Grape Seed Proanthocyanidins Inhibit Replication of the Dengue Virus by Targeting NF-kB and MAPK-Mediated Cyclooxygenase-2 Expression

Dengue virus (DENV) infection is a serious global health issue as it causes severe dengue hemorrhagic fever and dengue shock syndrome. Since no approved therapies are available to treat DENV infection, it is necessary to develop new agents or supplements that can do this. In this study, grape seed proanthocyanidins extract (GSPE), which is widely consumed as a dietary supplement, dose-dependently suppressed the replication of four DENV serotypes. The inhibitory mechanism demonstrated that GSPE downregulated DENV-induced aberrant cyclooxygenase-2 (COX-2) expression, revealing that the inhibitory effect of the GSPE on DENV replication involved targeting DENV-induced COX-2 expression. Mechanistic studies on signaling regulation have demonstrated that GSPE significantly reduced COX-2 expression by inactivating NF-κB and ERK/P38 MAPK signaling activities. Administrating GSPE to DENV-infected suckling mice reduced virus replication, mortality, and monocyte infiltration of the brain. In addition, GSPE substantially reduced the expression of DENV-induced inflammatory cytokines associated with severe dengue disease, including tumor necrosis factor-α, nitric oxide synthase, interleukin (IL)-1, IL-6, and IL-8, suggesting that GSPE has potential as a dietary supplement to attenuate DENV infection and severe dengue.

[1]  J. F. Fatriansyah,et al.  Molecular Docking and Molecular Dynamics Simulation of Fisetin, Galangin, Hesperetin, Hesperidin, Myricetin, and Naringenin against Polymerase of Dengue Virus , 2022, Journal of tropical medicine.

[2]  M. S. Jafri,et al.  In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin , 2021, Biology.

[3]  J. Pedraza-Chaverri,et al.  Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19 , 2021, Antioxidants.

[4]  G. Arunkumar,et al.  Current Understanding of the Pathogenesis of Dengue Virus Infection , 2020, Current Microbiology.

[5]  J. Chu,et al.  Betulinic Acid exhibits antiviral effects against dengue virus infection. , 2020, Antiviral research.

[6]  Kangliang Sheng,et al.  Grape seed proanthocyanidin extract ameliorates dextran sulfate sodium-induced colitis through intestinal barrier improvement, oxidative stress reduction, and inflammatory cytokines and gut microbiota modulation. , 2020, Food & function.

[7]  Y. Lim,et al.  Anti-dengue virus serotype 2 activity of tannins from porcupine dates , 2020, Chinese Medicine.

[8]  G. Cravotto,et al.  Mantonico and Pecorello Grape Seed Extracts: Chemical Characterization and Evaluation of In Vitro Wound-Healing and Anti-Inflammatory Activities , 2020, Pharmaceuticals.

[9]  I. Kim,et al.  Effects of grape seed extract on performance, immunity, antioxidant capacity, and meat quality in Pekin ducks , 2020, Poultry science.

[10]  A. Almulla,et al.  Effect of Black Grape Seed Extract (Vitis vinifera) on Biofilm Formation of Methicillin-Resistant Staphylococcus aureus and Staphylococcus haemolyticus , 2019, Current Microbiology.

[11]  S. Robledo,et al.  In vitro and in silico anti-dengue activity of compounds obtained from Psidium guajava through bioprospecting , 2019, BMC Complementary and Alternative Medicine.

[12]  V. Verardo,et al.  Grape Seeds Proanthocyanidins: An Overview of In Vivo Bioactivity in Animal Models , 2019, Nutrients.

[13]  S. Dey,et al.  Grape seed extract: having a potential health benefits , 2019, Journal of Food Science and Technology.

[14]  V. Mariappan,et al.  Oxidative stress response in the pathogenesis of dengue virus virulence, disease prognosis and therapeutics: an update , 2019, Archives of Virology.

[15]  I. Herrera-Camacho,et al.  Antiviral and immunomodulatory effects of polyphenols on macrophages infected with dengue virus serotypes 2 and 3 enhanced or not with antibodies , 2019, Infection and drug resistance.

[16]  Yee‐Shin Lin,et al.  The monocyte-macrophage-mast cell axis in dengue pathogenesis , 2018, Journal of Biomedical Science.

[17]  S. Hsu,et al.  Lucidone suppresses dengue viral replication through the induction of heme oxygenase-1 , 2018, Virulence.

[18]  Feng Li,et al.  Grape Seed Procyanidin Extract Reduces Arsenic-Induced Renal Inflammatory Injury in Male Mice. , 2017, Biomedical and environmental sciences : BES.

[19]  C. Liaw,et al.  Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents , 2017, Scientific Reports.

[20]  M. Wainberg,et al.  Identification of resveratrol analogs as potent anti‐dengue agents using a cell‐based assay , 2017, Journal of medical virology.

[21]  Yee‐Shin Lin,et al.  Resveratrol treatment reveals a novel role for HMGB1 in regulation of the type 1 interferon response in dengue virus infection , 2017, Scientific Reports.

[22]  J. Lozano-Sánchez,et al.  Cocoa and Grape Seed Byproducts as a Source of Antioxidant and Anti-Inflammatory Proanthocyanidins , 2017, International journal of molecular sciences.

[23]  Bing-Hung Chen,et al.  Grape Seed Extract Attenuates Hepatitis C Virus Replication and Virus-Induced Inflammation , 2016, Front. Pharmacol..

