Eun Yong Chung

Artemisolide from Artemisia asiatica: nuclear factor-kappaB (NF-kappaB) inhibitor suppressing prostaglandin E2 and nitric oxide production in macrophages.

Aerial parts ofArtemisia asiatica (Compositae) have been traditionally used as an oriental medicine for the treatment of inflammatory and ulcerogenic diseases. In the present study, artemisolide was isolated as a nuclear factor (NF)-κB inhibitor fromA. asiatica by activity-guided fractionation. Artemisolide inhibited NF-κB transcriptional activity in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7 with an IC50 value of 5.8 μM. The compound was also effective in blocking NF-κB transcriptional activities elicited by the expression vector encoding the NF-κB p65 or p50 subunits bypassing the inhibitory kB degradation signaling NF-κB activation. The macrophages markedly increased their PGE2 and NO production upon exposure to LPS alone. Artemisolide inhibited LPS-induced PGE2 and NO production with IC50 values of 8.7 μM and 6.4 μM, respectively, but also suppressed LPS-induced synthesis of cyclooxygenase (COX)-2 or inducible NO synthase (iNOS). Taken together, artemisolide is a NF-κB inhibitor that attenuates LPS-induced production of PGE2 or NOvia down-regulation of COX-2 or iNOS expression in macrophages RAW 264.7. Therefore, artemisolide could represent and provide the anti-inflammatory principle associated with the traditional medicine,A. asiatica.

Anti-inflammatory mode of isoflavone glycoside sophoricoside by inhibition of interleukin-6 and cyclooxygenase-2 in inflammatory response.

Soy, high dietary intake for the oriental population, is a main source of isoflavonoids. Sophoricoside (SOP) an isoflavone glycoside was isolated from immature fruits ofSophora japonica (Leguminosae family) and its inhibitory effect on chemical mediators involved in inflammatory response was investigated in this study. SOP inhibited the interleukin (IL)-6 bioactivity with an IC50 value of 6.1 μM whereas it had no effects on IL-1(3 and TNF-α bioactivities. SOP was identified as a selective inhibitor of cyclooxygenase (COX)-2 activity with an IC50 value of 4.4 μM, but did not show inhibitory effect on the synthesis of COX-2. However, SOP had no effect on the production of reactive oxygen species including superoxide anions and nitric oxide. These results revealed thatin vitro anti-inflammatory action of SOP is significantly different from that of genistein known as a phytoestrogen of soy products. This experimental study has documented an importance of dietary soy isoflavonoids as multifunctional agents beneficial to human health, and will help to clarify protective mechanisms of SOP against inflammatory con-ditions.

Novel iminobenzoxathiolone compound inhibits nuclear factor-κB activation targeting inhibitory κB kinase β and down-regulating interleukin-1β expression in lipopolysaccharide-activated macrophages

Benzoxathiolone derivatives have been reported to show pharmacological potentials in the psoriasis and acne. However, molecular basis for these pharmacological properties is little known. We postulated that the derivatives could mediate some of their pharmacological actions by modulating nuclear factor (NF)-kappaB activation, which is closely linked to the inflammatory and immune disorders. In this study, a novel iminobenzoxathiolone LYR-71 of 6-methyl-2-propylimino-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one has been demonstrated to inhibit in vitro catalytic activity of inhibitory kappaB (IkappaB) kinase beta (IKKbeta), a key enzyme required for NF-kappaB activation, with an IC(50) value of 7 microM. LYR-71 inhibited IKKbeta-mediated phosphorylation of cytoplasmic IkappaBalpha in lipopolysaccharide (LPS)-activated macrophages, and sequentially preventing IkappaBalpha degradation as well as transcriptional activation of NF-kappaB. Furthermore, LYR-71 down-regulated LPS-induced transcription of interleukin (IL)-1beta or other cytokines in the cells, and inhibited expression vector IKKbeta-elicited IL-1beta promoter activity. Taken together, LYR-71 was an efficient inhibitor of IKKbeta, preventing NF-kappaB activation in macrophages, and this mechanism of action could contribute its down-regulatory effect on LPS-induced expression of inflammatory cytokines at the transcription level.

Anti-inflammatory effects of N1-Benzyl-4-methylbenzene-1,2-diamine (JSH-21) analogs on nitric oxide production and nuclear factor-kappa B transcriptional activity in lipopolysaccharide-stimulated macrophages RAW 264.7

N1-Benzyl-4-methylbenzene-1,2-diamine (JSH-21) and its analogs were chemically synthesized and their anti-inflammatory potentials investigated. JSH-21 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7 in a dose-dependent manner, with an IC50 value of 9.2 μM, where pyrrolidine dithiocarbamate and parthenolide as positive controls exhibited IC50 values of 29.3 and 3.6 μM, respectively. The inhibitory effect of JSH-21 on the NO production was attributable to its down-regulatory action on LPS-induc-ible NO synthase (iNOS), which was documented by iNOS promoter activity. In the mechanism of the anti-inflammatory action, JSH-21 exhibited inhibitory effects on LPS-induced DNA binding activity and transcriptional activity of nuclear factor-kappa B(NF-kB). Structural analogs of JSH-21 also inhibited both the LPS-induced NO production andNF-kB transcriptional activity, where diamine substitution at positions 1 and 2 of JSH-21 seems to play an important role in the anti-inflammatory activity.

The benzoxathiolone LYR-71 down-regulates interferon-γ-inducible pro-inflammatory genes by uncoupling tyrosine phosphorylation of STAT-1 in macrophages

Background and purpose:  Benzoxathiolone derivatives have shown anti‐inflammatory and immunomodulatory potential in acne and psoriatic disorders. However, little is known about the molecular basis for these pharmacological effects. In this study, we decided to investigate the anti‐inflammatory actions of a benzoxathiolone derivative LYR‐71, 6‐methyl‐2‐propylimino‐6,7‐dihydro‐5H‐benzo[1,3]oxathiol‐4‐one, in interferon (IFN)‐γ‐activated macrophages.