PMID- 34248643
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240402
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 12
DP  - 2021
TI  - IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by 
      Inducing Autophagy.
PG  - 695712
LID - 10.3389/fphar.2021.695712 [doi]
LID - 695712
AB  - Aberrant activation of NLRP3 inflammasome has been implicated in several 
      inflammatory diseases. Autophagy is one of the primary mechanisms that regulate 
      NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 
      inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 
      inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK 
      pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was 
      interesting to observe that IIIM-941 did not show any inhibitory activity against 
      LPS induced pro-inflammatory cytokines TNF-alpha and IL-6. The anti-NLRP3 activity of 
      IIIM-941 was significantly reversed when we attempted to block autophagy by using 
      either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. 
      Further, we found that IIIM-941 downregulated the expression of NLRP3 and 
      prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect 
      in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in 
      three different mice models. The anti-inflammatory effect of IIIM-941 was highly 
      significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly 
      effective in suppressing MSU induced IL-1beta in the air pouch model of inflammation 
      without affecting the levels of TNF-alpha and IL-6. Finally, oral efficacy of 
      IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in 
      mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored 
      further for the development of therapies against diseases such as Alzheimer's 
      disease and Parkinson's disease, where hampered autophagy and NLRP3 activation 
      play a crucial role in the pathological development.
CI  - Copyright (c) 2021 Ali, Gupta, Wani, Sharma, Abdullaha, Kour, Choudhary, Bharate, 
      Singh and Kumar.
FAU - Ali, Mehboob
AU  - Ali M
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Gupta, Mehak
AU  - Gupta M
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Wani, Abubakar
AU  - Wani A
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Department of Immunology, St Jude Children's Hospital, Memphis, TN, United 
      States.
FAU - Sharma, Ankita
AU  - Sharma A
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Abdullaha, Mohd
AU  - Abdullaha M
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
AD  - Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of 
      Integrative Medicine, Jammu, India.
FAU - Kour, Dilpreet
AU  - Kour D
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Choudhary, Sushil
AU  - Choudhary S
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Bharate, Sandip B
AU  - Bharate SB
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
AD  - Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of 
      Integrative Medicine, Jammu, India.
FAU - Singh, Gurdarshan
AU  - Singh G
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Kumar, Ajay
AU  - Kumar A
AD  - PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
LA  - eng
PT  - Journal Article
DEP - 20210625
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC8267097
OTO - NOTNLM
OT  - AMP kinase
OT  - ASC oligomerization
OT  - CAMKK2
OT  - NLRP3 inflammasome
OT  - autophagy
OT  - calcium/calmodulin-dependent kinase kinase 2
OT  - inflammation
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/07/13 06:00
MHDA- 2021/07/13 06:01
PMCR- 2021/06/25
CRDT- 2021/07/12 05:46
PHST- 2021/04/15 00:00 [received]
PHST- 2021/06/15 00:00 [accepted]
PHST- 2021/07/12 05:46 [entrez]
PHST- 2021/07/13 06:00 [pubmed]
PHST- 2021/07/13 06:01 [medline]
PHST- 2021/06/25 00:00 [pmc-release]
AID - 695712 [pii]
AID - 10.3389/fphar.2021.695712 [doi]
PST - epublish
SO  - Front Pharmacol. 2021 Jun 25;12:695712. doi: 10.3389/fphar.2021.695712. 
      eCollection 2021.