Nobiletin, an active component of Wenyang Yiqi formula, alleviates constipation associated depression through targeting MAPT to inhibit the MAPK signaling pathway.

BACKGROUND: Slow transit constipation (STC) is a common gastrointestinal disorder that is often accompanied by depression. Nobiletin is a natural compound that has been shown to have anti-inflammatory and anti-depressant effects. PURPOSE: To study the effects of nobiletin extracted from Wenyang Yiqi Formula 19 (WYF) on STC accompanied by depression and the related mechanism in STC mouse models. METHODS: In this study, the effects of nobiletin on STC accompanied by depression were investigated in both an STC animal model and an in vitro study. The animal model was induced by loperamide, and the in vitro study used Interstitial cells of Cajal (ICCs) isolated from STC mice. The efficacy of nobiletin was assessed by comparing various parameters, including stool particle counts, moisture content, intestinal propulsive rate, colon histopathology, microtubule-associated protein-tau (MAPT) expression in colon tissue, serum levels of TNF-α, IL-1ß, IL-6, IFN-γ, and the levels of MAPK pathway-related proteins among three experimental groups. RESULTS: Nobiletin treatment significantly improved stool particle counts, moisture content, intestinal propulsive rate, and colon histopathology in the STC animal model. Nobiletin also decreased MAPT expression in colon tissue and serum levels of TNF-α, IL-1ß, IL-6, IFN-γ, and the levels of MAPK pathway-related proteins. In the in vitro study, nobiletin treatment reversed the increased cell proliferation and cell apoptosis observed in ICC isolated from the STC model. CONCLUSION: The findings of this study indicate that nobiletin exhibits promising therapeutic potential in addressing STC accompanied by depression. This potential may be attributed to its ability to regulate the function of ICC by targeting MAPT.

Transcutaneous Electrical Acustimulation Improves Constipation Symptoms and Accelerates Colonic Transit in Patients With Slow Transit Constipation Through Autonomic Mechanism.

OBJECTIVES: Nearly half of patients with slow transit constipation (STC) are not completely satisfied with their traditional remedies. We aimed to evaluate the therapeutic value and possible involved mechanism of transcutaneous electrical acustimulation (TEA) at ST36 in patients with STC. MATERIALS AND METHODS: Seventy patients with STC were randomly divided into TEA (n = 35) and sham-TEA (n = 35) to undergo a two-week treatment with TEA at ST36 or sham point. After the two-week treatment, 18 patients from each group randomly underwent a few physiological tests, including the electrocardiogram (ECG), anorectal manometry, colon transit test, and blood drawing. After a two-week washout period, TEA was performed in both groups for two weeks. RESULTS: Spontaneous bowel movements per week were increased, and scores of constipation symptoms were decreased, after a two-week blind TEA but not sham-TEA, which were sustained after a two-week washout period. Improvement in quality of life and psychologic states also was observed with blind TEA treatment. Mechanistically, the two-week blind TEA accelerated colon transit assessed by barium strip excretion rate (the effect was sustained after a two-week washout period), enhanced vagal nerve activity evaluated by the spectral analysis of heart rate variability derived from the ECG, and decreased circulating vasoactive intestinal peptide. CONCLUSIONS: Noninvasive TEA relieves constipation and improves quality of life and psychologic states in patients with STC, and the effects are sustained for ≥two weeks. The therapeutic effects of TEA may be attributed to the acceleration of colon transit and decrease of vasoactive intestinal peptide mediated through the vagal mechanism.

[Research progress of mechanisms of acupuncture in treating slow transit constipation].

As an important part of the traditional Chinese medicine treatment system, acupuncture therapy has been used in the treatment of slow transit constipation (STC) for a long time and has achieved good clinical effects. This article reviews research on the effects of acupuncture therapy on STC published in recent years, focusing on the mechanism of acupuncture on the enteric nervous system, neurotransmitters, interstitial cells of Cajal, smooth muscle cells, gastrointestinal motility, psychological factors and intestinal microecology of STC, in order to provide reference for the clinical application and mechanism research of acupuncture in the treatment of STC in the future.

Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial.

Opioids change gut motility, and opium tincture has been used for treatment of chronic diarrhoea for centuries. However, the effects have never been documented in controlled trials. We aimed to investigate the effects of opium tincture on gastrointestinal transit and motility, frequency of bowel movements, stool consistency, gastrointestinal symptoms and sedation. Twenty healthy subjects were included in this randomized controlled trial. Opium tincture or placebo was each applied for 9 days. Gastrointestinal transit and motility were investigated with the 3D-transit system. Bowel movements and gastrointestinal symptoms were recorded daily. General cognition, reaction time, memory and electroencephalography were used to assess effects on the central nervous system. Opium tincture doubled colonic transit (49 vs. 23 h, p < 0.001), decreased antegrade colonic movements (p < 0.05), reduced daily bowel movements (0.7 vs. 1.2, p < 0.001) and increased stool consistency (Type 3 vs. Type 4, p < 0.001). No changes in general cognition, reaction time or memory were observed, and minor changes of power observed by electroencephalography did not indicate sedation. This study is the first to show that opium tincture has anti-propulsive properties in the healthy gut, while no sedative effects were seen. This indicates that opium tincture is a relevant and safe treatment option in chronic diarrhoea.

Zhizhu decoction alleviates slow transit constipation by regulating aryl hydrocarbon receptor through gut microbiota.

CONTEXT: Slow transit constipation (STC), the most common type of constipation, seriously affects the life of patients. Zhizhu decoction (ZZD), a traditional Chinese medicine compound, has is effective against functional constipation, but the mechanism is still unclear. OBJECTIVE: This research explores the mechanism of ZZD on STC from the perspective of metabolomics and gut microbiota. MATERIALS AND METHODS: Fifty-four C57BL/6 mice were randomly divided into six groups (n = 9): control (control); STC (model); positive control (positive); low-dose (5 g/kg; L-ZZD), medium-dose (10 g/kg; M-ZZD), and high-dose (20 g/kg; H-ZZD) ZZD treatment. Following treatment of mice with ZZD for two weeks, the changes in intestinal motility, colon histology, intestinal neurotransmitters, and aryl hydrocarbon receptor (AHR) pathway determined the effects of ZZD on the pathophysiology of STC. LC-MS targeting serum metabolomics was used to analyze the regulation of ZZD on neurotransmitters, and 16S rRNA high-throughput sequencing was used to detect the regulation of the gut microbiome. RESULTS: ZZD had the highest content of naringin (6348.1 mg/L), and could significantly increase the 24 h defecations (1.10- to 1.42-fold), fecal moisture (1.14-fold) and intestinal transport rate (1.28-fold) of STC mice, increased the thickness of the mucosal and muscular tissue (1.18- to 2.16-fold) and regulated the neurotransmitters in the colon of STC mice. Moreover, ZZD significantly activated the AHR signaling pathway, and also affected the composition of gut microbiota in STC mice. DISCUSSION AND CONCLUSIONS: The beneficial effect and the possible mechanism of ZZD on STC could provide a theoretical basis for the broader clinical application of ZZD.

Ji-Chuan decoction ameliorates slow transit constipation via regulation of intestinal glial cell apoptosis.

