Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation

Yin,Jianqiao; Liang,Yichao; Wang,Dalu; Yan,Zhaopeng; Yin,Hongzhuan; Wu,Di; Su,Qi

doi:10.3892/ijmm.2017.3301

Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation

Authors:
- Jianqiao Yin
- Yichao Liang
- Dalu Wang
- Zhaopeng Yan
- Hongzhuan Yin
- Di Wu
- Qi Su
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Affiliations: Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: December 1, 2017 https://doi.org/10.3892/ijmm.2017.3301
Pages: 649-658
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Constipation is a common affliction which causes discomfort and affects the quality of life of affected individuals. Naringenin (NAR), a natural flavonoid widely found in citrus fruits and tomatoes, has been reported to exhibit various pharmacological effects, such as anti-inflammatory, anti-atherogenic, anti-mutagenic, hepatoprotective and anticancer effects. Increasing evidence has indicated that NAR has potential for use in the treatment of constipation. Thus, the aim of this study was to evaluate the laxative effects of NAR in mice with loperamide-induced (Lop-induced) constipation. The data indicated that NAR relieved Lop-induced constipation in mice based on the changes of fecal parameters (numbers, weight and water content), the intestinal charcoal transit ratio and the histological alteration. ELISA revealed that NAR regulated the production levels of gastrointestinal metabolic components, such as motilin (MTL), gastrin (Gas), endothelin (ET), substance P (SP), acetylcholinesterase (AChE) and vasoactive intestinal peptide (VIP) in serum. The expression levels of enteric nerve-related factors, glial cell line-derived neurotrophic factor (GDNF), transient receptor potential vanilloid 1 (TRPV1), nitric oxide synthase (NOS), c-Kit, stem cell factor (SCF) and aquaporin 3 (AQP3) were examined by western blot analysis and RT-PCR analysis. The results of this study suggest that NAR relieves Lop-induced constipation by increasing the levels of interstitial cells of Cajal markers (c-Kit and SCF), as well as AQP3. Thus, NAR may be effective as a candidate in patients suffering from lifestyle-induced constipation.

