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Background and Objective: Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) was increasingly recognized as one of the most severe acute hyperimmune response of coronavirus disease 2019 (COVID-19). Clofazimine (CFZ) has attracted attention due to its anti-inflammatory property in immune diseases as well as infectious diseases. However, the role and potential molecular mechanism of CFZ in anti-inflammatory responses remain unclear.

Methods: We analyze the protein expression profiles of CFZ and LPS from Raw264.7 macrophages using quantitative proteomics. Next, the protective effect of CFZ on LPS-induced inflammatory model is assessed, and its underlying mechanism is validated by molecular biology analysis.

Results: LC-MS/MS-based shotgun proteomics analysis identified 4746 (LPS) and 4766 (CFZ) proteins with quantitative information. The key proteins and their critical signal transduction pathways including TLR4/NF-κB/HIF-1α signaling was highlighted, which was involved in multiple inflammatory processes. A further analysis of molecular biology revealed that CFZ could significantly inhibit the proliferation of Raw264.7 macrophages, decrease the levels of TNF-α and IL-1β, alleviate lung histological changes and pulmonary edema, improve the survival rate, and down-regulate TLR4/NF-κB/HIF-1α signaling in LPS model.

Conclusion: This study can provide significant insight into the proteomics-guided pharmacological mechanism study of CFZ and suggest potential therapeutic strategies for infectious disease.

