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Evidence-based Complementary and... 2022Miller (Aloe) known as a common succulent perennial herb had been traditionally used in constipation for more than 1,000 years. Aloe contained anthraquinones and other...
Miller (Aloe) known as a common succulent perennial herb had been traditionally used in constipation for more than 1,000 years. Aloe contained anthraquinones and other active compounds which had laxative effect and could modulate constipation. However, the therapeutic effects and mechanisms of aloe in constipation were still unclear. To explore the therapeutic effects and mechanisms of aloe in treating constipation, we employed network pharmacology, molecular docking, and mice experiments in this study. Our network pharmacology indicated that beta-carotene, sitosterol, campest-5-en-3beta-ol, CLR, arachidonic acid, aloe-emodin, quercetin, and barbaloin were the main active ingredients of aloe in treating constipation. Besides, the MAPK signaling pathway was the principal pathway utilized by aloe in treating constipation. Molecular docking results revealed that beta-carotene and sitosterol were acting as interference factors in attenuating inflammation by binding to an accessory protein of ERK, JNK, AKT, and NF-B p65. Otherwise, in vivo experiments, we used diphenoxylate-induced constipation mice model to explore the therapeutic effects and mechanisms of aloe. Results showed that aloe modulated the constipation mice by reducing the discharge time of first melena, improving the fecal conditions, increasing the gastric intestinal charcoal transit ratio, and improving the intestinal secretion in small intestine. Besides, aloe played an important regulation in promoting intestinal motility sufficiency and the levels of neurotransmitters balance with 5-HT, SP, and VIP on constipation mice. Moreover, aloe significantly inhibited the mRNA and proteins expressions of ERK, JNK, AKT and NF-B p65 in colon. Our study proved that aloe could reverse diphenoxylate-induced changes relating to the intestinal motility, intestinal moisture, and inhibition of the MAPK (ERK, JNK)/AKT/NF-B p65 inflammatory pathway. Our study provided experimental evidences of the laxative effect of aloe, which was beneficial to the further research and development of aloe.
PubMed: 35571728
DOI: 10.1155/2022/6225758 -
Animal Models and Experimental Medicine Apr 2022We aimed to reveal the mechanism of functional constipation in the treatment of Atractylodes macrocephala Koidz. (AMK) and Paeonia lactiflora Pall. (PLP).
Network pharmacological prediction and molecular docking analysis of the combination of Atractylodes macrocephala Koidz. and Paeonia lactiflora Pall. in the treatment of functional constipation and its verification.
BACKGROUND
We aimed to reveal the mechanism of functional constipation in the treatment of Atractylodes macrocephala Koidz. (AMK) and Paeonia lactiflora Pall. (PLP).
METHODS
The main active ingredients of AMK and PLP were screened by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform. A database of functional constipation targets was established by GeneCard and OMIM. An "ingredient-target" network map was constructed with Cytoscape software (version 3.7.1), and molecular docking analysis was performed on the components and genes with the highest scores. The rats in the normal group were given saline, and those in the other groups were given 10 mg/kg diphenoxylate once a day for 14 days. The serum and intestinal tissue levels of adenosine monophosphate (cAMP), protein kinase A (PKA), and adenylyl cyclase (AC) of the rats and aquaporin (AQP)1, AQP3, and AQP8 were measured.
RESULTS
AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation. After treatment with AMK, PLP, or mosapride, the serum and intestinal tissue levels of AC, cAMP, and PKA were significantly downregulated. Groups receiving AMK and PLP or mosapride exhibited a reduction in the level of AQP1, AQP3, and AQP8 to varying degrees.
CONCLUSION
Molecular docking analysis revealed that AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation. Studies have confirmed that AMK and PLP can also affect AC, cAMP, and PKA. AC, cAMP, and PKA in model rats were significantly downregulated. AQP expression is closely related to AC, cAMP, and PKA. AMK and PLP can reduce the expression of AQP1, AQP3, and AQP9 in the colon of constipated rats.
Topics: Animals; Aquaporins; Atractylodes; Constipation; Cyclic AMP-Dependent Protein Kinases; Medicine, Chinese Traditional; Molecular Docking Simulation; Paeonia; Rats
PubMed: 35451570
DOI: 10.1002/ame2.12226 -
Annals of Translational Medicine Mar 2022Functional constipation (FC) is a common gastrointestinal (GI) disorder characterized by symptoms of constipation without a clear physiologic or anatomic cause. Gut...
