New Insights in Natural Bioactive Compounds for Periodontal Disease: Advanced Molecular Mechanisms and Therapeutic Potential.

Periodontal disease is a chronic inflammatory condition that destroys the tooth-supporting structures due to the host's immune response to microbial biofilms. Traditional periodontal treatments, such as scaling and root planing, pharmacological interventions, and surgical procedures, have significant limitations, including difficulty accessing deep periodontal pockets, biofilm recolonization, and the development of antibiotic resistance. In light of these challenges, natural bioactive compounds derived from plants, herbs, and other natural sources offer a promising alternative due to their anti-inflammatory, antioxidant, antimicrobial, and tissue-regenerative properties. This review focuses on the molecular mechanisms through which bioactive compounds, such as curcumin, resveratrol, epigallocatechin gallate (EGCG), baicalin, carvacrol, berberine, essential oils, and Gum Arabic, exert therapeutic effects in periodontal disease. Bioactive compounds inhibit critical inflammatory pathways like NF-κB, JAK/STAT, and MAPK while activating protective pathways such as Nrf2/ARE, reducing cytokine production and oxidative stress. They also inhibit the activity of matrix metalloproteinases (MMPs), preventing tissue degradation and promoting healing. In addition, these compounds have demonstrated the potential to disrupt bacterial biofilms by interfering with quorum sensing, targeting bacterial cell membranes, and enhancing antibiotic efficacy.Bioactive compounds also modulate the immune system by shifting the balance from pro-inflammatory to anti-inflammatory responses and promoting efferocytosis, which helps resolve inflammation and supports tissue regeneration. However, despite the promising potential of these compounds, challenges related to their poor bioavailability, stability in the oral cavity, and the absence of large-scale clinical trials need to be addressed. Future strategies should prioritize the development of advanced delivery systems like nanoparticles and hydrogels to enhance bioavailability and sustain release, alongside long-term studies to assess the effects of these compounds in human populations. Furthermore, combining bioactive compounds with traditional treatments could provide synergistic benefits in managing periodontal disease. This review aims to explore the therapeutic potential of natural bioactive compounds in managing periodontal disease, emphasizing their molecular mechanisms of action and offering insights into their integration with conventional therapies for a more comprehensive approach to periodontal health.