Vivek R Nerurkar

University of Hawaiʻi at Mānoa, Honolulu, Hawaii, United States

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Publications (118)373.12 Total impact

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    ABSTRACT: The envelope and precursor membrane (prM) proteins of dengue virus (DENV) are present on the surface of immature virions. During maturation, prM protein is cleaved by furin protease into pr peptide and membrane (M) protein. While previous studies mainly focusing on the pr region have identified several residues important for DENV replication, the functional role of M protein, particularly the α-helical domain (MH) which is predicted to undergo a large conformational change during maturation, remains largely unknown. In this study, we investigated the role of nine highly conserved MH domain residues in the replication cycle of DENV by site-directed mutagenesis in a DENV1 prME expression construct and found that alanine substitutions introduced to four highly conserved residues at the C-terminus and one at the N-terminus of the MH domain greatly affect the production of both virus-like particles and replicon particles. Eight out of the nine alanine mutants affected the entry of replicon particles, which correlated with the impairment in prM cleavage. Moreover, seven mutants were found to have reduced prM-E interaction at low pH, which may inhibit the formation of smooth immature particles and exposure of prM cleavage site during maturation, thus contributing to inefficient prM cleavage. Taken together, this is the first report showing that highly conserved MH domain residues, located at 20 to 38 amino acids downstream from the prM cleavage site, can modulate the prM cleavage, maturation of particles and virus entry. The highly conserved nature of these residues suggests potential targets of antiviral strategy.
    The Journal of biological chemistry. 10/2014;
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    ABSTRACT: Diabetes is a significant risk factor for developing West Nile virus (WNV)-associated encephalitis (WNVE) in humans, the leading cause of arboviral encephalitis in the United States. Using a diabetic mouse model (db/db), we recently demonstrated that diabetes enhanced WNV replication and the susceptibility of mice to WNVE. Herein, we have examined immunological events in the brain of wild type (WT) and db/db mice after WNV infection. We hypothesized that WNV-induced migration of protective leukocytes into the brain is attenuated in the presence of diabetes, leading to a high viral load in the brain and severe disease in diabetic mice. Nine-week old C57BL/6 WT and db/db mice were infected with WNV. Leukocyte infiltration, expression of cell adhesion molecules (CAM), neuroinflammatory responses, activation of astrocytes, and neuronal death were analyzed using immunohistochemistry, qRT-PCR, flow cytometry, and western blot. We demonstrate that infiltration of CD45+ leukocytes and CD8+T cells was significantly reduced in the brains of db/db mice, which was correlated with attenuated expression of CAM such as E-selectin and ICAM-1. WNV infection in db/db mice was associated with an enhanced inflammatory response in the brain. mRNA and protein levels of key chemokines such as CXCL10, CXCL1, CCL2, CCL5, CCL3, and G-CSF, and cytokines such as IL-1beta, TNF, IL-6, IFNgamma, and IL-1alpha were significantly elevated in the brains of db/db mice compared to WT mice. Elevated levels of cytokines also correlated with increased astrocytes activation and neuronal damage in the brains of db/db mice. These data suggest that reduced leukocytes recruitment, in part, due to lower levels of CAM results in failure to clear WNV infection from the brain leading to increased production of inflammatory molecules, which mediates increased neuronal death and mortality in db/db mice. This is the first study to elucidate the expression of CAM and their correlation with the migration of leukocytes, specifically cytotoxic CD8+ T cells, in increasing disease severity in the diabetic mouse model.
    Journal of Neuroinflammation 04/2014; 11(1):80. · 4.35 Impact Factor
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    ABSTRACT: Dengue, an arboviral disease, is caused by four distinct serotypes of dengue virus (DENV 1-4). While most of the cases are asymptomatic, some develop a febrile illness (dengue fever) or progress towards the more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Dengue is caused by an enveloped positive sense RNA virus of approximatiely 11-kb in the genus Flavivirus of the Flaviviridae family and is transmitted by mosquitoes of the genus Aedes. Aedes aegypti (Ae. aegypti) is the primary vector of dengue viruses followed by Aedes albopictus (Ae. albopictus). The mosquito becomes infected when it feeds on an infected human during the 5 days period of viremia. The ability of a mosquito to ingest, replicate and transmit a virus is know as vector competence or vector susceptibility to the virus. For a virus to succeed in infecting the mosquito it must cross multiple barriers: the midgut infection barrier, the midgut escape barrier and the salivary glands infection barrier. Differences in susceptibility have been observed amongst Ae. albopictus populations which has a significant impact on the course of the dengue outbreak.
