A preclinical study on the protective effect of melatonin against methotrexate-induced small intestinal damage: effect mediated by attenuation of nitrosative stress, protein tyrosine nitration, and PARP activation

Kolli, Viswa Kalyan; Kanakasabapathy, Indirani; Faith, Minnie; Ramamoorthy, Hemalatha; Isaac, Bina; Natarajan, Kasthuri; Abraham, Premila

doi:10.1007/s00280-013-2115-z

Cited by 38 publications

(32 citation statements)

References 37 publications

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“…Additionally, our map indicates a clear link between MTX and dysbiosis, which to date has not been explicitly unrevealed, although enterocolitis is a known toxic effect of MTX, linked to the induced nitroxidative stress (Kolli et al, 2008, 2013). This is a critical fact as the known adverse effects of MTX, generally described as immunodepressive, appear to be composed not only by the known oxidative organ stress, but also by an added dysbiosis, possibly mediated by an overload on STAT3.…”

Section: Resultsmentioning

confidence: 72%

Multi-omic landscape of rheumatoid arthritis: re-evaluation of drug adverse effects

Tieri

Zhou

Zhu

et al. 2014

Front. Cell Dev. Biol.

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Objective: To provide a frame to estimate the systemic impact (side/adverse events) of (novel) therapeutic targets by taking into consideration drugs potential on the numerous districts involved in rheumatoid arthritis (RA) from the inflammatory and immune response to the gut-intestinal (GI) microbiome.Methods: We curated the collection of molecules from high-throughput screens of diverse (multi-omic) biochemical origin, experimentally associated to RA. Starting from such collection we generated RA-related protein-protein interaction (PPI) networks (interactomes) based on experimental PPI data. Pharmacological treatment simulation, topological and functional analyses were further run to gain insight into the proteins most affected by therapy and by multi-omic modeling.Results: Simulation on the administration of MTX results in the activation of expected (apoptosis) and adverse (nitrogenous metabolism alteration) effects. Growth factor receptor-bound protein 2 (GRB2) and Interleukin-1 Receptor Associated Kinase-4 (IRAK4, already an RA target) emerge as relevant nodes. The former controls the activation of inflammatory, proliferative and degenerative pathways in host and pathogens. The latter controls immune alterations and blocks innate response to pathogens.Conclusions: This multi-omic map properly recollects in a single analytical picture known, yet complex, information like the adverse/side effects of MTX, and provides a reliable platform for in silico hypothesis testing or recommendation on novel therapies. These results can support the development of RA translational research in the design of validation experiments and clinical trials, as such we identify GRB2 as a robust potential new target for RA for its ability to control both synovial degeneracy and dysbiosis, and, conversely, warn on the usage of IRAK4-inhibitors recently promoted, as this involves potential adverse effects in the form of impaired innate response to pathogens.

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Section: Resultsmentioning

confidence: 72%

Multi-omic landscape of rheumatoid arthritis: re-evaluation of drug adverse effects

Tieri

Zhou

Zhu

et al. 2014

Front. Cell Dev. Biol.

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“…Interventions that reduce oxidative stress produce beneficial effects in animal models of colitis, suggesting a potential application of antioxidant agents in IBD. Moreover, the demonstrated protective effects of melatonin in murine models of colitis are associated frequently with a reduction of the oxidative stress . Because melatonin is able to cross the membranes, we cannot exclude that its radical‐scavenging and antioxidant abilities can be important, also in our model, to justify the observed anti‐inflammatory activities.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, the local physiological role of melatonin at the GIT is poorly characterized. In recent years, several in vivo studies showed that melatonin, administered intraperitoneally at high dose, has anti‐inflammatory effects in models of intestinal bowel disease (IBD) . This protection is mainly related with the prevention of nitro‐oxidative stress as well as with the reduction of inflammatory cell infiltration.…”

