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World Journal of Gastroenterology Sep 2022Slow transit constipation (STC) is a common intestinal disease with increasing incidence. STC results from various factors, such as the enteric nervous system and...
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.
Topics: Acetylcholine; Animals; Apoptosis; Constipation; Diphenoxylate; Gastrointestinal Transit; Mice; Neuroglia; Proto-Oncogene Proteins c-akt; Quercetin; Taurine
PubMed: 36160643
DOI: 10.3748/wjg.v28.i34.5007 -
Food Research International (Ottawa,... May 2021Slow transit constipation (STC) has become an epidemic medical problem. There are several kinds of drugs for constipation; however, each drug has its limitations. The...
Slow transit constipation (STC) has become an epidemic medical problem. There are several kinds of drugs for constipation; however, each drug has its limitations. The gut microbiota has a close relationship with STC. Lactulose is an effective drug for constipation because it is a kind of bulking laxative and microbioecologic, and it relieves the syndromes of STC. We found that the Chinese Herb Solid Drink (CHSD), which contains medicine food homologous materials such as psyllium husk, sweetalmond, semen sesami nigrum, and hemp seed, has a similar effect on relieving constipation as lactulose, although it has different effects on the gut microbiota. We investigated the mechanisms of CHSD in rats with STC, induced by diphenoxylate, via constipation index and enzyme linked immunosorbent assay (ELISA) analyses using serum and 16S rDNA amplicon and gas chromatography-mass spectroscopy (GC-MS). CHSD enhanced the relative abundance of some types of gut microbiota, such as Blautia, Ruminococcus, Roseburia, Coprococcus, Lachnospira, and Phascolarctobacterium, while lactulose enhanced the relative abundance of Blautia, Phascolarctobacterium, Eubacterium, and Akkernansia in diphenoxylate-induced STC rats. Both CHSD and lactulose enhanced the level of short-chain fatty acids in the faeces of rats; however, the composition of those were different between the two drugs. From the perspective of the gut neuroendocrine system, both CHSD and lactulose could elevate neurotransmitters, such as motilin (MTL) and substance P (SP), which promote intestinal peristalsis and reduce the expression of vasoactive intestinal peptide, which inhibits intestinal peristalsis in the serum of STC rats. CHSD could elevate gastrin expression, which also promoted intestinal peristalsis in serum, while lactulose did not have this effect. Our findings suggest that CHSD may be an effective and safe therapeutic choice for STC.
Topics: Animals; China; Constipation; Diphenoxylate; Gastrointestinal Microbiome; Lactulose; Pharmaceutical Preparations; Rats
PubMed: 33992373
DOI: 10.1016/j.foodres.2021.110273 -
International Journal of Biological... Jul 2019The aim of this study is to probe new functions of a polysaccharide from Spirulina platensis (PSP) on constipation and intestinal microbiota in mice....
The aim of this study is to probe new functions of a polysaccharide from Spirulina platensis (PSP) on constipation and intestinal microbiota in mice. Diphenoxylate-induced constipation in mice was treated with different doses of PSP, followed by examining the defecation patterns, levels of acetyl cholinesterase (AchE), nitric oxide (NO), and tissue section histopathology. The composition of intestinal microbiota was determined by genome sequencing analysis of the 16S rDNA. This study found that the average molecular weight of PSP was 29, 600 Da, and mainly monosaccharides of PSP were rhamnose (24.7%), glucose (16.15%) and galactose (13.32%). The beneficial effects of PSP treatment include defecation improvement, increase of AchE activity, reduction of NO concentration, renovation of the damaged intestinal villus and affection on the expression of some related genes in the constipated mice. In addition, PSP had significant effects on the gut microbiota, showing the enhancement in abundance of beneficial bacteria including Akkermansia, Lactobacillus, Butyricimonas, Candidatus Arthromitus and Prevotella, and the reduction in abundance of harmful bacteria such as Clostridium and Dorea. The present s uncovered a new function of PSP, indicating that PSP could be used in constipation therapies.
Topics: Animals; Chorionic Villi; Constipation; Defecation; Diphenoxylate; Gene Expression Regulation; Intestines; Male; Mice; Mice, Inbred ICR; Neurotransmitter Agents; Polysaccharides, Bacterial; Spirulina; Water
PubMed: 31054300
DOI: 10.1016/j.ijbiomac.2019.04.209 -
Laxative Effects of Yangyin Tongmi Capsule on a Model of Diphenoxylate-Induced Constipation in Mice.Evidence-based Complementary and... 2020Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is...
Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is used in the treatment of constipation, while the underlying mechanisms remain unknown. Herein, this work attempted to prove the effects of YTC on constipation treatment and its possible mechanisms. KM mice were randomly divided into four groups ( = 10/group) and treated with double distilled water (Control), diphenoxylate (Model: 10 mg/kg), or diphenoxylate plus low-dose YTC (L-YTC: 0.6 g/kg) or high-dose YTC (H-YTC: 1.2 g/kg). The data indicated that YTC can significantly shorten the discharge time of the first black stool, improve intestinal propulsion rate, and increase the water content and quantity of feces in mice. ELISA suggested that YTC regulate the content of intestinal hormones and neurotransmitters, such as motilin (MTL), gastrin (GT), somatostatin (SST), substance P (SP), acetylcholine (Ach), and nitric oxide (NO). The expression levels of aquaporin 3 (AQP3) and aquaporin 8 (AQP8) in the colon were examined by immunohistochemistry. In the meantime, the expression levels of P2X2, C-kit, and stem cell factor (SCF) in the colon were examined by western blot analysis. The results of this study suggest that YTC has mitigative effects on diphenoxylate-induced constipation by regulating the content of intestinal hormones and neurotransmitters and regulating the expression of related proteins in the colon.
PubMed: 32148532
DOI: 10.1155/2020/1471824 -
Cureus Feb 2023The clinical course of a patient with chemotherapy-related diarrhea (CRD) refractory to standard therapy was monitored over the course of 21 days. The patient was...
The clinical course of a patient with chemotherapy-related diarrhea (CRD) refractory to standard therapy was monitored over the course of 21 days. The patient was minimally responsive to traditional treatment options, including bismuth subsalicylate, diphenoxylate-atropine, loperamide, octreotide, and oral (PO) steroids, and exhibited reportable improvements with the addition of intravenous (IV) methylprednisolone to other antidiarrheal agents. We present a case of CRD in an 82-year-old female. She was initiated on chemotherapy three weeks prior and has experienced severe diarrhea since her initiation. Despite the use of first-line antidiarrheal therapies, including loperamide, diphenoxylate-atropine, and octreotide, both subcutaneously and via continuous infusion drip, no infectious cause was found. She also received the non-absorbing corticosteroid budesonide, but her diarrhea persisted. After experiencing severe hypotension and hypovolemia secondary to profuse diarrhea, she was placed on IV steroids, which quickly reduced her symptoms. The patient was then transitioned to oral steroids and discharged on a tapering regimen. We recommend using IV steroids to treat CRD if first-line therapies fail. Utilizing IV steroids efficiently and effectively can decrease the symptoms of persistent diarrhea and lead to rapid recovery.
PubMed: 36895532
DOI: 10.7759/cureus.34634 -
The Oncologist Aug 2019Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter...
BACKGROUND
Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome.
SUBJECTS, MATERIALS, AND METHODS
Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated.
RESULTS
Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4.
CONCLUSION
Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome.
IMPLICATIONS FOR PRACTICE
Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarrhea; Female; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Patient Safety; Phenylalanine; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome
PubMed: 30651397
DOI: 10.1634/theoncologist.2018-0236 -
Frontiers in Pharmacology 2021Poisoning is a type of accidental injury and it is considered a major public health problem worldwide. Oral drug poisoning in children is an important cause of...
Poisoning is a type of accidental injury and it is considered a major public health problem worldwide. Oral drug poisoning in children is an important cause of accidental injury and even death. It is a common critical emergency in the field of pediatrics. Once a child unintentionally takes an overdose, regardless of whether it caused poisoning or not, they should be admitted to the hospital for emergency treatment. Acute poisoning in children most frequently occurs through the digestive tract. Drug poisoning can happen in children of all ages. In children younger than 1 year, drug poisoning is mostly caused by the parents during feeding, while in children aged 1-3 years, it predominantly occurs as a result of an accident. A case of diagnosis and treatment of a child with diphenoxylate-atropine poisoning is reported herein. The early manifestation of this child was acute toxic encephalopathy with clinical manifestations of a coma, convulsions, and respiratory depression. A brain MRI showed extensive damage to the bilateral caudate nucleus, lenticular nucleus, parietal lobe, precuneus lobe, and occipital lobe. Accidental administration of a large dose of diphenoxylate results in severe clinical symptoms and can cause obvious diffuse brain damage.
PubMed: 33912057
DOI: 10.3389/fphar.2021.646530 -
Journal of Medicinal Food Feb 2017Constipation is a common disorder that is a significant source of morbidity among people around the world ranging from 2% to 28%. Dendrobium officinale Kimura et Migo is...
Constipation is a common disorder that is a significant source of morbidity among people around the world ranging from 2% to 28%. Dendrobium officinale Kimura et Migo is a traditional herbal medicine and health food used for tonicity of the stomach and promotion of body fluid production in China. This study aimed to prepare the ultrafine powder of Dendrobium officinale (UDO) and investigate its laxative effect and potential mechanism in mice with diphenoxylate-induced constipation. Results indicated that the mean diameter (d) of UDO obtained by ball milling was 6.56 μm. UDO (62.5, 125, and 250 mg/kg, p.o.) could significantly enhance the gastrointestinal transit ratio and promote fecal output. Moreover, UDO treatment resulted in significant increases in the serum levels of acetylcholinesterase (AChE), gastrin (Gas), motilin (MTL), and substance P (SP), and obviously decreased serum contents of somatostatin (SS). Taken together, UDO, which can be easily obtained through milling to a satisfactory particle size, exhibited obvious laxative effect in diphenoxylate-induced constipated mice, and the mechanism might be associated with elevated levels of AChE, Gas, MTL, SP, and reduced production of SS. UDO has the potential for further development into an alternative effective diet therapy for constipation.