BACKGROUND: Slow transit constipation (STC) is a common intestinal disease with increasing incidence. STC results from various factors, such as the enteric nervous system and metabolic changes. As a classical formula of traditional Chinese medicine, Ji-Chuan decoction (JCD) has been extensively and effectively used in STC treatment, yet its pharmacological mechanism remains unclear. AIM: To explore the integrated regulatory pattern of JCD against STC through hyphenated techniques from metabolism, network pharmacology and molecular methods. METHODS: STC model mice were generated by intragastric administration of compound diphenoxylate (10 mg/kg/d) for 14 d. The STC mice in the low dose of JCD (3.04 g/kg), middle dose of JCD (6.08 g/kg) and high dose of JCD (12.16 g/kg) groups were orally administered JCD solution once a day for 2 wk. The acetylcholine (ACH) level was examined by enzyme-linked immunosorbent assay. The pathological features of colon tissue were observed by hematoxylin and eosin staining. The differentially expressed metabolites and metabolic pathways were tested by nontargeted metabolomics. The main targets and core ingredients of JCD were identified by network pharmacology, and the expression of AKT was confirmed by immunohistochemistry. Finally, the pathways involved in JCD treatment were predicted using a combination of differentially expressed metabolites and targets, and intestinal glial cell apoptosis was demonstrated by immunofluorescence. RESULTS: JCD significantly promoted intestinal motility, increased the levels of the excitatory neurotransmitter ACH and reduced intestinal inflammation in STC mice. Untargeted metabolomics results showed that JCD significantly restored metabolic dysfunction and significantly affected taurine and hypotaurine metabolism. Network pharmacology and molecular experiments showed that JCD regulates AKT protein expression, and the core component is quercetin. Combined analysis demonstrated that apoptosis may be an important mechanism by which JCD relieves constipation. Further experiments showed that JCD reduced enteric glial cell (EGC) apoptosis. CONCLUSION: This work demonstrated that reducing EGC apoptosis may be the critical mechanism by which JCD treats STC. These findings call for further molecular research to facilitate the clinical application of JCD.

Research progress in the treatment of slow transit constipation by traditional Chinese medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Slow transit constipation (STC) is a common gastrointestinal disorder seriously impacting patients' quality of life. At present, although conventional chemical drugs effectively control STC symptoms in the short term, the long-term effects are poor, and the side effects are significant. In this regard, traditional Chinese medicine (TCM) offers an opportunity for STC treatment. Many pharmacological and clinical studies have confirmed this efficacy of TCM with multiple targets and mechanisms. AIM OF THE STUDY: This review attempted to summarize the characteristics of TCM (compound prescriptions, single Chinese herbs, and active ingredients) for STC treatment and discussed their efficacy based on analyzing the pathogenesis of STC. MATERIALS AND METHODS: The information was acquired from different databases, including PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases. We then focused on the recent research progress in STC treatment by TCM. Finally, the future challenges and trends are proposed. RESULTS: TCM has good clinical efficacy in the treatment of STC with multi-mechanisms. Based on the theory of syndrome differentiation, five kinds of dialectical treatment for STC by compound TCM prescriptions were introduced, namely: Nourishing Yin and moistening the intestines; Promoting blood circulation and removing blood stasis; Warming Yang and benefiting Qi; Soothing the liver and regulating Qi; and Benefiting Qi and strengthening the spleen. In addition, six single Chinese herbs and eight active ingredients also show good efficacy in STC treatment. CONCLUSIONS: TCM, especially compound prescriptions, has bright prospects in treating STC attributed to its various holistic effects.

Clinical translation of advanced colonic drug delivery technologies.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

The Short-Term Effects and Tolerability of Low-Viscosity Soluble Fibre on Gastroparesis Patients: A Pilot Clinical Intervention Study.

Gastroparesis is a motility disorder that causes severe gastric symptoms and delayed gastric emptying, where the majority of sufferers are females (80%), with 29% of sufferers also diagnosed with Type-1 or Type-2 diabetes. Current clinical recommendations involve stringent dietary restriction and includes the avoidance and minimization of dietary fibre. Dietary fibre lowers the glycaemic index of food, reduces inflammation and provides laxation. Lack of dietary fibre in the diet can affect long-term gastrointestinal health. Our previously published rheological study demonstrated that "low-viscosity" soluble fibres could be a potentially tolerable source of fibre for the gastroparetic population. A randomised controlled crossover pilot clinical study was designed to compare Partially-hydrolysed guar gum or PHGG (test fibre 1), gum Arabic (test fibre 2), psyllium husk (positive control) and water (negative control) in mild-to-moderate symptomatic gastroparesis patients (requiring no enteral tube feeding). The principal aim of the study was to determine the short-term physiological effects and tolerability of the test fibres. In n = 10 female participants, post-prandial blood glucose, gastroparesis symptoms, and breath test measurements were recorded. Normalized clinical data revealed that test fibres PHGG and gum Arabic were able to regulate blood glucose comparable to psyllium husk, while causing far fewer symptoms, equivalent to negative control. The test fibres did not greatly delay mouth-to-caecum transit, though more data is needed. The study data looks promising, and a longer-term study investigating these test fibres is being planned.

