Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Timely reperfusion is considered an optimal treatment for AMI. Paradoxically, the procedure of reperfusion can itself cause myocardial tissue injury. Therefore, a strategy to minimize the reperfusion‐induced myocardial tissue injury is vital for salvaging the healthy myocardium. Herein, we investigated the cardioprotective effects of fisetin, a natural flavonoid, against ischemia/reperfusion (I/R) injury (IRI) using a Langendorff isolated heart perfusion system. I/R produced significant myocardial tissue injury, which was characterized by elevated levels of lactate dehydrogenase and creatine kinase in the perfusate and decreased indices of hemodynamic parameters. Furthermore, I/R resulted in elevated oxidative stress, uncoupling of the mitochondrial electron transport chain, increased mitochondrial swelling, a decrease of the mitochondrial membrane potential, and induction of apoptosis. Moreover, IRI was associated with a loss of the mitochondrial structure and decreased mitochondrial biogenesis. However, when the animals were pretreated with fisetin, it significantly attenuated the I/R‐induced myocardial tissue injury, blunted the oxidative stress, and restored the structure and function of mitochondria. Mechanistically, the fisetin effects were found to be mediated via inhibition of glycogen synthase kinase 3β (GSK3β), which was confirmed by a biochemical assay and molecular docking studies.

Dental caries, the most common oral disease, is a major public healthcare burden and affects more than three billion people worldwide. The contemporary understanding of the need for a healthy microbiome and the emergence of antimicrobial resistance has resulted in an urgent need to identify compounds that curb the virulence of pathobionts without microbial killing. Through this study, we have demonstrated for the first time that 5,6,7-trihydroxyflavone (Baicalein) significantly downregulates crucial caries-related virulence phenotypes in Streptococcus mutans. Baicalein significantly inhibited biofilm formation by Streptococcus mutans UA159 (MBIC₅₀ = 200 μM), without significant growth inhibition. Notably, these concentrations of baicalein did not affect the commensal S. gordonii. Strikingly, baicalein significantly reduced cell surface hydrophobicity, autoaggregation and acid production by S. mutans. Mechanistic studies (qRT-PCR) showed downregulation of various genes regulating biofilm formation, surface attachment, quorum sensing, acid production and competence. Finally, we demonstrate the potential translational value of baicalein by reporting synergistic interaction with fluoride against S. mutans biofilms.

Despite the substantial research advancements on oral diseases, dental caries remains a major healthcare burden. A disease of microbial dysbiosis, dental caries is characterised by the formation of biofilms that assist demineralisation and destruction of the dental hard tissues. While it is well understood that this is a multi-kingdom biofilm-mediated disease, it has been elucidated that acid producing and acid tolerant bacteria play pioneering roles in the process. Specifically, Streptococcus mutans houses major virulence pathways that enable it to thrive in the oral cavity and cause caries. This pathogen adheres to the tooth substrate, forms biofilms, resists external stress, produces acids, kills closely related species, and survives the acid as well as the host clearance mechanisms. For an organism to be able to confer such virulence, it requires a large and complex gene network which synergise to establish disease. In this review, we have charted how these multi-faceted genes control several caries-related functions of Streptococcus mutans. In a futuristic thinking approach, we also briefly discuss the potential roles of omics and machine learning, to ease the study of non-functional genes that may play a major role and enable the integration of experimental data.

Aims To investigate the effects of trans‐cinnamaldehyde (TC) and its synergistic activity with chlorhexidine and fluoride against S. mutans . Methods and Results S. mutans UA159 was treated with TC alone and in combination with chlorhexidine or sodium fluoride. The synergy profile was analyzed using the Zero Interaction Potency model. TC showed strong synergism (synergy score of 21.697) with chlorhexidine, but additive effect (synergy score of 5.298) with fluoride. TC and the combinations were tested for acid production (glycolytic pH drop) and biofilm formation by S. mutans , and nitric oxide production in macrophages. TC significantly inhibited sucrose‐dependent biofilm formation and acid production by S. mutans . Mechanistic studies were carried out by qRT‐ PCR based transcriptomic studies which showed that TC acts by impairing genes related to metabolism, quorum sensing, bacteriocin expression, stress tolerance and biofilm formation. Conclusions TC potentiates chlorhexidine and sodium fluoride in inhibiting S. mutans biofilms and virulence through multiple mechanisms. This study sheds significant new light on the potential to develop TC as an anti‐caries treatment. Significance and Impact of the Study Oral diseases were classified as a “silent epidemic” in the US Surgeon General’s Report on Oral Health. Two decades later, >4 billion people are still affected worldwide by caries, having significant effects on the quality of life. There is an urgent need to develop novel compounds and strategies to combat dental caries. Here, we prove that trans‐cinnamaldehyde (TC) downregulates multiple pathways and potentiates the chlorhexidine and fluoride to prevent S. mutans biofilms and virulence. This study sheds significant new light on the potential to develop TC in combination with chlorhexidine or fluoride as novel treatments to arrest dental caries.