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Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis

Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
D’Ascola, Angela;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Irrera, Natasha;
Affiliation
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina ,Messina ,Italy
Ettari, Roberta;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Bitto, Alessandra;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Pallio, Giovanni;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Mannino, Federica;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Atteritano, Marco;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Campo, Giuseppe M.;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Minutoli, Letteria;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Arcoraci, Vincenzo;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Squadrito, Violetta;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Picciolo, Giacomo;
Affiliation
Department of Clinical and Experimental Medicine, University of Messina ,Messina ,Italy
Squadrito, Francesco;
Affiliation
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina ,Messina ,Italy
Altavilla, Domenica

Introduction: Drug combination is widely used to treat chronic inflammatory diseases. A similar strategy might be worth of interest to design plant-derived natural products to treat inflammatory conditions. Curcumin is a natural phenolic compound which shares anti-inflammatory activity with both flavocoxid, a flavonoid mixture of baicalin and catechin, and β-caryophyllene, a bicyclic sesquiterpene. The aim of this study was to investigate the synergy potential of curcumin with both flavocoxid and β-caryophyllene in human articular chondrocytes triggered with lipopolysaccharide (LPS), in an experimental in vitro model of osteoarthritis. Materials and Methods: Human articular chondrocytes were stimulated with LPS alone or in combination with different treatments. Total RNA was extracted 4 h after treatment to study interleukin 1β (IL-1β), NF-κB, and STAT3 mRNA expression. A drug combination study was designed choosing 5 doses to demonstrate a synergistic effect of compounds, according to Chou and Talalay method. A median-effect equation was applied and finally, the combination index (CI) was used to clarify the nature of the compounds interaction (synergistic versus additive versus antagonistic inhibitory effects); CI < 1, CI = 1, and CI > 1 indicated synergistic, additive, and antagonistic effects, respectively. Results: LPS prompted IL-1β expression. Curcumin, flavocoxid and β-caryophyllene suppressed IL-1β expression with different IC 50 . A synergistic action for the reduction of the inflammatory phenotype in human chondrocytes was observed for the combination curcumin-flavocoxid with a percentage from 10% to 90%, and for the combination curcumin-β-caryophyllene from 50% to 90%. IC 50 doses of either flavocoxid, β-caryophyllene and curcumin alone or in combination were safe and did not affect cell vitality. Moreover, the same IC 50 doses reduced the transcription factors NF-κB and STAT3 mRNA expression and interestingly the effects of the combinations were greater than the natural products alone, thus suggesting that the site where the synergy takes place could be at the signal transduction level. Discussion: The results suggest that curcumin synergizes with either flavocoxid or β-caryophyllene, exerting an anti-inflammatory activity and thus strongly suggesting the potential of a dual combination of these compounds for the management of osteoarthritis and unmasking a new feature of these natural products.

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License Holder: Copyright © 2019 D’Ascola, Irrera, Ettari, Bitto, Pallio, Mannino, Atteritano, Campo, Minutoli, Arcoraci, Squadrito, Picciolo, Squadrito and Altavilla

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