Novel alantolactone derivative AL-04 exhibits potential anti-inflammatory activity via modulation of iNOS, COX-2 and NF-κB
Copyright © 2022 Elsevier Ltd. All rights reserved..
Natural compounds and their synthesized analogues continue to be valuable sources in the discovery and development of novel anti-inflammatory agents. AL-04 is a thiol analogue derived from a natural sesquiterpene alantolactone, that demonstrated potential anti-inflammatory activity in vitro in comparison to its parent compound. However, the anti-inflammatory mechanism of action of AL-04 has not been elucidated. In this context, we investigated the signaling pathway that primarily mediate the anti-inflammatory activity of AL-04 and its effect on principal inflammatory mediators including iNOS, COX-2 and ROS. Furthermore, the anti-inflammatory activity was investigated in vivo in carrageenan induced paw oedema model in addition to the exploration of anti-nociceptive activity and acute toxicity. The results suggested that treatment with AL-04 significantly decreased the LPS-induced upregulation of pro-inflammatory cytokines and mediators in addition to the downregulated transcription of TNF-α and IL-6 in RAW 264.7 cell line. Furthermore, mRNA and the protein expression of COX-2 and iNOS were also significantly attenuated with AL-04 at a concentration of 10 µM. Western blot studies further suggested that AL-04 downregulated LPS-stimulated NF-κB p65 expression. In addition to this the anti-inflammatory activity of AL-04 was demonstrated in carrageenan induced paw oedema model with significant inhibition of oedema in a dose-dependent manner. The anti-inflammatory activity of AL-04 was further demonstrated in balb/c mice by inhibition of leukocyte migration and vascular permeability. Besides, AL-04 also inhibited thermally and chemically induced pain in tail-flick and acetic acid induced writing assays respectively in balb/c mice suggesting the analgesic potential of the compound. Acute toxicity studies further suggested the appreciable safety of AL-04 at high dose of 2000 mg/kg with no indications of toxicity or changes in biochemical and haematological parameters. Overall, the study insinuates the anti-inflammatory potential of AL-04 and paves way for further exploration of the compound as a safer therapeutic anti-inflammatory agent.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:158 |
|---|---|
| Enthalten in: |
Cytokine - 158(2022) vom: 01. Okt., Seite 155978 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kumar, Anil [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 08.09.2022 Date Revised 28.09.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.cyto.2022.155978 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM344413624 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM344413624 | ||
| 003 | DE-627 | ||
| 005 | 20231226022718.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.cyto.2022.155978 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1147.xml |
| 035 | |a (DE-627)NLM344413624 | ||
| 035 | |a (NLM)35921792 | ||
| 035 | |a (PII)S1043-4666(22)00187-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Kumar, Anil |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel alantolactone derivative AL-04 exhibits potential anti-inflammatory activity via modulation of iNOS, COX-2 and NF-κB |
| 264 | 1 | |c 2022 | |
| 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 08.09.2022 | ||
| 500 | |a Date Revised 28.09.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Natural compounds and their synthesized analogues continue to be valuable sources in the discovery and development of novel anti-inflammatory agents. AL-04 is a thiol analogue derived from a natural sesquiterpene alantolactone, that demonstrated potential anti-inflammatory activity in vitro in comparison to its parent compound. However, the anti-inflammatory mechanism of action of AL-04 has not been elucidated. In this context, we investigated the signaling pathway that primarily mediate the anti-inflammatory activity of AL-04 and its effect on principal inflammatory mediators including iNOS, COX-2 and ROS. Furthermore, the anti-inflammatory activity was investigated in vivo in carrageenan induced paw oedema model in addition to the exploration of anti-nociceptive activity and acute toxicity. The results suggested that treatment with AL-04 significantly decreased the LPS-induced upregulation of pro-inflammatory cytokines and mediators in addition to the downregulated transcription of TNF-α and IL-6 in RAW 264.7 cell line. Furthermore, mRNA and the protein expression of COX-2 and iNOS were also significantly attenuated with AL-04 at a concentration of 10 µM. Western blot studies further suggested that AL-04 downregulated LPS-stimulated NF-κB p65 expression. In addition to this the anti-inflammatory activity of AL-04 was demonstrated in carrageenan induced paw oedema model with significant inhibition of oedema in a dose-dependent manner. The anti-inflammatory activity of AL-04 was further demonstrated in balb/c mice by inhibition of leukocyte migration and vascular permeability. Besides, AL-04 also inhibited thermally and chemically induced pain in tail-flick and acetic acid induced writing assays respectively in balb/c mice suggesting the analgesic potential of the compound. Acute toxicity studies further suggested the appreciable safety of AL-04 at high dose of 2000 mg/kg with no indications of toxicity or changes in biochemical and haematological parameters. Overall, the study insinuates the anti-inflammatory potential of AL-04 and paves way for further exploration of the compound as a safer therapeutic anti-inflammatory agent | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Acute toxicity | |
| 650 | 4 | |a Anti-inflammatory activity | |
| 650 | 4 | |a Carrageenan induced paw oedema | |
| 650 | 4 | |a Cyclooxygenase | |
| 650 | 4 | |a Cytokines | |
| 650 | 4 | |a Inducible nitric oxide | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Lactones |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a NF-kappa B |2 NLM | |
| 650 | 7 | |a Sesquiterpenes, Eudesmane |2 NLM | |
| 650 | 7 | |a Nitric Oxide |2 NLM | |
| 650 | 7 | |a 31C4KY9ESH |2 NLM | |
| 650 | 7 | |a Carrageenan |2 NLM | |
| 650 | 7 | |a 9000-07-1 |2 NLM | |
| 650 | 7 | |a Nitric Oxide Synthase Type II |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Cyclooxygenase 2 |2 NLM | |
| 650 | 7 | |a EC 1.14.99.1 |2 NLM | |
| 650 | 7 | |a alantolactone |2 NLM | |
| 650 | 7 | |a M7GSN5Q1M6 |2 NLM | |
| 700 | 1 | |a Kour, Gurleen |e verfasserin |4 aut | |
| 700 | 1 | |a Chibber, Pankaj |e verfasserin |4 aut | |
| 700 | 1 | |a Saroch, Diksha |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Chetan |e verfasserin |4 aut | |
| 700 | 1 | |a Ahmed, Zabeer |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cytokine |d 1994 |g 158(2022) vom: 01. Okt., Seite 155978 |w (DE-627)NLM012645575 |x 1096-0023 |7 nnns |
| 773 | 1 | 8 | |g volume:158 |g year:2022 |g day:01 |g month:10 |g pages:155978 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.cyto.2022.155978 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 158 |j 2022 |b 01 |c 10 |h 155978 | ||