Preservation of superior rectal artery in laparoscopically assisted subtotal colectomy with ileorectal anastomosis for slow transit constipation.

BACKGROUND: Slow transit constipation (STC) has traditionally been considered as a functional disorder. However, evidence is accumulating that suggests that most of the motility alterations in STC might be of a neuropathic etiology. If the patient does not meet the diagnosis of pelvic outlet obstruction and poorly response to conservative treatment, surgical intervention with subtotal colectomy may be effective. The most unwanted complication of the procedure is anastomotic leakage, however, preservation of the superior rectal artery (SRA) may reduce its incidence. AIM: To evaluate the preservation of the SRA in laparoscopically assisted subtotal colectomy with ileorectal anastomosis in STC patients. METHODS: This was a single-center retrospective observational study. STC was diagnosed after a series of examinations which included a colonic transit test, anal manometry, a balloon expulsion test, and a barium enema. Eligible patients underwent laparoscopically assisted total colectomy with ileorectal anastomosis and were examined between January 2016 and January 2018. The operation time, blood loss, time to first flatus, length of hospital days, and incidence of minor or major complications were recorded. RESULTS: A total of 32 patients (mean age, 42.6 years) who had received laparoscopic assisted subtotal colectomy with ileorectal artery anastomosis and preservation of the SRA. All patients were diagnosed with STC after a series of examinations. The mean operative time was 151 min and the mean blood loss was 119 mL. The mean day of first time to flatus was 3.0 d, and the mean hospital stay was 10.6 d. There were no any patients conversions to laparotomy. Post-operative minor complications including 1 wound infection and 1 case of ileus. There was no surgical mortality. No anastomosis leakage was noted in any of the patients. CONCLUSION: Laparoscopically assisted subtotal colectomy with ileorectal anastomosis and preservation of the SRA can significantly improve bowel function with careful patient selection. Sparing the SRA may protect against anastomosis leakage.

New device for active gastric mechanical stimulation.

BACKGROUND: Gastroparesis is a chronic stomach disorder and effective treatment is the aim of different strategies. Alternative therapies consist of an electrical stimulation of the stomach to evoke a response in the gastric activity. We present the development and in vivo application of an electromagnet system to induce a mechanical stimulus in the stomach aiming for gastric contractile responses. METHODS: The electromagnet system consisted of an implantable magnet and an external drive coil. We implanted the magnet at the greater curvature of the gastric body in rats. We applied an alternating current to the drive coils, inducing mechanical stimulation of the gastric wall. We measured the gastric contraction activity and gastric electrical activity in response to the stimulus using AC biosusceptometry and electrogastrography. Moreover, we used the phenol red to evaluate the stimulus effects on gastrointestinal transit. KEY RESULTS: The stimulus increased the spectral intensity and signal-to-noise ratio significantly of gastric contraction activity and gastric electrical activity. Furthermore, we found a lower phenol red retention in the stomach in rats without stimulus. No significant differences were found in frequency and root mean square amplitude. CONCLUSIONS & INFERENCES: We developed a new simple electromagnet system that evoked a contraction and gastric electrical response using a mechanical stimulus and decreased gastric emptying time. The system is an accessible tool and may contribute to gastroparesis studies in animals.

The protective effects of yellow tea extract against loperamide-induced constipation in mice.

