@PHDTHESIS{ 2020:1505976487,
 	title = {Impact of sesquiterpene lactones on the cutaneous inflammatory response. A systematic review, in silico, in vitro and in vivo integrated approach.},
 	year = {2020},
 	url = "https://bdtd.unifal-mg.edu.br:8443/handle/tede/1651",
 	abstract = "Sesquiterpene lactones (SL) are indicated as potential scaffolds for anti-inflammatory drug
 design. However, cutaneous hypersensitivity reactions are proposed as limitations for SL
 therapeutic use. In addition, the anti-inflammatory applicability of SL remains underestimated
 since the impact of SL on inflammatory nociception and tissue repair are overlooked. Therefore,
 we initially developed a systematic review investigated the impact of SL on the skin and skinrelated
 cells. Then, we investigated the impact of tagitinin F (TAG-F) on LPS-challenge
 macrophages, carrageenan-induced paw edema and mechanical hyperalgesia, and excisional
 skin wounds in mice. Thirty studies and forty-nine SL were analyzed in our systematic review.
 In vivo studies indicated that most SL induced cutaneous contact dermatitis associated with
 edema, erythema, and inflammatory infiltrate. Conversely, in vitro evidence indicated a dosedependent
 anti-inflammatory effect of SL, which were mainly associated to NF-κB, cytokines,
 5-lipoxygenase (5-LOX) and cyclooxygenase (COX-2) downregulation in keratinocytes,
 fibroblasts and cells involved in cutaneous immunological responses. From molecular docking,
 different affinity between SL and the enzymes 5-LOX, COX-2, MMP-1, 2 and 9 was identified.
 The current evidence supports the cutaneous immunomodulatory effects of SL. Although in
 vitro and in vivo studies indicate opposite anti- or pro-inflammatory effects, this contradiction
 exhibits a dose-dependent component. In our experimental study, RAW 264.7 macrophages in
 culture were challenge with LPS and treated with TAG-F (10, 50, 100, 500 μM). The paw of
 BALB/c mice was injected with carrageenan, treated with 0.5% and 1% TAG-F and evaluated
 during 6h post-treatment. Excisional wounds were also produced in BALB/c mice and treated
 with 0.5% and 1% TAG-F during 7 days. Our results indicated a consistent dose-dependent
 downregulation in 5-LOX, COX-1 and COX-2, matrix metalloproteinase (MMP-1 and MMP-
 2) activity; as well as attenuation in prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and
 tumor necrosis factor-α (TNF-α) production in both models in vitro and in vivo. In vivo, TAGF
 also attenuated carrageenan-induced paw oedema and mechanical hyperalgesia in mice. From
 the excisional skin wound, TAG-F was also effective in reducing neutrophils and macrophages
 infiltration and stimulating collagen deposition in the scar tissue, accelerating tissue maturation.
 Together, our findings indicate that the anti-inflammatory effect of TAG-F is more
 comprehensive than previously suggested, exerting a significant impact on the control of
 inflammatory pain and modulating central metabolic processes linked to skin wounds healing.",
 	publisher = {Universidade Federal de Alfenas},
 	scholl = {Programa de Pós-Graduação em Biociências Aplicada à Saúde},
 	note = {Instituto de Ciências Biomédicas}
}