Titel:	Proteomic analysis and identification reveal the anti-inflammatory mechanism of clofazimine on lipopolysaccharide-induced acute lung injury in mice.
Autor/in / Beteiligte Person:	Yang, B ; Gao, Z ; Li, QS ; Zhang, XY ; Song, L ; Wang, YN ; Wang, XY ; Ji, LL ; Xu, HL ; Xie, H ; Feng, FK ; Li, XP ; Li, W ; Wang, R ; Wang, GS
Link:	Full Text Finder (Volltext)
Zeitschrift:	Inflammation research : official journal of the European Histamine Research Society ... [et al.], Jg. 71 (2022-11-01), Heft 10-11, S. 1327-1345
Veröffentlichung:	Basel, Switzerland : Birkhäuser, c1995-, 2022
Medientyp:	academicJournal
ISSN:	1420-908X (electronic)
DOI:	10.1007/s00011-022-01623-w
Schlagwort:	Animals Mice Anti-Inflammatory Agents pharmacology Anti-Inflammatory Agents therapeutic use Chromatography, Liquid Clofazimine Lipopolysaccharides pharmacology Lung pathology NF-kappa B metabolism Proteomics Tandem Mass Spectrometry Toll-Like Receptor 4 metabolism Acute Lung Injury chemically induced Acute Lung Injury drug therapy Acute Lung Injury metabolism Respiratory Distress Syndrome COVID-19 Drug Treatment
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Inflamm Res] 2022 Nov; Vol. 71 (10-11), pp. 1327-1345. <i>Date of Electronic Publication: </i>2022 Aug 13. MeSH Terms: Acute Lung Injury* / chemically induced ; Acute Lung Injury* / drug therapy ; Acute Lung Injury* / metabolism ; Respiratory Distress Syndrome* ; COVID-19 Drug Treatment* ; Animals ; Mice ; Anti-Inflammatory Agents / pharmacology ; Anti-Inflammatory Agents / therapeutic use ; Chromatography, Liquid ; Clofazimine ; Lipopolysaccharides / pharmacology ; Lung / pathology ; NF-kappa B / metabolism ; Proteomics ; Tandem Mass Spectrometry ; Toll-Like Receptor 4 / metabolism References: Respir Physiol Neurobiol. 2007 Dec 15;159(3):350-9. (PMID: 17604701) ; Cell Tissue Res. 2022 Jan;387(1):111-121. (PMID: 34669021) ; Antimicrob Agents Chemother. 2016 May 23;60(6):3470-9. (PMID: 27021320) ; J Hepatol. 2021 Jan;74(1):168-184. (PMID: 33038433) ; Inflamm Res. 2020 Sep;69(9):883-895. (PMID: 32647933) ; Immunol Rev. 2016 Jan;269(1):228-47. (PMID: 26683156) ; Nature. 2019 Sep;573(7775):590-594. (PMID: 31511697) ; J Exp Med. 2018 Sep 3;215(9):2413-2428. (PMID: 30093533) ; Cell Cycle. 2022 Jul 19;:1-14. (PMID: 35852392) ; Respir Physiol Neurobiol. 2015 Apr;209:52-8. (PMID: 25466727) ; Nat Rev Mol Cell Biol. 2019 May;20(5):285-302. (PMID: 30659282) ; J Surg Res. 2015 Mar;194(1):273-80. (PMID: 25491174) ; Clin Exp Allergy. 2016 Mar;46(3):397-410. (PMID: 26685098) ; Nature. 2014 May 29;509(7502):582-7. (PMID: 24870543) ; Immunopharmacol Immunotoxicol. 2022 Jun;44(3):387-399. (PMID: 35306954) ; Open Biol. 2020 Sep;10(9):200160. (PMID: 32961074) ; J Immunol. 2019 Dec 15;203(12):3325-3338. (PMID: 31732533) ; Eur Respir J. 2021 Jul 1;58(1):. (PMID: 33334945) ; FASEB J. 2021 May;35(5):e21512. (PMID: 33811692) ; Shock. 2022 Feb 1;57(2):212-220. (PMID: 34172615) ; Semin Respir Crit Care Med. 2019 Feb;40(1):31-39. (PMID: 31060086) ; Signal Transduct Target Ther. 2021 Aug 18;6(1):308. (PMID: 34408131) ; Diagnostics (Basel). 2020 Dec 06;10(12):. (PMID: 33291238) ; Expert Rev Respir Med. 2010 Dec;4(6):773-83. (PMID: 21128752) ; Respirology. 2021 Nov;26(11):1027-1040. (PMID: 34605114) ; Gastroenterology. 2007 Jun;132(7):2313-9. (PMID: 17570206) ; Inflamm Res. 2021 Apr;70(4):407-428. (PMID: 33640999) ; Gastroenterology. 2020 Nov;159(5):1763-1777.e14. (PMID: 32652144) ; EMBO J. 2021 Sep 15;40(18):e108249. (PMID: 34296442) ; Mol Pharm. 2015 Jul 6;12(7):2517-27. (PMID: 25909959) ; Int J Mol Sci. 2021 Feb 20;22(4):. (PMID: 33672738) ; Int J Mol Sci. 2021 Mar 04;22(5):. (PMID: 33806560) ; Annu Rev Immunol. 2009;27:693-733. (PMID: 19302050) ; Proc Natl Acad Sci U S A. 2019 May 14;116(20):9714-9722. (PMID: 31048504) ; Nature. 2021 May;593(7859):418-423. (PMID: 33727703) ; Lancet. 2019 Sep 14;394(10202):953-966. (PMID: 31526739) ; J Dtsch Dermatol Ges. 2017 Aug;15(8):801-827. (PMID: 28763601) ; Expert Opin Ther Targets. 2018 May;22(5):401-408. (PMID: 29658361) ; Int Immunopharmacol. 2020 Jul;84:106520. (PMID: 32325405) ; Cell Chem Biol. 2017 Aug 17;24(8):993-1004.e4. (PMID: 28781126) ; Nat Commun. 2015 Mar 31;6:6637. (PMID: 25824719) ; Mol Neurobiol. 2022 Feb;59(2):916-931. (PMID: 34797521) ; J Neurol Sci. 2021 Nov 15;430:120023. (PMID: 34678659) ; Inflamm Res. 2022 Aug;71(7-8):741-758. (PMID: 35612604) ; Sci Rep. 2015 May 27;5:10333. (PMID: 26015371) ; Haematologica. 2020 Apr;105(4):971-986. (PMID: 31371410) ; Inflamm Res. 2018 May;67(5):445-453. (PMID: 29497773) ; J Clin Microbiol. 2020 May 26;58(6):. (PMID: 32245835) ; Theranostics. 2021 Jan 1;11(1):316-329. (PMID: 33391477) ; J Eur Acad Dermatol Venereol. 2001 May;15(3):257-9. (PMID: 11683294) ; Nat Genet. 2021 Apr;53(4):500-510. (PMID: 33782605) ; Int J Infect Dis. 2020 Dec;101:29-32. (PMID: 33007455) Contributed Indexing: Keywords: Acute lung injury; Acute respiratory distress syndrome; Anti-inflammatory; Clofazimine; Lipopolysaccharide; Proteomics Substance Nomenclature: 0 (Anti-Inflammatory Agents) ; D959AE5USF (Clofazimine) ; 0 (Lipopolysaccharides) ; 0 (NF-kappa B) ; 0 (Toll-Like Receptor 4) Entry Date(s): Date Created: 20220813 Date Completed: 20221102 Latest Revision: 20221207 Update Code: 20240513 PubMed Central ID: PMC9376043

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Proteomic analysis and identification reveal the anti-inflammatory mechanism of clofazimine on lipopolysaccharide-induced acute lung injury in mice.