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MD-2 as the Target of Nonlipid Chalcone in the Inhibition of Endotoxin LPS-Induced TLR4 Activity.
Roh, Eunmiri,Lee, Heun-Sik,Kwak, Jeong-Ah,Hong, Jin Tae,Nam, Sang-Yoon,Jung, Sang-Hun,Lee, Joo Young,Kim, Nam Doo,Han, Sang-Bae,Kim, Youngsoo University of Chicago Press 2011 The Journal of Infectious Diseases Vol.203 No.7
<P>Myeloid differentiation 2 (MD-2) recognizes endotoxin lipopolysaccharide (LPS), which is required for Toll-like receptor 4 (TLR4) activity. MD-2 represents a more attractive therapeutic target than TLR4 for intervention in severe inflammatory disorders due to microbial infection. Here, we suggest MD-2 as a molecular target of nonlipid chalcone in the inhibition of LPS-induced cellular inflammation. A chalcone derivative, 2',4-dihydroxy-6'-isopentyloxychalcone (JSH) competitively displaced LPS from MD-2, and was fitted into the ligand-binding site on the crystal structure of MD-2 under the most energetically favorable simulation. JSH nullified TLR4 activation mechanism and sequentially inhibited nuclear factor-관B (NF-관B) activation that involves the phosphorylation and degradation of inhibitory 관Bs and the nuclear import and transcriptional activity of NF-관B in LPS-activated macrophages. Moreover, JSH suppressed NF-관B-target inflammatory genes such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1관 (IL-1관) and IL-6. Taken together, this study assigns the chalcone structure as an LPS antagonist binding to MD-2 with therapeutic potential against inflammatory conditions.</P>
Roh, Eunmiri,Yun, Cheong-Yong,Young Yun, Ji,Park, Dongsun,Doo Kim, Nam,Yeon Hwang, Bang,Jung, Sang-Hun,Park, Sun Ki,Kim, Yun-Bae,Han, Sang-Bae,Kim, Youngsoo The Society for Investigative Dermatology, Inc 2013 The Journal of investigative dermatology Vol.133 No.4
Microphthalmia-associated transcription factor (MITF) is inducible in response to cAMP and has a pivotal role in the melanocyte-specific expression of tyrosinase for skin pigmentation. Here we suggest that the cAMP-binding site of protein kinase A (PKA) is a target in the inhibition of the melanogenic process in melanocytes, as evidenced from the molecular mechanism of small molecules such as bisabolangelone (BISA) and Rp-adenosine 3′,5′-cyclic monophosphorothioate (Rp-cAMPS). BISA is a sesquiterpene constituent of Angelica koreana, a plant of the Umbelliferae family, whose roots are used as an alternative medicine. BISA competitively inhibited cAMP binding to the regulatory subunit of PKA and fitted into the cAMP-binding site on the crystal structure of PKA under the most energetically favorable simulation. In α-melanocyte-stimulating hormone (α-MSH)–activated melanocytes, BISA and Rp-cAMPS nullified cAMP-dependent PKA activation, dissociating catalytic subunits from an inactive holoenzyme complex. They resultantly inhibited cellular phosphorylation of the cAMP-responsive element-binding protein (CREB) or another transcription factor SOX9, thus downregulating the expression of MITF or the tyrosinase gene with decreased melanin production. Taken together, this study defined the antimelanogenic mechanism of BISA or Rp-cAMPS with a notable implication of the cAMP-binding site of PKA as a putative target ameliorating melanocyte-specific hyperpigmented disorder.
