Daikenchuto (Da-Jian-Zhong-Tang) ameliorates intestinal fibrosis by activating myofibroblast transient receptor potential ankyrin 1 channel.

Abstract

AIM:

To investigate the anti-fibrotic effects of the traditional oriental herbal medicine Daikenchuto (DKT) associated with transient receptor potential ankyrin 1 (TRPA1) channels in intestinal myofibroblasts.

METHODS:

Inflammatory and fibrotic changes were detected in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) chronic colitis model of wild-type and TRPA1-knockout (TRPA1-KO) mice via pathological staining and immunoblotting analysis. Ca2+ imaging experiments examined the effects of DKT and its components/ingredients on intestinal myofibroblast (InMyoFib) cell TRPA1 channel function. Pro-fibrotic factors and transforming growth factor (TGF)-β1-associated signaling were tested in an InMyoFib cell line by qPCR and immunoblotting experiments. Samples from non-stenotic and stenotic regions of the intestines of patients with Crohn's disease (CD) were used for pathological analysis.

RESULTS:

Chronic treatment with TNBS caused more severe inflammation and fibrotic changes in TRPA1-KO than in wild-type mice. A one-week enema administration of DKT reduced fibrotic lesions in wild-type but not in TRPA1-KO mice. The active ingredients of DKT, i.e., hydroxy α-sanshool and 6-shogaol, induced Ca2+ influxes in InMyoFib, and this was antagonized by co-treatment with a selective TRPA1 channel blocker, HC-030031. DKT counteracted TGF-β1-induced expression of Type I collagen and α-smooth muscle actin (α-SMA), which were accompanied by a reduction in the phosphorylation of Smad-2 and p38-mitogen-activated protein kinase (p38-MAPK) and the expression of myocardin. Importantly, 24-h incubation with a DKT active component Japanese Pepper increased the mRNA and protein expression levels of TRPA1 in InMyoFibs, which in turn negatively regulated collagen synthesis. In the stenotic regions of the intestines of CD patients, TRPA1 expression was significantly enhanced.

CONCLUSION:

The effects of DKT on the expression and activation of the TRPA1 channel could be advantageous for suppressing intestinal fibrosis, and benefit inflammatory bowel disease treatment.

• Authors: Keizo Hiraishi, Lin-Hai Kurahara, Miho Sumiyoshi, Yao-Peng Hu, Kaori Koga, Miki Onitsuka, Daibo Kojima, Lixia Yue, Hidetoshi Takedatsu, Yu-Wen Jian, Ryuji Inoue
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 24 Issue 35 Pg. 4036-4053 (Sep 21 2018) ISSN: 2219-2840 [Electronic] United States
• PMID: 30254408 (Publication Type: Journal Article)

Chemical References

• Plant Extracts
• TRPA1 Cation Channel
• TRPA1 protein, human
• Trpa1 protein, mouse
• dai-kenchu-to
• Trinitrobenzenesulfonic Acid

Topics

• Adult
• Animals
• Cell Line
• Chronic Disease (drug therapy)
• Colitis (chemically induced, drug therapy, pathology)
• Colon (cytology, drug effects, pathology, surgery)
• Crohn Disease (pathology, surgery)
• Disease Models, Animal
• Fibrosis
• Humans
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Myofibroblasts (metabolism)
• Panax
• Plant Extracts (pharmacology, therapeutic use)
• TRPA1 Cation Channel (genetics, metabolism)
• Trinitrobenzenesulfonic Acid (toxicity)
• Zanthoxylum
• Zingiberaceae