Section: Introductionmentioning

confidence: 99%

Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin‐1β

Mannino

Caradonna

Cruciata

et al. 2019

Journal of Pineal Research

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Melatonin is the main secretory product of the pineal gland, and it is involved in the regulation of periodic events. A melatonin production independent of the photoperiod is typical of the gut. However, the local physiological role of melatonin at the intestinal tract is poorly characterized. In this study, we evaluated the anti‐inflammatory activities of melatonin in an in vitro model of inflamed intestinal epithelium. To this purpose, we assessed different parameters usually associated with intestinal inflammation using IL‐1β‐stimulated Caco‐2 cells. Differentiated monolayers of Caco‐2 cells were preincubated with melatonin (1 nmol/L‐50 μmol/L) and then exposed to IL‐1β. After each treatment, different inflammatory mediators, DNA‐breakage, and global DNA methylation status were assayed. To evaluate the involvement of melatonin membrane receptors, we also exposed differentiated monolayers to melatonin in the presence of luzindole, a MT1 and MT2 antagonist. Our results showed that melatonin, at concentrations similar to those obtained in the lumen gut after ingestion of dietary supplements for the treatment of sleep disorders, was able to attenuate the inflammatory response induced by IL‐1β. Anti‐inflammatory effects were expressed as both a decrease of the levels of inflammatory mediators, including IL‐6, IL‐8, COX‐2, and NO, and a reduced increase in paracellular permeability. Moreover, the protection was associated with a reduced NF‐κB activation and a prevention of DNA demethylation. Conversely, luzindole did not reverse the melatonin inhibition of stimulated‐IL‐6 release. In conclusion, our findings suggest that melatonin, through a local action, can modulate inflammatory processes at the intestinal level, offering new opportunities for a multimodal management of IBD.

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“…We demonstrated that nimesulide prevented the increase of oxidants, decrease of antioxidants and histopathologic damage by MTX in the intestinal tissue. Kolli et al demonstrated that higher dose of MTX then we used led to oxidative mucosal damage in the rat small intestines [14]. However, it was also reported that even lower doses of MTX (2.5 mg/kg) leads to marked oxidative damage in rat small intestines [3].…”

Section: Discussionmentioning

confidence: 99%

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

et al. 2016

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Intestinal mucositis is one of the major problems in the patients receiving cancer treatment. Nimesulide is a drug with antioxidant, antiinflammatory and antiulcer features. We aimed to investigate the effect of nimesulide on the small intestine mucositis induced by methotrexate (MTX) in rats. Experimental animals were divided into the control group, MTX group (MTXG) and nimesulide+MTX administered group (NMTXG) with eight rats per group. The control and MTXG groups were given distilled water by gavage and the NMTXG was given nimesulide 100 mg/kg orally. After one hour, the NMTXG and MTXG rat groups were administered oral MTX 5 mg/kg. This procedure was repeated once a day for 15 days and the rats were sacrificed. The duodenum and jejunum of each rat was removed for the assessment of biochemical markers and histopathological evaluation. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels were significantly higher in the duodenal and jejunal tissues of the animals which received MTX, compared to the control and NMTXG (P<0.001). Also, the levels of total glutathione (tGSH), glutathione reductase (GSHRd), glutathione peroxidase (GSHPx), catalase (CAT) and superoxide dismutase (SOD) were significantly lower in the MTXG (P<0.001) compared to other groups. MTX led to villus and crypt epithelial damage and inflammation containing marked PMNL and eosinophils in the intestinal tissues histopathologically. Whereas, there was only mild irregularities in the villus structures of the NMTXG. Nimesulide protected the small intestines against damage by MTX. Intestinal mucositis caused by MTX may be preventable by co-administered nimesulide.

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A preclinical study on the protective effect of melatonin against methotrexate-induced small intestinal damage: effect mediated by attenuation of nitrosative stress, protein tyrosine nitration, and PARP activation

Abstract: Because of its versatility in protecting against nitro-oxidative stress and reducing inflammation, we suggest that melatonin could be beneficial in ameliorating MTX-induced enteritis in humans.

Cited by 38 publications

References 37 publications

Multi-omic landscape of rheumatoid arthritis: re-evaluation of drug adverse effects

Multi-omic landscape of rheumatoid arthritis: re-evaluation of drug adverse effects

Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin‐1β

Effects of nimesulide on the small intestine mucositis induced by methotrexate in rats

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