A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation.

Respiratory syncytial virus (RSV) and influenza A virus are leading causes of acute lower respiratory infectious disease. Respiratory diseases caused by RSV and influenza A virus result in serious economic burden and life-threatening disease for immunocompromised people. With the revelation that p38 mitogen-activated protein kinase (MAPK) activity in host cells is crucial for infection and replication of RSV and influenza A virus, inhibition of p38 MAPK activity has been suggested as a potential antiviral therapeutic strategy. However, the low selectivity and high toxicity of the p38 MAPK inhibitors necessitate the development of better inhibitors. Herein, we report the synthesis of a novel p38 MAPK inhibitor, NJK14047, with high kinase selectivity. In this work, it was demonstrated that NJK14047 inhibits RSV- and influenza A-mediated p38 MAPK activation in epithelial cells. Subsequently, NJK14047 treatment resulted in decreased viral replication and viral mRNA synthesis. In addition, secretion of interleukin-6 from infected cells was greatly diminished by NJK14047, suggesting that it can ameliorate immunopathological responses to RSV and influenza A. Collectively, the results suggest that NJK14047 has therapeutic potential to treat respiratory viral infection through the suppression of p38 MAPK activation, which is suggested to be an essential step for respiratory virus infection.

Negative regulation of RIG-I-mediated antiviral signaling by TRK-fused gene (TFG) protein.

RIG-I (retinoic acid inducible gene I)-mediated antiviral signaling serves as the first line of defense against viral infection. Upon detection of viral RNA, RIG-I undergoes TRIM25 (tripartite motif protein 25)-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that TRK-fused gene (TFG) protein, previously identified as a TRIM25-interacting protein, binds TRIM25 upon virus infection and negatively regulates RIG-I-mediated type-I IFN signaling. RIG-I-mediated IFN production and nuclear factor (NF)-κB signaling pathways were upregulated by the suppression of TFG expression. Furthermore, vesicular stomatitis virus (VSV) replication was significantly inhibited by small inhibitory hairpin RNA (shRNA)-mediated knockdown of TFG, supporting the suppressive role of TFG in RIG-I-mediated antiviral signaling. Interestingly, suppression of TFG expression increased not only RIG-I-mediated signaling but also MAVS (mitochondrial antiviral signaling protein)-induced signaling, suggesting that TFG plays a pivotal role in negative regulation of RNA-sensing, RIG-I-like receptor (RLR) family signaling pathways.

Antiviral activity of carnosic acid against respiratory syncytial virus.

BACKGROUND: Human respiratory syncytial virus (hRSV) is a leading cause of severe lower respiratory infection and a major public health threat worldwide. To date, no vaccine or effective therapeutic agent has been developed. In a screen for potential therapeutic agents against hRSV, we discovered that an extract of Rosmarinus officinalis exerted a strong inhibitory effect against hRSV infection. Subsequent studies identified carnosic acid as a bioactive constituent responsible for anti-hRSV activity. Carnosic acid has been shown to exhibit potent antioxidant and anti-cancer activities. Anti-RSV activity of carnosic acid was further investigated in this study. METHODS: Effects of extracts from various plants and subfractions from R. officinalis on hRSV replication were determined by microneutralization assay and plaque assay. Several constituents were isolated from ethyl acetate fraction of R. officinalis and their anti-RSV activities were assessed by plaque assay as well as reverse-transcription quantitative PCR to determine the synthesis of viral RNAs. RESULTS: Among the tested bioactive constituents of R. officinalis, carnosic acid displayed the most potent anti-hRSV activity and was effective against both A- and B-type viruses. Carnosic acid efficiently suppressed the replication of hRSV in a concentration-dependent manner. Carnosic acid effectively suppressed viral gene expression without inducing type-I interferon production or affecting cell viability, suggesting that it may directly affect viral factors. A time course analysis showed that addition of carnosic acid 8 hours after infection still effectively blocked the expression of hRSV genes, further suggesting that carnosic acid directly inhibited the replication of hRSV. CONCLUSIONS: The current study demonstrates that carnosic acid, a natural compound that has already been shown to be safe for human consumption, has anti-viral activity against hRSV, efficiently blocking the replication of this virus. Carnosic acid inhibited both A- and B- type hRSV, while it did not affect the replication of influenza A virus, suggesting that its antiviral activity is hRSV-specific. Collectively, this study suggests the need for further evaluation of carnosic acid as a potential treatment for hRSV.

12-Week Exercise Training of Knee Joint and Squat Movement Improves Gait Ability in Older Women.

This study analyzed the effects of an exercise training program consisting of a knee joint complex exercise device (leg-link system) with digitally controlled active motion function and squat movement on physical fitness and gait ability of elderly women aged 70 or above. Fifty four (54) elderly women aged 70 or above were divided into three groups as control group (n = 18), aerobic training group (n = 18), and combined training group with resistance and aerobic exercise (n = 18). Health-related physical fitness, gait ability-related physical fitness, and the temporal and spatial parameters of gait ability were compared. The health-related physical fitness after the 12-week training was not significantly altered in control group, whereas combined training group showed significant increase in all factors (p < 0.05) and aerobic training group showed significant increase (p < 0.05) only in the physical efficiency index. The gait ability-related physical fitness and all items of the temporal and spatial parameters of gait were found to have significantly increased (p < 0.05) in combined training group after the 12-week exercise training; however, in aerobic training group, only the factors related to muscular endurance and balance showed significant increase (p < 0.05). This study suggested that the exercise training consisting of knee joint complex exercise with digitally controlled active motion function and squat exercise for strengthening lower extremities and core muscles had positive effects on enhancing the ambulatory competence in elderly women.