    Biomedical Sciences Symposium, John A. Burns School of Medicine, University of Hawai`i; 04/2014
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    Moti L Chapagain, Vivek R Nerurkar
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    ABSTRACT: Replication of flaviviruses (family Flaviviridae) occurs in specialized virus-induced membrane structures (IMS). The cellular composition of these IMS varies for different flaviviruses implying different organelle origins for IMS biogenesis. The role of flavivirus non-structural (NS) proteins for the alteration of IMS remains controversial. In this report, we demonstrate that West Nile virus strain New York 99 (WNVNY99) remodels the endoplasmic reticulum (ER) membrane to generate specialized IMS. Within these structures, we observed an element of the cis-Golgi, viral double-stranded RNA, and viral-envelope, NS1, NS4A and NS4B proteins using confocal immunofluorescence microscopy. Biochemical analysis and microscopy revealed that NS4B lacking the 2K-signal peptide associates with the ER membrane where it initiates IMS formation in WNV-infected cells. Co-transfection studies indicated that NS4A and NS4B always remain co-localized in the IMS and are associated with the same membrane fractions, suggesting that these proteins function cooperatively in virus replication and may be an ideal target for antiviral drug discovery.
    PLoS ONE 01/2014; 9(1):e84040. · 3.53 Impact Factor
  • Mukesh Kumar, Vivek R. Nerurkar
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    ABSTRACT: To determine whether cellular miRNAs play a role in West Nile virus (WNV) neuropathogenesis, we evaluated WNV-infected mice brain for the expression profile of miRNAs, their potential functions and their correlation with genes involved in inflammatory pathways. A total of 528 miRNAs and 168 mRNA genes were examined. One hundred thirty-nine miRNAs were significantly differentially expressed in WNV-infected mice brain. Ingenuity pathway analysis demonstrated that these miRNAs and their target genes are involved in pathways related to inflammatory response, immune-cell trafficking and cell death. Moreover, we demonstrate an inverse correlation between WNV-modulated miRNAs and their target neuroinflammatory genes in the same mice brain. We demonstrate that miR-196a, miR-202-3p, miR-449c, and miR-125a-3p target multiple genes involving cytokines, chemokines, and apoptotic genes, which belong to different signaling pathways that play critical role in WNV neuropathogenesis. Functional studies targeting specific miRNA are warranted to develop therapeutics for the management of WNV disease.
    Virology 01/2014; s 452–453:143–151. · 3.35 Impact Factor
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    ABSTRACT: Herein we demonstrate that infection of mice with West Nile virus (WNV) Eg101 provides protective immunity against lethal challenge with WNV NY99. Our data demonstrated that WNV Eg101 is largely non-virulent in adult mice when compared to WNV NY99. By day 6 after infection, WNV-specific IgM and IgG antibodies, and neutralizing antibodies were detected in the serum of all WNV Eg101 infected mice. Plaque reduction neutralization test data demonstrated that serum from WNV Eg101 infected mice neutralized WNV Eg101 and WNV NY99 strains with similar efficiency. Three weeks after infection, WNV Eg101 immunized mice were challenged subcutaneously or intracranially with lethal dose of WNV NY99 and observed for additional three weeks. All the challenged mice were protected against disease and no morbidity and mortality was observed in any mice. In conclusion, our data for the first time demonstrate that infection of mice with WNV Eg101 induced high titers of WNV specific IgM and IgG antibodies, and cross-reactive neutralizing antibodies, and the resulting immunity protected all immunized animals from both subcutaneous and intracranial challenge with WNV NY99. These observations suggest that WNV Eg101 may be a suitable strain for the development of a vaccine in humans against virulent strains of WNV.
    Viruses. 01/2014; 6(6):2328-2339.
