The Antiviral Effect of High-Molecular Weight Poly-Gamma-Glutamate against Newcastle Disease Virus on Murine Macrophage Cells

This study demonstrates the capacity of HM-γ-PGA treatment to significantly protect murine macrophage cells (RAW 264.7 cells) against NDV infection. Such protection can be explained by the induction of antiviral state of HM-γ-PGA in RAW 264.7 cells via TLR4-mediated IRF-3, IRF-7, IFN-β, and IFN-related gene induction as shown in time-dependent changes in mRNA expression confirmed by polymerase chain reaction (PCR). Moreover, the present research also showed that HM-γ-PGA can induce proinflammatory cytokine secretion in RAW 264.7 as measured by enzyme-linked immunosorbent assay (ELISA). Therefore, our findings suggest that HM-γ-PGA can be a potential antiviral substance that can inhibit NDV infection through its stimulation of antiviral state on RAW 264.7 cells. These results have been consistent with the previous studies showing that HM-γ-PGA can protect RAW 264.7 cells and mice against influenza infection. However, it should be noted that although murine macrophage cells are susceptible to NDV, they are not the natural host cells of the virus; thus further in vivo and in vitro studies involving chicken and chicken immune cells are needed to fully assess the efficacy and applicability of HM-γ-PGA in the poultry industry

The Impact of International Migration on Unemployment Rates in Urban America: Testing Different Theoretical Approaches

This study examines the influence of international migration on unemployment rates in urban America. For this purpose, this study first applies competition and discrimination and assimilation views in examining whether the size and composition of immigrant populations in American metropolitan areas affect urban unemployment rates. Based on local human capital and labor market views, this study also explores whether urban unemployment rates are affected by local human capital (education) and urban labor markets (employment distributions by class of workers), both of which vary with the size and compositions of local immigrant populations. Using a sample of the 301 Primary Metropolitan Statistical Areas /Metropolitan Statistical Areas (PMSAs/MSAs) in 1990 and 2000, this study employs regression models to test four hypotheses. First, the result supports to some degree competition and discrimination and assimilation views. The empirical findings show that more concentration of international migrants in urban areas, including recent immigrant cohorts, tends to increase urban unemployment rates. Second, the models of local human capital also support that growing college graduates play a role in reducing urban unemployment rates after controlling for the volume of immigrant population. However, there are conflicting impacts of local labor market (employment conditions) on urban unemployment rates

Epidemiology of Complex Regional Pain Syndrome: A Retrospective Chart Review of 150 Korean Patients

Complex regional pain syndrome (CRPS) is a chronically painful and disabling disorder. However, no data are available even on the epidemiology of CRPS in Korea. This study was undertaken to retrospectively assess the epidemiologic characteristics of CRPS in 150 consecutive patients at a tertiary chronic pain center from March 2002 to February 2006. Information was obtained regarding patients' demographics, nature of injury, and treatment modalities. Seventy-one percent of patients had CRPS type I. The mean 11-point verbal numerical rating scale score at initial examinations and at the time of study were 8.0 and 5.7, respectively. Thirty-two percent of patients showed no change or increase in pain intensity during follow-up at our pain center. The mean duration of CRPS symptoms prior to our pain center evaluation and prior to the time of study were 27 months and 50 months, respectively. These patients had seen on average 5 different physicians before being referred to our center. This study shows that the majority of CRPS patients were referred to our center after more than 2 yr of symptoms. The clinical implication of such delayed transfer and strategies to avoid this problem are discussed

Identification of Gene Expression Signature Modulated by Nicotinamide in a Mouse Bladder Cancer Model

BACKGROUND: Urinary bladder cancer is often a result of exposure to chemical carcinogens such as cigarette smoking. Because of histological similarity, chemically-induced rodent cancer model was largely used for human bladder cancer studies. Previous investigations have suggested that nicotinamide, water-soluble vitamin B3, may play a key role in cancer prevention through its activities in cellular repair. However, to date, evidence towards identifying the genetic alterations of nicotinamide in cancer prevention has not been provided. Here, we search for the molecular signatures of cancer prevention by nicotinamide using a N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced urinary bladder cancer model in mice. METHODOLOGY/PRINCIPAL FINDINGS: Via microarray gene expression profiling of 20 mice and 233 human bladder samples, we performed various statistical analyses and immunohistochemical staining for validation. The expression patterns of 893 genes associated with nicotinamide activity in cancer prevention were identified by microarray data analysis. Gene network analyses of these 893 genes revealed that the Myc and its associated genes may be the most important regulator of bladder cancer prevention, and the gene expression signature correlated well with protein expression data. Comparison of gene expression between human and mouse revealed that BBN-induced mouse bladder cancers exhibited gene expression profiles that were more similar to those of invasive human bladder cancers than to those of non-invasive human bladder cancers. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that nicotinamide plays an important role as a chemo-preventive and therapeutic agent in bladder cancer through the regulation of the Myc oncogenic signature. Nicotinamide may represent a promising therapeutic modality in patients with muscle-invasive bladder cancer