Topics: Animals; Constipation; Dendrobium; Female; Gastrins; Gastrointestinal Transit; Humans; Laxatives; Male; Mice; Mice, Inbred ICR; Motilin; Plant Extracts; Substance P
PubMed: 28146409
DOI: 10.1089/jmf.2016.3827 -
Zhen Ci Yan Jiu = Acupuncture Research Feb 2022To observe the effect of electroacupuncture (EA) of "Tianshu"(ST25) and "Dachangshu"(BL25) on the intestinal transit function, expression level of glial cell-derived...
OBJECTIVE
To observe the effect of electroacupuncture (EA) of "Tianshu"(ST25) and "Dachangshu"(BL25) on the intestinal transit function, expression level of glial cell-derived neurotrophic factor (GDNF) and methylation level of GDNF gene promoter region in colon tissue of rats with slow transit constipation (STC), so as to explore its mechanisms underlying improvement of STC.
METHODS
Male Sprague-Dawley (SD) rats were randomized into control, saline, model and EA groups (=16 in each group). The STC model was replicated by gavage of compound diphenoxylate suspension (10 mL· kg· d) for 28 days. Rats of the saline group received the same dose of normal saline via gavage. EA (2 Hz/15 Hz, 0.1-1 mA) was applied to bila-teral ST25 and BL25 for 15 min, once daily for 14 days. The intestinal transmission function (the intestinal propulsion rate) was assessed by recording the first black grain stool discharge time and the number and weight of the discharged stool grains in 30 min after gavage of the activated carbon suspension (1 mL/100 g, 150 g/L). The score of fecal trait and the weight of stool within 24 h were recorded. The ultrastructural changes of Cajal interstitial cells in the colon tissue were observed by transmission electron microscope. The expression levels of GDNF protein and mRNA in the colon tissue were detected by using Western blot and real-time fluorescent quantitative PCR, separately, and changes of methylation level in the promoter region of GDNF gene detected by using Bisulfite sequencing method.
RESULTS
Compared with the control group, the time of the 1 black stool grain discharging was obviously prolonged, and the number and weight of the discharged black stool grains were significantly decreased in the mo-del group (<0.05), suggesting a success of STC. The weight and trait score of stool in 24 h, intestinal propulsive rate, and the expression levels of GDNF protein and mRNA were significantly lower in the model group than in the control group (<0.01, <0.05). After EA, the weight and trait score of stool within 24 h, intestinal propulsive rate,and the expression levels of GDNF protein and mRNA were significantly increased in the EA group in contrast to the model group (<0.01,<0.05). The total CpGs methylation level of GDNF gene in colon tissue was considerably higher in the model group than in the control group (<0.05), and markedly lower in the EA group than in the model group (<0.05). No significant differences were found between the control and saline groups in all the above-mentioned indexes (>0.05).
CONCLUSION
EA of back-shu and front-mu acupoints can effectively improve symptoms of constipation and intestinal transport function in STC rats, which may be related to its function in up-regulating the expression of GDNF and down-regulating the methylation level in the promoter region of GDNF gene in colon tissue.
Topics: Acupuncture Points; Animals; Constipation; Electroacupuncture; Gastrointestinal Motility; Glial Cell Line-Derived Neurotrophic Factor; Male; Methylation; Rats; Rats, Sprague-Dawley
PubMed: 35218624
DOI: 10.13702/j.1000-0607.20210253 -
Frontiers in Pharmacology 2022Constipation is a common syndrome and a worldwide healthy problem. Constipation patients are becoming younger, with a 29.6% overall prevalence in children, which has...
Constipation is a common syndrome and a worldwide healthy problem. Constipation patients are becoming younger, with a 29.6% overall prevalence in children, which has captured significant attention because of its epigenetic rejuvenation and recurrent episodes. Despite the usage of rhubarb extract to relieve constipation, novel targets and genes implicated in target-relevant pathways with remarkable functionalities should still be sought for. We established a reliable constipation model in C57B/6N male mice using intragastric administration diphenoxylate, and the eligible subjects received 600 mg/25 g rhubarb extract to alleviate constipation. Resultant constipation was morphological and genetically compared with the specimen from different groups. Constipation mice exhibited thicker muscle layers, higher levels of cytokines, including IL-17 and IL-23, and lower content of IL-22. Bacterial abundance and diversity varied tremendously. Notably, the alterations were reversed following rhubarb extract treatment. Additionally, Constipation also had a substantial impact on short-chain fatty acids (SCFAs), medium- and long-chain fatty acids (MLCFAs), and the expression of SCFA receptors, GPR41 and GPR43. This thesis has provided insight that rhubarb extract promoted the flexibility of collagen fiber, reduced pro-inflammatory cytokines, enhanced anti-inflammatory cytokines, and maintained gut microflora balance with potential impacts on the fatty acid and polyamine metabolism.
PubMed: 36545319
DOI: 10.3389/fphar.2022.1048134