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    ABSTRACT: The envelope (E) of dengue virus (DENV) is the major target of neutralizing antibodies and vaccine development. After biosynthesis E protein forms a heterodimer with precursor membrane (prM) protein. Recent reports of infection enhancement by anti-prM monoclonal antibodies (mAbs) suggest anti-prM responses could be potentially harmful. Previously, we studied a series of C-terminal truncation constructs expressing DENV type 4 prM/E or E proteins and found the ectodomain of E protein alone could be recognized by all 12 mAbs tested, suggesting E protein ectodomain as a potential subunit immunogen without inducing anti-prM response. The characteristics of DENV E protein ectodomain in the absence of prM protein remains largely unknown.
    PLoS ONE 01/2014; 9(6):e100641. · 3.53 Impact Factor
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    Chengxiang Wu, Vivek R Nerurkar, Yuanan Lu
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    ABSTRACT: Host cellular tRNALys3 is exclusively utilized by human immunodeficiency virus type 1 (HIV-1) as a primer for the replication step of reverse transcription (RTion). Consequently, the priming step of HIV-1 RT constitutes a potential target for anti-HIV-1 intervention. Previous studies indicated that a mutant tRNALys3 with 7-nucleotide substitutions in the 3[prime] terminus resulted in aberrant HIV-1 RTion from the trans-activation response region (TAR) and inhibition of HIV-1 replication. However, the mutant tRNALys3 also directed HIV-1 RTion from the normal primer-binding site (PBS) with potentially weakened anti-HIV-1 activity. To achieve improved targeting of HIV-1 RTion at sites not including the PBS, a series of mutant tRNALys3 with extended lengths of mutations containing up to 18 bases complementary to their targeting sites were constructed and characterized. A positive correlation between the length of mutation in the 3[prime] PBS-binding region of tRNALys3 and the specificity of HIV-1 RTion initiation from the targeting site was demonstrated, as indicated by the potency of HIV-1 inhibition and results of priming assays. Moreover, two mutant tRNALys3s that targeted the IN-encoding region and Env gene, respectively, both showed a high anti-HIV-1 activity, suggesting that not only the TAR, but also distant sites downstream of the PBS could be effectively targeted by mutant tRNALys3. To increase the expression of mutant tRNALys3, multiple-copy expression cassettes were introduced into target cells with increased anti-HIV-1 potency. These results highlight the importance of the length of complementarity between the 3[prime] terminus of the mutant tRNALys3 and its target site, and the feasibility of targeting multiple sites within the HIV-1 genome through mutant tRNALys3. Intervention of the HIV-1 genome conversion through mutant tRNALys3 may constitute an effective approach for development of novel therapeutics against HIV-1 replication and HIV-1-associated diseases.
    Retrovirology 10/2013; 10(1):112. · 5.66 Impact Factor
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    ABSTRACT: We evaluated the FDA cleared InBios Dengue virus (DENV) IgM Capture ELISA for qualitative detection of anti-DENV IgM antibodies from 79 serum samples obtained from dengue-infected patients or suspected cases. Agreement, sensitivity and specificity of InBios assay compared to 'gold standard' in-house DENV IgM Capture ELISA was 94, 92 and 94%, respectively. We conclude that InBios DENV IgM Capture ELISA can be effectively used for rapid diagnosis of acute or recent DENV infection.
    Journal of clinical microbiology 07/2013; · 4.16 Impact Factor
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    ABSTRACT: West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans. WNV-induced innate immune response including production of antiviral cytokines is critical for controlling virus infection. The adaptor protein ASC mediates a critical step in innate immune signaling by bridging the interaction between the pathogen recognition receptors and caspase-1 in inflammasome complexes but its role in WNV immunopathogenesis is not defined. Herein, we demonstrate that ASC is essential for IL-1β production and development of effective host immunity against WNV. ASC-deficient mice exhibited increased susceptibility to WNV infection and reduced survival was associated with enhanced virus replication in the peripheral tissues and CNS. Infection of cultured bone marrow derived dendritic cells showed that ASC was essential for the activation of caspase-1, a key component of inflammasome assembly. ASC(-/-) mice exhibited attenuated levels of pro-inflammatory cytokines in the serum. Intriguingly, infected ASC(-/-) mice also displayed reduced levels of IFN-α and IgM in the serum, indicating the overall protective role of ASC in restricting WNV infection. However, brains from ASC(-/-) mice displayed unrestrained inflammation including elevated levels of pro-inflammatory cytokines and chemokines such as IFNγ, CCL2 and CCL5, which correlated with more pronounced activation of the astrocytes, enhanced infiltration of peripheral immune cells in the CNS and increased neuronal cell death. Collectively, our data provides new insights into the role of ASC as an essential modulator of inflammasome-dependent and -independent immune response to effectively control WNV infection.
