Orally administered salecan ameliorates methotrexate-induced intestinal mucositis in mice
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Methotrexate (MTX) is a widely used cancer chemotherapy agent. The efficacy of MTX is often limited by serious side effects, such as intestinal mucositis. The aim of this study was to evaluate the protective effect of water-soluble β-glucan salecan on MTX-induced intestinal toxicity in mice.
Intestinal mucositis was induced in C57BL/6 mice by intraperitoneal injection of MTX for two consecutive days. Mice were orally administrated with saline or salecan for 6 days before MTX injection and continued to the end of the study. Several histological and biochemical parameters were measured in the jejunum.
Orally administration of salecan improved the severity of intestinal mucositis in a dose-dependent manner, as evidenced by the well-maintained mucosal architecture and body weight in salecan-treated groups. Salecan treatment inhibited MTX-induced oxidative stress and effectively scavenged free radicals both in vitro and in vivo. Metabolomics analysis revealed that salecan treatment reversed the intestinal metabolic profiling changes in mice with MTX-induced mucositis. Salecan treatment modulated the innate immunity through the regulation of TLR and Dectin1 expression in the jejunum, thus protecting mice from MTX-induced intestinal damage.
Salecan has potential advantages in the treatment of MTX-induced intestinal mucositis, and its protective effect is mainly attributed to its antioxidant and immunomodulatory properties.
KeywordsMethotrexate Intestine mucositis Salecan Antioxidant Metabonomics
This work was supported by the grant from National Nature Science Foundation of China (Numbers 31671220, 31471111).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 2.Edwin SL, Chan MD, Bruce N, Cronstein MD (2013) Mechanisms of action of methotrexate. Bull Hosp Jt Dis 71(Suppl 1):S5–S8Google Scholar
- 4.Pico J-L, Avila-Garavito A, Naccache P (1998) Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 3(6):446–451Google Scholar
- 18.Pears MR, Cooper JD, Mitchison HM, Mortishire-Smith RJ, Pearce DA, Griffin JL (2005) High resolution 1H NMR-based metabolomics indicates a neurotransmitter cycling deficit in cerebral tissue from a mouse model of Batten disease. J Biol Chem 280(52):42508–42514. https://doi.org/10.1074/jbc.M507380200 CrossRefGoogle Scholar
- 19.Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B (Methodol) 57(1):289–300Google Scholar
- 20.Dok-Go H, Lee KH, Kim HJ, Lee EH, Lee J, Song YS, Lee Y-H, Jin C, Lee YS, Cho J (2003) Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res 965(1):130–136. https://doi.org/10.1016/S0006-8993(02)04150-1 CrossRefGoogle Scholar
- 21.Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47(3):469–474. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x CrossRefGoogle Scholar
- 23.Shinomol GK, Muralidhara (2007) Differential induction of oxidative impairments in brain regions of male mice following subchronic consumption of Khesari dhal (Lathyrus sativus) and detoxified Khesari dhal. Neurotoxicology 28(4):798–806. https://doi.org/10.1016/j.neuro.2007.03.002 CrossRefGoogle Scholar
- 25.Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB, Mucositis Study Section of the Multinational Association for Supportive Care in C, International Society for Oral O (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100(9 Suppl):1995–2025. https://doi.org/10.1002/cncr.20162 CrossRefGoogle Scholar
- 27.Huang CC, Hsu PC, Hung YC, Liao YF, Liu CC, Hour CT, Kao MC, Tsay GJ, Hung HC, Liu GY (2005) Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis 10(4):895–907. https://doi.org/10.1007/s10495-005-2947-z CrossRefGoogle Scholar
- 30.Fijlstra M, Schierbeek H, Voortman G, Dorst KY, van Goudoever JB, Rings EHHM, Tissing WJE (2012) Continuous enteral administration can enable normal amino acid absorption in rats with methotrexate-induced gastrointestinal mucositis. J Nutr 142(11):1983–1990. https://doi.org/10.3945/jn.112.165209 CrossRefGoogle Scholar
- 31.McHardy IH, Goudarzi M, Tong M, Ruegger PM, Schwager E, Weger JR, Graeber TG, Sonnenburg JL, Horvath S, Huttenhower C, McGovern DPB, Fornace AJ, Borneman J, Braun J (2013) Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships. Microbiome 1(1):17. https://doi.org/10.1186/2049-2618-1-17 CrossRefGoogle Scholar
- 32.Stringer AM, Gibson RJ, Bowen JM, Logan RM, Ashton K, Yeoh ASJ, Al-Dasooqi N, Keefe DMK (2009) Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol 90(5):489–499. https://doi.org/10.1111/j.1365-2613.2009.00671.x CrossRefGoogle Scholar
- 33.Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh ASJ, Hamilton J, Keefe DMK (2009) Gastrointestinal microflora and mucins may play a critical role in the development of 5-fluorouracil-induced gastrointestinal mucositis. Exp Biol Med 234(4):430–441. https://doi.org/10.3181/0810-rm-301 CrossRefGoogle Scholar
- 34.Zhou B, Xia X, Wang P, Chen S, Yu C, Huang R, Zhang R, Wang Y, Lu L, Yuan F, Tian Y, Fan Y, Zhang X, Shu Y, Zhang S, Bai D, Wu L, Xu H, Yang L (2018) Induction and amelioration of methotrexate-induced gastrointestinal toxicity are related to immune response and gut microbiota. EBioMed 33:122–133. https://doi.org/10.1016/j.ebiom.2018.06.029 CrossRefGoogle Scholar
- 39.Wong DV, Lima-Junior RC, Carvalho CB, Borges VF, Wanderley CW, Bem AX, Leite CA, Teixeira MA, Batista GL, Silva RL, Cunha TM, Brito GA, Almeida PR, Cunha FQ, Ribeiro RA (2015) The adaptor protein Myd88 is a key signaling molecule in the pathogenesis of irinotecan-induced intestinal mucositis. PLoS One 10(10):e0139985. https://doi.org/10.1371/journal.pone.0139985 CrossRefGoogle Scholar