BACKGROUND
Functional constipation (FC) is a common gastrointestinal (GI) disorder characterized by symptoms of constipation without a clear physiologic or anatomic cause. Gut microbiome dysbiosis has been postulated to be a factor in the development of FC, and treatment with probiotic regimens, including strains of , has demonstrated efficacy in managing symptoms. To further understand the role of in GI health, we conducted an animal study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of a specific sub-strain, Lp3a, on FC.
METHODS
For the animal study, male Kunming mice were treated with doses of Lp3a ranging from 0.67 to 2.00 g/kg or an equivalent amount of placebo for 15 days prior to the induction of constipation via 20 mL/kg of 25% diphenoxylate solution. GI motility parameters including intestinal motion and stool amount were then assessed. In the human study, 120 patients with FC were randomized to treatment [ Lp3a; 2×1.0×10 (colony forming units; CFU) ×7 days] or control groups (n=60 each). The primary endpoint was survey information on FC signs/symptoms. Participants and observers were blinded to group allocation. A subset of 20 Lp3a treated patients underwent pre- and post-treatment 16 s ribosomal ribonucleic acid (rRNA) gene sequencing. Whole genome sequencing (WGS) of Lp3a was also performed.
RESULTS
Lp3a-treated mice showed significantly improved intestinal motion, reduced time to first defecation, and increased stool amounts. Similarly, patients in the treatment group (n=59) reported significant improvements in FC signs/symptoms compared to controls (n=58; all P<0.05). Although 16 s rRNA sequencing revealed no significant variations between pre- and post-treatment samples, WGS of Lp3a itself revealed several biological pathways that may underlie the relief of FC symptoms in animals and humans, including methane and fatty acid metabolism and bile acid biosynthesis.
CONCLUSIONS
We found that the use of the novel probiotic sub-strain, Lp3a, led to clinically significant improvements in FC in both mice and humans, and identified the potential biological mechanisms underlying this activity.
PubMed: 35434041
DOI: 10.21037/atm-22-458 -
American Journal of Translational... 2022Constipation is a common gastrointestinal problem worldwide. Its impact on health can range from an unpleasant problem to being seriously troublesome. When lifestyle... (Review)
Review
Constipation is a common gastrointestinal problem worldwide. Its impact on health can range from an unpleasant problem to being seriously troublesome. When lifestyle modification fails to deal with constipation, laxatives are the mainstay of therapy. There are several types of laxatives currently available; however, there still remains a need for better laxatives because certain currently available laxatives are not appropriate for or accessible to some patients. Preclinical experiments to study the laxative potential of substances/products of interest are vital to improving that situation. The selection of appropriate experimental models for assessing the laxative activities of substances/products under investigation is crucial to achieving valid and meaningful results. This article provides a scoping review of the literature, outlining, and summarizing models currently being used in preclinical experiments assessing the laxative activities of substances/products under investigation. The review includes both screening models, e.g., the isolated organ bath system, fecal assessment and intestinal transit assay, and confirmation models, e.g., constipation models. Chemical substances/drugs used to induce constipation in constipation models, e.g., loperamide, diphenoxylate, montmorillonite, and clonidine, as well as standard laxative agents used as a positive control in experimental models, e.g., bisacodyl, carbachol, lactulose, sodium picosulfate, castor oil, phenolphthalein, and yohimbine, are described in detail. The purpose of this article is to assist researchers in the design and implementation of preclinical experimental models for assessing laxative activities of substances/products under investigation to achieve valid and meaningful preclinical results prior to experimentation in humans.
PubMed: 35273679
DOI: No ID Found -
Oxidative Medicine and Cellular... 2022The - (ZhiShi, ZS-) (BaiZhu, BZ) pairs are often found in herbal formulas for constipation. The volatile oils of ZS and BZ (ZBVO) have good pharmacological activity...
BACKGROUND
The - (ZhiShi, ZS-) (BaiZhu, BZ) pairs are often found in herbal formulas for constipation. The volatile oils of ZS and BZ (ZBVO) have good pharmacological activity against constipation, but the mechanism for treatment of slow transit constipation (STC) remains unclear.
METHOD
A rat model using diphenoxylate tablets was constructed to investigate if transdermal administration of ZBVO would mediate intestinal microorganisms and fecal metabolites and improve STC symptoms. The regulatory effects of ZBVO at 0.15, 0.30, and 0.60 mL kg d on STC rats were assessed by measuring fecal water content, intestinal propulsion rate, histopathology, expression of gastrointestinal hormones, brain and intestinal peptides, and inflammatory factors. The changes in intestinal flora of STC rats were analyzed by 16S rRNA gene sequencing. Moreover, the untargeted fecal metabolomics analysis was performed by ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometer (UPLC-Q-TOF-MS) technology.
