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( Nirmala Tilija Pun ),( Amit Subedi ),( Mi Jin Kim ),( Pil Hoon Park ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Adiponectin,an adipokine predominantly produced from adipose tissue,exhibited potent anti-inflammatory properties.in particular,it inhibits production df pro-inflammatory cyto-kines,including tumor necrosis factor-a(TNF-a),in macrophages.Autophagy,an intracellu-lar self-digestion process,has been recently shown to rengulate inflammatory responses.in the present study,we investigated the role of autophagy induction in the suppression of-Li-popolysaccharide(LPS)-induced TNF-a expression by giobular adiponectin(gAcrp)and its potential mechanisms.Herein,we found that gAcrp treatment increased espressin of genes related with autophagy,including Atg5 and microtubule-associated protein light chain(LC3B),induced autophagosome formation and autophagy flux in RAW264.7macro-phages.Similar results were observed in primary macrophages isolated peritoneum of mice.interestingly,inhibition of autophagy by pretreatment with Bafilomycin A1 or knocking down of LC3B gene restored suppression of TNF-a espression,tumor necrosis factor re-ceptor-associated factor 6(TRAF6)espression and p38MAPK phosphorylation by gAcrp.implying a critical role of autophagy induction in the debelopment of tolerance to LPS-in-duced TNF-a expression bygAcrp.Wealso found that knocking-down of FoxO3A,a fork-head box O member of transcription factor,biocked gAcrp-induced espression of LC3ll and Atg5.Moreover,gene silencing of Silent information regulator 1(SIRT1)blocked both gAcrp-induced nuclear translocation of FoxO3A and LC3ll expression.Finally,pretreatment with ROS inhibitors,prevented gAcrp-induced SIRT1 espression and further generated in-hibitory effects on gAcrp-induced autophagy,indicating role of ROS production in gAcrp-induced SIRT1 espression and subsequent autophagy induction.Taken together,these findings indicate that globular adiponectin suppresses LPS-induced TNF-a expression,at least in part,via autophagy activation,Furthermore,SIRT1-FoxO3A axis plays a crucial role in gAcro-induced autophagy in macerophages.
Nirmala Tilija Pun,장원준,정철호 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.5
Autophagy is a self-degradation process in whichthe cytoplasmic cargoes are delivered to the lysosomes fordegradation. As the cargoes are degraded/recycled, theautophagy process maintains the cellular homeostasis. Anticancertherapies induce apoptosis and autophagy concomitantly,and the induced autophagy normally prevents stressresponses that are being induced. In such cases, the inhibitionof autophagy can be a reasonable strategy to enhancethe effi cacy of anti-cancer therapies. However, recent studieshave shown that autophagy induced by anti-cancer drugscauses cell death/apoptosis induction, indicating a controversialrole of autophagy in cancer cell survival or death/apoptosis. Therefore, in the present review, we aimed to assessthe signaling mechanisms involved in autophagy and celldeath/apoptosis induction during anti-cancer therapies. Thisreview summarizes the process of autophagy, autophagy fl uxand its blockade, and measurement and interpretation ofautophagy fl ux. Further, it describes the signaling pathwaysinvolved in the blockade of autophagy fl ux and the role ofsignaling molecules accumulated by autophagy blockade incell death/apoptosis in various cancer cells during anti-cancertherapies. Altogether, it implies that factors such as typesof cancer, drug therapies, and characteristics of autophagyshould be evaluated before targeting autophagy for cancertreatment.
