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Endale, Mehari,Kim, Sung Dae,Lee, Whi Min,Kim, Sangseop,Suk, Kyoungho,Cho, Jae Youl,Park, Hwa Jin,Wagley, Yadav,Kim, Suk,Oh, Jae-Wook,Rhee, Man Hee American Physiological Society 2010 American journal of physiology. Cell physiology Vol.298 No.3
<P>Regulator of G protein signaling (RGS) family members, such as RGS2, interact with Gα subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and attenuating the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. They are also reported to regulate G protein-effector interactions and form multiprotein signaling complexes. Ischemic stress-induced changes in RGS2 expression have been described in astrocytes, and these changes are associated with intracellular signaling cascades, suggesting that RGS2 upregulation may be an important mechanism by which astrocytes may regulate RGS2 function in response to physiological stress. However, information on the functional roles of stress-induced modulation of RGS2 protein expression in astrocyte function is limited. We report the role of ischemic stress in RGS2 protein expression in rat C6 astrocytoma cells and primary mouse astrocytes. A marked increase in RGS2 occurred after ischemic stress induced by chemicals (sodium azide and 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real ischemia). RGS2 mRNA expression was markedly enhanced by 1 h of exposure to chemical ischemia or 6 h of OGD followed by 2 or 6 h of recovery, respectively. This enhanced expression in primary astrocytes and C6 cells was restored to baseline levels after 12 h of recovery from chemically induced ischemic stress or 4-6 h of recovery from OGD. RGS2 protein was also significantly expressed at 12-24 h of recovery from ischemic insult. Ischemia-induced RGS2 upregulation was associated with enhanced apoptosis. It significantly increased annexin V-positive cells, cleaved caspase-3, and enhanced DNA ladder formation and cell cycle arrest. However, a small interfering RNA (siRNA)-mediated RGS2 knockdown reversed the apoptotic cell death associated with ischemia-induced RGS2 upregulation. Upregulated RGS2 was significantly inhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin, a potent inhibitor of PKCδ, completely abrogated the increased RGS2 expression. We also examine whether ischemia-induced RGS2-mediated apoptosis is affected by siRNA-targeted endogenous PKCδ downregulation or its phosphorylation. Although RGS2 upregulation was not affected, siRNA transfection significantly suppressed endogenous PKCδ mRNA and protein expressions. Ischemia-induced PKCδ phosphorylation and caspase-3 cleavage were dose dependently inhibited by PKCδ knockdown, and this endogenous PKCδ suppression reversed ischemia-induced annexin V-positive cells. This study suggests that ischemic stress increases RGS2 expression and that this condition contributes to enhanced apoptosis in C6 cells and primary astrocytes. The signaling it follows may involve PKCδ and p38 MAPK pathways.</P>
Mehari Endale,Jae Chan Song,Man Hee Rhee,Kwang-Hyeon Liu,Taek-Kyum Kim,Joong Goo Kwon,Kyung Sik Park,Ki-Myung Chung,Tae Wan Kim 한국실험동물학회 2011 Laboratory Animal Research Vol.27 No.4
Suaeda asparagoides (Miq.) has long been used as a Korean folk herbal medicine for the treatment of functional gastrointestinal disorders. However, reports on its pharmacological activity on gastrointestinal motility are scarce. The present study investigated the effects of Suaeda asparagoides water fraction of the extract (SAWF) on antral motility in vitro. Muscle strips from rat gastric antrum were set up in an organ bath in a circular orientation. SAWF (100 μg/mL) inhibited the spontaneous contraction of antral circular muscle strips. These inhibitory effects were not significantly affected by tetrodotoxin (1 μM), Nω-Nitro-Larginine methyl ester hydrochloride (100 μM), 1H-(1, 2, 4)oxadiazolo(4, 3-a)quinoxalin-1-one (10 μM), ryanodine (10 μM) and phentolamine (10 μM). SAWF-induced inhibition was mostly restored by cyclopiazonic acid (10 μM). Furthermore, the β-adrenergic receptor antagonist, propranolol (10 μM), abolished SAWFinduced inhibition. These results suggest that SAWF may exert its activity on gastrointestinal smooth muscle via â-adrenergic receptors and sarcoplasmic reticulum Ca2+ ATPase.
