A Study on the Anti-NF-kappa B, Anti-Candida, and Antioxidant Activities of Two Natural Plant Hormones: Gibberellin A4 and A7

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Nani, Bruno Dias ; Rosalen, Pedro Luiz ; Lazarini, Josy Goldoni ; Orlandi Sardi, Janaina de Cassia ; Romario-Silva, Diego ; de Araujo, Leonardo Pereira ; Beker dos Reis, Mateus Silva ; Breseghello, Isadora ; Cunha, Thiago Mattar ; de Alencar, Severino Matias ; Freitas da Silveira, Nelson Jose ; Franchin, Marcelo

• Document type: Journal article
• Source: PHARMACEUTICS; v. 14, n. 7, p. 11-pg., 2022-07-01.

Abstract

Introduction: Gibberellins (GA) are terpenoids that serve as important plant hormones by acting as growth and response modulators against injuries and parasitism. In this study, we investigated the in vitro anti-NF-kappa B, anti-Candida, and antioxidant activity of gibberellin A4 (GA4) and A7 (GA7) compounds, and further determined their toxicity in vivo. Methods: GA4 and GA7 in vitro toxicity was determined by MTT method, and nontoxic concentrations were then tested to evaluate the GA4 and GA7 anti-NF-kappa B activity in LPS-activated RAW-luc macrophage cell culture (luminescence assay). GA4 in silico anti-NF-kappa B activity was evaluated by molecular docking with the software "AutoDock Vina", "MGLTools", "Pymol", and "LigPlot+", based on data obtained from "The Uniprot database", "Protein Data Bank", and "PubChem database". The GA4 and GA7 in vitro anti-Candida effects against Candida albicans (MYA 2876) were determined (MIC and MFC). GA7 was also evaluated regarding the viability of C. albicans preformed biofilm (microplate assay). In vitro antioxidant activity of GA4 and GA7 was evaluated against peroxyl radicals, superoxide anions, hypochlorous acid, and reactive nitrogen species. GA4 and GA7 in vivo toxicity was determined on the invertebrate Galleria mellonella larvae model. Results: Our data show that GA4 at 30 mu M is nontoxic and capable of reducing 32% of the NF-kappa B activation on RAW-luc macrophages in vitro. In vitro results were confirmed via molecular docking assay (in silico), since GA4 presented binding affinity to NF-kappa B p65 and p50 subunits. GA7 did not present anti-NF-kappa B effects, but exhibited anti-Candida activity with low MIC (94 mM) and MFC (188 mM) values. GA7 also presented antibiofilm properties at 940 mM concentration. GA4 did not present anti-Candida effects. Moreover, GA4 and GA7 showed antioxidant activity against peroxyl radicals, but did not show scavenging activity against the other tested radicals. Both compounds did not affect the survival of G. mellonella larvae, even at extremely high doses (10 g/Kg). Conclusion: Our study provides preclinical evidence indicating that GA4 and GA7 have a favorable low toxicity profile. The study also points to GA4 and GA7 interference with the NF-kappa B via, anti-Candida activity, and a peroxyl radical scavenger, which we argue are relevant biological effects. (AU)

• FAPESP's process: 15/26864-7 - Bioprospection of active compounds from organic propolis with activity on neutrophil migration in inflammatory process.
• Grantee: Bruno Dias Nani
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/09898-0 - Bioprospection of novel anti-inflammatory molecules from natural Brazilian native products
• Grantee: Pedro Luiz Rosalen
• Support Opportunities: Regular Research Grants