Renoprotective effects of laxative linaclotide: Inhibition of acute kidney injury and fibrosis in a rat model of renal ischemia-reperfusion.

Ischemia-reperfusion (I/R) leads to tissue damage in transplanted kidneys, resulting in acute kidney injury (AKI) and chronic graft dysfunction, which critically compromises transplant outcomes, such as graft loss. Linaclotide, a guanylate cyclase C agonist clinically approved as a laxative, has recently been identified to exhibit renoprotective effects in a chronic kidney disease (CKD) model. This study evaluates the therapeutic effects of linaclotide on AKI triggered by I/R in a rat model with an initial comparison with other laxatives. Here, we show that linaclotide administration resulted in substantial reduction in serum creatinine levels, reflective of enhanced renal function. Histological examination revealed diminished tubular damage, and Sirius Red staining confirmed less collagen deposition, collectively indicating preserved structural integrity and mitigation of fibrosis. Further analysis demonstrated lowered expression of TGF-ß and associated fibrotic markers, α-SMA, MMP2, and TIMP1, implicating the downregulation of the fibrogenic TGF-ß pathway by linaclotide. Furthermore, one day after I/R insult, linaclotide profoundly diminished macrophage infiltration and suppressed critical pro-inflammatory cytokines such as TNF, IL-1ß, and IL-6, signifying its potential to disrupt initial inflammatory mechanisms integral to AKI pathology. These findings suggest that linaclotide, with its established safety profile, could extend its benefits beyond gastrointestinal issues and potentially serve as a therapeutic intervention for organ transplantation. Additionally, it could provide immediate and practical insights into selecting laxatives for managing patients with AKI or CKD, regardless of the cause, and for those receiving dialysis or transplant therapy.

Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT3 receptor antagonist, ondansetron.

BACKGROUND: Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron. METHODS: A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content. KEY RESULTS: Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose. CONCLUSION & INFERENCES: Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.

Network pharmacology combined with an animal model to reveal the material basis and mechanism of Amomum villosum in alleviating constipation in mice.

Constipation is a prevalent gastrointestinal disorder, with its prevalence showing an annual upward trend. There are many factors involved in the occurrence of constipation, such as abnormal smooth muscle contraction and disorders of gastrointestinal hormone secretion. Amomum villosum (A. villosum) has been proven to be effective in improving digestive system diseases, but there is no report on improving constipation. Therefore, we used network pharmacology prediction combined with animal experiments to explore the key active components of A. villosum and their pharmacological mechanisms. The results of network pharmacological prediction showed that ß-sitosterol was the key laxative compound of A. villosum, which may play a laxative role by activating the adrenoceptor alpha 1 A-myosin light chain (ADRA1A-MLC) pathway. Further animal experiments showed that ß-sitosterol could significantly shorten the time to first black stool; increase faecal weight, faecal number, and faecal water content; and promote gastrointestinal motility. ß-sitosterol may promote intestinal motility by upregulating the expression of ADRA1A and myosin light chain 9 (Myl9) mRNA and protein in the colon, thereby activating the ADRA1A-MLC signalling pathway. In addition, it is possible to improve constipation symptoms by regulating serum neurotransmitters and gastrointestinal motility-related factors, such as the serum content of 5-hydroxytryptamine (5-HT) and acetylcholinesterase (AchE) and the mRNA expression of 5-hydroxytryptamine receptor 4 (5-HT4), stem cell factor (SCF), stem cell factor receptor (c-Kit) and smooth muscle myosin light chain kinase (smMLCK) in the colon. These results lay a foundation for the application of A. villosum and ß-sitosterol in constipation.