    Journal of Virology 01/2013; · 5.08 Impact Factor
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    ABSTRACT: West Nile virus (WNV) encephalitis is characterized by neuroinflammation, neuronal loss and blood-brain barrier (BBB) disruption. However, the mechanisms associated with the BBB disruption are unclear. Complex interactions between the tight junction proteins (TJP) and the adherens junction proteins (AJP) of the brain microvascular endothelial cells are responsible for maintaining the BBB integrity. Herein, we characterized the relationship between the BBB disruption and expression kinetics of key TJP, AJP and matrix metalloproteinases (MMPs) in the mice brain. A dramatic increase in the BBB permeability and extravasation of IgG was observed at later time points of the central nervous system (CNS) infection and did not precede virus-CNS entry. WNV-infected mice exhibited significant reduction in the protein levels of the TJP ZO-1, claudin-1, occludin and JAM-A, and AJP β-catenin and vascular endothelial cadherin, which correlated with increased levels of MMP-1, -3 and -9 and infiltrated leukocytes in the brain. Further, intracranial inoculation of WNV also demonstrated increased extravasation of IgG in the brain, suggesting the role of virus replication in the CNS in BBB disruption. These data suggest that altered expression of junction proteins is a pathological event associated with WNV infection and may explain the molecular basis of BBB disruption. We propose that WNV initially enters CNS without altering the BBB integrity and later virus replication in the brain initiates BBB disruption, allowing enhanced infiltration of immune cells and contribute to virus neuroinvasion via the 'Trojan-horse' route. These data further implicate roles of multiple MMPs in the BBB disruption and strategies to interrupt this process may influence the WNV disease outcome.
    Journal of General Virology 03/2012; 93(Pt 6):1193-203. · 3.13 Impact Factor
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    ABSTRACT: Clinicoepidemiological data suggest that type 2 diabetes is associated with increased risk of West Nile virus encephalitis (WNVE). However, no experimental studies have elucidated the role of diabetes in WNV neuropathogenesis. Herein, we employed the db/db mouse model to understand WNV immunopathogenesis in diabetics. Nine-week old C57BL/6 WT and db/db mice were inoculated with WNV and mortality, virus burden in the periphery and brain, and antiviral defense responses were analyzed. db/db mice were highly susceptible to WNV disease, exhibited increased tissue tropism and mortality than the wild-type mice, and were unable to clear the infection. Increased and sustained WNV replication was observed in the serum, peripheral tissues and brain of db/db mice, and heightened virus replication in the periphery was correlated with enhanced neuroinvasion and replication of WNV in the brain. WNV infection in db/db mice was associated with enhanced inflammatory response and compromised antiviral immune response characterized by delayed induction of IFN-α, and significantly reduced concentrations of WNV-specific IgM and IgG antibodies. The compromised immune response in db/db mice correlated with increased viremia. These data suggest that delayed immune response coupled with failure to clear the virus leads to increased mortality in db/db mice. In conclusion, this study provides unique mechanistic insight into the immunopathogenesis of WNVE observed in diabetics and can be used to develop therapeutics for the management of WNVE among diabetic patients.