Yellow tea, a rare type tea from China, has a rich breadth of functional ingredients and benefits the gastrointestinal tract. However, it is not clear whether the yellow tea extract can alleviate constipation. Therefore, we used loperamide-induced constipation in mice to evaluate the effects of yellow tea extract. Fifty Kunming mice were randomly divided into five groups: normal, model, low-dose yellow tea extract, low-dose yellow tea extract prevention group, and high-dose yellow tea extract prevention group. Mice were administered yellow tea extract for 5 weeks followed by loperamide-induced constipation for the final 2 weeks. The results showed that yellow tea extract alleviated constipation symptoms by improving the fecal water content, defecation weight, and gastrointestinal transit rate. Yellow tea extract intervention also protected colon tissue, regulated serum neurotransmitters, and decreased the vasoactive intestinal peptide level. Furthermore, qRT-PCR indicated that yellow tea extract regulated genes associated with the constipation state, raised 5-HT3 and 5-HT4 and reduced AQP3 and AQP4 mRNA expression. Moreover, we found that yellow tea extract changed the gut microbiota composition. Community diversity and richness were increased and principal co-ordinate analysis demonstrated that the yellow tea extract prophylaxis groups differed from the model group. Difference analysis indicated that yellow tea extract increased Roseburia, Lachnospiraceae_UCG-006, and Bifidobacterium and decreased norank_f_Clostridiales_vadinBB60_group, unclassified_o_Bacteroidales, and Bacteroides, which are correlated with constipation. Based on these results, we believe that regular yellow tea consumption can effectively alleviate constipation.

Effectiveness of Biofeedback Therapy on Quality of Life in Patients with Dyssynergic Defecation Disorder.

BACKGROUND: The first option to be considered in the treatment of functional defecation disorder is to correct the dyssynergia. However, limited studies exist to show the effectiveness of biofeedback. OBJECTIVE: We evaluated the effect of biofeedback on the severity of constipation, quality of life, and anorectal manometry in patients with dyssynergic defecation in which the biofeedback method was applied. METHODS: Effectiveness of biofeedback method on the quality of life of 24 dyssynergic defecation patients according to Rome III criteria after clinical and balloon expulsion tests (BETs) and colonic transit time was measured. Data were collected with patient identification form, Bristol Stool Chart, Constipation Quality of Life Scale forms, Visual Analogue Scale, diaphragmatic breathing exercises form, constipation diary, and constipation biofeedback monitoring form. Dyssnergic defecation cases received 6-week biofeedback training. For the same timeframe, the control group had a catheter into the rectum without any intervention. RESULTS: Constipation severity was reduced in both groups before biofeedback to post-biofeedback (P < .05). Anal canal pressure, BET, colonic transit time, and quality of life significantly improved in biofeedback patients compared with controls. CONCLUSIONS: Biofeedback has a favorable effect on therapy and quality of life in dyssynergic defecation cases.

[Therapeutic effect and mechanism of Shouhui Tongbian Capsules on slow transit constipation model mice].

Shouhui Tongbian Capsules was used to explore the therapeutic effect and potential mechanism on slow transit constipation model mice induced by loperamide hydrochloride. In the experiment, loperamide hydrochloride-induced ICR mice were used as the model of slow transit constipation. Fifty ICR mice were divided into the blank group, model group and high, medium and low dose groups of Shouhui Tongbian Capsules extract(100, 200 and 400 mg·kg~(-1)). The model group and the administration groups were then modeled using loperamide hydrochloride intragastrically to obtain slow transit constipation. After successful modeling, high, medium and low doses of drugs were given to each drug group by intragastric administration. After 14 days of administration, the first defecation time, 6 h defecation grain number, 6 h defecation wet weight and dry weight, black feces discharged within 6 h and the fecal water content were measured. Intestinal tissues were taken for c-Kit and SCF immunohistochemical sections to detect the expression of c-Kit and SCF in the blank group, model group and high, medium and low dose groups of the medicinal extract of Shouhui Tongbian Capsules. The tissue changes in the intestinal wall of mice were detected by HE staining. At the same time, partial intestinal tissues were taken to test the activity of ATP synthase and isocitrate dehydrogenase in intestinal tissues of mice. RESULTS:: showed that Shouhui Tongbian Capsules effectively improved the symptoms of slow transit constipation in ICR mice and promoted intestinal movement. Shouhui Tongbian Capsules obviously shortened the time of discharging black stool for the first time, improved the intestinal propulsion rate, increased the water content and amount of feces, and improved the constipation symptoms. Mechanism study revealed that Shouhui Tongbian Capsules increased ATP synthase activity and mitochondrial isocitrate dehydrogenase activity in intestinal tissue, and up-regulated c-Kit/SCF signaling pathway to promote interstitial Cajal cells proliferation, intestinal nerve transmission, intestinal motility and transport capacity.

