Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization
Copyright © 2021 Elsevier Inc. All rights reserved..
NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1β and IL-18. Therefore, IL-1β is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1β biologicals. The therapies targeting IL-1β 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-1β from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1β. 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-1β 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:423 |
|---|---|
| Enthalten in: |
Toxicology and applied pharmacology - 423(2021) vom: 15. Juli, Seite 115582 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Gupta, Mehak [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 22.06.2021 Date Revised 22.06.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.taap.2021.115582 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM325692033 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM325692033 | ||
| 003 | DE-627 | ||
| 005 | 20231225192956.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.taap.2021.115582 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1085.xml |
| 035 | |a (DE-627)NLM325692033 | ||
| 035 | |a (NLM)34019860 | ||
| 035 | |a (PII)S0041-008X(21)00189-7 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Gupta, Mehak |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 22.06.2021 | ||
| 500 | |a Date Revised 22.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1β and IL-18. Therefore, IL-1β is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1β biologicals. The therapies targeting IL-1β 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-1β from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1β. 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-1β 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ASC | |
| 650 | 4 | |a Caspase-1 | |
| 650 | 4 | |a IL-1β | |
| 650 | 4 | |a Macrophages | |
| 650 | 4 | |a NLRP3 inflammasome | |
| 650 | 4 | |a Saffron | |
| 650 | 4 | |a Safranal | |
| 650 | 7 | |a CARD Signaling Adaptor Proteins |2 NLM | |
| 650 | 7 | |a Cyclohexenes |2 NLM | |
| 650 | 7 | |a NLR Family, Pyrin Domain-Containing 3 Protein |2 NLM | |
| 650 | 7 | |a NLRP3 protein, human |2 NLM | |
| 650 | 7 | |a Pycard protein, mouse |2 NLM | |
| 650 | 7 | |a Terpenes |2 NLM | |
| 650 | 7 | |a safranal |2 NLM | |
| 650 | 7 | |a 4393FR07EA |2 NLM | |
| 700 | 1 | |a Wani, Abubakar |e verfasserin |4 aut | |
| 700 | 1 | |a Ahsan, Aitizaz Ul |e verfasserin |4 aut | |
| 700 | 1 | |a Ali, Mehboob |e verfasserin |4 aut | |
| 700 | 1 | |a Chibber, Pankaj |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Surjeet |e verfasserin |4 aut | |
| 700 | 1 | |a Digra, Sanjeev K |e verfasserin |4 aut | |
| 700 | 1 | |a Datt, Manish |e verfasserin |4 aut | |
| 700 | 1 | |a Bharate, Sandip B |e verfasserin |4 aut | |
| 700 | 1 | |a Vishwakarma, Ram A |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Gurdarshan |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Ajay |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Toxicology and applied pharmacology |d 1959 |g 423(2021) vom: 15. Juli, Seite 115582 |w (DE-627)NLM000010979 |x 1096-0333 |7 nnns |
| 773 | 1 | 8 | |g volume:423 |g year:2021 |g day:15 |g month:07 |g pages:115582 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.taap.2021.115582 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 423 |j 2021 |b 15 |c 07 |h 115582 | ||