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1	Bassotti G and Blandizzi C: Understanding and treating refractory constipation. World J Gastrointest Pharmacol Ther. 5:77–85. 2014. View Article : Google Scholar : PubMed/NCBI
2	Bassotti G: Understanding constipation treatment: do we need to strain to obtain better results? Expert Opin Drug Metab Toxicol. 9:387–389. 2013. View Article : Google Scholar : PubMed/NCBI
3	Mostafa SM, Bhandari S, Ritchie G, Gratton N and Wenstone R: Constipation and its implications in the critically ill patient. Br J Anaesth. 91:815–819. 2003. View Article : Google Scholar : PubMed/NCBI
4	Ouyang A and Locke GR 3rd: Overview of neurogastroenterology-gastrointestinal motility and functional GI disorders: classification, prevalence, and epidemiology. Gastroenterol Clin North Am. 36:485–498. 2007. View Article : Google Scholar : PubMed/NCBI
5	Wang HL: Understanding the pathogenesis of slow-transit constipation: one step forward. Dig Dis Sci. 60:2216–2218. 2015. View Article : Google Scholar : PubMed/NCBI
6	He CL, Burgart L, Wang L, Pemberton J, Young-Fadok T, Szurszewski J and Farrugia G: Decreased interstitial cell of cajal volume in patients with slow-transit constipation. Gastroenterology. 118:14–21. 2000. View Article : Google Scholar
7	Andromanakos NP, Pinis SI and Kostakis AI: Chronic severe constipation: current pathophysiological aspects, new diagnostic approaches, and therapeutic options. Eur J Gastroenterol Hepatol. 27:204–214. 2015. View Article : Google Scholar : PubMed/NCBI
8	Chan OT, Chiles L, Levy M, Zhai J, Yerian LM, Xu H, Xiao SY, Soffer EE, Conklin JL, Dhall D, et al: Smoothelin expression in the gastrointestinal tract: implication in colonic inertia. Appl Immunohistochem Mol Morphol. 21:452–459. 2013. View Article : Google Scholar
9	Renugadevi J and Prabu SM: Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol. 62:171–181. 2010. View Article : Google Scholar
10	Ekambaram G, Rajendran P, Magesh V and Sakthisekaran D: Naringenin reduces tumor size and weight lost in N-methyl-N′-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Nutr Res. 28:106–112. 2008. View Article : Google Scholar : PubMed/NCBI
11	Yang ZH, Yu HJ, Pan A, Du JY, Ruan YC, Ko WH, Chan HC and Zhou WL: Cellular mechanisms underlying the laxative effect of flavonol naringenin on rat constipation model. PLoS On. 3:pp. e33482008, View Article : Google Scholar
12	Yamamoto T, Watabe K, Nakahara M, Ogiyama H, Kiyohara T, Tsutsui S, Tamura S, Shinomura Y and Hayashi N: Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic db/db mice. J Gastroenterol Hepatol. 23:660–667. 2008. View Article : Google Scholar : PubMed/NCBI
13	Chai Y, Huang Y, Tang H, Tu X, He J, Wang T, Zhang Q, Xiong F, Li D and Qiu Z: Role of stem cell growth factor/c-Kit in the pathogenesis of irritable bowel syndrome. Exp Ther Med. 13:1187–1193. 2017. View Article : Google Scholar : PubMed/NCBI
14	Wald A: Chronic constipation: advances in management. Neurogastroenterol Motil. 19:4–10. 2007. View Article : Google Scholar
15	Wintola OA, Sunmonu TO and Afolayan AJ: The effect of Aloe ferox Mill. in the treatment of loperamide-induced constipation in Wistar rats. BMC Gastroenterol. 10:952010. View Article : Google Scholar : PubMed/NCBI
16	Kakino M, Tazawa S, Maruyama H, Tsuruma K, Araki Y, Shimazawa M and Hara H: Laxative effects of agarwood on low-fiber diet-induced constipation in rats. BMC Complemen. Altern Med. 10:682010.
17	Hughes S, Higgs NB and Turnberg LA: Loperamide has antisecretory activity in the human jejunum in vivo. Gut. 25:931–935. 1984. View Article : Google Scholar : PubMed/NCBI
18	Yamada K and Onoda Y: Comparison of the effects of T-1815, yohimbine and naloxone on mouse colonic propulsion. J Smooth Muscle Res. 29:47–53. 1993. View Article : Google Scholar : PubMed/NCBI
19	Sohji Y, Kawashima K and Shimizu M: [Pharmacological studies of loperamide, an anti-diarrheal agent. II. Effects on peristalsis of the small intestine and colon in guinea pigs (author's transl)]. Nihon Yakurigaku Zasshi. 74:155–163. 1978.In Japanese. View Article : Google Scholar : PubMed/NCBI
20	Lee HY, Kim JH, Jeung HW, Lee CU, Kim DS, Li B, Lee GH, Sung MS, Ha KC, Back HI, et al: Effects of Ficus carica paste on loperamide-induced constipation in rats. Food Chem Toxicol. 50:895–902. 2012. View Article : Google Scholar
21	Kakino M, Izuta H, Ito T, Tsuruma K, Araki Y, Shimazawa M, Oyama M, Iinuma M and Hara H: Agarwood induced laxative effects via acetylcholine receptors on loperamide-induced constipation in mice. Biosci Biotechnol Biochem. 74:1550–1555. 2010. View Article : Google Scholar : PubMed/NCBI