Shrestha, Aastha,Pun, Nirmala Tilija,Park, Pil-Hoon The Korean Society of Applied Pharmacology 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.5
Adiponectin, a hormone predominantly originated from adipose tissue, has exhibited potent anti-inflammatory properties. Accumulating evidence suggests that autophagy induction plays a crucial role in anti-inflammatory responses by adiponectin. However, underlying molecular mechanisms are still largely unknown. Association of Bcl-2 with Beclin-1, an autophagy activating protein, prevents autophagy induction. We have previously shown that adiponectin-induced autophagy activation is mediated through inhibition of interaction between Bcl-2 and Beclin-1. In the present study, we examined the molecular mechanisms by which adiponectin modulates association of Bcl-2 and Beclin-1 in macrophages. Herein, we demonstrated that globular adiponectin (gAcrp) induced increase in the expression of AUF1 and ZFP36L1, which act as mRNA destabilizing proteins, both in RAW 264.7 macrophages and primary peritoneal macrophages. In addition, gene silencing of AUF1 and ZFP36L1 caused restoration of decrease in Bcl-2 expression and Bcl-2 mRNA half-life by gAcrp, indicating crucial roles of AUF1 and ZFP36L1 induction in Bcl-2 mRNA destabilization by gAcrp. Moreover, knock-down of AUF1 and ZFP36L1 enhanced interaction of Bcl-2 with Beclin-1, and subsequently prevented gAcrp-induced autophagy activation, suggesting that AUF1 and ZFP36L1 induction mediates gAcrp-induced autophagy activation via Bcl-2 mRNA destabilization. Furthermore, suppressive effects of gAcrp on LPS-stimulated inflammatory mediators expression were prevented by gene silencing of AUF1 and ZFP36L1 in macrophages. Taken together, these results suggest that AUF1 and ZFP36L1 induction critically contributes to autophagy induction by gAcrp and are promising targets for anti-inflammatory responses by gAcrp.
( Aastha Shrestha ),( Nirmala Tilija Pun ),( Pil-hoon Park ) 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.5
Adiponectin, a hormone predominantly originated from adipose tissue, has exhibited potent anti-inflammatory properties. Accumulating evidence suggests that autophagy induction plays a crucial role in anti-inflammatory responses by adiponectin. However, underlying molecular mechanisms are still largely unknown. Association of Bcl-2 with Beclin-1, an autophagy activating protein, prevents autophagy induction. We have previously shown that adiponectin-induced autophagy activation is mediated through inhibition of interaction between Bcl-2 and Beclin-1. In the present study, we examined the molecular mechanisms by which adiponectin modulates association of Bcl-2 and Beclin-1 in macrophages. Herein, we demonstrated that globular adiponectin (gAcrp) induced increase in the expression of AUF1 and ZFP36L1, which act as mRNA destabilizing proteins, both in RAW 264.7 macrophages and primary peritoneal macrophages. In addition, gene silencing of AUF1 and ZFP36L1 caused restoration of decrease in Bcl-2 expression and Bcl-2 mRNA half-life by gAcrp, indicating crucial roles of AUF1 and ZFP36L1 induction in Bcl-2 mRNA destabilization by gAcrp. Moreover, knock-down of AUF1 and ZFP36L1 enhanced interaction of Bcl-2 with Beclin-1, and subsequently prevented gAcrp-induced autophagy activation, suggesting that AUF1 and ZFP36L1 induction mediates gAcrp-induced autophagy activation via Bcl-2 mRNA destabilization. Furthermore, suppressive effects of gAcrp on LPS-stimulated inflammatory mediators expression were prevented by gene silencing of AUF1 and ZFP36L1 in macrophages. Taken together, these results suggest that AUF1 and ZFP36L1 induction critically contributes to autophagy induction by gAcrp and are promising targets for anti-inflammatory responses by gAcrp.
Kim, Mi Jin,Kim, Eun Hye,TiliJa Pun, Nirmala,Chang, Jae-Hoon,Kim, Jung-Ae,Jeong, Jee-Heon,Choi, Dong Young,Kim, Sang-Hyun,Park, Pil-Hoon MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.6
<P>The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed inflammasomes activation in murine peritoneal macrophages judged by prevention of interleukin-1β (IL-1β) maturation, caspase-1 activation, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, and pyroptotic cell death. Interestingly, pretreatment with 3-methyl adenine, a pharmacological inhibitor of autophagy, abrogated the suppressive effects of gAcrp on IL-1β secretion and caspase-1 activation, indicating the crucial role of autophagy induction in gAcrp-modulation of the inflammasome activation. In addition, inhibition of 5′Adenosine monophaspahate (AMP)-activated protein kinase (AMPK) signaling abolished suppressive effect of gAcrp on inflammasomes activation. Furthermore, autophagy induction or inhibition of the inflammasome activation by gAcrp was not observed in macrophages deficient in AMPK. Taken together, these results indicate that adiponectin inhibits LPS-primed inflammasomes activation in macrophages via autophagy induction and AMPK signaling-dependent mechanisms.</P>