Torilin Inhibits Inflammation by Limiting TAK1-Mediated MAP Kinase and NF- <i>κ</i> B Activation
Endale, Mehari,Kim, Tae-Hwan,Kwak, Yi-Seong,Kim, Na-Mi,Kim, Seung-Hyung,Cho, Jae Youl,Yun, Bong-Sik,Rhee, Man-Hee Hindawi Publishing Corporation 2017 Mediators of inflammation Vol.2017 No.-
<P>Torilin, a sesquiterpene isolated from the fruits of<I> Torilis japonica,</I> has shown antimicrobial, anticancer, and anti-inflammatory properties. However, data on the mechanism of torilin action against inflammation is limited. This study aimed at determining the anti-inflammatory property of torilin in LPS-induced inflammation using in vitro model of inflammation. We examined torilin's effect on expression levels of inflammatory mediators and cytokines in LPS-stimulated RAW 264.7 macrophages. The involvement of NF-kB and AP-1, MAP kinases, and adaptor proteins were assessed. Torilin strongly inhibited LPS-induced NO release, iNOS, PGE<SUB>2</SUB>, COX-2, NF-<I>α</I>, IL-1<I>β</I>, IL-6, and GM-CSF gene and protein expressions. In addition, MAPKs were also suppressed by torilin pretreatment. Involvement of ERK1/2, P38<SUP>MAPK</SUP>, and JNK1/2 was further confirmed by PD98059, SB203580, and SP600125 mediated suppression of iNOS and COX-2 proteins. Furthermore, torilin attenuated NF-kB and AP-1 translocation, DNA binding, and reporter gene transcription. Interestingly, torilin inhibited TAK1 kinase activation with the subsequent suppression of MAPK-mediated JNK, p38, ERK1/2, and AP-1 (ATF-2 and c-jun) activation and IKK-mediated I-<I>κ</I>B<I>α</I> degradation, p65/p50 activation, and translocation. Together, the results revealed the suppression of NF-<I>κ</I>B and AP-1 regulated inflammatory mediator and cytokine expressions, suggesting the test compound's potential as a candidate anti-inflammatory agent.</P>
Man Hee Rhee,Mehari Endale,SM Kamruzzaman,Whi Min Lee,Hwa-Jin Park,Myung-Jo Yoo,Jae Youl Cho 대한의생명과학회 2008 Biomedical Science Letters Vol.14 No.3
In previous works, we found that solvent extract of Opuntia humifusa Raf., a member of the lactaceae family, displayed potent anti-oxidative and anti-inflammatory activities. Thus, all solvent fractions, except for the water layer, showed potent scavenging effects. According to activity-guided fractionation, one of active radical scavenging principles in the ethyl acetate fraction was found to be taxifolin. In this study, we investigated whether taxifolin showed anti-oxidative activity. In addition, taxifolin modulated nitric oxide (NO) release and the expression of pro-inflammatory cytokine mRNA such as interleukin-1β (IL-1β), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF-α. Taxifolin showed potent anti-oxidant activity with the IC?? of 8.5±1.4 and 9.3±1.0 μM using xanthine/xanthine oxidase (XO) assay and 2,2-Diphenyl-lpicrylhydrazyl radical (DPPH) assay, respectively. We next determined the role of taxifolin on the immunomodulating activity using murine macrophage cell line RAW264.7 cells. Taxifolin dosedependently inhibited NO production in lipopolysaccharide (LPS)-activated RAW264.7. It also significantly blocked the expression of inducible NO synthase (iNOS) mRNA in the LPS-stimulated RAW264.7 cells. In addition, taxifolin potently suppressed the expression of IL-1β, IL-6 and GM-CSF mRNA in LPS-activated RAW264.7 cells, but not that of TNF-α. Moreover, taxifolin significantly inhibited the transcriptional activity of nuclear factor-κB (NF-κB) and activator protein -1 (AP-1). These results suggest that taxifolin may downregulate inflammatory iNOS, IL-1β, IL-6 and GM-CSF gene expressions through inhibition of NF-K and AP-1 activation in LPS-stimulated RAW264.7 cells.
