| 2018 | Potential inhibitory effects of the traditional herbal prescription Hyangso-san against skin inflammation via inhibition of chemokine production and inactivation of STAT1 in HaCaT keratinocytes. | Mol Med Rep | Inflammatory skin disease are caused by multiple factors, including susceptibility genes, and immunologic and environmental factors, and are characterized by an increase in epidermal thickness and the infiltration of macrophages, keratinocytes, mast cells, eosinophils and other inflammatory cells. Keratinocytes may serve an important role in the pathogenesis of inflammatory skin diseases. The traditional herbal decoction Hyangso‑san (HSS) has been used to treat symptoms of the common cold, including headache, pantalgia, fever and chills. However, to the best of our knowledge, there is no evidence regarding whether HSS has an effect on inflammatory skin diseases. The present study investigated the anti‑skin inflammation activity of HSS using the HaCaT human keratinocyte cell line. The mRNA expression and production of inflammatory chemokines, including C‑C motif chemokine ligand 22 (CCL22), CCL5, CCL17, and interleukin (IL)‑8, was measured using reverse transcription polymerase chain reaction and ELISA analyses. Moreover, we evaluated the effect of HSS on signal transducer and activator of transcription 1 (STAT1) pathway in HaCaT cells. The cells were stimulated with tumor necrosis factor‑α (TNF‑α) and interferon‑γ (IFN‑γ) to induce an inflammatory reaction. In the TNF‑α‑ and IFN‑γ‑stimulated cells, the production and expression of inflammatory chemokines were observed, including CCL22, CCL5, CCL17 and IL‑8. In addition, stimulation with TNF‑α and IFN‑γ increased the phosphorylation and nuclear translocation of STAT1 in HaCaT cells. By contrast, HSS extract treatment inhibited TNF‑α‑ and IFN‑γ‑induced STAT1 activation. Results from the present study indicated that HSS exhibited inhibitory effects on TNF‑α‑ and IFN‑γ‑mediated chemokine production and expression by targeting STAT1 in keratinocytes. Overall, the results indicated that HSS may be a potential candidate therapeutic drug for inflammatory skin diseases such as atopic dermatitis. |
| 2015 | Repurposing of prochlorperazine for use against dengue virus infection. | J Infect Dis | The increasing prevalence of dengue virus (DENV) infection presents serious disease and economic burdens in countries where dengue epidemics are occurring. Despite the clinical importance, no DENV vaccine or anti-DENV drug is available. In this study, we found that prochlorperazine (PCZ), a dopamine D2 receptor (D2R) antagonist approved to treat nausea, vomiting, and headache in humans has potent in vitro and in vivo antiviral activity against DENV infection. PCZ can block DENV infection by targeting viral binding and viral entry through D2R- and clathrin-associated mechanisms, respectively. Administration of PCZ immediately or 6 hours after DENV infection in a Stat1-deficient mouse model completely protected against or delayed lethality. Overall, PCZ showed a previously unknown antiviral effect against DENV infection, and D2R may play a role in the DENV life cycle. Prophylactic and/or therapeutic treatment with PCZ might reduce viral replication and relieve the clinical symptoms of patients with dengue. |
| 2010 | Safety, Tolerability, and Immunogenicity of Interferons. | Pharmaceuticals (Basel) | Interferons (IFNs) are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1, have found wide application for the treatment of chronic viral hepatitis and remitting relapsing multiple sclerosis respectively. Type II IFN, or IFN gamma, is used principally for the treatment of chronic granulomatous disease, while the recently discovered type III IFNs, also known as IFN lambda or IL-28/29, are currently being evaluated for the treatment of chronic viral hepatitis. IFNs are in general well tolerated and the most common adverse events observed with IFNα or IFNβ therapy are "flu-like" symptoms such as fever, headache, chills, and myalgia. Prolonged treatment is associated with more serious adverse events including leucopenia, thrombocytopenia, increased hepatic transaminases, and neuropsychiatric effects. Type I IFNs bind to high-affinity cell surface receptors, composed of two transmembrane polypeptides IFNAR1 and IFNAR2, resulting in activation of the Janus kinases Jak1 and Tyk2, phosphorylation and activation of the latent cytoplasmic signal transducers and activators of transcription (STAT1) and STAT2, formation of a transcription complex together with IRF9, and activation of a specific set of genes that encode the effector molecules responsible for mediating the biological activities of type I IFNs. Systemic administration of type I IFN results in activation of IFN receptors present on essentially all types of nucleated cells, including neurons and hematopoietic stem cells, in addition to target cells. This may well explain the wide spectrum of IFN associated toxicities. Recent reports suggest that certain polymorphisms in type I IFN signaling molecules are associated with IFN-induced neutropenia and thrombocytopenia in patients with chronic hepatitis C. IFNγ binds to a cell-surface receptor composed of two transmembrane polypeptides IFGR1 and IFGR2 resulting in activation of the Janus kinases Jak1 and Jak2, phosphorylation of STAT1, formation of STAT1 homodimers, and activation of a specific set of genes that encode the effector molecules responsible for mediating its biological activity. In common with type I IFNs, IFNγ receptors are ubiquitous and a number of the genes activated by IFNγ are also activated by type I IFNs that may well account for a spectrum of toxicities similar to that associated with type I IFNs including "flu-like" symptoms, neutropenia, thrombocytopenia, and increased hepatic transaminases. Although type III IFNs share the major components of the signal transduction pathway and activate a similar set of IFN-stimulated genes (ISGs) as type I IFNs, distribution of the IFNλ receptor is restricted to certain cell types suggesting that IFNλ therapy may be associated with a reduced spectrum of toxicities relative to type I or type II IFNs. Repeated administration of recombinant IFNs can cause in a break in immune tolerance to self-antigens in some patients resulting in the production of neutralizing antibodies (NABs) to the recombinant protein homologue. Appearance of NABs is associated with reduced pharmacokinetics, pharmacodynamics, and a reduced clinical response. The lack of cross-neutralization of IFNβ by anti-IFNα NABs and vice versa, undoubtedly accounts for the apparent lack of toxicity associated with the presence of anti-IFN NABs with the exception of relatively mild infusion/injection reactions. |