tan 1 ✉ Resveratrol (RES) is a natural polyphenol with potential as an adjunctive therapeutic modality for periodontitis. However, its inferior pharmacokinetics and toxicity concerns about its commonly used solvent dimethyl sulfoxide (DMSO) hinder translation to clinical applicability. Our study aimed to investigate the comparative antimicrobial properties of RES and its analogues (pterostilbene [PTS], oxyresveratrol [OXY] and piceatannol [PIC]), utilizing 2-hydroxypropyl-β-cyclodextrin (HpβCD) as a solubiliser, which has a well-documented safety profile and FDA approval. These properties were investigated against Fusobacterium nucleatum, a key periodontal pathogen. PTS demonstrated the most potent antibacterial effects in HPβCD, with MIC > 60-fold lower than that of RES, OXY and PIC. In addition, PTS inhibited F. nucleatum biofilm formation. PTS exerted antimicrobial effects by eliciting leakage of cellular contents, leading to loss of bacterial cell viability. PTS also conferred immunomodulatory effects on F. nucleatum-challenged macrophages via upregulation of antioxidant pathways and inhibition of NF-κB activation. Given the superior antimicrobial potency of PTS against F. nucleatum compared to RES and other analogues, and coupled with its immunomodulatory properties, ptS complexed with HpβCD holds promise as a candidate nutraceutical for the adjunctive treatment of periodontitis.

Periodontitis is a common chronic inflammatory disease driven by the interaction between a dysbiotic oral microbiome and the dysregulated host immune-inflammatory response. Naturally derived nutraceuticals, such as resveratrol and its analogs, are potential adjunctive therapies in periodontal treatment due to their antimicrobial and anti-inflammatory properties. Furthermore, different analogs of resveratrol and the choice of solvents used may lead to varying effects on therapeutic properties. This review presents the current findings and gaps in our understanding on the potential utility of resveratrol and its analogs in periodontal treatment.