PMID: 

Nutr Metab Cardiovasc Dis. 2019 Sep 30. Epub 2019 Sep 30. PMID: 31791634

Abstract Title: 

Grape seed procyanidin suppresses inflammation in cigarette smoke-exposed pulmonary arterial hypertension rats by the PPAR-γ/COX-2 pathway.

Abstract: 

BACKGROUND AND AIM: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, which is mainly caused by inflammation. Inhibiting inflammation can relieve PAH. Grape seed procyanidin (GSP) possesses remarkable anti-inflammatory property and vascular protective function. In this experiment, we verified the anti-inflammatory property of GSP in cigarette smoke-exposed PAH rats and revealed its molecular mechanism.METHODS AND RESULTS: In vivo, 45 Sprague Dawley (SD) rats were divided into 5 groups randomly, treated with normoxia/cigarette smoke (CS)/GSP + CS/CS + solvent/GSP. After GSP + CS administration, a decrease in mPAP, PVR, RVHI, WT%, and WA% was detected in the rats as compared to those treated with CS. In vitro, the proliferation of pulmonary arterial smooth muscle cells (PASMCs) caused by cigarette smoke extract (CSE) was effectively attenuated with GSP + CSE administration. Furthermore, GSP significantly increased the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) together with thelowered expression level of cyclooxygenase 2 (COX-2) in PASMCs co-incubated with CSE.CONCLUSION: These findings indicate that GSP ameliorates inflammation by the PPAR-γ/COX-2 pathway and finally inhibits the proliferation of PASMCs, which leads to pulmonary vascular remodeling.

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PMID: 

Aust Endod J. 2019 Dec 8. Epub 2019 Dec 8. PMID: 31814249

Abstract Title: 

Antimicrobial effectiveness of grape seed extract against Enterococcus faecalis biofilm: A Confocal Laser Scanning Microscopy analysis.

Abstract: 

This study evaluated the antimicrobial effectiveness of 6.5% Vitis vinifera grape seed extract (GSE) against Enterococcus faecalis biofilm using confocal laser scanning microscopy (CLSM). Saline solution (SS), 5.25% sodium hypochlorite (NaOCl) and 2% chlorhexidine (CHX) were used for comparison. Dentin discs were inoculated with E. faecalis strain establishing a 3-week-old biofilm. Discs (n = 10) were exposed to 5.25% NaOCl, 2% CHX, 6.5% GSE and SS (negative control) for 10 min. Discs were stained with the fluorescent LIVE/DEAD-BacLight™ dye and analysed using CLSM. The proportion of dead cells in biofilm was analysed using one-way anova and Tukey tests (P < 0.05). A higher proportion of dead cells was found in GSE group compared with CHX and SS (P < 0.05). NaOCl group was associated with the highest proportion of dead cells (P < 0.05). GSE presented antimicrobial activity against E. faecalis; however, NaOCl was the most effective irrigant solution. GSE was more effective than CHX and SS.

PMID: 

J Food Biochem. 2019 Aug ;43(8):e12962. Epub 2019 Jun 28. PMID: 31368542

Abstract Title: 

The plant flavonoid, fisetin alleviates cigarette smoke-induced oxidative stress, and inflammation in Wistar rat lungs.

Abstract: 

In the present study, we tested the antioxidant and anti-inflammatory potential of the plant flavonoid, fisetin against cigarette smoke-induced oxidative stress, and inflammation in rat lungs. Male Wistar rats were chronically exposed to cigarette smoke (CS) with or without administration of fisetin. Fisetin administration to CS-exposed rats resulted in a significant reduction in neutrophils and macrophages in bronchoalveolar lavage fluid as well as malondialdehyde, 3-nitrotyrosine, 8-isoprostane, tumor necrosis factor-alpha, interleukin-1beta, granulocyte macrophage-colony stimulating factor, interleukin-4, and interleukin-10 levels in lung tissues compared to those in CS-exposed rats not treated with fisetin. Fisetin also significantly augmented lung hemoxinase-1, glutathione peroxidase-2, reduced glutathione, superoxide dismutase, nitric oxide, and nuclear factor erythroid 2-related factor (Nrf2) levels in CS-exposed rats. In addition, a marked reversal in CS-induced histopathological changes was noted in fisetin-treated rats. Collectively, these data demonstrate the potential of fisetin to blunt CS-induced oxidative stress and inflammation in the lung and to prevent tissue damage via the Nrf2-mediated upregulation of antioxidant gene expression. PRACTICAL APPLICATIONS: In the present study, we found that the plant flavonoid, fisetin significantly abrogated the oxidative stress, inflammation, and tissue damage induced by cigarette smoke, a powerful pro-oxidant in rat lungs. Additionally, fisetin markedly reversed cigarette smoke-induced increases in neutrophil and macrophage cell populations in bronchoalveolar lavage fluid. These findings are particularly significant considering the association of cigarette smoking with increased oxidative stress and inflammation, which are central to the pathologies of a wide variety of chronic diseases including chronic obstructive pulmonary disease, cancer, and cardiovascular diseases. Therefore, the present work underscores the beneficial effects of the regular consumption of plant-based foods with medicinal properties for the effective prevention of these chronic diseases.