22	Liu Y, Zhao XR, Wang R, Qiu GQ and Zhang M: Effect of Zhizhuwan on gastrointestinal peptide concentrations in plasma of diabetic gastroenteropathy with constipation patients. Zhongguo Zhong Yao Za Zhi. 33:2966–2968. 2008.In Chinese.
23	Suo H, Zhao X, Qian Y, Li G, Liu Z, Xie J and Li J: Therapeutic effect of activated carbon-induced constipation mice with Lactobacillus fermentum Suo on treatment. Int J Mol Sci. 15:21875–21895. 2014. View Article : Google Scholar : PubMed/NCBI
24	Iijima K, Koike T, Abe Y and Shimosegawa T: Cutoff serum pepsinogen values for predicting gastric acid secretion status. Tohoku J Exp Med. 232:293–300. 2014. View Article : Google Scholar : PubMed/NCBI
25	Fevang J, Ovrebø K, Myking O, Grong K and Svanes K: Role of endothelin in the circulatory changes associated with small bowel strangulation obstruction in pigs: effects of the endothelin receptor antagonist bosentan. J Surg Res. 96:224–232. 2001. View Article : Google Scholar : PubMed/NCBI
26	Yik YI, Farmer PJ, King SK, Chow CW, Hutson JM and Southwell BR: Gender differences in reduced substance P (SP) in children with slow-transit constipation. Pediatr Surg Int. 27:699–704. 2011. View Article : Google Scholar : PubMed/NCBI
27	Moriya R, Fujikawa T, Ito J, Shirakura T, Hirose H, Suzuki J, Fukuroda T, Macneil DJ and Kanatani A: Pancreatic polypeptide enhances colonic muscle contraction and fecal output through neuropeptide Y Y₄ receptor in mice. Eur J Pharmacol. 627:258–264. 2010. View Article : Google Scholar
28	King SK, Sutcliffe JR, Ong SY, Lee M, Koh TL, Wong SQ, Farmer PJ, Peck CJ, Stanton MP, Keck J, et al: Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow-transit constipation. Neurogastroenterol Motil. 22:883–892. 2010. View Article : Google Scholar : PubMed/NCBI
29	Geppetti P and Trevisani M: Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function. Br J Pharmacol. 141:1313–1320. 2004. View Article : Google Scholar : PubMed/NCBI
30	Rodrigues DM, Li AY, Nair DG and Blennerhassett MG: Glial cell line-derived neurotrophic factor is a key neurotrophin in the postnatal enteric nervous system. Neurogastroenterol Moti. 23:e44–e56. 2011. View Article : Google Scholar
31	Saffrey MJ: Cellular changes in the enteric nervous system during ageing. Dev Biol. 382:344–355. 2013. View Article : Google Scholar : PubMed/NCBI
32	Chen F, Yu Y, Wang P, Dong Y, Wang T, Zuo X and Li Y: Brain-derived neurotrophic factor accelerates gut motility in slow-transit constipation. Acta Physiol (Oxf). 212:pp. 226–238. 2014, View Article : Google Scholar
33	Peregud DI, Yakovlev AA, Stepanichev MY, Onufriev MV, Panchenko LF and Gulyaeva V: Expression of BDNF and TrkB phosphorylation in the rat frontal cortex during morphine withdrawal are NO dependent. Cell Mol Neurobiol. 36:839–849. 2015. View Article : Google Scholar : PubMed/NCBI
34	Tomita R, Igarashi S, Fujisaki S and Tanjoh K: The effects of neurotensin in the colon of patients with slow transit constipation. Hepatogastroenterology. 54:1662–1666. 2007.PubMed/NCBI
35	Xu J, Chen Y, Liu S and Hou X: Electroacupuncture regulates apoptosis/proliferation of intramuscular interstitial cells of cajal and restores colonic motility in diabetic constipation rats. Evid Based Complement Alternat Med. 584179:2013. View Article : Google Scholar
36	Farrugia G: Interstitial cells of Cajal in health and disease. Neurogastroenterol Motil. 20:54–63. 2008. View Article : Google Scholar
37	Yu CS, Kim HC, Hong HK, Chung DH, Kim HJ, Kang GH and Kim JC: Evaluation of myenteric ganglion cells and interstitial cells of Cajal in patients with chronic idiopathic constipation. Int J Colorectal Dis. 17:253–258. 2002. View Article : Google Scholar : PubMed/NCBI
38	Mostafa RM, Moustafa YM and Hamdy H: Interstitial cells of Cajal, the Maestro in health and disease. World J Gastroenterol. 16:3239–3248. 2010. View Article : Google Scholar : PubMed/NCBI
39	Parthasarathy G, Chen J, Chia N, O'Connor HM, Gaskins HR and Bharucha AE: Reproducibility of assessing fecal microbiota in chronic constipation. Neurogastroenterol Motil. 29:1–10. 2017. View Article : Google Scholar : PubMed/NCBI
40	Silberstein C, Kierbel A, Amodeo G, Zotta E, Bigi F, Berkowski D and Ibarra C: Functional characterization and localization of AQP3 in the human colon. Braz J Med Biol Res. 32:1303–1313. 1999. View Article : Google Scholar : PubMed/NCBI
41	Kon R, Ikarashi N, Hayakawa A, Haga Y, Fueki A, Kusunoki Y, Tajima M, Ochiai W, Machida Y and Sugiyama K: Morphine-induced constipation develops with increased aquaporin-3 expression in the colon via increased serotonin secretion. Toxicol Sci. 145:337–347. 2015. View Article : Google Scholar : PubMed/NCBI