RESULTS
The results showed that ZBVO had a modulating effect on STC by increasing the fecal water content and intestinal propulsion rate. Transdermal administration of ZBVO decreased serum levels of interleukin 6 (IL-6) and tumor necrosis factor- (TNF-) and increased the levels of gastrin (GAS) and substance P (SP). In addition, ZBVO increased 5-hydroxytryptamine (5-HT) levels and decreased vasoactive intestinal peptide (VIP) levels in colon and hippocampus tissues. The results of intestinal microbiota showed that ZBVO improved the diversity and abundance of intestinal microbiota and changed the community composition by decreasing and increasing , , and . And the feces metabolomics found that nicotinate and nicotinamide metabolism, purine metabolism, citrate cycle (TCA cycle), pyruvate metabolism, arachidonic acid metabolism, pyrimidine metabolism, and primary bile acid biosynthesis were modulated.
CONCLUSION
These findings suggest that ZBVO can alleviate STC symptoms by promoting intestinal peristalsis, increasing fecal water content, regulating gastrointestinal hormone level, reducing the inflammatory response, and regulating brain and intestinal peptides after transdermal administration. And structural changes in the intestinal microbiota are closely related to host metabolism and intestinal microbiota destroyed in STC modeling could be significantly improved by the ZBVO, which provides a reference for the development of aromatic drug macrohealth products.
Topics: Administration, Cutaneous; Animals; Citrus; Constipation; Disease Models, Animal; Gastrointestinal Microbiome; Metabolomics; Oils, Volatile; Rats; Rats, Sprague-Dawley
PubMed: 35087623
DOI: 10.1155/2022/9965334 -
Pharmaceutical Biology Dec 2021Wei Chang An (WCA) is a commercial prescription developed for the coordination of gastrointestinal movement.
CONTEXT
Wei Chang An (WCA) is a commercial prescription developed for the coordination of gastrointestinal movement.
OBJECTIVE
To investigate the role of WCA in the regulation of diarrhoea and constipation in rats.
MATERIAL AND METHODS
The diarrhoea and constipation models were prepared by gavage of and diphenoxylate hydrochloride. Rats were randomized equally ( = 6) into the normal group given saline daily, the positive group given Pinaverium Bromide (13.5 mg/kg) or Sennoside A (0.1 mg/kg) and three WCA-treated groups (22, 44, and 88 mg/kg) by gavage daily for 7 consecutive days. The effects of WCA were assessed by a series of faecal symptoms and histopathology. Gastrointestinal parameters were determined by ELISA. The effect of WCA on gastrointestinal tissues was evaluated by strip assay. Expression of ROCK-1 and MLCK was measured by RT-PCR and Western blotting.
RESULTS
Data from Bristol stool form scale, diarrhoea index, visceral sensitivity, defaecation time, and intestinal propulsive rate showed that WCA protected rats against diarrhoea and constipation ( < 0.01). The up-regulation of Substance P and 5-hydroxytryptamine in diarrhoea rats and down-regulation of Substance P and vasoactive intestinal polypeptide in constipation rats were inhibited by WCA ( < 0.05). WCA stimulated the gastrointestinal strip contractions but inhibited ACh-induced contractions ( < 0.01). The decreased ROCK-1 and MLCK expression in diarrhoea rats and increased in constipation rats were suppressed by WCA ( < 0.01).
CONCLUSIONS
WCA has both antidiarrhea and anti-constipation effects, suggesting its bidirectional role in gastrointestinal modulation, and providing evidence of WCA for irritable bowel syndrome treatment.
Topics: Animals; Constipation; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Gastrointestinal Motility; Irritable Bowel Syndrome; Male; Myosin-Light-Chain Kinase; Rats; Rats, Wistar; rho-Associated Kinases
PubMed: 34711130
DOI: 10.1080/13880209.2021.1991383 -
JCO Oncology Practice Feb 2022The financial toxicity of anticancer drugs is well-documented, but little is known about the costs of drugs used to manage cancer-associated symptoms. (Review)
Review
PURPOSE
The financial toxicity of anticancer drugs is well-documented, but little is known about the costs of drugs used to manage cancer-associated symptoms.
