Detection of <i>N</i>‐nitroso‐bile acids at 285 nm in reverse‐phase HPLC

Araki, Yoshio; Mukaisyo, Ken-ichi; Sugihara, Hiroyuki; Fujiyama, Yoshihide; Hattori, Takanori

doi:10.1002/jssc.200800230

Cited by 9 publications

(7 citation statements)

References 11 publications

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“…DNA adducts originating from N ‐nitroso‐bile acids have also been detected in the glandular stomach from our gastric cancer model . Furthermore, N ‐nitroso‐bile acids reportedly stabilize under acidic conditions . These findings suggest that N ‐nitroso‐bile acids appear to be involved in the occurrence of EAC from Barrett's esophagus in patients with healthy acid‐secreting stomachs.…”

Section: Barrett's Carcinogensissupporting

confidence: 60%

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Barretts's carcinogenesis

Mukaisho

Kanai

Kushima

et al. 2019

Pathology International

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Barrett's esophagus is considered a precancerous lesion of esophageal adenocarcinoma (EAC). Long‐segment Barrett's esophagus, which is generally associated with intestinal metaplasia, has a higher rate of carcinogenesis than short‐segment Barrett's esophagus, which is mainly composed of cardiac‐type mucosa. However, a large number of cases reportedly develop EAC from the cardiac‐type mucosa which has the potential to involve intestinal phenotypes. There is no consensus regarding whether the definition of Barrett's epithelium should include intestinal metaplasia. Basic researches using rodent models have provided information regarding the origins of Barrett's epithelium. Nevertheless, it remains unclear whether differentiated gastric columnar epithelium or stratified esophageal squamous epithelium undergo transdifferentiation into the intestinal‐type columnar epithelium, transcommittment into the columnar epithelium, or whether the other pathways exist. Reflux of duodenal fluid including bile acids into the stomach may occur when an individual lies down after eating, which could cause the digestive juices to collect in the fornix of the stomach. N‐nitroso‐bile acids are produced with nitrites that are secreted from the salivary glands, and bile acids can drive expression of pro‐inflammatory cytokines via EGFR or the NF‐κB pathway. These steps may contribute significantly to carcinogenesis.

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Section: Barrett's Carcinogensissupporting

confidence: 60%

“…117,118 Furthermore, N-nitroso-bile acids reportedly stabilize under acidic conditions. 119 These findings suggest that N-nitroso-bile acids appear to be involved in the occurrence of EAC from Barrett's esophagus in patients with healthy acid-secreting stomachs.…”

Section: Activation Of Nf-κbmentioning

confidence: 78%

Barretts's carcinogenesis

Mukaisho

Kanai

Kushima

et al. 2019

Pathology International

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“…We developed not only EACs but also esophageal squamous cell carcinomas (ESCCs) in the rat reflux models (reflux model) . Our previous study also revealed that N ‐nitroso bile acid‐mutagenic derivatives of bile acids produced in vivo under highly acidic conditions could stimulate EAC . However, we also observed EACs in modified Levrat models with total gastrectomy suggesting that the tumors could be induced by exposure to unmodified nonmutagenic bile acids in the absence of gastric acid …”

Section: Introductionmentioning

confidence: 85%

Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid‐induced cancer development

et al. 2019

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Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC‐DR, established from a metastatic thoracic lesion. ESCC‐DRtca2M was prepared by treating ESCC‐DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose‐6‐phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF‐κB) (p65) and O‐linked N‐Acetylglucosamine (O‐GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O‐GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line‐based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF‐κB (p65) and O‐GlcNAc were expressed more highly in ESCC‐DRtca2M than in the other cell lines. Moreover, ESCC‐DRtca2M cells had additional chromosomal abnormalities in excess of ESCC‐DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF‐κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line‐based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF‐κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.

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“…We have studied the role of bile salts in the gut lumen when considering the pathogenesis and disease-promoting factors for experimental and clinical gastrointestinal diseases (25,26,(33)(34)(35)(36)(37). In the course of these investigations, it has been revealed that bile salts exhibit mainly cytotoxic but also certain stimulatory effects towards the intestinal epithelium (38).…”

Section: Discussionmentioning

confidence: 99%

The herbal medicine rikkunshito exhibits strong and differential adsorption properties for bile salts

Araki

Mukaisho

Fujiyama

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. Anti-secretory drugs, particularly proton pump inhibitors (PPIs), are the preferred treatment agents for patients with gastroesophageal reflux disease (GERD). However, refractory GERD, which may manifest as an incomplete or lack of response to PPI therapy, is common. Despite the administration of PPIs for symptomatic control, duodenogastroesophageal reflux (DGER) containing bile is successfully controlled in only one-third of patients. It has previously been reported that the traditional Japanese herbal medicine rikkunshito, which has a prokinetic action on gastric emptying, exhibits clinically therapeutic effects against GERD and DGER that does not respond to PPIs. However, the precise mechanisms responsible for the effects of rikkunshito are still unknown. It has been suggested that the cytotoxicity of the bile salts in the gut lumen is important in GERD and DGER. The aim of the present study was to investigate whether rikkunshito is able to adsorb bile salts through the mechanism by which it ameliorates the symptoms of GERD and DGER. The binding capacities of rikkunshito for bile salts were measured using Langmuir's method. The morphology of rikkunshito was also observed by light microscopy. Rikkunshito strongly adsorbed bile salts. The binding capabilities of rikkunshito were far beyond those of a typical dietary fiber, α-cellulose, or an oral adsorbent. In addition, rikkunshito had higher binding capacities for hydrophobic bile salts as compared with hydrophilic bile salts. In conclusion, rikkunshito has a great capacity to adsorb bile salts. This may be part of the mechanism(s) responsible for the therapeutic effects of rikkunshito in patients with GERD and DGER.

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Detection of N‐nitroso‐bile acids at 285 nm in reverse‐phase HPLC

Cited by 9 publications

References 11 publications

Barretts's carcinogenesis

Barretts's carcinogenesis

Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid‐induced cancer development

The herbal medicine rikkunshito exhibits strong and differential adsorption properties for bile salts

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