## 3 Polyphenols as Potential Agents in TMD
### Molecular Mechanisms of Polyphenols Targeting Inflammation
#### 3.1.1 Curcumin  
Curcumin [1,7-bis(4-hydroxy-3 methoxyphenyl)-1,6-heptadien3,5-dione], a bright yellow-orange vegetable pigment, is a bioactive component isolated from rhizome of turmeric _Curcuma longa_[51]. The antioxidant and anti-inflammatory activities of curcumin have been widely investigated, evidencing its potential protective role in the prevention and treatment of several degenerative pathologies [52; 53; 54]. Compelling evidence has shown the role of curcumin on the extracellular matrix protein metabolism of articular chondrocytes through the modulation of inflammatory mediator production, supporting that oral or topical administration of curcumin significantly delayed the initiation and progression of OA in animal models [55; 56]. The potential protective effect of curcumin in the management of OA has been explored in human synovial fibroblasts and mouse models of arthritis, reducing joint inflammation mainly through the inhibition of NF-kB activation and translocation promoted by IL-1\(\upbeta\) and PGE2 and NO production [55; 56; 57; 58; 59; 60; 61]. The reduced expression of NF-kB by curcumin has been associated with the suppression of pro-inflammatory genes and inhibition of downstream products, including COX-2, VEGF, and MMPs in chondrocytes, preventing the cartilage degradation [29; 55; 57; 58]. It has also been shown that curcumin (5-20 \(\upmu\)M) reduces joint inflammation by affecting cartilage remodeling and inhibiting proteoglycan synthesis, through the inhibitory effect on MMP activity, strongly involved in the destruction of cartilage [61; 62; 63].  
One of the mechanisms by which curcumin promotes the protective effect against the cartilage loss is mediated by its anti-apoptotic role in chondrocyte. Enhanced apoptosis of chondrocytes is considered an important factor in the development and progression of cartilage joint degeneration. Indeed, the increase of intracellular ROS production and IL-1\(\upbeta\) which occurs during the cartilage joint degeneration, associated with mitochondrial dysfunction, stimulate the apoptotic process through  
Figure 2: Suggested mechanisms triggered by polyphenols in the prevention of temporomandibular disorders (TMD).  
their interaction with different signal transduction pathways [29; 64; 65]. It has been described that curcumin (20 uM) significantly reduces the apoptosis of chondrocytes, by modulating key apoptotic biomarkers such as caspase-3 and PARP [66].  
It is also worthwhile to mention the involvement of autophagy in the progression of cartilage joint damage [67; 68]. Autophagy is a basal cellular mechanism of selective removal of damaged cytoplasmic components to maintain cellular homeostasis during stress conditions and it is a required process in the chondrocyte apoptosis [69]. It is not surprising that dysregulated autophagy is involved in the articular cartilage destruction and proteoglycan loss, relating to apoptotic cell death induction [67; 69]. In fact, this molecule also decreases the apoptosis of chondrocytes induced by IL-1\(\beta\), promoting an anti-apoptotic mechanism that involves autophagy activation by MAPK/ERK1/2 signaling pathway [70].  
It has been also reported that the protective role of curcumin in the cartilage matrix degradation is mediated by the inhibition of Akt/mTOR signaling pathway, resulting in enhanced autophagy in a mouse model of OA [71]. Moreover, recent evidence reports that curcumin could modulate the Nrf2/ARE signaling pathway that is involved in the protection of cartilage damage, maintaining cartilage homeostasis, and inhibiting apoptosis in OA chondrocytes [72]. Indeed, curcumin, inhibiting inflammation, oxidative stress, and the matrix degradation of TMJ inflammatory chondrocytes promotes cartilage protection [73].