Anti-inflammatory effect of the monoterpene myrtenol is dependent on the direct modulation of neutrophil migration and oxidative stress.

Myrtenol is a bicyclic monoterpene with anti-inflammatory properties. However, the mechanisms involved are partially unknown. Here, we investigated the effect of myrtenol during experimental chronic arthritis and the possible modulating activity of oxidative stress and neutrophil migration. Complete Freund's Adjuvant (CFA)-sensitized rats were treated with vehicle (1 mL/kg, po), myrtenol (12.5, 25 or 50 mg/kg, po), indomethacin (10 mg/kg, po) or dexamethasone (0.4 mg/kg) followed by intra-articular injection of CFA (0.5 mg/mL, 50 µL per joint). Then, paw edema and articular incapacitation (paw elevation time) were evaluated for 14 days. On the last day, a blood concentration superoxide dismutase (SOD) and nitrite was determined. In another experimental setting, human neutrophils were incubated with vehicle (sterile saline, 1 mL) or myrtenol (10-100 ng/mL) and the in vitro chemotaxis to N-formylmethionine-leucyl-phenylalanine (fMLP) (10-7 M/well) was evaluated. In addition, antiinflammatory effect of myrtenol was investigated in carrageenan-induced peritonitis. We found that CFA induced a prominent paw swelling and incapacitation of the joint, which were significantly prevented by myrtenol (P < 0.05). In addition, blood accumulation nitrite was attenuated by myrtenol when compared with vehicle-treated CFA group (P < 0.05). Furthermore, plasma levels of SOD were significantly increased by myrtenol versus vehicle-treated CFA group (P < 0.05). Moreover, fMLP-triggered neutrophil chemotaxis and carrageenan-induced peritonitis were markedly prevented by myrtenol (P < 0.05). Therefore, myrtenol showed anti-inflammatory and antinociceptive effects on experimental chronic arthritis, which seems to be related to the direct modulation of neutrophil migration and antioxidant activity.

Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives.

PURPOSE: Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis. METHODS: A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion. RESULTS: Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1ß contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis. CONCLUSIONS: IL-1ß, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.

The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis.

Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL-1 and IL-18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL-1ß (405%), IL-18 (365%), COX-2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL-18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.