microscopically. The frequency of the micronucleated polychromatic erythrocytes (MnPCEs), micronucleated normochromatic erythrocyte (MnNCEs), and polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte (PCE/PCE + NCE) ratios was calculated.Results: Injection of GSE significantly decreased the frequency of MnPCEs (P

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PMID: 

Int J Mol Sci. 2019 Jul 2 ;20(13). Epub 2019 Jul 2. PMID: 31269652

Abstract Title: 

Pro-Apoptotic Effect of Grape Seed Extract on MCF-7 Involves Transient Increase of Gap Junction Intercellular Communication and Cx43 Up-Regulation: A Mechanism of Chemoprevention.

Abstract: 

Growing evidence suggests dietary antioxidants reduce the risk of several cancers. Grape seeds extracts (GSE) are a rich source of polyphenols known to have antioxidant, chemopreventive and anticancer properties. Herein, we investigated the in vitro effects and putative action mechanisms of a grape seed extract (GSE) on human breast cancer cells (MCF-7). The effects of GSE were evaluated on cell proliferation, apoptosis and gap-junction-mediated cell-cell communications (GJIC), as basal mechanism involved in the promotion stage of carcinogenesis. GSE (0.05-100μg/mL) caused a significant dose- and time-dependent inhibition of MCF-7 viability and induced apoptotic cell death, as detected by Annexin-V/Propidium Iodide. Concurrently, GSE induced transient but significant enhancement of GJIC in non-communicating MCF-7 cells, as demonstrated by the scrape-loading/dye-transfer (SL/DT) assay and an early and dose-dependent re-localization of the connexin-43 (Cx43) proteins on plasma membranes, as assayed by immunocytochemistry. Finally, real-time-PCR has evidenced a significant increase inmRNA expression. The results support the hypothesis that the proliferation inhibition and pro-apoptotic effect of GSE against this breast cancer cell model are mediated by the GJIC improvement via re-localization of Cx43 proteins and up-regulation ofgene, and provide further insight into the action mechanisms underlying the health-promoting action of dietary components.

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