The Neuroinflammasome in Alzheimer’s Disease and Cerebral Stroke

Aim/Background: This review investigated a patient with Alzheimer’s disease (AD) treated with 4,4’-diaminodiphenyl sulfone (DDS) as a neuroinflammasome competitor. Methods: We monitored AD’s progression through numeric clinical staging (NCS) with a new biomarker. NCS was determined by the presence of AD symptoms and neuropsychiatric (NP) symptoms caused by anti-AD (AAD) drugs (D) as a biomarker. We also monitored the function of DDS for stroke in a no-intake emergency state. Results: By introducing (D), AD’s progression was monitored through NCS staging. AAD side effects and neuropsychiatric symptoms were identified. DDS was stopped in patients with stroke with NCS 6 caused by AAD, and it rapidly proceeded to cerebral infarct. Conclusions: AAD can occasionally exacerbate AD and stroke. DDS can alleviate mild cognitive impairment (MCI), early AD and stroke. We clinically confirmed the role of DDS as a neuroinflammasome competitor after stroke. DDS preserved neuronal survival within 24–55 h in the Seoul Study cohort

Dapsone is an anticatalysis for Alzheimer's disease exacerbation

Brain inflammation generally accelerates neurodegeneration. Alzheimer's disease (AD) triggers an innate immune response by activating a cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. Our study investigated patients with leprosy and AD. They were treated with dapsone (4,4′-diaminodiphenyl sulfone, DDS) as a neuroinflammasome competitor and cGAS/STING pathway inhibitor. Four groups were defined: Treatment (T) 1: DDS prescribed AD diagnosed, T 2: DDS prescribed AD undiagnosed, T 3 DDS unprescribed AD diagnosed, and T 4: DDS unprescribed AD undiagnosed. Dapsone effects on AD can be clearly distinguished according to dapsone presence or absence. T1:T3 proved that the incidence of AD was significantly reduced by dapsone. T2:T3 proved that the prevalence of AD was significantly high without dapsone. T1:T4 proved that the prevalence decreased when taking dapsone. Our study demonstrates that dapsone can prevent AD exacerbation and may represent a preventive therapeutic option for exacerbated AD

Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis-induced pro-inflammatory response in murine microglia

<p>Abstract</p> <p>Background</p> <p>Activated microglia elicits a robust amount of pro-inflammatory cytokines, which are implicated in the pathogenesis of tuberculosis in the central nervous system (CNS). However, little is known about the intracellular signaling mechanisms governing these inflammatory responses in microglia in response to <it>Mycobacterium tuberculosis </it>(Mtb).</p> <p>Methods</p> <p>Murine microglial BV-2 cells and primary mixed glial cells were stimulated with sonicated Mtb (s-Mtb). Intracellular ROS levels were measured by staining with oxidative fluorescent dyes [2',7'-Dichlorodihydrofluorescein diacetate (H₂DCFDA) and dihydroethidium (DHE)]. NADPH oxidase activities were measured by lucigenin chemiluminescence assay. S-Mtb-induced MAPK activation and pro-inflammatory cytokine release in microglial cells were measured using by Western blot analysis and enzyme-linked immunosorbent assay, respectively.</p> <p>Results</p> <p>We demonstrate that s-Mtb promotes the up-regulation of reactive oxygen species (ROS) and the rapid activation of mitogen-activated protein kinases (MAPKs), including p38 and extracellular signal-regulated kinase (ERK) 1/2, as well as the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-12p40 in murine microglial BV-2 cells and primary mixed glial cells. Both NADPH oxidase and mitochondrial electron transfer chain subunit I play an indispensable role in s-Mtb-induced MAPK activation and pro-inflammatory cytokine production in BV-2 cells and mixed glial cells. Furthermore, the activation of cytosolic NADPH oxidase p47phox and MAPKs (p38 and ERK1/2) is mutually dependent on s-Mtb-induced inflammatory signaling in murine microglia. Neither TLR2 nor dectin-1 was involved in s-Mtb-induced inflammatory responses in murine microglia.</p> <p>Conclusion</p> <p>These data collectively demonstrate that s-Mtb actively induces the pro-inflammatory response in microglia through NADPH oxidase-dependent ROS generation, although the specific pattern-recognition receptors involved in these responses remain to be identified.</p

Benserazide, the first allosteric inhibitor of Coxsackievirus B3 3C protease

AbstractCoxsackievirus B3 is the main cause of human viral myocarditis and cardiomyopathy. Virally encoded Coxsackievirus 3C protease (3Cpro) plays an essential role in viral proliferation. Here, benserazide was discovered as a novel inhibitor from a drug library screen targeting Coxsackievirus 3Cpro using a FRET-based enzyme assay. Benserazide, whose chemical structure has no electrophilic functional groups, was characterized as a non-competitive inhibitor by enzyme kinetic studies. A molecular docking study with benserazide and its analogs indicated that a novel putative allosteric binding site was involved. Specifically, a 2,3,4-trihydroxybenzyl moiety was determined to be a key pharmacophore for the enzyme’s inhibitory activity. We suggest that the putative allosteric binding site may be a novel target for future therapeutic strategies