Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice

Yasuda, Masashi; Kato, Shinichi; Yamanaka, Naoaki; Iimori, Maho; Utsumi, Daichi; Kitahara, Yumeno; Iwata, Kazuo; Matsuno, Kuniharu; Amagase, Kikuko; Yabe‐Nishimura, Chihiro; Takeuchi, Koji

doi:10.1152/ajpgi.00535.2011

Cited by 53 publications

(60 citation statements)

References 44 publications

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“…Inhibition of ROS production by apocynin, an antioxidant and a nonselective NOX inhibitor in leukocytes (Heumuller et al, 2008), reduced the severity of colonic inflammation (Mouzaoui et al, 2014;Ramonaite et al, 2014). We also reported that NOX1-deficient mice exhibited resistance to intestinal mucositis induced by an anticancer agent, 5-fluorouracil (Yasuda et al, 2012). Thus, the role for NOX1-derived ROS in the pathogenesis of gut inflammation has been controversial.…”

Section: Introductionmentioning

confidence: 85%

NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid–Induced Murine Colitis

Yokota

Tsuzuki

Shimada

et al. 2016

J Pharmacol Exp Ther

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NOX1/NADPH oxidase, a nonphagocytic isoform of reactive oxygen species-producing enzymes, is highly expressed in the colon, but the physiologic and pathophysiologic roles of this isoform are not fully understood. The present study investigated the role of NOX1 in the development of colonic inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. Intrarectal injection of TNBS caused severe colitis accompanied by body weight loss, diarrhea, and increased myeloperoxidase (MPO) activity in wild-type (WT) mice. In contrast, the severity of colitis was significantly attenuated in NOX1-deficient (NOX1KO) mice (the inhibitions of macroscopic damage score, body weight loss, diarrhea score, and MPO activity were 73.1%, 36.8%, 83.3%, and 98.4%, respectively). TNBS-induced upregulation of inflammatory cytokines (tumor necrosis factor (TNF)-a and interleukin (IL)-1b), chemokines (CXCL1 and CXLC2), and inducible nitric oxide synthase (iNOS) was also significantly less in NOX1KO than in WT mice (the inhibitions were 100.8%, 89.0%, 63.5%, 96.7%, and 97.1%, respectively). Expression of NOX1 mRNA was detected not only in the lamina propria but also in peritoneal macrophages isolated from WT mice. Increased expression of TNF-a, IL-1b, and iNOS in peritoneal macrophages exposed to lipopolysaccharide was significantly attenuated in macrophages isolated from NOX1KO mice (68.1%, 67.0%, and 79.3% inhibition, respectively). These findings suggest that NOX1/NADPH oxidase plays an important role in the pathogenesis of TNBS-induced colonic inflammation via upregulation of inflammatory cytokines, chemokines, and iNOS. NOX1 in colonic macrophages may become a potential target in pharmacologic intervention for inflammatory bowel disease.

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Section: Introductionmentioning

confidence: 85%

NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid–Induced Murine Colitis

Yokota

Tsuzuki

Shimada

et al. 2016

J Pharmacol Exp Ther

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“…32,33) In this study, HST inhibited completely 5-FU-induced diarrhea, although HST inhibited partially gene expression of CXCL1, protein levels of ELA2 and MPO in vivo. While further studies are necessary to clarify the difference, these findings may indicate that HST also inhibits 5-FUinduced apoptosis, resulting in attenuation of diarrhea.…”

Section: Discussionmentioning

confidence: 49%

Active Ingredients of Hange-shashin-to, Baicalelin and 6-Gingerol, Inhibit 5-Fluorouracil-Induced Upregulation of CXCL1 in the Colon to Attenuate Diarrhea Development