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PMID: 

Biofactors. 2019 Oct 21. Epub 2019 Oct 21. PMID: 31634424

Abstract Title: 

Fisetin, a phytopolyphenol, targets apoptotic and necroptotic cell death in HepG2 cells.

Abstract: 

Fisetin (3,7,3',4'-tetrahydroxyflavone), a bioactive dietary flavonoid, intrigued scientists for its anticancer potential against various cancer types. We investigated the fisetin-induced inhibition of growth and survival of human hepatocellular carcinoma. Fisetin decreased cell viability and proliferation of HepG2 cells as revealed from MTT and clonogenicity assays. Cell cycle arrest in the G2/M phase was observed. Annexin V/propidium iodide (PI) staining followed by flow cytometry revealed that fisetin induced both apoptosis and necroptosis in HepG2 cells. Apoptotic cells were significantly increased on fisetin treatment as observed in morphological evaluations and 4',6-diamidino-2-phenylindole and Acridine orange staining. Flow cytometry, fluorescence imaging, and 2', 7'-dichlorofluorescein diacetate analyses showed an increase in reactive oxygen species (ROS) generation on fisetin treatment. Pretreatment with N-acetyl cysteine inhibited ROS production and also rescued mitochondrial membrane potential in HepG2 cells. The underlying mechanisms of apoptosis and necroptosis were determined by analysis of their respective signaling molecules using qRT-PCR and Western blotting. Fisetin showed a marked increase in the expression of TNFα and IKκB with a decrease in NF-κB, pNF-κB and pIKκB expression. Fisetin reduced the expression of Bcl2, and elevated levels of Bax, caspase-3, and PARP and thus induced apoptosis in HepG2 cells. zVAD suppressed the fisetin-induced expression of caspase-8, RIPK1, RIPK3, and MLKL as opposed tofisetin treatment. Nec-1 + fisetin could not completely block necroptosis, which warrants further investigation. Taken together, our findings demonstrate that the fisetin exhibited anti-proliferative effects on HepG2 cells through apoptosis and necroptosis via multiple signaling pathways. Fiestin has potential as a therapeutic agent against hepatocellular carcinoma.

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PMID: 

Int Heart J. 2019 Nov 30 ;60(6):1398-1406. Epub 2019 Oct 31. PMID: 31666455

Abstract Title: 

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction.

Abstract: 

Atrial inflammation and fibrosis are the critical processes involved in atrial fibrillation (AF) after myocardial infarction (MI). Fisetin is a dietary flavonoid that has shown forceful anti-inflammatory and anti-proliferative properties in diverse models of disease. However, fisetin's role in atrial inflammation, fibrosis, and AF vulnerability post-MI remains completely unknown.Rats were subjected to MI surgery, by left anterior descending coronary artery ligation or sham operation, and treated with DMSO or fisetin via intraperitoneal injection. After 28 days, echocardiographic parameters were performed, and AF inducibility was tested. We further evaluated the inflammation, fibrosis of left atria (LA), and related signal pathways by RT-PCR, Western blot, and staining analysis.Compared to the MI group, fisetin treatment improved cardiac function, inhibited macrophage recruitment into the LA and production of IL-1β and TNF-α, and attenuated adverse atrial fibrosis following acute myocardial infarction (AMI). Electrophysiological recordings, using an isolated perfused heart, showed that MI-induced higher inducibility of AF and prolonged AF duration, interatrial conduction time (IACT), atrial effective refractory period (AERP) were significantly alleviated by fisetin. Mechanistically, fisetin markedly increased phosphorylated AMPK (p-AMPK) levels and suppressed NF-κB p65, p38MAPK, and smad3 phosphorylation in the LA post-MI.We demonstrate that fisetin improves LA expansion, cardiac function, atrial inflammation, fibrosis, and vulnerability to AF following MI by possibly regulating AMPK/NF-κB p65 and p38MAPK/smad3 signaling pathways.