The rhizomes of Atractylodes macrocephala relieve loperamide-induced constipation in rats by regulation of tryptophan metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Constipation is one of the most prevalent gastrointestinal tract diseases that seriously affects health-related quality of human life and requires effective treatments without side effect. The rhizome of Atractylodes macrocephala Koidz. (Compositae), called Atractylodes Macrocephala Rhizome (AMR), a commonly used traditional Chinese medicine, has been used to relieve the clinical symptoms of patients with constipation. AIM OF THE STUDY: To reveal the dose-dependent laxative effect and potential mechanism of AMR on loperamide-induced slow transit constipation (STC) rats. MATERIALS AND METHODS: Loperamide-induced constipation rat model was established and the dose-dependent laxative effect of AMR was investigated. Untargeted metabolomics based on an UPLC-Q/TOF-MS technique combined with western blot analysis was used to explain the potential mechanism of AMR relieve loperamide-induced constipation in rats. RESULTS: The results showed that medium dose of AMR (AMR-M, 4.32 g raw herb/kg) and high dose of AMR (AMR-H, 8.64 g raw herb/kg) treatments significantly increased the fecal water content, Bristol score, gastrointestinal transit rate, and recovered the damaged colon tissues of constipated rats, but low dose of AMR (AMR-L, 2.16 g raw herb/kg) did not show laxative effect. Both AMR-M and AMR-H treatments also remarkably reduced the serum levels of vasoactive intestinal peptide (VIP), somatostatin (SS) and dopamine (DA), and increased the levels of motilin (MTL), gastrin (GAS) and 5-hydroxytryptamine (5-HT). Urine metabolomics revealed that constipation development was mainly ascribed to the perturbed tryptophan metabolism, and AMR-M and AMR-H markedly corrected the abnormal levels of five urine tryptophan metabolites, namely 4,6-dihydroxyquinoline, indole, 4,8-dihydroxyquinoline, 5-hydroxytryptamine, and kynurenic acid. Additionally, western blot analysis confirmed that the abnormal expression of rate-limiting enzyme involving in tryptophan metabolism, including tryptophan hydroxylase (TPH), monoamine oxidase (MAO) and indoleamine-2,3-dioxygenase (IDO) in the colon of constipated rats, were mediated by AMR-M and AMR-H. CONCLUSIONS: The findings provide insight into the mechanisms of STC and AMR could be developed as new therapeutic agent for prevention or healing of constipation.

Flavonoids in Amomum tsaoko Crevost et Lemarie Ameliorate Loperamide-Induced Constipation in Mice by Regulating Gut Microbiota and Related Metabolites.

Amomum tsaoko (AT) is a dietary botanical with laxative properties; however, the active ingredients and mechanisms are still unclear. The active fraction of AT aqueous extract (ATAE) for promoting defecation in slow transit constipation mice is the ethanol-soluble part (ATES). The total flavonoids of ATES (ATTF) were the main active component. ATTF significantly increased the abundance of Lactobacillus and Bacillus and reduced the dominant commensals, such as Lachnospiraceae, thereby changing the gut microbiota structure and composition. Meanwhile, ATTF changed the gut metabolites mainly enriched in pathways such as the serotonergic synapse. In addition, ATTF increased the serum serotonin (5-HT) content and mRNA expression of 5-hydroxytryptamine receptor 2A (5-HT2A), Phospholipase A2 (PLA2), and Cyclooxygenase-2 (COX2), which are involved in the serotonergic synaptic pathway. ATTF increased Transient receptor potential A1 (TRPA1), which promotes the release of 5-HT, and Myosin light chain 3(MLC3), which promotes smooth muscle motility. Notably, we established a network between gut microbiota, gut metabolites, and host parameters. The dominant gut microbiota Lactobacillus and Bacillus, prostaglandin J2 (PGJ2) and laxative phenotypes showed the most significant associations. The above results suggest that ATTF may relieve constipation by regulating the gut microbiota and serotonergic synaptic pathway and has great potential for laxative drug development in the future.

Time-dependent laxative effect of sennoside A, the core functional component of rhubarb, is attributed to gut microbiota and aquaporins.

