Dengue virus (DENV) infection and replication induces oxidative stress, which further contributes to the progression and pathogenesis of the DENV infection. Modulation of host antioxidant molecules may be a useful strategy for interfering with DENV replication. In this study, we showed that induction or exogenous overexpression of heme oxygenase-1 (HO-1), an antioxidant enzyme, effectively inhibited DENV replication in DENV-infected Huh-7 cells. This antiviral effect of HO-1 was attenuated by its inhibitor tin protoporphyrin (SnPP), suggesting that HO-1 was an important cellular factor against DENV replication. Biliverdin but not carbon monoxide and ferrous ions, which are products of the HO-1 on heme, mediated the HO-1-induced anti-DENV effect by non-competitively inhibiting DENV protease, with an inhibition constant (Ki) of 8.55 ± 0.38 μM. Moreover, HO-1 induction or its exogenous overexpression, rescued DENV-suppressed antiviral interferon response. Moreover, we showed that HO-1 induction by cobalt protoporphyrin (CoPP) and andrographolide, a natural product, as evidenced by a significant delay in the onset of disease and mortality, and virus load in the infected mice’s brains. These findings clearly revealed that a drug or therapy that induced the HO-1 signal pathway was a promising strategy for treating DENV infection.

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BACKGROUND AND PURPOSEThis study aimed to evaluate the anti-hepatitis C virus (HCV) activity of andrographolide, a diterpenoid lactone extracted from Andrographis paniculata, and to identify the signalling pathway involved in its antiviral action. EXPERIMENTAL APPROACHUsing HCV replicon and HCVcc infectious systems, we identified anti-HCV activity of andrographolide by measuring protein and RNA levels. A reporter activity assay was used to determine transcriptional regulation of anti-HCV agents. A specific inhibitor and short hairpin RNAs were used to investigate the mechanism responsible for the effect of andrographolide on HCV replication. KEY RESULTSIn HCV replicon and HCVcc infectious systems, andrographolide time-and dose-dependently suppressed HCV replication. When combined with IFN-α, an inhibitor targeting HCV NS3/4A protease (telaprevir), or NS5B polymerase (PSI-7977), andrographolide exhibited a significant synergistic effect. Andrographolide up-regulated the expression of haeme oxygenase-1 (HO-1), leading to increased amounts of its metabolite biliverdin, which was found to suppress HCV replication by promoting the antiviral IFN responses and inhibiting NS3/4A protease activity. Significantly, these antiviral effects were attenuated by an HO-1-specific inhibitor or HO-1 gene knockdown, indicating that HO-1 contributed to the anti-HCV activity of andrographolide. Andrographolide activated p38 MAPK phosphorylation, which stimulated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated HO-1 expression, and this was found to be associated with its anti-HCV activity. CONCLUSIONS AND IMPLICATIONSOur results demonstrate that andrographolide has the potential to control HCV replication and suggest that targeting the Nrf2-HO-1 signalling pathway might be a promising strategy for drug development.

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The purpose of this study was to determine if a distinctive characteristic exists in the pattern of movement (scapular elevation and upward rotation to reduce impingement) and associated muscular activities during arm elevation in subjects with shoulder impingement (SI) that is associated with the severity of the disease. Fourteen subjects (7 amateur athletes and 7 student athletes) with SI and 7 controls performed arm elevation in the scapular plane. Scapular kinematics (upward rotation, elevation, tipping, and scapulohumeral rhythm) and muscular activity [upper trapezius (UT), lower trapezius (LT), serratus anterior (SA), and deltoid] were measured by an electromagnetic motion tracking system and surface electromyography, respectively. Subjects with SI had greater elevation of the scapula (11.9 mm, p < 0.005) and less peak scapular posterior tipping (10.68, p < 0.02) than controls. In more severe subjects (amateur athletes), the elevation and posterior tipping of the scapula were correlated with an increase in the UT (R ¼ À0.818, p ¼ 0.025) and a decrease in SA (R ¼ 0.772, p ¼ 0.040) activity, respectively. Our results identified a characteristic compensatory scapular elevation to reduce impingement during arm elevation in subjects with SI. Assessing scapular elevation during arm elevation may be a useful functional marker for evaluating impingement status and associated muscle function. Additionally, SA and LT muscle strengthening may improve SI. ß

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As with other elements of the peripheral auditory system, spiral ganglion neurons display specializations that vary as a function of location along the tonotopic axis. Previous work has shown that voltage-gated K+ channels and synaptic proteins show graded changes in their density that confers rapid responsiveness to neurons in the high frequency, basal region of the cochlea and slower, more maintained responsiveness to neurons in the low frequency, apical region of the cochlea. In order to understand how voltage-gated calcium channels (VGCCs) may contribute to these diverse phenotypes, we identified the VGCC α-subunits expressed in the ganglion, investigated aspects of Ca2+-dependent neuronal firing patterns, and mapped the intracellular and intercellular distributions of seven VGCC α-subunits in the spiral ganglion in vitro. Initial experiments with qRT-PCR showed that eight of the ten known VGCC α-subunits were expressed in the ganglion and electrophysiological analysis revealed firing patterns that were consistent with the presence of both LVA and HVA Ca2+ channels. Moreover, we were able to study seven of the α-subunits with immunocytochemistry, and we found that all were present in spiral ganglion neurons, and that three of them were neuron-specific (CaV1.3, CaV2.2, and CaV3.3). Further characterization of neuron-specific α-subunits showed that CaV1.3 and CaV3.3 were tonotopically-distributed, whereas CaV2.2 was uniformly distributed in apical and basal neurons. Multiple VGCC α-subunits were also immunolocalized to Schwann cells, having distinct intracellular localizations, and, significantly, appearing to distinguish putative compact0 (CaV2.3, CaV3.1) from loose (CaV1.2) myelin. Electrophysiological evaluation of spiral ganglion neurons in the presence of TEA revealed Ca2+ plateau potentials with slopes that varied proportionately with the cochlear region from which neurons were isolated. Because afterhyperpolarizations were minimal or absent under these conditions, we hypothesize that differential density and/or kinetics of one or more of the VGCC α-subunits could account for observed tonotopic differences. These experiments have set the stage for defining the clear multiplicity of functional control in neurons and Schwann cells of the spiral ganglion.

The association between type 1 diabetes mellitus (T1DM) and asthma remains controversial and has led to new interest in these 2 disorders. The purpose of this study was to examine the associations among young people with T1DM and asthma and offer a clinical demonstration of the balance between Th1 and Th2 responses.We conducted a retrospective cohort study by using data from the National Health Insurance (NHI) system of Taiwan. The cohort consisted of 3545 T1DM cases and 14,180 controls established during the 1998 to 2011 period. Of the 3545 T1DM patients, 55.1% were girls and 26.5% were in the age group <8 years.The overall incidence of asthma was 47% higher in the T1DM cohort than in the control cohort (6.49 vs 4.42 per 1000 person-y), with an adjusted hazard ratio (HR) of 1.34 (95% confidence interval [CI] = 1.11–1.62). Moreover, T1DM patients who visited the emergency room (ER) more than twice for diabetes had a higher adjusted HR of 17.4 (95% CI = 12.9–23.6) of developing asthma. The adjusted HR of asthma was 38.6 (95% CI = 28.5–52.2) in T1DM patients who had been hospitalized more than twice for diabetes.We observed a significantly higher incidence of asthma in young patients with T1DM than in the general population. Among young people of T1DM with more ER visits or frequent hospitalization because of diabetes mellitus were associated with risk of asthma, may indicate that poor glycemic control significantly contributes to asthma risk.