Nitric oxide plays a critical role in methotrexate-induced hyperplasia of enterochromaffin cells containing 5-hydroxytryptamine in rat small intestine

Takano, Yuho; Hirano, Megumi; Machida, Takuji; Obara, Yusuke; Hamaue, Naoya; Fujita, Kana; Taniguchi, Masafumi; Endo, Tomoko; Shiga, Saki; Machida, Maiko; Iizuka, Kenji; Hirafuji, Masahiko

doi:10.1016/j.jphs.2019.09.001

Cited by 9 publications

(10 citation statements)

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“…Significant hyperplasia of enterochromaffin cells has been reported to occur following a single administration of methotrexate at a dose of 50 mg/kg [5], but this is almost completely inhibited by l-NAME [6]. The administration of methotrexate at 12.5 mg/kg for 4 consecutive days (with an equivalent final total dose of 50 mg/kg) induced moderate hyperplasia of enterochromaffin cells, with l-NAME potentiating the hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that the role of endogenous NO in 5-HT synthesis varies between a single and a consecutive administration of methotrexate. In fact, among the 3 types of NOS, only iNOS is induced by a single administration of methotrexate [6], whereas constitutive NOS (cNOS), that is, endothelial NOS and neuronal NOS, is induced by a consecutive administration of methotrexate [7]. Tanaka et al [14] have reported that prior administration of l-NAME to rats exacerbates gastrointestinal injury induced by indomethacin, while it is prevented when l-NAME is administered 6 h after administration of indomethacin.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that a single administration of methotrexate (50 mg/kg) to rats potentiates the intestinal 5-HT synthesis associated with the hyperplasia of enterochromaffin cells [5]. Furthermore, we determined that the nitric oxide (NO) produced by inducible NO synthase (iNOS) is required for the methotrexate-induced ileal 5-HT synthesis [6]. Interestingly, the role of endogenous NO in the intestinal mucosal injury differs between rats treated with a single and a consecutive administration of methotrexate, even when the total dose is the same [7].…”

Section: Introductionmentioning

confidence: 99%

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Role of Nitric Oxide in the Change of 5-Hydroxytryptamine Synthesis in the Intestine by a Consecutive Administration of Methotrexate to Rats

et al. 2020

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This study aimed to investigate whether the consecutive administration of methotrexate affects 5-hydroxytryptamine (5-HT) synthesis in the rat small intestine. Rats received methotrexate at a dose of 12.5 mg/kg intraperitoneally on 4 consecutive days. N G-nitro-L-arginine methyl ester (L-NAME) was given subcutaneously to inhibit nitric oxide (NO) synthase. Methotrexate moderately altered 5-HT synthesis, whereas the combined administration of methotrexate and L-NAME significantly changed 5-HT synthesis in the rat ileal tissue. These results suggest that endogenous NO has an antagonistic role in the induction of 5-HT synthesis in rats following the consecutive administration of methotrexate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Nitric Oxide in the Change of 5-Hydroxytryptamine Synthesis in the Intestine by a Consecutive Administration of Methotrexate to Rats

et al. 2020

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“…4) We also found that nitric oxide (NO) produced by inducible NO synthase (iNOS) plays a critical role in the methotrexate-induced hyperplasia of enterochromaffin cells in the intestine. 6) The C57BL/6 mouse was the first mouse strain whose genome was fully sequenced in 2002. This strain is widely used as physiological or pathophysiological models for in vivo experiments and is also often applied to generate transgenic or knockout mouse models, including NOS knockout mice.…”

Section: Introductionmentioning

confidence: 99%

“…Our results show that methotrexate significantly induces hyperplasia of enterochromaffin cells and iNOS expression in mouse intestine, and the effects of methotrexate are similar to those previously found in rats. 4,6)…”

Section: Introductionmentioning

confidence: 99%

Methotrexate Induces Hyperplasia of Enterochromaffin Cells in Mouse Jejunum

et al. 2021

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5-Hydroxytryptamine (5-HT) is synthesized by L-tryptophan hydroxylase (TPH) and is stored mainly in enterochromaffin cells of the mucosal epithelium. We previously reported that administration of methotrexate, an anticancer agent, to rats caused hyperplasia of enterochromaffin cells, and nitric oxide (NO) might be involved in the underlying mechanism. The aim of this study was to clarify the effect of methotrexate on hyperplasia of enterochromaffin cells in mice. C57BL/6J mice were intraperitoneally injected with methotrexate or saline as a control. Methotrexate caused an increase in the number of TPH-expressing cells (i.e., enterochromaffin cells) in the jejunum. Methotrexate also increased inducible, but not constitutive, NOS mRNA expression. Our results indicate that methotrexate potentiates 5-HT synthesis in mice, as we previously found in rats.

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Bacillus Subtilis Promotes the Release of 5-HT to Regulate Intestinal Peristalsis in STC Mice via Bile Acid and Its Receptor TGR5 Pathway

Chen

Feng

et al. 2021

Dig Dis Sci

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Background Slow transit constipation (STC) is caused by intestinal peristalsis dysfunction and is closely associated with disturbance of the intestinal microecological balance. Bacillus subtilis plays a positive role in the treatment of STC, but its mechanism needs to be further explored. Aims The purpose of the present study was to explore the effects and mechanism of B. subtilis on the pathophysiology of STC. Methods A STC mouse model was established with compound diphenoxylate, following which B. subtilis was used to treat STC. The effects and possible mechanism of B. subtilis on STC were investigated by assessing intestinal motility, histology of the colon, release of 5-HT in enterochromaffin cells (ECs) and the TGR5/TRPA1 pathway. Moreover, LC-MS targeted metabolomics was used to analyze the regulation of Bacillus subtilis on bile acid metabolisms in STC mice. Results Bacillus subtilis significantly increased 24 h defecations, fecal moisture and intestinal transport rate of STC mice, improved pathological damage of the colon and showed protective effects on the intestinal tract. The release of 5-HT from ECs and the bile acid receptor TGR5/TRPA1 pathway were significantly increased in STC mice treated with B. subtilis. In addition, the metabolomics results showed that the bile acid contents of STC mice were significantly decreased, and B. subtilis could increase the bile acid composition and content of STC mice. Conclusion Bacillus subtilis regulates intestinal peristalsis of STC by promoting the release of 5-HT from ECs through bile acid metabolism and its receptor TGR5 pathway and plays a positive role in the treatment of STC.

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Nitric oxide plays a critical role in methotrexate-induced hyperplasia of enterochromaffin cells containing 5-hydroxytryptamine in rat small intestine

Cited by 9 publications

References 20 publications

Role of Nitric Oxide in the Change of 5-Hydroxytryptamine Synthesis in the Intestine by a Consecutive Administration of Methotrexate to Rats

Role of Nitric Oxide in the Change of 5-Hydroxytryptamine Synthesis in the Intestine by a Consecutive Administration of Methotrexate to Rats

Methotrexate Induces Hyperplasia of Enterochromaffin Cells in Mouse Jejunum

Bacillus Subtilis Promotes the Release of 5-HT to Regulate Intestinal Peristalsis in STC Mice via Bile Acid and Its Receptor TGR5 Pathway

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