## 3 Polyphenols as Potential Agents in TMD
### Molecular Mechanisms of Polyphenols Targeting Inflammation
#### Resveratrol  
Resveratrol (3,4',5-trihydroxystilbene) is a phytoalexin, belonging to the polyphenol class of stilbenes and it can be found in several food sources, including grapes, berries, peanuts, red wine, dark chocolate, and tea [68; 74]. Wide ranges of pharmacological properties for human health have been attributed to resveratrol, including the protection against diabetes, neurodegenerative diseases, cancer, aging, obesity, and cardiovascular diseases [75]. Based on these observations, resveratrol has been proposed as an ideal candidate in improving the TMJ inflammatory pain, by regulating the release of inflammatory cytokines and preventing the progression of cartilage damage. Accumulating evidence is going in this direction. To support this view, _in vitro_ and animal model studies have focused on the role of resveratrol on OA pathogenesis. As an example, it has been demonstrated that supplementation of resveratrol (22.5 and 45 mg/kg) for 12 weeks prevents the progression of OA in C57 BL/6 J mice fed a high-fat diet, by decreasing the type II collagen degradation and inhibiting the chondrocyte apoptosis [76]. The suppression of apoptosis in chondrocytes by resveratrol has also been shown in a traumatic OA-induced persistent mechanical hyperalgesia in a rat model (ACLT plus Mmx rat model), where administration of resveratrol (5 mg/kg) increases the percentage of S phase cells of the cell cycle by the increase of miR8a expression [77]. This approach has been supported by the observation that chondrocyte apoptosis in the OA rats could be associated with the expression of miR-18a, through the reduction in ATM protein kinase expression, which is the target gene of miR-18a involved in chondrocyte proliferation [77]. Moreover, the ability of resveratrol to protect articular chondrocytes is associated with the inhibitory action on MMPs expression, through a mechanism mediated by the inhibition of IL-1\(\beta\)-induced activation of IKB, resulting in the modulation of the NF-kB inflammatory pathway [78]. It has also been shown that improvement in cartilage degeneration could be obtained after intra-articular injection of resveratrol in an experimental model of C57 BL/6 mice induced-OA. In this model, resveratrol could activate autophagy by regulating the AMPK/mTOR signaling pathway, with a consequent increase of LC3, ULK1, and Beclin1 autophagic markers, demonstrating that the promotion of chondrocyte autophagy is one of the main important mechanisms by which resveratrol exerts its chondrocytes effect [79]. An attractive hypothesis suggests the involvement of aryl hydrocarbon receptor (Ahr) in the collagen destruction, through several mechanisms related to pro-inflammatory cytokine production and bone metabolism modulation [80]. Thus, it is worthwhile to evidence that resveratrol (IC50 6 uM) is a strong AhR competitive antagonist, resulting in the inhibitory effects of AhR activation,downregulating oxidative stress and inflammation in several preclinical models, including chondrocytes and rabbit model of OA [80, 81]. The cartilage degeneration process is also induced by SIRT-1 (silent information regulator 2 type 1, also known as sirutin 1) enzymatic activity, regulating the expression of extracellular matrix (ECM)-related protein bone homeostasis in OA and promoting mesenchymal stem cell differentiation [82]. Indeed, the increased chondrocyte apoptosis associated with cartilage breakdown in SIRT-1-deficient mice has been demonstrated, confirming the role of SIRT-1 in cartilage destruction [83]. It is not surprising that activators of SIRT-1, including resveratrol, represent an interesting strategy to counteract the progression of cartilage damage, relating to their potential application in TMJ-related OA. Accumulating evidence has supported this view, reporting that resveratrol could exert a chondrocytes role by increasing SIRT-1 protein expression in a dose-dependent manner (25 and/or 50 \(\upmu\)M) [82].