# (-)-Fenchone Ameliorates TNBS-Induced Colitis
## 3 Discussion
The histomorphological evaluation confirms the reduction in the inflammatory infiltrate in the group treated with (-)-fenchone. These results are related to a decrease in the migration of inflammatory cells. Oxidative stress plays an important role in the pathophysiology of inflammation, as lipid peroxidation can exacerbate free radical chain reactions and activate the release of inflammatory mediators [38; 39]. Chronic inflammation causes overactivation of the immune system and triggers high levels of ROS that reduce levels of endogenous antioxidants. This process induces the formation of damage in the mucosal layer and bacterial invasion, which in turn stimulates the immune response and contributes to the progression of IBDs [40]. In both the acute and chronic models, (-)-fenchone (150 mg/kg) increased (\(p\) < 0.001) the GSH and SOD levels compared to the colitig group, restoring baseline levels. SOD is part of the enzymatic antioxidant system that forms the first line of defense against superoxide anions and hydrogen peroxide [41; 42]. GSH participates in the non-enzymatic system that protects the integrity and permeability of the cell membrane, promotes the assembly of mucin oligomers, and helps in the maintenance of immune function and the maintenance of protein structure [43]. In addition, the treatment with (-)-fenchone (150 mg/kg) reduced (\(p\) < 0.001) the levels of MDA and MPO compared to the colitic group; these enzymes participate in the lipid peroxidation process, activating the epithelium, which favors the infiltration of neutrophils, the synthesis and release of cytokines by macrophages, among other mediators that contribute to oxidative stress [43]. Thus, the anti-inflammatory effect found in our study may be related to the inhibition of toxic lipoperoxides and/or due to the promotion of the synthesis of endogenous antioxidants. The monoterpenes carvacrol [44] and menthol [45] have been shown to reduce MPO-mediated lipoperoxidation and increase antioxidant defenses. ROS are second messengers for the activation of signal transduction pathways that induce inflammation, such as the signaling pathways of mitogen-activated protein kinases (MAPKs) and NF-\(\kappa\)B, a transcription factor that binds to gene promoters, targeting and triggering the transcription of inflammatory cytokines and chemokines [46; 47]. Treatment with (-)-fenchone in both the acute and chronic phases significantly reduced (\(p\) < 0.001) immunostaining for NF-\(\kappa\)B, as well as reduced levels of inflammatory cytokines (\(p\) < 0.001) IL-1\(\beta\) and TNF-\(\alpha\); these cytokines participate in the innate immune response and play a key role in disrupting the state of intestinal homeostasis and are involved in the recruitment of granulocytes and increased TH17 activity [11; 48]. The main mechanism for controlling responses in the gut is the activation of regulatory T cells (Treg), which play an important role in the maintenance of gastrointestinal homeostasis and secrete immunoregulatory cytokines such as IL-10 and TGF-\(\beta\); these cytokinessuppress macrophage-mediated inflammatory responses and effector T cells [11; 49]. In our study, treatment with (-)-fenchone restored levels (\(p<0.001\)) of IL-10 and increased immunostaining (\(p<0.001\)) for TGF-\(\beta\) when compared to the colitic group. In IBDs, a reduced expression of TGF-\(\beta\) in the mucosa has been observed, which leads to inadequate conditioning of dendritic cells and the perpetuation of the inflammatory state [11]. In our study, treatment with (-)-fenchone in the acute and chronic phases reduced the levels of inflammatory cytokines (TNF-\(\alpha\) and IL-1\(\beta\)) considered responsible for amplifying and maintaining chronic inflammation in IBDs and kept the cytokines IL-10 and TGF-\(\beta\) close to baseline, suggesting an immunomododulatory effect. [PERSON] et al.