PART 2 Aqueous Extracts Of Herba Cistanche Promoted Intestinal Motility in Loperamide-Induced Constipation Rats By Ameliorating The Interstitial Cells Of Cajal
Mar 05, 2022
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4. Discussion
Constipation is a highly common disorder characterized by poor bowel movements. It greatly diminishes the quality of life and brings about huge economic burdens on both patients and national health insurance [32]. Natural products and medicinal food now attract ever-increasing attention because of their potential to become new drugs used for the treatment of constipation [37, 38]. Therefore, we studied the therapeutic effects of the AEHC on loperamide-induced constipated rats. Loperamide, atropine-diphenoxylate, and morphine are widely used to induce constipation in laboratory animals. Among the three drugs, loperamide induces a prolonged duration of stool evacuation and a delay of intestinal luminal transit, since it inhibits both water secretion and smooth movement in the intestinal wall [39]. Analysis of body weight in this study did not find any difference within each group. After the experiment, no difference was found either. The low-dosage group of AEHC still saw the lowest body weight, yet the model group and the normal group witnessed the highest body weight. Constipation is generally a functional disease. Slow transit constipation induced in this study did not affect nutrient uptake of the rats and their body weight during the experiment. Differences in amounts of feces of the rats and their moisture content did not exist between groups before modeling; however, they both decreased remarkably after modeling and the moisture content of feces increased after using AEHC at different dosages. After studying the propellant rate of carbon powder of the colon.
of rats, the model group saw an obvious decrease of the rate, while it remained normal in low-dosage, medium-dosage, and high-dosage groups of AEHC. The results showed that loperamide-induced chronic transit constipation treated with different dosages of Herba Cistanche can recover the propellant function of the colon to different degrees. Gastrointestinal hormones are high-performance bioactive substances secreted by endocrine cells of gastrointestinal mucosa and pancreas, possessing effects of both excitement and inhibition to regulate gastrointestinal motor function [40, 41], of which GAS, MTL, and SS have a major effect. The former two hormones stimulate the secretion of digestive juice, constrict gastrointestinal smooth muscle, promote the movement of gastrointestinal contents, and excite gastrointestinal motility. SS, on the contrary, inhibits the secretion of digestive juice, contraction of gastrointestinal smooth muscle, and gastrointestinal emptying [42]. GAS and MTL levels in the colon tissue of the model group were found to be the lowest, indicating that the modeling method certainly lowered the concentration of GAS and MTL in colon tissue. As the main gastrointestinal hormones of colonic motility, the concentration of GAS and MTL increased by different dosages of AEHC and thus enhanced colonic motility. In contrast, SS level in the colon tissue of the model group was the highest, indicating that the modeling method can promote the concentration of SS in colon tissue. CGRP is one of the most powerful vasodilators and its relaxation effect is 10-fold stronger than the contraction effect. As an important neurotransmitter or neuromodulator that regulates digestive functions, CGRP can inhibit the majority of gastrointestinal motility and the secretion of various digestive juices [43]. The concentration of CGRP in the model group was higher than Group A, indicating that the modeling method can increase CGRP concentration in the colon tissue, which may also be one of the factors for reduced colonic peristalsis which will result in constipation. CGRP concentration in the colon tissue of AEHC groups was lower than that in the model group, suggesting that AEHC had a relatively weak inhibitory effect on colon movement. c-Kit is a transmembrane protein. The stem cell factor (SCF) of its ligand is produced by neuron cells and smooth muscle cells. It promotes the development and differentiation of ICC and maintains its normal physiological function. c-Kit labeling indirectly reflects the quantity and density of ICC [44, 45]. In addition, the ICC cell plays a key role in regulating gastrointestinal motility and acts as the pacemaker of gastrointestinal movement. So, some disorders of gastrointestinal motility may find a decline in the quantity and function of ICC cells. According to previous studies, cell counts in the colon of patients with chronic transit constipation were reduced. Hence, the present study observed the colonic cells of rats by using specific expression and immunohistochemical techniques. Compared with the normal group, the number of cells in the model group decreased remarkably but increased after treatment. The study showed that ICC cells and stem cell factors (SCF) are closely related to c-kit/SCF signal pathway. SCF is the natural ligand ofc-kit expressed in various tissues of the body but mainly
produced by the stromal cells in the bone marrow. Every c-kit monomer combines with an SCF through the extracellular domains 1–3. After SCF dimerization, the structure of the c-kit monomer changes and produces homodimerization, which then results in the autophosphorylation of amino acid residue in the cell membrane and stimulates various second signal molecules to regulate the cellular functions of ICC. The second signal molecule is phosphatidylinositol 3-kinase (PI3K), an apolipoprotein that converts 4,5- diphosphoinositide into 3,4,5-triphosphoinositide through the combination with tyrosine 721 of c-kit. Previous research showed that PI3K inhibitors Wortmannin and LY294002 gave rise to abnormal development of ICC by blocking the signal [46]. Our experiment found that c-kit and SCF protein and mRNA expressions in the model group decreased at first but then increased in AEHC groups of different dosages, albeit at below-normal levels. mRNA expression of PI3K increased remarkably. Therefore, SCF/c-kit may take effect through PI3K. The results showed that AEHC could regulate the smooth muscle of the gastrointestinal tract by increasing the quantity of ICC cells. The low dosage of AEHC had no significant effect on constipation, while its medium dosage and high dosage shortened the first defecation time of the rats, increased moisture content of the feces, improved propellant rate of the colon, refined the quantity of the feces, increased GAS, MTL, and CCK levels, and strengthened the colonic contractility. The effective dosage of AEHC is initially 20 g/d after conversion, which is equivalent to the medium dosage and high dosage in this study.
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5. Conclusions
AEHC promotes intestinal motility by improving ICC function and regulating neurotransmitters in this study, which proved that AEHC has the potential to treat and prevent constipation. The extracts improved the slow-wave production of the colon and regulated the rhythm of the contractive activity SCF mRNA quantity PI3K mRNA quantity c-Kit mRNA quantity12 Evidence-Based Complementary and Alternative Medicine of smooth muscle by increasing ICC quantity through the PI3K/SCF/c-kit signal pathway. However, furthermore detailed experimental studies might improve understanding of the other molecular pathways of AEHC in curing STC and help guide prospective clinical studies evaluating its effects and safety.
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Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors’ Contributions
Shuai Yan and Yin-Zi Yue contributed equally to this work. All authors have approved the final paper.
Acknowledgments
This work was supported by a grant from the National Natural Science Foundation of China (NSFC) and funded by the Chinese Government (81573979). The study was also supported by the technology project of Jiangsu Provincial Administration of Traditional Chinese Medicine, China (no. YB2017061), the Suzhou Scientific and Technological Development Program, China (no. SYSD2015172), the Project of Suzhou Industrial Technology Innovation, China (no. SYSD2016136, no. SYS201775, and no. SYS201776), and the College Project of Suzhou Hospital of Traditional Chinese Medicine, China (YQN2015007). The authors gratefully acknowledge financial support from a project funded by China Postdoctoral Science Foundation (2017M620220).
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