PMID- 34019860 OWN - NLM STAT- MEDLINE DCOM- 20210622 LR - 20210622 IS - 1096-0333 (Electronic) IS - 0041-008X (Linking) VI - 423 DP - 2021 Jul 15 TI - Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization. PG - 115582 LID - S0041-008X(21)00189-7 [pii] LID - 10.1016/j.taap.2021.115582 [doi] AB - NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1beta and IL-18. Therefore, IL-1beta is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1beta biologicals. The therapies targeting IL-1beta through inhibition of NLRP3 inflammasome are thus being actively explored. We identified safranal, a small molecule responsible for the essence of saffron as a potential inhibitor of the NLRP3 inflammasome. Safranal significantly suppressed the release of IL-1beta from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1beta. Safranal markedly suppressed the expression of NLRP3 and its ATPase activity. Safranal treatment enhanced the expression of NRF2, whereas, si-RNA mediated silencing of Nrf2 abrogated the anti-NLRP3 effect of safranal. Furthermore, safranal inhibited ASC oligomerization and formation of ASC specks. Safranal also displayed anti-NLRP3 activity in multiple mice models. Treatment of animals with safranal reduced the production of IL-1beta in ATP elicited peritoneal inflammation, MSU induced air pouch inflammation, and MSU injected foot paw edema in mice. Thus, our data projects safranal as a potential preclinical drug candidate against NLRP3 inflammasome triggered chronic inflammation. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Gupta, Mehak AU - Gupta M AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. FAU - Wani, Abubakar AU - Wani A AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. FAU - Ahsan, Aitizaz Ul AU - Ahsan AU AD - Cytogenetics Laboratory, Department of Zoology, Panjab University, Chandigarh, India. FAU - Ali, Mehboob AU - Ali M AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. FAU - Chibber, Pankaj AU - Chibber P AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. FAU - Singh, Surjeet AU - Singh S AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. FAU - Digra, Sanjeev K AU - Digra SK AD - Department of Paediatrics, Government Medical College, Jammu, India. FAU - Datt, Manish AU - Datt M AD - Biological and Life Sciences Division, School of Arts and Sciences, Ahmedabad University, Ahmedabad, Gujarat 380009, India. FAU - Bharate, Sandip B AU - Bharate SB AD - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Medicinal Chemistry Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India. FAU - Vishwakarma, Ram A AU - Vishwakarma RA AD - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Medicinal Chemistry Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India. FAU - Singh, Gurdarshan AU - Singh G AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: singh_gd@iiim.res.in. FAU - Kumar, Ajay AU - Kumar A AD - PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address: ajaykumar@iiim.res.in. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210518 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (CARD Signaling Adaptor Proteins) RN - 0 (Cyclohexenes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Pycard protein, mouse) RN - 0 (Terpenes) RN - 4393FR07EA (safranal) SB - IM MH - Animals MH - CARD Signaling Adaptor Proteins/*antagonists & inhibitors/*metabolism MH - Cell Line MH - Cells, Cultured MH - Cyclohexenes/*pharmacology/therapeutic use MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Inflammation/chemically induced/drug therapy/metabolism MH - Mice MH - Mice, Inbred BALB C MH - NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists & inhibitors/*metabolism MH - Terpenes/*pharmacology/therapeutic use OTO - NOTNLM OT - ASC OT - Caspase-1 OT - IL-1beta OT - Macrophages OT - NLRP3 inflammasome OT - Saffron OT - Safranal EDAT- 2021/05/22 06:00 MHDA- 2021/06/23 06:00 CRDT- 2021/05/21 20:13 PHST- 2020/09/30 00:00 [received] PHST- 2021/05/14 00:00 [revised] PHST- 2021/05/16 00:00 [accepted] PHST- 2021/05/22 06:00 [pubmed] PHST- 2021/06/23 06:00 [medline] PHST- 2021/05/21 20:13 [entrez] AID - S0041-008X(21)00189-7 [pii] AID - 10.1016/j.taap.2021.115582 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2021 Jul 15;423:115582. doi: 10.1016/j.taap.2021.115582. Epub 2021 May 18.