Kim, Byung Hak,Roh, Eunmiri,Lee, Hwa Young,Lee, In-Jeong,Ahn, Byeongwoo,Jung, Sang-Hun,Lee, Heesoon,Han, Sang-Bae,Kim, Youngsoo American Society for Pharmacology and Experimental 2008 Molecular pharmacology Vol.73 No.4
<P>Benzoxathiole derivatives have been used in the treatment of acne and have shown cytostatic, antipsoriatic, and antibacterial properties. However, little is known about the molecular basis for these pharmacological properties, although nuclear factor (NF)-kappaB activation is closely linked to inflammation and cell proliferation. Here, we demonstrate that the novel small-molecule benzoxathiole 6,6-dimethyl-2-(phenylimino)-6,7-dihydro-5H-benzo-[1,3]oxathiol-4-one (BOT-64) inhibits NF-kappaB activation with an IC(50) value of 1 muM by blocking inhibitory kappaB(IkappaB) kinase beta (IKKbeta), and suppresses NF-kappaB-regulated expression of inflammatory genes in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. BOT-64 inhibits IKKbeta-mediated IkappaBalpha phosphorylation in LPS-activated macrophages, resulting in sequential prevention of downstream events, including proteolytic degradation of IkappaBalpha, DNA binding ability, and transcriptional activity of NF-kappaB. BOT-64 inhibits LPS-inducible IKKbeta activity in the cells and catalytic activity of highly purified IKKbeta. Moreover, the effect of BOT-64 on cell-free IKKbeta was abolished by substitution of Ser-177 and Ser-181 residues in the activation loop of IKKbeta to glutamic acid residues, indicating a direct interaction site of benzoxathiole. BOT-64 attenuates NF-kappaB-regulated expression of inflammatory genes such as inducible nitric-oxide synthase, cyclooxygenase-2, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in LPS-activated or expression vector IKKbeta-transfected macrophages. Furthermore, BOT-64 dose-dependently increases the survival rates of endotoxin LPS-shocked mice.</P>
Lee, Hwa Dong,Lee, Won‐,Hee,Roh, Eunmiri,Seo, Chang‐,Seob,Son, Jong‐,Keun,Lee, Seung Ho,Hwang, Bang Yeon,Jung, Sang‐,Hun,Han, Sang‐,Bae,Kim, Youngsoo Blackwell Publishing Ltd 2011 Experimental dermatology Vol.20 No.9
<P><B>Abstract: </B> Microphthalmia‐associated transcription factor (MITF) is inducible in response to cAMP through the cAMP‐responsive element–binding protein (CREB) and plays a pivotal role in the melanocyte‐specific expression of tyrosinase or tyrosinase‐related proteins (TRPs) for melanin biosynthesis. Manassantin A from <I>Saururus chinensis</I> inhibits cAMP‐induced melanin production in B16 melanoma cells. Here, we focused on molecular basis of the antimelanogenic activity. Manassantin A consistently inhibited the cAMP elevator 3‐isobutyl‐1‐methylxanthine (IBMX)‐ or dibutyryl cAMP‐induced melanin production in B16 cells or in melan‐a melanocytes by down‐regulating the expression of <I>tyrosinase</I> or <I>TRP1</I> gene. Moreover, manassantin A suppressed MITF induction through IBMX‐activated CREB pathway, directly inhibiting the Ser‐133 phosphorylation of CREB. However, manassantin A did not affect IBMX‐increased cAMP levels in these cells but also other cAMP‐dependent melanogenic pathways through post‐translational modifications of MITF. This putative molecular mechanism of manassantin A in the inhibition of melanin production suggests its pharmacological potential in skin hyperpigmentation.</P>
Study on IL-5 Inhibitory Activity of Novel Chromenone Derivatives
Eeda Venkateswararao,Vinay K. Sharma,Ki-Cheul Lee,Eunmiri Roh,Youngsoo Kim,Sang-Hun Jung 충남대학교 약학대학 의약품개발연구소 2013 藥學論文集 Vol.28 No.-
A novel series of chromenone analogs were synthesized and evaluated for their inhibitory activity against interleukin-5. Among them compounds 5-(cyclohexylmethoxy)-N-(4-hydroxy-3-(hydroxymethyl)phenyl)-4-oxo-4H-chromene-3-carboxamide (8e, 54% inhibition at 30 μM) and ethyl 3-(5-(cyclohexylmethoxy)- 4-oxo-4H-chromene-3-carboxamido)benzoate (8g, 62% inhibition at 30 μM) showed the most potent activity. The SAR activity of these chromenones indicated that the bulky substituents at ring B increases the inhibition against IL-5 though none of the compound showed potent inhibition. The reason for less activity of the chromenones 8a-h may be due to the rigidity of amine linkage.