    PLoS ONE 01/2012; 7(8):e44682. · 3.53 Impact Factor
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    ABSTRACT: The envelope (E) protein of dengue virus (DENV) is the major immunogen for dengue vaccine development. At the C-terminus are two α-helices (EH1 and EH2) and two transmembrane domains (ET1 and ET2). After synthesis, E protein forms a heterodimer with the precursor membrane (prM) protein, which has been shown as a chaperone for E protein and could prevent premature fusion of E protein during maturation. Recent reports of enhancement of DENV infectivity by anti-prM monoclonal antibodies (mAbs) suggest the presence of prM protein in dengue vaccine is potentially harmful. A better understanding of prM-E interaction and its effect on recognition of E and prM proteins by different antibodies would provide important information for future design of safe and effective subunit dengue vaccines. In this study, we examined a series of C-terminal truncation constructs of DENV4 prME, E and prM. In the absence of E protein, prM protein expressed poorly. In the presence of E protein, the expression of prM protein increased in a dose-dependent manner. Radioimmunoprecipitation, sucrose gradient sedimentation and pulse-chase experiments revealed ET1 and EH2 were involved in prM-E interaction and EH2 in maintaining the stability of prM protein. Dot blot assay revealed E protein affected the recognition of prM protein by an anti-prM mAb; truncation of EH2 or EH1 affected the recognition of E protein by several anti-E mAbs, which was further verified by capture ELISA. The E protein ectodomain alone can be recognized well by all anti-E mAbs tested. A C-terminal domain (EH2) of DENV E protein can affect the expression and stability of its chaperone prM protein. These findings not only add to our understanding of the interaction between prM and E proteins, but also suggest the ectodomain of E protein alone could be a potential subunit immunogen without inducing anti-prM response.
    PLoS ONE 01/2012; 7(12):e52600. · 3.53 Impact Factor
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    ABSTRACT: Immunopathogenesis studies employing West Nile virus (WNV) mice model are important for the development of antivirals and vaccines against WNV. Since antibodies produced in mice early during WNV infection are essential for clearing virus from the periphery, it is important to detect early and persistent anti-WNV antibodies. ELISA and plaque reduction neutralization tests are traditionally used for detection of anti-WNV antibodies and WNV-neutralizing antibodies, respectively. Although these assays are sensitive and specific, they are expensive and time consuming. Microsphere immunoassays (MIA) are sensitive, specific, allow for high throughput, are cost effective, require less time to perform than other methods, and require low serum volumes. Several assay parameters such as serum heat-inactivation (HI) and dilution can alter WNV MIA sensitivity. We examined the effect of these parameters on WNV E-protein MIA (WNV E-MIA) for the enhanced detection of anti-WNV IgM and IgG antibodies. WNV E-MIA was conducted using serial dilutions of HI and non-HI (NHI) serum collected at various time points from mice inoculated with WNV. HI significantly enhanced detection of IgM and IgG antibodies as compared to NHI serum. WNV IgM and IgG antibodies in HI sera were detected earlier at day 3 and IgM antibodies persisted up to day 24 after infection. HI serum at 1∶20 dilution was found to be optimal for detection of both IgM and IgG antibodies as compared to higher-serum dilutions. Further, addition of exogenous complement to the HI serum decreased the WNV E-MIA sensitivity. These results suggest that serum-HI and optimal dilution enhance WNV E-MIA sensitivity by eliminating the complement interference, thereby detecting low-titer anti-WNV antibodies during early and late phases of infection. This improved MIA can also be readily employed for detection of low-titer antibodies for detection of other infectious agents and host proteins.
    PLoS ONE 01/2012; 7(9):e45851. · 3.53 Impact Factor
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    James F Kelley, Pakieli H Kaufusi, Vivek R Nerurkar
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    ABSTRACT: We previously demonstrated that dengue virus (DENV) nonstructural 4B protein (NS4B) induced dengue hemorrhagic fever (DHF)-associated immunomediators in THP-1 monocytes. Moreover, cleavage of NS4AB polyprotein by the NS2B3 protease, significantly increased immunomediator production to levels found after DENV infection. In this report using primary human microvascular endothelial cells (HMVEC) transwell permeability model and HMVEC monolayer, we demonstrate that the immunomediators secreted in the supernatants of DENV-infected monocytes increase HMVEC permeability and expression of ICAM-1, VCAM-1 and E-selectin. Moreover, maturation of NS4B via cleavage of 2KNS4B is sufficient to induce immunomediators that cause HMVEC phenotypic changes, which appear to be synergistically induced by TNFα and IL-8. These data suggest that therapies targeting the maturation steps of NS4B, particularly 2KNS4B processing, may reduce overall DHF-associated immunomediator levels, thereby reducing DHF-associated morbidity and mortality. Alternatively, TNFα inhibitors may be a valid intervention strategy during the later stages of infection to prevent DHF progression.