METHODS
We reviewed relevant guidelines and compiled drugs used to manage seven cancer-associated symptoms (anorexia and cachexia, chemotherapy-induced peripheral neuropathy, constipation, diarrhea, exocrine pancreatic insufficiency, cancer-associated fatigue, and chemotherapy-induced nausea and vomiting). Using GoodRx website, we identified the retail price (cash price at retail pharmacies) and lowest price (discounted, best-case scenario of out-of-pocket costs) for patients without insurance for each drug or formulation for a typical fill. We describe lowest prices here.
RESULTS
For anorexia and cachexia, costs ranged from $5 US dollars (USD; generic olanzapine or mirtazapine tablets) to $1,156 USD (brand-name dronabinol solution) and varied widely by formulation of the same drug or dosage: for olanzapine 5 mg, $5 USD (generic tablet) to $239 USD (brand-name orally disintegrating tablet). For chemotherapy-induced peripheral neuropathy, costs of duloxetine varied from $12 USD (generic) to $529 USD (brand-name). For constipation, the cost of sennosides or polyethylene glycol was <$15 USD, whereas newer agents such as methylnaltrexone were expensive ($1,001 USD). For diarrhea, the cost of generic loperamide or diphenoxylate-atropine tablets was <$15 USD. For exocrine pancreatic insufficiency, only brand-name formulations were available, range of cost, $1,072 USD-$1,514 USD. For cancer-associated fatigue, the cost of generic dexamethasone or dexmethylphenidate was <$15 USD, whereas brand-name modafinil was more costly ($1,284 USD). For a 4-drug nausea and vomiting prophylaxis regimen, costs ranged from $181 USD to $1,430 USD.
CONCLUSION
We highlight the high costs of many symptom control drugs and the wide variation in the costs of these drugs. These findings can guide patient-clinician discussions about cost-effectively managing symptoms, while promoting the use of less expensive formulations when possible.
Topics: Antineoplastic Agents; Drug Costs; Drugs, Generic; Financial Stress; Humans; Neoplasms; Pharmacies
PubMed: 34558297
DOI: 10.1200/OP.21.00466 -
Journal of Biosciences 2021Slow transit constipation (STC) is a gastrointestinal disorder characterized by abnormal prolonged colonic transit time, which affects the life quality of many people....
Slow transit constipation (STC) is a gastrointestinal disorder characterized by abnormal prolonged colonic transit time, which affects the life quality of many people. The decrease number of interstitial cells of Cajal (ICCs) is involved in the pathogenesis of STC. However, the molecular mechanism of loss of ICCs in STC remains unclear, making it difficult to develop new agents for the disease. In this study, we investigated the mechanism of decreasing ICCs in the pathogenesis of STC. We constructed the STC model rats by using atropine and diphenoxylate. A series of methods were used including immunofluorescence and immunochemistry staining, western blot, qRT-PCR, exosomes extraction and exosomes labeling. The results indicate that ICCs decreased in the STC rats accompanied with the macrophages activation. Further studies suggested that macrophages decreased the cell viability of ICCs by secretion exosomes containing miR-34c-5p. miR-34c5p targeted the 3Ꞌ -UTR of stem cell factor(SCF) mRNA and regulated the expression of SCF negatively. In conclusion, we demonstrated a novel regulatory mechanism of ICCs cell viability in STC. We found that exosome miR-34c-5p mediate macrophage-ICCs cross-talk. M1 macrophages derived exosomes miR-34c-5p decreased ICCs cell viability by directly targeting SCF.
Topics: Analgesics, Opioid; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Atropine; Cell Survival; Constipation; Diphenoxylate; Exosomes; Gastrointestinal Motility; Gene Expression Regulation; Interstitial Cells of Cajal; Macrophages; MicroRNAs; Muscarinic Antagonists; Proto-Oncogene Proteins c-kit; RNA, Messenger; Rats; Rats, Sprague-Dawley; Stem Cell Factor
PubMed: 34544909
DOI: No ID Found -
Drug Design, Development and Therapy 2021The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan...
AIM
The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. subsp. HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation.
METHODS
Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay.
RESULTS
Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner.
CONCLUSION
LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent.
Topics: Animals; Aquaporin 3; Cattle; Constipation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diphenoxylate; Disease Models, Animal; Female; Lactococcus lactis; Mice; Mice, Inbred ICR; Probiotics; Signal Transduction; Somatostatin; Vasoactive Intestinal Peptide; Yogurt
PubMed: 34007157
DOI: 10.2147/DDDT.S309675 -
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