No abstract

Asthma has become substantially more prevalent in recent decades and is one of the foremost contributors to morbidity and mortality in industrialized countries. Corticosteroids are among the most effective medications for the treatment of asthma, but some patients do not respond well to corticosteroid treatment. In this study, we characterized the responses to an allergen and identified potential molecular targets of dexamethasone (Dex) treatment in acute asthma. Female BALB/c mice sensitized to ovalbumin (OVA) were challenged with aerosolized OVA for 1 week. During the challenge period, mice were treated daily with Dex by intraperitoneal injection. Phosphate-buffered saline treated and non-challenged mice served as control. Histological evaluation of OVA-induced mice revealed airway inflammation and goblet cell hyperplasia. In addition, interleukin 4 levels and interferon-gamma levels were increased and decreased, respectively. These changes were moderated by Dex treatment. Protein expression profiles were compared in each experimental group by two-dimensional gel electrophoresis and identified using matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry. Some proteins were increased, while others were decreased by Dex treatment. These results indicated that the regulation of protein expression might play a role in the immunological and pathological development of asthma and could be targeted for therapeutic intervention. These results may assist in the development of quantitative diagnostic markers to monitor disease progression or responses to therapy using proteomic approaches.

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Cytokines/chemokines play key roles in modulating disease progression in human immunodeficiency virus (HIV) infection. Although it is known that early HIV-1 infection is associated with increased production of proinflammatory cytokines, the relationship between cytokine levels and HIV-1 pathogenesis is not clear. The concentrations of 18 cytokines/chemokines in 30 HIV-1 negative and 208 HIV-1 positive plasma samples from Korean patients were measured by the Luminex system. Early HIV-1 infection was classified according to the Fiebig stage (FS) based on the characteristics of the patients infected with HIV-1. Concentrations of interleukin-12 (IL-12), interferon-inducible protein-10 (IP-10), macrophage inflammatory protein-1α (MIP-1α) and regulated upon activation, normal T cells expressed and secreted (RANTES) were increased significantly during the early stage of HIV-1 infection (FS II-IV) compared with the HIV-1-negative group. Of these cytokines, an elevated level of IP-10 was the only factor to be correlated positively with a higher viral load during the early stages of HIV-1 infection (FS II-IV) in Koreans (R = 0.52, P < 0.0005). Therefore, these results suggest that IP-10 may be an indicator for HIV-1 viremia and associated closely with viral replication in patients with early HIV-1 infection.

The 1,5‐dialkyl‐6‐(arylselenenyl)uracils 10a‐h and ‐2‐thiouracils 10i‐p have been synthesized as potential anti‐HIV‐1 agents. Cyclization of N‐alkyl‐N'‐[3,3‐di(methylthio)‐2‐alkylacryloyl]ureas 6a‐d and ‐thioureas 6e‐h in acetic acid either containing a catalytic amount of methanesulfonic acid at 80°or containing 1 equivalent of methanesulfonic acid at room temperature afforded 1,5‐dialkyl‐6‐(methylthio)uracils 7a‐d in 84–96% yields and 1,5‐dialkyl‐5,6‐dihydro‐6,6‐di(methylthio)‐2‐thiouracils 11a‐d in 88–99% yields, respectively. Oxidation of 7a‐d and 11a‐d with either 3‐chloroperoxybenzoic acid in benzene or aqueous sodium periodate solution in methanol gave 1,5‐dialkyl‐6‐(methylsulfonyl)uracils 8a‐d in 88–98% yields and 1,5‐dialkyl‐6‐(methylsulfinyl)‐2‐thiouracils 12a‐d in 57–73% yields, respectively, which were subsequently treated with arylselenol 9a‐b in ethanolic sodium hydroxide solution to afford 10a‐p in 6099% yields. Of these compounds, 6‐[(3,5‐dimethylphenyl)selenenyl]‐5‐isopropyl‐1‐(3‐phenylpropyl)uracil (10h) inhibited HIV‐1 replication in MT‐4 cells at a 50% effective concentration (EC50) of 0.0006 μM with a selective index of 44833, which is 7.7‐fold more potent than AZT.