Sakai

Tabata

Kimura

et al. 2017

Biological & Pharmaceutical Bulletin

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5-Fluorouracil (5-FU)is widely used as an anti cancer drug and is known to cause severe diarrhea. Recently we suggested that levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophil recruitment in the colonic mucosa were drastically increased by the 5-FU administration in mice. Hange-shashin-to (HST) is prescribed in Japan for treat gastritis, stomatitis, and inflammatory diarrhea. We therefore examined the effects of HST and its active ingredients on 5-FU-induced CXCL1 upregulation in cultured colon tissue, and also examined the effects of HST on 5-FU-induced diarrhea development in the mouse. The distal colon isolated from the mouse was incubated with 5-FU and HST. Mice were given 5-FU (50 mg/kg, intraperitoneally (i.p.)) daily for four days. HST (300 mg/kg, per os ( p.o.)) was administered 30 min before mice received 5-FU. mRNA levels of CXCL1 in the colon were examined using quantitative RT-PCR. 5-FU enhanced CXCL1 mRNA in the colon but the effect by 5-FU was markedly suppressed by application of HST and its active ingredients, baicalein and 6-gingerol. Nuclear factor kappa B (NF-κB) was activated by 5-FU treatment in cultured colon tissue, which was also suppressed by HST and the combination of baicalein and 6-gingerol. Furthermore, HST reduced 5-FU-induced diarrhea development. Under such experimental condition, CXCL1 gene, protein levels of neutrophil elastase and myeloperoxidase upregulation induced by 5-FU in the colon was attenuated by HST. These findings suggest that HST, especially baicalein and 6-gingerol, prevent the development of neutrophil recruitment and diarrhea by the inhibition of NF-κB activity.

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“…27) The pathogenesis of 5-FU-induced intestinal mucositis remains unclear, but is considered to be a consequence of various processes, including abnormal inflammation and apoptosis, together with cellular hypoproliferation and direct cytotoxicity. 28) We demonstrated that apoptosis in the intestinal crypt was caused by the upregulation of TNF-α-induced caspase-3/8 activations. 29) Ramosetron and ondansetron clearly suppressed the upregulation of TNF-α expression and subsequent caspase-3/8 activations in the intestinal crypt in response to 5-FU.…”

Section: Anti-intestinal Inflammatory Effects Of the 5-ht 3 Receptor mentioning

confidence: 85%

Role of Serotonin 5-HT<sub>3</sub> Receptors in Intestinal Inflammation

Kato

2013

Biological & Pharmaceutical Bulletin

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Serotonin (5-hydroxytryptamine; 5-HT), a well-characterized neurotransmitter in the central nervous system, plays a crucial role in regulating mood, body temperature, sleep, appetite, and metabolism. Serotonin is synthesized in the serotonergic neuron of the central nervous system; however, approximately 90% of serotonin is synthesized and localized in the gastrointestinal (GI) tract, especially in the enterochromaffin (EC) cells. In the GI tract, serotonin mediates control over a variety of physiological functions such as contraction/relaxation of smooth muscle, and peristaltic and secretory reflexes, directly or indirectly through intrinsic primary afferent neurons. The receptors mediating the action of serotonin are mainly classified into 7 major groups known as the 5-HT1 to 5-HT7 receptors. The 5-HT3 receptor is distinguished from among the other 5-HT receptor subtypes because it is only a ligand-gated ion channel, whereas the other subtypes serve as G protein-coupled receptors. The 5-HT3 receptor, which is generally considered to be localized in the central and peripheral nervous systems, is involved in processes associated with emotion, cognition, memory, pain perception, and GI functions including secretion and motility. Recently, an increasing number of findings have provided evidence of the important role of the 5-HT3 receptor in the regulation of inflammatory and immune responses. In fact, several 5-HT3 receptor antagonists have been reported to ameliorate intestinal inflammation. Therefore, this review focuses on the role of 5-HT3 receptors in the pathogenesis of intestinal inflammation.

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Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice

Cited by 53 publications

References 44 publications

NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid–Induced Murine Colitis

NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid–Induced Murine Colitis

Active Ingredients of Hange-shashin-to, Baicalelin and 6-Gingerol, Inhibit 5-Fluorouracil-Induced Upregulation of CXCL1 in the Colon to Attenuate Diarrhea Development

Role of Serotonin 5-HT<sub>3</sub> Receptors in Intestinal Inflammation

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