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PMID: 

J Nutr Biochem. 2019 Nov 25 ;77:108253. Epub 2019 Nov 25. PMID: 31835147

Abstract Title: 

Oral flavonoid fisetin treatment protects against prolonged high-fat-diet-induced cardiac dysfunction by regulation of multicombined signaling.

Abstract: 

Excess high-fat diet (HFD) intake predisposes the occurrence of obesity-associated heart injury, but the mechanism is elusive. Fisetin (FIS), as a natural flavonoid, has potential activities to alleviate obesity-induced metabolic syndrome. However, the underlying molecular mechanisms of FIS against HFD-induced cardiac injury remain unclear. The present study was to explore the protective effects of FIS on cardiac dysfunction in HFD-fed mice. We found that FIS alleviated HFD-triggered metabolic disorder by reducing body weight, fasting blood glucose and insulin levels, and insulin resistance. Moreover, FIS supplements significantly alleviated dyslipidemia in both mouse hearts and cardiomyocytes stimulated by metabolic stress. FIS treatment abolished HFD-induced inflammatory response in heart tissues through suppressing TNF receptor-1/TNF receptor-associated factor-2 (Tnfr-1/Traf-2) signaling. Furthermore, FIS induced a strong reduction in the expression of fibrosis-related genes, contributing to the inhibition of fibrosis by inactivating transforming growth factor (Tgf)-β1/Smads/Erk1/2 signaling. Collectively, these results demonstrated that FIS could be a promising therapeutic strategy for the treatment of obesity-associated cardiac injury.

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PMID: 

Curr Microbiol. 2019 Dec 5. Epub 2019 Dec 5. PMID: 31807847

Abstract Title: 

Effect of Black Grape Seed Extract (Vitis vinifera) on Biofilm Formation of Methicillin-Resistant Staphylococcus aureus and Staphylococcus haemolyticus.

Abstract: 

Grape seeds are considered one of the most important sources for phenolic and other compounds and is globally consumed for the biological value of its active ingredients. The increasing prevalence of Methicillin-resistant Staphylococcus aureus-related infections has become a very challenging health issue worldwide. This work aims at examining the antibacterial activity of alcoholic extract of black grape seeds (Vitis vinifera) against biofilm formation by Staphylococcus aureus and Staphylococcus haemolyticus. Staphylococcal bacterial isolates were first clinically confirmed using the VITEK-2compact system (ID and AST), and four isolates were selected depending on virulence and resistance to different types of antibiotics. The ability of S. aureus and S. haemolyticus isolates to form biofilm was examined using a standardized 96-well microtiter plate method. Furthermore, the effect of Moxifloxacin and Penicillin G with MIC, sub-MIC and sub-sub-MIC in preventing S. aureus and S. haemolyticus biofilm production, as well as that of the grape seed extract (180 mg/ml) were tested against biofilm formation. Our data indicate that all of the Staphylococcal bacterial isolates were able to produce biofilm which was prevented by the methanolic extracts of the crude seeds of Vitis vinifera rich in galloylated catechin esters of gallic acid. A significant (P 

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PMID: 

Mol Neurobiol. 2019 Dec 12. Epub 2019 Dec 12. PMID: 31832973

Abstract Title: 

Gallic Acid Attenuated LPS-Induced Neuroinflammation: Protein Aggregation and Necroptosis.

