Intestinal, portal, and peripheral profiles of daikenchuto (<scp>TU</scp>‐100)'s active ingredients after oral administration

Watanabe, Junko; Kaifuchi, Noriko; Mutoh, T.; Fukutake, Miwako; Nishiyama, Mitsue; Yamamoto, Masahiro; Kono, Toru

doi:10.1002/prp2.165

Cited by 17 publications

(25 citation statements)

References 40 publications

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“…Shogaols are converted to various metabolites in the EPCs . Thus, free gingerols and shogaols are present only in trace amounts in portal and peripheral blood . Consequently, stimulation of TRPA1 located in cells other than ECCs and EPCs by gingerols and shogaols is assumed to be minimal.…”

Section: Discussionmentioning

confidence: 67%

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Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus

Tsuchiya

Kubota

Ohbuchi

et al. 2016

Neurogastroenterology Motil

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Key Points • TRPA1 expresses in enterochromaffin cells (ECC) and may be involved in gut motility. • Here, we investigated the effect of TRPA1 agonists, including high-quality traditional Japanese medicine daikenchuto (TU-100), in three different systems: (i) a manipulation-induced postoperative ileus model, (ii) in vitro culture of small intestinal (SI) segments and (iii) a model ECC. • TRPA1 was found to be indispensable for coordinated peristaltic motility and TRPA1 agonists improve SI transit. Further research is required to determine whether ECC are involved. Abstract Background Stimulation of transient receptor potential ankyrin 1 (TRPA1), which abundantly expressed in enterochromaffin cells (ECC), has been reported to exert apparently contradictory results in in vitro contractility and in vivo gastrointestinal (GI) transit evaluations. The pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) has been reported to be beneficial for postoperative ileus (POI) and accelerate GI transit in animals and humans. TU-100 was recently shown to increase intestinal blood flow via stimulation of TRPA1 in the epithelial cells of the small intestine (SI). Methods The effects of various TRPA1 agonists on motility were examined in a manipulation-induced murine POI model, in vitro culture of SI segments and an ECC model cell line, RIN-14B. Key Results Orally administered TRPA1 agonists, aryl isothiocyanate (AITC) and cinnamaldehyde (CA), TU-100 ingredients, [6]-shogaol (6S) and c-sanshool (GS), improved SI transit in a POI model. The effects of AITC, 6S and GS but not CA were abrogated in TRPA1-deficient mice. SI segments show periodic peristaltic motor activity whose periodicity disappeared in TRPA1-deficient mice. TU-100 augmented the motility. AITC, CA and 6S increased 5-HT release from isolated SI segments and the effects of all these compounds except for CA were lost in TRPA1-deficient mice. 6S and GS induced a release of 5-HT from RIN-14B cells in a dose-and TRPA1-dependent manner. Conclusions & Inferences Intraluminal TRPA1 stimulation is a potential therapeutic strategy for GI motility disorders. Further investigation is required to determine whether 5-HT and/or ECC are involved in the effect of TRPA1 on motility.

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Section: Discussionmentioning

confidence: 67%

“…Previous studies on TU‐100 pharmacology and pharmacokinetics suggest this could be a promising TRPA1‐targeting prokinetic drug candidate. Moreover, the administration route for TU‐100 (oral only), absorption properties and the conjugation/metabolism of TU‐100 are also favorable.…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus

Tsuchiya

Kubota

Ohbuchi

et al. 2016

Neurogastroenterology Motil

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“…Meyer (Araliaceae). Ginsenosides are transported to the colon with minimal absorption, although Zanthoxylum fruit components (hydroxysanshools) and ginger components (gingerols), which are constituents of DKT, are rapidly absorbed and enter the systemic circulation . Therefore, we focused on the direct effect of GRb1 on intestinal epithelial cells by using a wound‐healing assay.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rb1 promotes intestinal epithelial wound healing through extracellular signal‐regulated kinase and Rho signaling

Toyokawa

Takagi

Uchiyama

et al. 2018

J of Gastro and Hepatol

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Background and Aim Daikenchuto, a traditional Japanese herbal medicine, has been reported to exhibit anti‐inflammatory effects against intestinal inflammation. However, whether daikenchuto has a therapeutic effect against intestinal mucosal injuries remains unclear. Thus, the aim of this study was to determine the effect of daikenchuto on intestinal mucosal healing. Methods Colitis was induced in male Wistar rats by using trinitrobenzenesulfonic acid. Daikenchuto (900 mg/kg/day) was administered for 7 days after the induction of colitis. Thereafter, intestinal mucosal injuries were evaluated by determining the colonic epithelial regeneration ratio ([area of epithelial regeneration/area of ulcer] × 100). Restoration of rat intestinal epithelial cells treated with daikenchuto and its constituent herbs (Zanthoxylum fruit, processed ginger, and ginseng) and ginsenoside Rb1, which is a ginseng ingredient, was evaluated using a wound‐healing assay. Results The colon epithelial regeneration ratio in the daikenchuto‐treated rats was significantly higher than that in the control rats. Daikenchuto, ginseng, and ginsenoside Rb1 enhanced wound healing, and the ginsenoside Rb1‐induced enhancement was inhibited by extracellular signal‐regulated kinase and Rho inhibitors. Conclusions Daikenchuto and its constituent, ginsenoside Rb1, promoted wound healing. Because mucosal healing is one of the most important therapeutic targets in patients with inflammatory bowel disease, ginsenoside Rb1 may be a novel therapeutic agent against intestinal mucosal damage such as that occurring in intestinal bowel disease.

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“…2014; Watanabe et al. 2015). In these studies, TU‐100 exerted pharmacological effects in mice similar to its clinical efficacy in humans and blood concentrations of its major ingredients were in range to human data after ingestion of TU‐100.…”

Section: Methodsmentioning

confidence: 99%

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

Hasebe

Ueno

Musch

et al. 2016

Pharmacology Res & Perspec

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Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long‐term of these agents. Daikenchuto, TU‐100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet‐incorporated TU‐100 was administered to mice over a period of several weeks. T‐RFLP and 454 pyrosequencing were performed to analyze the time‐dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU‐100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU‐100 components in plasma and in stool samples were measured by LC‐MS/MS. Cecal and stool short‐chain fatty acids were measured by GC‐MS. Dietary administration of TU‐100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU‐100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU‐100 promotes changes in gut microbiota enhancing metabolic capacity of TU‐100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general.

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Intestinal, portal, and peripheral profiles of daikenchuto (TU‐100)'s active ingredients after oral administration

Cited by 17 publications

References 40 publications

Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus

Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus

Ginsenoside Rb1 promotes intestinal epithelial wound healing through extracellular signal‐regulated kinase and Rho signaling

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

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