Considering Natural products the relationship of p38 MAPK pathway with signaling of pressure and inflammatory/infectious stimuli, we have dedicated to understanding the potential of modulating this pathway to influence the expression of some pro inflammatory cytokines that are especially relevant for variety mediated destruction of mineralized and nonmineralized tissues in periodontal disease. In vitro evidence for the significance of p38 MAPK Hesperidin dissolve solubility to periodontal disease is largely derived from studies demonstrating the important part of this signaling pathway to the regulation of expression of inflammatory cytokines that are highly relevant to the disease process. The cytokines directly or indirectly regulated by p38 MAPK include IL 1B, IL 4, IL 6, IFN?, TNF, NO, PGE2, MMP 13, RANKL in a variety of cell types connected with adaptive and innate immune responses. This part of p38 on regulation of related cytokines has been confirmed also for resident periodontal cells, especially gingival and periodontal ligament Inguinal canal fibroblasts. The actual fact that p38 MAPK regulates the expression of various inflammatory mediators is very important for therapeutic purposes if one considers that targeting expression of a single cytokine may not be successful due to settlement of its biological function by other pro inflammatory cytokines. But, a substantial problem for this method is represented by two characteristics of signaling E7050 pathways: 1) branching, which allows the organization of complex signaling networks, just because a given signaling intermediate can be activated by different upstream activators, and this same intermediate signaling protein can also activate different downstream effectors, and 2) multivalency, which describes the diversity of effects a given signaling pathway might have on cell biology, depending on the character of external stimulation, duration and intensity of stimulation, cell type and differentiation status. The branching of signaling pathways enables multiple regulation points across the pathway and may compensate a decline in exercise of other signaling pathways trough cross talk. Ergo, depending on the level targeted for modulation in a given signaling pathway, inhibition of a given signaling pathway might have unwanted side effects on the activity of other signaling pathways and therefore on the cytokine network. As an example, targeted inhibition of upstream MAP3Ks, such as MEK1, two or three individually result in very different patterns of gene expression despite of the fact that these kinases are upstream activators of JNK MAPkinase. However, MEK3 can also be an activator of p38 MAPK. We have noticed crosstalk between ERK and p38 MAPK signaling pathways in fibroblasts even though targeting p38 MAPK, that is downstream in the signaling pathways.