Control of colonic motility using electrical stimulation to modulate enteric neural activity.

Electrical stimulation of the enteric nervous system (ENS) is an attractive approach to modify gastrointestinal transit. Colonic motor complexes (CMCs) occur with a periodic rhythm, but the ability to elicit a premature CMC depends, at least in part, upon the intrinsic refractory properties of the ENS, which are presently unknown. The objectives of this study were to record myoelectric complexes (MCs, the electrical correlates of CMCs) in the smooth muscle and 1) determine the refractory periods of MCs, 2) inform and evaluate closed-loop stimulation to repetitively evoke MCs, and 3) identify stimulation methods to suppress MC propagation. We dissected the colon from male and female C57BL/6 mice, preserving the integrity of intrinsic circuitry while removing the extrinsic nerves, and measured properties of spontaneous and evoked MCs in vitro. Hexamethonium abolished spontaneous and evoked MCs, confirming the necessary involvement of the ENS for electrically evoked MCs. Electrical stimulation reduced the mean interval between evoked and spontaneous CMCs (24.6 ± 3.5 vs. 70.6 ± 15.7 s, P = 0.0002, n = 7). The absolute refractory period was 4.3 s (95% confidence interval (CI) = 2.8-5.7 s, R2 = 0.7315, n = 8). Electrical stimulation applied during fluid distention-evoked MCs led to an arrest of MC propagation, and following stimulation, MC propagation resumed at an increased velocity (n = 9). The timing parameters of electrical stimulation increased the rate of evoked MCs and the duration of entrainment of MCs, and the refractory period provides insight into timing considerations for designing neuromodulation strategies to treat colonic dysmotility.NEW & NOTEWORTHY Maintained physiological distension of the isolated mouse colon induces rhythmic cyclic myoelectric complexes (MCs). MCs evoked repeatedly by closed-loop electrical stimulation entrain MCs more frequently than spontaneously occurring MCs. Electrical stimulation delivered at the onset of a contraction temporarily suppresses the propagation of MC contractions. Controlled electrical stimulation can either evoke MCs or temporarily delay MCs in the isolated mouse colon, depending on timing relative to ongoing activity.

Antioxidant activity and laxative effects of tannin-enriched extract of Ecklonia cava in loperamide-induced constipation of SD rats.

To investigate the role of tannin-enriched extracts of Ecklonia cava (TEE) on the regulation of oxidative balance and laxative activity in chronic constipation, we investigated alterations after exposure to TEE, on constipation phenotypes, muscarinic cholinergic regulation, and oxidative stress responses in the transverse colons of SD rats with loperamide (Lop)-induced constipation. This extract contains high levels of total condensed tannin content (326.5 mg/g), and exhibited high inhibitory activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. TEE treatment induced significant improvements in reactive oxygen species (ROS) production, superoxide dismutase (SOD) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation in primary smooth muscles of rat intestine cells (pRISMCs) and transverse colon of constipation model. Also, Lop+TEE treated groups showed alleviated outcomes for the following: most stool parameters, gastrointestinal transit, and intestine length were remarkably recovered; a similar recovery pattern was observed in the histopathological structure, mucin secretion, water channel expression and gastrointestinal hormones secretion in the transverse colon; expressions of muscarinic acetylcholine receptors M2/M3 (mAChR M2/M3) and their mediators on muscarinic cholinergic regulation were significantly recovered. Taken together, these results provide the first evidence that TEE stimulates oxidative stress modulation and muscarinic cholinergic regulation when exerting its laxative effects in chronic constipation models.

Electroacupuncture accelerates the delayed intestinal transit in POI by suppressing M1 like muscularis macrophages and IL6 secretion.