High-Performance Ultraviolet Photodetector Based on a Zinc Oxide Nanoparticle@Single-Walled Carbon Nanotube Heterojunction Hybrid Film.

A hybrid film consisting of zinc oxide nanoparticles (ZnO NPs) and carbon nanotubes (CNTs) is formed on a glass substrate using a simple and swift spin coating process for the use in ultraviolet photodetectors (UV PDs). The incorporation of various types of CNTs into ZnO NPs (ZnO@CNT) enhances the performance of UV PDs with respect to sensitivity, photoresponse, and long-term operation stability when compared with pristine ZnO NP films. In particular, the introduction of single-walled CNTs (SWNTs) exhibits a superior performance when compared with the multiwalled CNTs (MWNTs) because SWNTs can not only facilitate the stability of free electrons generated by the O2 desorption on ZnO under UV irradiation owing to the built-in potential between ZnO and SWNT heterojunctions, but also allow facile and efficient transport pathways for electrons through SWNTs with high aspect ratio and low defect density. Furthermore, among the various SWNTs (arc-discharged (A-SWNT), Hipco (H-SWNT), and CoMoCat (C-SWNT) SWNTs), we demonstrate the ZnO@A-SWNT hybrid film exhibits the best performance because of higher conductivity and aspect ratio in A-SWNTs when compared with those of other types of SWNTs. At the optimized conditions for the ZnO@A-SWNT film (ratio of A-SWNTs and ZnO NPs and electrode distance), ZnO@A-SWNT displays a sensitivity of 4.9 × 103 % with an on/off current ratio of ~104 at the bias of 2 V under the UV wavelength of 365 nm (0.47 mW/cm2). In addition, the stability in long-term operation and photoresponse time are significantly improved by the introduction of A-SWNTs into the ZnO NP film when compared with the bare ZnO NPs film.

Inhibition of HIV-1 reactivation by a telomerase-derived peptide in a HSP90-dependent manner.

A peptide vaccine designed to induce T-cell immunity to telomerase, GV1001, has been shown to modulate cellular signaling pathways and confer a direct anti-cancer effect through the interaction with heat shock protein (HSP) 90 and 70. Here, we have found that GV1001 can modulate transactivation protein-mediated human immunodeficiency virus (HIV)-1 transactivation in an HSP90-dependent manner. GV1001 treatment resulted in significant suppression of HIV-1 replication and rescue of infected cells from death by HIV-1. Transactivation of HIV-long terminal repeat (LTR) was inhibited by GV1001, indicating that GV1001 suppressed the transcription from proviral HIV DNA. The anti-HIV-1 activity of GV1001 was completely abrogated by an HSP90-neutralizing antibody, indicating that the antiviral activity depends on HSP90. Further mechanistic studies revealed that GV1001 suppresses basal NF-κB activation, which is required for HIV-1 LTR transactivation in an HSP90-dependent manner. Inhibition of LTR transactivation by GV1001 suggests its potential to suppress HIV-1 reactivation from latency. Indeed, PMA-mediated reactivation of HIV-1 from latent infected cells was suppressed by GV1001. The results suggest the potential therapeutic use of GV1001, a peptide proven to be safe for human use, as an anti-HIV-1 agent to suppress the reactivation from latently infected cells.

Regulation of MDA5-MAVS Antiviral Signaling Axis by TRIM25 through TRAF6-Mediated NF-κB Activation.

Tripartite motif protein 25 (TRIM25), mediates K63-linked polyubiquitination of Retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. Here, we demonstrate that TRIM25 is required for melanoma differentiation-associated gene 5 (MDA5) and MAVS mediated activation of NF-κB and interferon production. TRIM25 is required for the full activation of NF-κB at the downstream of MAVS, while it is not involved in IRF3 nuclear translocation. Mechanical studies showed that TRIM25 is involved in TRAF6-mediated NF-κB activation. These collectively indicate that TRIM25 plays an additional role in RIG-I/MDA5 signaling other than RIG-I ubiquitination via activation of NF-κB.

Inhibition of respiratory syncytial virus replication and virus-induced p38 kinase activity by berberine.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infection and poses a major public health threat worldwide. No effective vaccines or therapeutics are currently available; berberine, an isoquinoline alkaloid from various medicinal plants, has been shown to exert antiviral and several other biological effects. Recent studies have shown that p38 mitogen-activated protein kinase (MAPK) activity is implicated in infection by and replication of viruses such as RSV and the influenza virus. Because berberine has previously been implicated in modulating the activity of p38 MAPK, its effects on RSV infection and RSV-mediated p38 MAPK activation were examined. Replication of RSV in epithelial cells was significantly reduced by treatment with berberine. Berberine treatment caused decrease in viral protein and mRNA syntheses. Similar to previously reported findings, RSV infection caused phosphorylation of p38 MAPK at a very early time point of infection, and phosphorylation was dramatically reduced by berberine treatment. In addition, production of interleukin-6 mRNA upon RSV infection was significantly suppressed by treatment with berberine, suggesting the anti-inflammatory role of berberine during RSV infection. Taken together, we showed that berberine, a natural compound already proven to be safe for human consumption, suppresses the replication of RSV. In addition, the current study suggests that inhibition of RSV-mediated early p38 MAPK activation, which has been implicated as an early step in viral infection, as a potential molecular mechanism.