Rhee, Man-Hee,Endale, Mehari,Kamruzzaman, SM,Lee, Whi-Min,Park, Hwa-Jin,Yoo, Myung-Jo,Cho, Jae-Youl The Korean Society for Biomedical Laboratory Scien 2008 Journal of biomedical laboratory sciences Vol.14 No.3
In previous works, we found that solvent extract of Opuntia humifusa Raf., a member of the lactaceae family, displayed potent anti-oxidative and anti-inflammatory activities. Thus, all solvent fractions, except for the water layer, showed potent scavenging effects. According to activity-guided fractionation, one of active radical scavenging principles in the ethyl acetate fraction was found to be taxifolin. In this study, we investigated whether taxifolin showed anti-oxidative activity. In addition, taxifolin modulated nitric oxide (NO) release and the expression of pro-inflammatory cytokine mRNA such as interleukin-$1{\beta}$ (IL-$1{\beta}$), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF-${\alpha}$. Taxifolin showed potent anti-oxidant activity with the $IC_{50}\;of\;8.5{\pm}1.4\;and\;9.3{\pm}1.0{\mu}M$ using xanthine/xanthine oxidase (XO) assay and 2,2-Diphenyl-lpicrylhydrazyl radical (DPPH) assay, respectively. We next determined the role of taxifolin on the immunomodulating activity using murine macrophage cell line RAW264.7 cells. Taxifolin dose-dependently inhibited NO production in lipopolysaccharide (LPS)-activated RAW264.7. It also significantly blocked the expression of inducible NO synthase (iNOS) mRNA in the LPS-stimulated RAW264.7 cells. In addition, taxifolin potently suppressed the expression of IL-$1{\beta}$, IL-6 and GM-CSF mRNA in LPS-activated RAW264.7 cells, but not that of TNF-${\alpha}$ Moreover, taxifolin significantly inhibited the transcriptional activity of nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and activator protein -1 (AP-1). These results suggest that taxifolin may downregulate inflammatory iNOS, IL-$1{\beta}$, IL-6 and GM-CSF gene expressions through inhibition of NF-K and AP-1 activation in LPS-stimulated RAW264.7 cells.
Sung Dae Kim(김성대),Whi Min Lee(이휘민),Mehari Endale(메하리 엔델),Jae Youl Cho(조재열),Hwa Jin Park(박화진),Jae Wook Oh(오재욱),Man Hee Rhee(이만휘) 한국생명과학회 2009 생명과학회지 Vol.19 No.11
RGS단백질은 G 단백질 신호전달작용에 있어서 신호를 억제하는 조절단백질로서 G 단백질 매개수용체(GPCR)의 활성을 억제하는 것으로 알려졌다. 그렇지만 캐너비노이드 수용체 CB2의 활성에 있어서 RGS 단백질의 조절효과에 관해서는 지금까지 알려져 있지 않다. 그러므로 본 연구에서 우리는 RGS2, 3, 4, 5와 캐너비노이드 수용체 CB2 cDNA를 동시에 HEK293 세포주에 발현시킨 후 각 RGS 단백질의 효과를 조사하였다. CB2 단백질을 발현하는 HEK293 세포주(CB2-HEK293)에서 CB2 효현제인 WIN55,212-2는 폴스콜린으로 유도된 cAMP response element (CRE) 활성을 억제하였다. 이러한 WIN55,212-2의 CRE 억제 활성은 RGS3에 의하여 차단되었지만 RGS2, 4, 및 RGS5에서는 관찰되지 않았다. 뿐만 아니라 RGS3 small interference RNA (siRNA)를 사용하여 내인성 RGS3 단백질의 발현을 저하시키면 WIN55,212-2에 의한 폴스콜린 유도 CRE 억제활성은 더욱 증강되었다. 이상의 결과는 캐너비노이드 수용체 CB2 신호전달작용에 있어서 RGS 단백질의 기능적 역할과 특히 내인성 RGS3의 캐너비노이드 수용체 CB2에 대한 선택적 작용을 나타낸다. RGS proteins have been identified as negative regulators of G protein signalling pathways and attenuate the activity of GPCR receptors. However, information on the regulatory effects of RGS proteins in the activity of cannabinoid receptors is limited. In this study, the role of RGS proteins on the signal transduction of the CB2 cannabinoid receptor was investigated in HEK293 cells co-transfected with CB2-receptors and plasmids encoding RGS2, RGS3, RGS4 and RGS5. Treatment of cells with WIN55, 212-2, a CB2 receptor agonist, inhibited forskolin-induced cAMP response element (CRE) activity in CB2-transfected HEK293 (CB2-HEK293) cells. This inhibitory effect of WIN 55, 212-2 on CRE activity was reversed by co-transfection of CB2-HEK293 cells with RGS3, but not with RGS2, RGS4 and RGS5. However, endogenous RGS3 protein knocked down by a small interfering siRNA targeting RGS3 gene enhanced inhibition of forskolin induced CRE activity via agonist induced CB2 receptor signal transduction. These results indicate the functional role of endogenous RGS protein in cannabinoid signaling pathways and define receptor-selective roles of endogenous RGS3 in modulating CRE transcriptional responses to agonist induced CB2 receptor activity.