    Virology 11/2011; 422(2):326-37. · 3.35 Impact Factor
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    ABSTRACT: Renewed interest in alternative medicine among diabetic individuals prompted us to investigate anti-diabetic effects of Morinda citrifolia (noni) in high-fat diet (HFD)-fed mice. Type 2 diabetes is associated with increased glucose production due to the inability of insulin to suppress hepatic gluconeogenesis and promote glycolysis. Insulin inhibits gluconeogenesis by modulating transcription factors such as forkhead box O (FoxO1). Based on microarray analysis data, we tested the hypothesis that fermented noni fruit juice (fNJ) improves glucose metabolism via FoxO1 phosphorylation. C57BL/6 male mice were fed a HFD and fNJ for 12 weeks. Body weights and food intake were monitored daily. FoxO1 expression was analysed by real-time PCR and Western blotting. Specificity of fNJ-associated FoxO1 regulation of gluconeogenesis was confirmed by small interfering RNA (siRNA) studies using human hepatoma cells, HepG2. Supplementation with fNJ inhibited weight gain and improved glucose and insulin tolerance and fasting glucose in HFD-fed mice. Hypoglycaemic properties of fNJ were associated with the inhibition of hepatic FoxO1 mRNA expression, with a concomitant increase in FoxO1 phosphorylation and nuclear expulsion of the proteins. Gluconeogenic genes, phosphoenolpyruvate C kinase (PEPCK) and glucose-6-phosphatase (G6P), were significantly inhibited in mice fed a HFD+fNJ. HepG2 cells demonstrated more than 80 % inhibition of PEPCK and G6P mRNA expression in cells treated with FoxO1 siRNA and fNJ. These data suggest that fNJ improves glucose metabolism via FoxO1 regulation in HFD-fed mice.
    The British journal of nutrition 10/2011; 108(2):218-28. · 3.45 Impact Factor
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    ABSTRACT: High levels of viremia and chemokines and cytokines underlie the progression of severe dengue disease. Dengue virus (DENV) preferentially infects peripheral blood monocytes, which secrete elevated levels of immunomediators in patients with severe disease. Further, DENV nonstructural proteins (NS) are capable of modifying intracellular signaling, including interferon inhibition. We demonstrate that peak secretions of immunomediators such as IL-6, IL-8, IP-10, TNFα or IFNγ in DENV-infected monocytes correlate with maximum virus production and NS4B and NS5 are primarily responsible for the induction of immunomediators. Furthermore, we demonstrate that sequential NS4AB processing initiated by the viral protease NS2B3(pro) and via the intermediate 2KNS4B significantly enhances immunomediator induction. While the 2K-signal peptide is not essential for immunomediator induction, it plays a synergistic role with NS4B. These data suggest that NS4B maturation is important during innate immune signaling in DENV-infected monocytes. Given similar NS4B topologies and polyprotein processing across flaviviruses, NS4B may be an attractive target for developing Flavivirus-wide therapeutic interventions.
    Virology 08/2011; 418(1):27-39. · 3.35 Impact Factor
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    ABSTRACT: Although beneficial to health, dietary phytonutrients are bitter, acid and/or astringent in taste and therefore reduce consumer choice and acceptance during food selection. Momordica charantia, commonly known as bitter melon has been traditionally used in Ayurvedic and Chinese medicine to treat diabetes and its complications. The aim of this study was to develop bitter melon-containing recipes and test their palatability and acceptability in healthy individuals for future clinical studies. A cross-sectional sensory evaluation of bitter melon-containing ethnic recipes was conducted among 50 healthy individuals. The primary endpoints assessed in this analysis were current consumption information and future intentions to consume bitter melon, before and after provision of attribute- and health-specific information. A convenience sample of 50, self-reported non-diabetic adults were recruited from the University of Hawaii. Sensory evaluations were compared using two-way ANOVA, while differences in stage of change (SOC) before and after receiving health information were analyzed by Chi-square (χ2) analyses. Our studies indicate that tomato-based recipes were acceptable to most of the participants and readily acceptable, as compared with recipes containing spices such as curry powder. Health information did not have a significant effect on willingness to consume bitter melon, but positively affected the classification of SOC. This study suggests that incorporating bitter foods in commonly consumed food dishes can mask bitter taste of bitter melon. Furthermore, providing positive health information can elicit a change in the intent to consume bitter melon-containing dishes despite mixed palatability results.
