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Purpose Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis. Methods iNOS-knockout (iNOS −/− ) and C57BL/6 (WT, wild type) animals ( n  = 5–6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility. Results Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS −/− mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS −/− mice when compared with wild-type animals that were given irinotecan. Conclusions This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.

Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

PurposeAnticancer-drug efficacy seems to involve the direct interaction with host immune cells. Although topoisomerase I (Top I) inhibitors have been suggested to block LPS-evoked inflammation, the interaction between these drugs and toll-like receptor 4 (TLR4) is unaddressed.MethodsSN-38, the active metabolite of the Top I inhibitor irinotecan, and TLR4 interaction was assessed using the in vitro luciferase nuclear factor-κB reporter assay, neutrophil migration to murine air-pouch, in silico simulation, and the thermal shift assay (TSA). Topotecan was used as a positive anti-inflammatory control.ResultsNon-cytotoxic concentrations of SN-38 attenuated LPS (a TLR4 agonist)-driven cell activation without affecting peptidoglycan (a TLR2 agonist)-activating response. Similarly, topotecan also prevented LPS-induced inflammation. Conversely, increasing concentrations of LPS reversed the SN-38 inhibitory effect. In addition, SN-38 abrogated LPS-dependent neutrophil migration and reduced TNF-α, IL-6, and keratinocyte chemoattractant levels in the air-pouch model, but failed to inhibit zymosan (a TLR2 agonist)-induced cell migration. A two-step molecular docking analysis indicated two potential binding sites for the SN-38 in the MD-2/TLR4 complex, the hydrophobic MD-2 pocket (binding energy of − 8.1 kcal/mol) and the rim of the same molecule (− 6.9 kcal/mol). The topotecan also bound to the MD-2 pocket. In addition, not only the lactone forms, but also the carboxylate conformations of both Top I inhibitors interacted with the MD-2 molecule. Furthermore, the TSA suggested the interaction of SN-38 with MD-2.ConclusionsTherefore, SN-38 inhibits acute inflammation by blocking LPS-driven TLR4 signaling. This mechanism seems to be shared by other Top I inhibitors.

Neurodegenerative diseases (NDs) are a group of chronic, progressive disorders characterized by the gradual loss of neurons that affect specific regions of the brain, which leads to deficits in specific functions (e.g., memory, movement, cognition). The mechanism that drives chronic progression of NDs remains elusive. Among the proposed underlying pathophysiological mechanisms, aggregation and accumulation of misfolded proteins and neuroinflammation have been credited to contribute to extensive neural loss. Therapeutic agents that confer neuroprotection by downregulating these shared characteristics could therefore have beneficial effects on a wide range of NDs. In this regard, a commonly used antibiotic, doxycycline (Doxy), has been shown to reduce the progression and severity of disease in different experimental models of neurodegeneration by counteracting these common features. This review will focus on the effects reported for Doxy regarding its neuroprotective properties, the “off-target” effects, thereby supporting its evaluation as a new therapeutic approach for diseases associated with a neurodegeneration.

BackgroundPrevious data have reported that the growth of established tumors may be facilitated by postsepsis disorder through changes in the microenvironment and immune dysfunction. However, the influence of postsepsis disorder in initial carcinogenesis remains elusive.MethodsIn the present work, the effect of postsepsis on inflammation-induced early carcinogenesis was evaluated in an experimental model of colitis-associated colorectal cancer (CAC). We also analyzed the frequency and role of intestinal T regulatory cells (Treg) in CAC carcinogenesis.ResultsThe colitis grade and the tumor development rate were evaluated postmortem or in vivo through serial colonoscopies. Sepsis-surviving mice (SSM) presented with a lower colonic DNA damage, polyp incidence, reduced tumor load, and milder colitis than their sham-operated counterparts. Ablating Treg led to restoration of the ability to develop colitis and tumor polyps in the SSM, in a similar fashion to that in the sham-operated mice. On the other hand, the growth of subcutaneously inoculated MC38luc colorectal cancer cells or previously established chemical CAC tumors was increased in SSM.ConclusionOur results provide evidence that postsepsis disorder has a dual effect in cancer development, inhibiting inflammation-induced early carcinogenesis in a Treg-dependent manner, while increasing the growth of previously established tumors.

Background and purpose: The discovery of chemical substances with carcinogenic properties has allowed the development of several experimental models of colorectal cancer (CRC). Classically, experimental models of CRC in mice have been evaluated through clinical or serial euthanasia. The present study aims to investigate the role of low endoscopy in the analysis of carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG). Methods: Thirty C57BL6 mice were divided into two groups: a control group with fifteen animals that underwent rectal instillation of saline solution on day 0 and a carcinogen group with fifteen animals that underwent a 100 mg/kg MNNG rectal instillation on day 0. In both groups, low endoscopies were performed on weeks 4 and 8. We used a validated endoscopic scoring system to evaluate the severity of colitis and colorectal tumor. Euthanasia was carried out at week 12. Results: We observed higher inflammation scores (p < 0.001) and a higher number of tumors (p < 0.05) in the MNNG group than the control group, both at weeks 4 and 8. A worsening of inflammation scores from the first to the second endoscopy was also noticeable in the MNNG group. There were no bowel perforations related to the procedure, and there was one death in the control group. Conclusion: Low endoscopy in experimental animals allows safe macroscopic evaluation of colorectal carcinogenesis without the need for euthanasia.