Abstract: 

Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a phenolic acid, is ubiquitous in almost all parts of the plant. In the present study, a neuroinflammatory rat model using intranigral infusion of lipopolysaccharides (LPS, 4 μg/μL) was employed to study the neuroprotective effect of GA which was orally administered daily. Compared with the vehicle-treated rats, systemic administration of GA (100 mg/kg) significantly attenuated LPS-induced increases in glial fibrillary acidic protein (a biomarker of activated astrocytes) and ED-1 (a biomarker of activated microglia), as well as inducible nitric oxide synthase (iNOS, a proinflammatory enzyme) and interleukin-1β (a proinflammatory cytokine), in the LPS-infused substantia nigra (SN) of rat brain. At the same time, GA attenuated LPS-induced elevation in heme oxygenase-1 level (a redox-regulated protein) and α-synuclein aggregation (a hallmark of CNS neurodegeneration), suggesting that GA is capable of inhibiting LPS-induced oxidative stress and protein conjugation. Furthermore, GA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and LPS-induced increases in receptor-interacting protein kinase (RIPK)-1 and RIPK-3 levels (biomarkers of necroptosis), indicating that GA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Moreover, an in vitro study was employed to investigate the anti-inflammatory effect of GA on BV2 microglial cells which were subjected to LPS (1 μg/mL) treatment. Consistently, co-incubation of GA diminished LPS-induced increases in iNOS mRNA and iNOS protein expression in the treated BV-2 cells as well as NO production in the culture medium. Theanti-oxidative activity of GA was evaluated using iron-induced lipid peroxidation of brain homogenates. After 3-h incubation at 37 °C, GA was more potent than glutathione and less potent than trolox in inhibiting iron-induced lipid peroxidation. Conclusively, the present study suggests that GA isanti-inflammatory via attenuating LPS-induced neuroinflammation, oxidative stress, and protein conjugation. Furthermore, GA prevented LPS-induced programmed cell deaths of nigrostriatal dopaminergic neurons of the rat brain, suggesting that GA may be neuroprotective by attenuating neuroinflammationin CNS neurodegenerative diseases.

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PMID: 

Foods. 2019 Aug 21 ;8(9). Epub 2019 Aug 21. PMID: 31438605

Abstract Title: 

Interaction Mechanism of Flavonoids andα-Glucosidase: Experimental and Molecular Modelling Studies.

Abstract: 

Flavonoids are known to play a role in hypoglycemia by inhibitingα-glucosidase. However, their interaction mechanism with α-glucosidase still needs to be elaborated. In this study, the α-glucosidase inhibitory activities of 15 flavonoids were investigated. Their molecular volume had a negative effect on inhibitory activity, while the number of phenolic hydroxyl groups on the B ring was positively correlated with inhibitory activity. To explain the significant differences in activity, the interaction behaviors of myricetin and dihydromyricetin, which have similar structures, were compared by spectrofluorimetry, molecular docking, and the independent gradient model (IGM). In the fluorescence analysis, myricetin exhibited a higher binding capacity. Based on molecular docking and IGM analysis, their non-covalent interactions with α-glucosidase could be visualized and quantified. It was found that they had different binding modes with the enzymes and that myricetin possessed stronger hydrogen bonding and van der Waals force interactions, which explained the thermodynamic results.

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PMID: 

Colloids Surf B Biointerfaces. 2019 Nov 11 ;186:110640. Epub 2019 Nov 11. PMID: 31835184

Abstract Title: 

Myricetin inhibits amyloid fibril formation of globular proteins by stabilizing the native structures.

Abstract: 

Myricetin has been identified as a naturally occurring flavonoid class of polyphenolic compound which shows multiple medical benefits including antidiabetic, anticancerous and antioxidant properties. Here, we report the protective effect of myricetin against in vitro amyloid fibril formation of selected globular proteins. The results reveal that myricetin is capable of inhibiting amyloid fibril formation of both insulin and serum albumin. Seed-induced aggregation of both proteins was also substantially suppressed in the presence of myricetin. Fluorescence quenching data indicated binding of myricetin with protein monomers as well as fibrils. The molecular docking studies revealed strong affinity of myricetin for both the native and partially unfolded conformation of proteins mediated by H-bonds and hydrophobic interactions. Myricetin was also observed to promote disassembly of mature amyloid fibrils. The results reveal that myricetin molecule has the potential for suppressing amyloid formation and such an inherent property may help in developing myricetin-based antiamyloid drugs.

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