    Nutrition Journal 07/2011; 10:78. · 2.65 Impact Factor
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    ABSTRACT: The rising epidemic of obesity is associated with cognitive decline and is considered as one of the major risk factors for neurodegenerative diseases. Neuroinflammation is a critical component in the progression of several neurological and neurodegenerative diseases. Increased metabolic flux to the brain during overnutrition and obesity can orchestrate stress response, blood-brain barrier (BBB) disruption, recruitment of inflammatory immune cells from peripheral blood and microglial cells activation leading to neuroinflammation. The lack of an effective treatment for obesity-associated brain dysfunction may have far-reaching public health ramifications, urgently necessitating the identification of appropriate preventive and therapeutic strategies. The objective of our study was to investigate the neuroprotective effects of Momordica charantia (bitter melon) on high-fat diet (HFD)-associated BBB disruption, stress and neuroinflammatory cytokines. C57BL/6 female mice were fed HFD with and without bitter melon (BM) for 16 weeks. BBB disruption was analyzed using Evans blue dye. Phosphate-buffered saline (PBS) perfused brains were analyzed for neuroinflammatory markers such as interleukin-22 (IL-22), IL-17R, IL-16, NF-κB1, and glial cells activation markers such as Iba1, CD11b, GFAP and S100β. Additionally, antioxidant enzymes, ER-stress proteins, and stress-resistant transcription factors, sirtuin 1 (Sirt1) and forkhead box class O transcription factor (FoxO) were analyzed using microarray, quantitative real-time RT-PCR, western immunoblotting and enzymatic assays. Systemic inflammation was analyzed using cytokine antibody array. BM ameliorated HFD-associated changes in BBB permeability as evident by reduced leakage of Evans blue dye. HFD-induced glial cells activation and expression of neuroinflammatory markers such as NF-κB1, IL-16, IL-22 as well as IL-17R were normalized in the brains of mice supplemented with BM. Similarly, HFD-induced brain oxidative stress was significantly reduced by BM supplementation with a concomitant reduction in FoxO, normalization of Sirt1 protein expression and up-regulation of Sirt3 mRNA expression. Furthermore, plasma antioxidant enzymes and pro-inflammatory cytokines were also normalized in mice fed HFD with BM as compared to HFD-fed mice. Functional foods such as BM offer a unique therapeutic strategy to improve obesity-associated peripheral inflammation and neuroinflammation.
    Journal of Neuroinflammation 06/2011; 8:64. · 4.35 Impact Factor

Publication Stats

1k Citations
373.12 Total Impact Points

Institutions

  • 1997–2014
    • University of Hawaiʻi at Mānoa
      • • Department of Tropical Medicine, Medical Microbiology and Pharmacology
      • • Department of Molecular Biosciences and Bioengineering
      • • Pacific Biosciences Research Center
      Honolulu, Hawaii, United States
  • 2001–2008
    • University of Hawai'i System
      Honolulu, Hawaii, United States
  • 2007
    • Aga Khan University Hospital, Karachi
      Kurrachee, Sindh, Pakistan
  • 2006
    • University of Hawaiʻi at Hilo
      Hilo, Hawaii, United States
  • 1996–2004
    • Honolulu University
      Honolulu, Hawaii, United States
  • 2000–2003
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 1991–1997
    • National Institutes of Health
      • Unit on Behavioral Neurogenetics
      Maryland, United States
  • 1994
    • The University of Western Ontario
      London, Ontario, Canada
  • 1992
    • Centers for Disease Control and Prevention
      • National Center for Emerging and Zoonotic Infectious Diseases
      Druid Hills, GA, United States