## 4 Discussion
### Proteins Analysis  
Bone resorption enrolls osteoclasts that secrete various molecular agents for bone degradation, mainly TNF-a, IL-1b, MMP, and free radicals. Furthermore, monocytes, macrophages, neutrophils, and lymphocytes also accumulate on the site, due to chronic inflammatory processes, which are stimulated to produce free radicals and liberate many types of mediators. Then, melatonin might be an adequate adjunctive therapy associated with NSPT to bring and improve treatment, limiting tissue destruction [14]. In addition, [PERSON] et al. [26] obtained excellent results in the melatonin group studying alveolar bone resorption in rats with periodontitis. It was reported that melatonin reduces the synthesis of prostaglandandins (PGE-2) and the up-regulation of a variety of pro-inflammatory cytokines [40], inhibits the adhesion of leuko  
Figure 2: Risk of bias for 6 included articles [30; 31; 32; 33; 34; 35]. cytes to endothelial cells [41], and attenuates transendothelial cell migration [42]. It also stimulates the release of IL-2 [43] and IL-6 [44]. Additionally, melatonin can inhibit acute inflammatory reactions [42]. Various proteins were analyzed in the included studies, such as IL-6, TNF-\(\alpha\), hs-CRP, MMP-9, IL-1b, MDA, and others. Regarding [PERSON] et al. 's [35] assessment, TNF-\(\alpha\) level and AIS scores, at 3 and 6-month, a statistically significant reduction in these two parameters was observed in the melatonin group (\(p<0.01\)), which is in agreement with [PERSON] et al. 's study [45], who obtained a reduction (in serum) of TNF-\(\alpha\) and other pro-inflammatory cytokines, following topical application of melatonin; in contrast, [PERSON] et al. 's study [32] did not report statistically significant results for TNF-\(\alpha\) reduction; there was no improvement, probably due to different samples/period of administration. [PERSON] et al. 's [32] values coincided with studies conducted by [PERSON] et al. [46] and [PERSON] et al. [47]. On the other hand, [PERSON] et al. [32] obtained a significant reduction in the inflammatory biomarkers IL-6 and hs-CRP (\(p=0.008\) and \(p=0.017\), respectively) in the intervention group. At baseline, IL-6 for the control and intervention groups were, respectively, 2.16 \(\pm\) 0.91 pg/mL and 2.0 \(\pm\) 0.92 pg/mL, in contrast to the results obtained after 8 weeks in the intervention group, which showed a statistically significant decrease of 1.42 \(\pm\) 0.73 pg/mL, compared to the control group 2.08 \(\pm\) 0.87 pg/mL, which had no statistical significance. [PERSON] et al. [30] considered the level of MMP-9 (collagenase), which has significantly involved in connective tissue destruction. After melatonin treatment, compared with the control site, there was a statistically significant reduction in the MMP-9 of \(-\)39.25 \(\pm\) 16.46% (\(p<0.001\)). That result was supported by [PERSON] et al. [48], which highlighted the effect of melatonin on MMP-9, in association with other diseases, such as rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis, proving significant inhibition of MMP-9 activity in a dose- and time-dependent manner. Other approaches to inhibit MMP-9 expression have been studied, such as developing reversible peptidomimetic hydroxamate inhibitors, concluding with negative results, due to a lack of specificity and toxic effects in physiological systems. This obstacle can be overcome through the medical delivery of melatonin. [PERSON] et al. [33] evaluated the intervention group's serum levels of IL-1b and MDA. Compared with the baseline results, there were decreased statistically significances (IL-1b with \(p=0.008\) and MDA with \(p<0.001\), respectively). At the same time, serum levels of SOD, GPx, CAT, and TAC significantly increased in the melatonin group. A significant increase in TAC (\(p<0.001\)) was also observed by [PERSON] et al. [30].