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Cytokine ; 142: 155475, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33667961

RESUMO

BACKGROUND: Progression of chronic inflammatory disease, atherosclerosis is a multifactorial process. Cluster of differentiation 36 (CD36) mediated downstream activation of Toll like receptor 2 (TLR2) and NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome signaling pathway actively participates during chronic inflammation. Nowadays, synergistic combinations of bioactive compounds attained priority in the field of drug discovery and development as therapeutic agents. An investigation regarding the anti-inflammatory potential of a novel drug formulation, BASk which is a combination of three bioactive compounds Betulinic acid (B):Apigenin (A):Skimmianine (Sk) remains the focus area of this research study. We also elucidate the molecular mechanism behind the therapeutic potential of BASk through CD36 mediated activation TLR2-NLRP3 signaling pathway. METHODS: OxLDL induced hPBMCs used to screen out a suitable combination of BASk via MTT, COX, LOX, NOS and MPO assays. Hypercholesterolemia is induced in rabbits by supplementing with 1% cholesterol + 0.5% cholic acid and treated with BASk (2:2:1) (5 mg/Kg) and atorvastatin (10 mg/Kg) for 60 days. CD36, TLR2, NLRP3, NFκB, cytokines, endothelial damage were quantified by reverse transcription, real time PCR, ELISA, flow cytometry and histopathology. RESULTS: hPBMCs pretreated with BASk at 2:2:1 ratio significantly decreased the activities of COX, 15-LOX, NOS and MPO on OxLDL induction than quercetin. Down regulation of CD36, TLR2, MyD88, TRAF6 by BASk further buttressed NLRP3 inflammasome activation mediated by the transcription factor NFκB. This is in correlation with the effect of BASk by balancing pro (IL-1ß, IL-18) and anti-inflammatory (TGF-ß) mediators in the aortic endothelial cells. CONCLUSION: BASk exerted its anti-inflammatory potential by reducing pro-inflammatory mediators during cholesterol supplementation via down regulating CD36 mediated TLR2 - NLRP3 inflammasome cascade. This deciphers a synergistic combination named BASk (2:2:1) as a novel drug formulation against chronic inflammatory disease, atherosclerosis.


Assuntos
Apigenina/farmacologia , Antígenos CD36/metabolismo , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica , Triterpenos Pentacíclicos/farmacologia , Quinolinas/farmacologia , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Araquidonato 15-Lipoxigenase/metabolismo , Aterosclerose/sangue , Biomarcadores/sangue , Sobrevivência Celular/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipídeos/sangue , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase/metabolismo , Peroxidase/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ácido Betulínico
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