Neuronal Nitric Oxide Synthase Is a Novel Biomarker for the Interstitial Cells of Cajal in Stress-Induced Diarrhea-Dominant Irritable Bowel Syndrome

Jang, Da Eun; Bae, Ji Hyun; Chang, Yoo Jin; Lee, Yoon Hoo; Nam, Ki Taek; Kim, Il Yong; Seong, Je Kyung; Lee, Yong Chan; Yeom, Su Cheong

doi:10.1007/s10620-018-4933-7

Cited by 16 publications

(10 citation statements)

References 52 publications

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“…Both sex mice seemed to induce IBS-D, but male mice exhibited a more significant difference in bowel motility under NMS ( Figure 3 B). The more pronounced IBS-D in male mice appeared similar to human clinical manifestations and our previous report [ 14 ].…”

Section: Resultssupporting

confidence: 90%

“…Recently, NanoLuc luciferase activity measurement through HiBiT has been reported as an endogenous gene expression analyzing method [ 23 ]. We previously reported that the nNOS expresses higher in the interstitial cell of Cajal in the stress-derived IBS mouse model [ 14 ], but other organs’ nNOS expression could not be analyzed. In this experiment, the nNOS was selected as the target gene, and we tried to analyze the increase in nNOS expression in stress-derived IBS after HiBiT KI mouse generation ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…IBS is a representative stress-related functional bowel disease with a prevalence of 10–20% [ 27 ] and is considered multifactorial, but the exact pathophysiological etiology is unclear. We already have reported that IBS-D increases nNOS expression in the interstitial cell of Cajal [ 14 ]. In this study, we tried to confirm the association of nNOS with stress and bowel motility using the in vivo detecting system.…”

Section: Discussionmentioning

confidence: 99%

“…IBS is a functional disorder causing irregular bowel movement and an etiology associated with psychological stress and infection [ 11 , 12 ]. Serotonin (5-HT) is well known to play a critical role in stress-related changes in gut motility, visceral sensitivity, and intestinal secretion [ 13 ]; also, we previously reported a correlation between nNOS and irritable bowel syndrome [ 14 ]. nNOS regulates physiological functions such as learning, memory, neurogenesis, and various human diseases [ 3 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we reported that nNOS is a novel biomarker of NMS-induced IBS-D type [ 14 ]. However, the correlation between nNOS expression and GI tract motility was not analyzed under stress-induced conditions.…”

Section: Introductionmentioning

confidence: 99%

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Positive Correlation between nNOS and Stress-Activated Bowel Motility Is Confirmed by In Vivo HiBiT System

Han

Lee

et al. 2021

Cells

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Neuronal nitric oxide synthase (nNOS) has various roles as a neurotransmitter. However, studies to date have produced insufficient data to fully support the correlation between nNOS and bowel motility. This study aimed to investigate the correlation between nNOS expression and gastrointestinal (GI) tract motility using a stress-induced neonatal maternal separation (NMS) mouse model. In this study, we generated a genetically modified mouse with the HiBiT sequence knock-in into the nNOS gene using CRISPR/Cas9 for analyzing accurate nNOS expression. nNOS expression was measured in the stomach, small intestine, large intestine, adrenal gland, and hypothalamus tissues after establishing the NMS model. The NMS model exhibited a significant increase in nNOS expression in large intestine, adrenal gland, and hypothalamus. Moreover, a significant positive correlation was observed between whole gastrointestinal transit time and the expression level of nNOS. We reasoned that NMS induced chronic stress and consequent nNOS activation in the hypothalamic-pituitary-adrenal (HPA) axis, and led to an excessive increase in intestinal motility in the lower GI tract. These results demonstrated that HiBiT is a sensitive and valuable tool for analyzing in vivo gene activation, and nNOS could be a biomarker of the HPA axis-linked lower intestinal tract dysfunction.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Positive Correlation between nNOS and Stress-Activated Bowel Motility Is Confirmed by In Vivo HiBiT System

Han

Lee

et al. 2021

Cells

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Knockdown of miR‐19a suppresses gastrointestinal dysmotility diarrhea after TBI by regulating VIP expression

Zhang

et al. 2023

Brain and Behavior

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Background and aims: Traumatic brain injury (TBI) is the main cause of death and can lead to a variety of physiological complications, including gastrointestinal dysfunction.The present study aimed to confirm the miR-19a-mediated suppression of diarrhea after TBI through the regulation of VIP expression.Methods: A rat model of TBI induced by controlled cortical injury was used to observe gastrointestinal morphology by opening the abdomen after TBI. After 72 h of injury, the fecal water content of the rats was measured. The end ileal segments were removed, and HE staining was used to observe the histopathological changes in the intestine. The levels of serum miR-19a and VIP mRNA were detected by qRT-PCR. ELISA was performed to detect VIP levels in serum. Immunohistochemistry was used to detect the level of VIP in ileal tissues, and immunofluorescence was used to detect c-kit expression in ileal tissue. CCK-8 assay was used to detect the cell viability of interstitial cells of Cajal (ICCs), and TUNEL assay was used to detect apoptosis of ICCs.Results: miR-19a and VIP were highly expressed in the serum of TBI rats, and the knockdown of miR-19a alleviated TBI-induced diarrhea. In addition, the overexpression of miR-19a or VIP inhibited the proliferation of ICCs, promoted apoptosis, and suppressed intracellular Ca 2+ levels, whereas miR-19a suppression had the opposite effects. A nonselective nitric oxide synthase inhibitor (L-NA), PKG inhibitors (KT-5823 and RP-8CPT-cGMPS), and a guanylate cyclase inhibitor (ODQ) restored the inhibitory effects of VIP on ICC proliferation, anti-apoptosis effects, and Ca 2+ concentrations.Ying An and Sheng Hu contributed equally to this study.

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Functional Implications and Clinical Potential of MicroRNAs in Irritable Bowel Syndrome: A Concise Review

et al. 2022

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Neuronal Nitric Oxide Synthase Is a Novel Biomarker for the Interstitial Cells of Cajal in Stress-Induced Diarrhea-Dominant Irritable Bowel Syndrome

Abstract: Our study demonstrates that early-life stress can influence to ICC and modulate bowel activity and that nNOS might be used as a biomarker for ICC stimulation in IBS.

Cited by 16 publications

References 52 publications

Positive Correlation between nNOS and Stress-Activated Bowel Motility Is Confirmed by In Vivo HiBiT System

Positive Correlation between nNOS and Stress-Activated Bowel Motility Is Confirmed by In Vivo HiBiT System

Knockdown of miR‐19a suppresses gastrointestinal dysmotility diarrhea after TBI by regulating VIP expression

Functional Implications and Clinical Potential of MicroRNAs in Irritable Bowel Syndrome: A Concise Review

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