BACKGROUND: Electroacupuncture (EA) at ST-36 could accelerate the delayed gastrointestinal (GI) motility in many GI motility dysfunction models, but the definite effect and mechanisms are unclear. In this study, we intended to investigate the effects of EA on intestinal manipulation (IM) mice model and involved mechanisms. METHODS: Male C57BL/6 mice were randomized into five groups: normal control, intestinal manipulation (IM), IM with sham EA (SEA), IM with high-frequency EA (HEA), and IM with low-frequency EA (LEA). The GI transit was evaluated. The infiltration of muscularis macrophages (MMφ) and its phenotype were analyzed with flow cytometry. Magnetic-activated cell sorting was applied to isolate MMφ, and the relationship between the MMφ and interstitial cells of Cajal (ICCs) was further investigated. RESULTS: (1) Compared with the IM group, HEA and LEA attenuated the delayed intestinal transit. (2) Both the HEA and LEA obviously reduced the MMφ and suppressed the M1 activation of the MMφ in the ileum. (3) EA restored the disrupted ICC networks through inhibiting the release of IL6 by the MMφ. CONCLUSION: (1) Electroacupuncture at acupoint ST-36 could accelerate the delayed intestinal transit in the IM murine model by restoring the ICC networks. (2) EA protected the ICCs through reducing the MMφ, inhibiting its M1 polarization and its IL6 secretion.

Deciphering the correlations between aging and constipation by metabolomics and network pharmacology.

From the points of view of phenomena and experience, aging and constipation are inextricably correlated. However, experimental support and underlying mechanisms are still lacking. The purpose of this study is to explore the relationships between aging and constipation from the perspectives of fecal metabolites and network pharmacology. The behavioral analyses of aging and constipation were carried out on both aging rats and constipation rats. We found that aging rats exhibited not only significant aging behaviors but also significant constipation behaviors, while constipation rats exhibited both significant constipation and aging behaviors. Additionally, fecal metabolomics was carried out and found that 23 metabolites were aging-related and 22 metabolites were constipation-related. Among them, there were 16 differential metabolites in common with 11 metabolic pathways. Network pharmacology was applied to construct the target-pathway network of aging and constipation, revealing that pathway in cancer was the most associated signaling pathway. The current findings will provide not only a novel perspective for understanding aging and constipation, but a theoretical association and understanding the traditional Chinese medicine theory and the Western medicine theory about aging and constipation, as well as support for the clinical research and development of medicine related to constipation in the elderly.

Aster tataricus alleviates constipation by antagonizing the binding of acetylcholine to muscarinic receptor and inhibiting Ca2+ influx.

BACKGROUND: The dried root and rhizome of Aster tataricus (RA), is a traditional Chinese medicine has been used for more than 2000 years with the function of antitussive, expectorant and antiasthmatic. Ancient books and modern pharmacological researches demonstrated that RA may have the function of moistening intestines and relieving constipation, but there was a lack of systematic evidence. The aim of this study was to comprehensively evaluate the efficacy and possible mechanisms of ethanol extract of Aster tataricus (ATE) in treating constipation from in vivo to in vitro. METHODS: In vivo, the ATE was studied in loperamide-induced constipation of mice. In vitro, different concentrations of ATE was tested separately or cumulatively on spontaneous and agonists-induced contractions of isolated rat duodenum strips. RESULTS: In vivo, at doses of 0.16, 0.8 g/mL, ATE showed significantly promotion of the small intestinal charcoal transit, decrease of the amount of remnant fecal, and increase of the content of fecal water in colon. In addition, ATE could effectively relieve colonic pathological damage caused by loperamide as well. In vitro, with the cumulative concentration increase of ATE from 0.8 to 6.4 mg/mL, it could significantly decrease the contraction caused by KCl or Ach, and gradually restore to near base tension value.Meanwhile, it could also partially but significantly inhibit the contractions induced by Ach and CaCl2 on rat duodenum in a concentration related manner. CONCLUSIONS: Taking all these findings together, it could be speculated that ATE may attenuate constipation mainly through antagonizing the binding of acetylcholine to muscarinic receptor, inhibiting Ca2+ influx and anti-inflammation.