PMID- 25691644
OWN - NLM
STAT- MEDLINE
DCOM- 20160111
LR  - 20181113
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 59
IP  - 5
DP  - 2015 May
TI  - Antileishmanial effect of 18beta-glycyrrhetinic acid is mediated by Toll-like 
      receptor-dependent canonical and noncanonical p38 activation.
PG  - 2531-9
LID - 10.1128/AAC.03997-14 [doi]
AB  - 18beta-Glycyrrhetinic acid (GRA), a natural immunomodulator, greatly reduced the 
      parasite load in experimental visceral leishmaniasis through nitric oxide (NO) 
      upregulation, proinflammatory cytokine expression, and NF-kappaB activation. For the 
      GRA-mediated effect, the primary kinase responsible was found to be p38, and 
      analysis of phosphorylation kinetics as well as studies with dominant-negative 
      (DN) constructs revealed mitogen-activated protein kinase kinase 3 (MKK3) and 
      MKK6 as the immediate upstream regulators of p38. However, detection of remnant 
      p38 kinase activity in the presence of both DN MKK3 and MKK6 suggested 
      alternative pathways of p38 activation. That residual p38 activity was attributed 
      to an autophosphorylation event ensured by the transforming growth factor 
      beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1)-p38 interaction and was 
      completely abolished upon pretreatment with SB203580 in DN MKK3/6 
      double-transfected macrophage cells. Further upstream signaling evaluation by way 
      of phosphorylation kinetics and transfection studies with DN constructs 
      identified TAK1, myeloid differentiation factor 88 (MyD88), interleukin 1 
      receptor (IL-1R)-activated kinase 1 (IRAK1), and tumor necrosis factor (TNF) 
      receptor-associated factor 6 (TRAF6) as important contributors to GRA-mediated 
      macrophage activation. Finally, gene knockdown studies revealed Toll-like 
      receptor 2 (TLR2) and TLR4 as the membrane receptors associated with GRA-mediated 
      antileishmanial activity. Together, the results of this study brought mechanistic 
      insight into the antileishmanial activity of GRA, which is dependent on the 
      TLR2/4-MyD88 signaling axis, leading to MKK3/6-mediated canonical and 
      TAB1-mediated noncanonical p38 activation.
CI  - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved.
FAU - Gupta, Purnima
AU  - Gupta P
AD  - Department of Biochemistry, Calcutta University, Kolkata, India.
FAU - Das, Pijush K
AU  - Das PK
AD  - Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical 
      Biology, Kolkata, India.
FAU - Ukil, Anindita
AU  - Ukil A
AD  - Department of Biochemistry, Calcutta University, Kolkata, India 
      aninditau@yahoo.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150217
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antiparasitic Agents)
RN  - 0 (Toll-Like Receptors)
RN  - 1449-05-4 (18alpha-glycyrrhetinic acid)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - P540XA09DR (Glycyrrhetinic Acid)
SB  - IM
MH  - Animals
MH  - Antiparasitic Agents/*pharmacology
MH  - Cell Line
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Glycyrrhetinic Acid/*analogs & derivatives/pharmacology
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Leishmania donovani/*drug effects
MH  - Mice
MH  - Parasitic Sensitivity Tests
MH  - Toll-Like Receptors/genetics/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/genetics/*metabolism
PMC - PMC4394830
EDAT- 2015/02/19 06:00
MHDA- 2016/01/12 06:00
PMCR- 2015/11/01
CRDT- 2015/02/19 06:00
PHST- 2014/07/30 00:00 [received]
PHST- 2015/02/05 00:00 [accepted]
PHST- 2015/02/19 06:00 [entrez]
PHST- 2015/02/19 06:00 [pubmed]
PHST- 2016/01/12 06:00 [medline]
PHST- 2015/11/01 00:00 [pmc-release]
AID - AAC.03997-14 [pii]
AID - 03997-14 [pii]
AID - 10.1128/AAC.03997-14 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2015 May;59(5):2531-9. doi: 10.1128/AAC.03997-14. 
      Epub 2015 Feb 17.