[24]  G. Cheng,et al.  Progress towards understanding the pathogenesis of dengue hemorrhagic fever , 2016, Virologica Sinica.

[25]  Q. Lu,et al.  Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways , 2016, Cancer Prevention Research.

[26]  Yen-Hsu Chen,et al.  Human heme oxygenase 1 is a potential host cell factor against dengue virus replication , 2016, Scientific Reports.

[27]  S. Alakurtti,et al.  Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo. , 2016, Journal of natural products.

[28]  D. D'Souza,et al.  Antiviral effects of grape seed extract against feline calicivirus, murine norovirus, and hepatitis A virus in model food systems and under gastric conditions. , 2015, Food microbiology.

[29]  M. Figueroa-Espinoza,et al.  Grape seed and apple tannins: emulsifying and antioxidant properties. , 2015, Food chemistry.

[30]  Yee‐Shin Lin,et al.  Dengue Virus Infection Causes the Activation of Distinct NF-κB Pathways for Inducible Nitric Oxide Synthase and TNF-α Expression in RAW264.7 Cells , 2015, Mediators of inflammation.

[31]  Neerja Kaushik-Basu,et al.  Characterization of the activity of 2'-C-methylcytidine against dengue virus replication. , 2015, Antiviral research.

[32]  M. Ladomery,et al.  Modulation of the antioxidant/pro-oxidant balance, cytotoxicity and antiviral actions of grape seed extracts. , 2013, Food chemistry.

[33]  D. Getts,et al.  Antiviral macrophage responses in flavivirus encephalitis , 2013, The Indian journal of medical research.

[34]  J. Farrar,et al.  Neurological complications of dengue virus infection , 2013, The Lancet Neurology.

[35]  D. D'Souza,et al.  Grape seed extract for foodborne virus reduction on produce. , 2013, Food microbiology.

[36]  P. Wong,et al.  Antiviral activity of four types of bioflavonoid against dengue virus type-2 , 2011, Virology Journal.

[37]  N. Hettiarachchy,et al.  Green tea and grape seed extracts — Potential applications in food safety and quality , 2011 .

[38]  Mohammad Afzal,et al.  Bactericidal effect of grape seed extract on methicillin-resistant Staphylococcus aureus (MRSA). , 2010, The Journal of toxicological sciences.

[39]  Ri-fu Yang,et al.  [Ultrasound-assisted subcritical water extraction of proanthocyanidins from defatted grape seed and its antioxidant activity]. , 2010, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[40]  B. Wu-Hsieh,et al.  Enhancement by Tumor Necrosis Factor Alpha of Dengue Virus-Induced Endothelial Cell Production of Reactive Nitrogen and Oxygen Species Is Key to Hemorrhage Development , 2009, Journal of Virology.

[41]  E. Harris,et al.  A Mouse Model for Studying Dengue Virus Pathogenesis and Immune Response , 2009, Annals of the New York Academy of Sciences.

[42]  Qin M. Chen,et al.  P38 MAPK mediates COX-2 gene expression by corticosterone in cardiomyocytes. , 2008, Cellular signalling.

[43]  D. Chang,et al.  Differential effects of triptolide and tetrandrine on activation of COX-2, NF-κB, and AP-1 and virus production in dengue virus-infected human lung cells , 2008, European Journal of Pharmacology.

[44]  F. Hofman,et al.  Both Virus and Tumor Necrosis Factor Alpha Are Critical for Endothelium Damage in a Mouse Model of Dengue Virus-Induced Hemorrhage , 2007, Journal of Virology.

[45]  L. Stark,et al.  Differential proinflammatory and angiogenesis-specific cytokine production in human pulmonary endothelial cells, HPMEC-ST1.6R infected with dengue-2 and dengue-3 virus. , 2006, Journal of virological methods.

[46]  D. Newman,et al.  Plants as a source of anti-cancer agents. , 2005, Journal of ethnopharmacology.

[47]  M. Guzmán,et al.  Dengue diagnosis, advances and challenges. , 2004, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[48]  Duane J. Gubler,et al.  Dengue and Dengue Hemorrhagic Fever , 1998, Clinical Microbiology Reviews.

[49]  Hongqian Chu,et al.  Grape-seed proanthocyanidins inhibit the lipopolysaccharide-induced inflammatory mediator expression in RAW264.7 macrophages by suppressing MAPK and NF-κb signal pathways. , 2016, Environmental toxicology and pharmacology.

[50]  R. Agarwal,et al.  Dietary feeding of grape seed extract prevents intestinal tumorigenesis in APCmin/+ mice. , 2010, Neoplasia.

[51]  C. Tsatsanis,et al.  Signalling networks regulating cyclooxygenase-2. , 2006, The international journal of biochemistry & cell biology.

[52]  M. Rossmann,et al.  A structural perspective of the flavivirus life cycle , 2005, Nature Reviews Microbiology.

[53]  J. Corbett,et al.  The role and regulation of COX-2 during viral infection. , 2003, Viral immunology.

[54]  John Shi,et al.  Polyphenolics in grape seeds-biochemistry and functionality. , 2003, Journal of medicinal food.

[55]  S. Mahajan,et al.  Grape seed extract proanthocyanidins downregulate HIV-1 entry coreceptors, CCR2b, CCR3 and CCR5 gene expression by normal peripheral blood mononuclear cells. , 2002, Biological research.