ETHNOPHARMACOLOGICAL RELEVANCE: Sennoside A is a natural anthraquinone component mainly derived from rhubarb and has been routinely used as a clinical stimulant laxative. However, long-term application of sennoside A may lead to drug resistance and even adverse reactions, thus limiting its clinical use. Therefore, to reveal the time-dependent laxative effect and potential mechanism of sennoside A is of critical importance. AIM OF THE STUDY: This study was conducted to investigate the time-dependent laxative effect of sennoside A and unveil its underlying mechanism from the perspective of gut microbiota and aquaporins (AQPs). MATERIALS AND METHODS: Based on a mouse constipation model, 2.6 mg/kg sennoside A was administered orally for 1, 3, 7, 14 and 21 days, respectively. The laxative effect was assessed by the fecal index and fecal water content, the histopathology of the small intestine and colon was evaluated by hematoxylin-eosin staining. Gut microbiota changes was observed by 16S rDNA sequencing, and colonic AQPs expression was analyzed by quantitative real-time polymerase chain reaction and western blotting. Partial least-squares regression (PLSR) was used to screen out the effective indicators contributing to the laxative effect of sennoside A. The effective indicators were then fitted to time by a drug-time curve model to analyze the trend of efficacy of sennoside A, and the optimal time of administration was derived by comprehensive analysis with a three-dimensional (3D) time-effect image. RESULTS: Sennoside A had a significant laxative effect at 7 days of administration with no pathological changes in the small intestine or colon; however, at 14 or 21 days of administration, the laxative effect diminished and slight damage to the colon was observed. Sennoside A affects the structure and function of gut microbes. The alpha diversity showed that the abundance and diversity of gut microorganisms reached the highest value after 7 days of administration. Partial least squares discriminant analysis showed that the composition of the flora was close to normal when administered for less than 7 days, but was closest to the composition of constipation over 7 days. The expression of aquaporin 3 (AQP3) and aquaporin 7 (AQP7) decreased gradually after the administration of sennoside A, with the lowest expression at 7 days, and then increased gradually afterwards, while the expression of aquaporin 1 (AQP1) was the opposite. The PLSR results showed that AQP1, AQP3, Lactobacillus, Romboutsia, Akkermansia and UCG_005 contributed more to the laxative effect of the fecal index, and after fitting with the drug-time curve model, each index showed a trend of increasing and then decreasing. The comprehensive evaluation of the 3D time-effect image concluded that the laxative effect of sennoside A reached its best after 7 days of administration. CONCLUSION: Sennoside A should be used in regular dosages for less than one week, as it provides significant relief of constipation and exhibits no colonic damage within 7 days of administration. In addition, Sennoside A exerts its laxative effect by regulating gut microbiota of Lactobacillus Romboutsia, Akkermansia and UCG_005 and water channels of AQP1 and AQP3.

A novel purgative mechanism of multiflorin A involves changing intestinal glucose absorption and permeability.

BACKGROUND: Multiflorin A (MA) is a potential active ingredient of traditional herbal laxative, Pruni semen, with unusual purgative activity and an unclear mechanism, and inhibiting intestinal glucose absorption is a promising mechanism of novel laxatives. However, this mechanism still lacks support and a description of basic research. PURPOSE: This study aimed to determine the main contribution of MA to the purgative activity of Pruni semen and elucidate the effect intensity, characteristics, site, and mechanism of MA in mice, and determine the novel mechanism of traditional herbal laxatives from the perspective of intestinal glucose absorption. METHODS: We induced diarrhoea in mice by administering Pruni semen and MA, and the defecation behaviour, glucose tolerance, and intestinal metabolism were analysed. The effects of MA and its metabolite on peristalsis of the intestinal smooth muscle were evaluated using an intestinal motility assay in vitro. Intestinal tight junction proteins, aquaporins, and glucose transporters expression were analysed using immunofluorescence; gut microbiota and faecal metabolites were analysed using 16S rRNA and liquid chromatography-mass spectrometry. RESULTS: MA administration (20 mg/kg) induced watery diarrhoea in over half of the experimental mice. The activity of MA in lowering peak postprandial glucose levels was synchronous with purgative action, with the acetyl group being the active moiety. MA was metabolised primarily in the small intestine, where it decreased sodium-glucose cotransporter-1, occludin, and claudin1 expression, then inhibited glucose absorption, resulting in a hyperosmotic environment. MA also increased the aquaporin3 expression to promote water secretion. Unabsorbed glucose reshapes the gut microbiota and their metabolism in the large intestine and the increasing gas and organic acid promoted defecation. After recovery, the intestinal permeability and glucose absorption function returned, and the abundance of probiotics such as Bifidobacterium increased. CONCLUSION: The purgative mechanism of MA involves inhibiting glucose absorption, altering permeability and water channels to promote water secretion in the small intestine, and regulating gut microbiota metabolism in the large intestine. This study is the first systematic experimental study on the purgative effect of MA. Our findings provide new insight into the study of novel purgative mechanisms.

Study on Anti-Constipation Effects of Hemerocallis citrina Baroni through a Novel Strategy of Network Pharmacology Screening.

Daylily (Hemerocallis citrina Baroni) is an edible plant widely distributed worldwide, especially in Asia. It has traditionally been considered a potential anti-constipation vegetable. This study aimed to investigate the anti-constipation effects of daylily from the perspective of gastro-intestinal transit, defecation parameters, short-chain organic acids, gut microbiome, transcriptomes and network pharmacology. The results show that dried daylily (DHC) intake accelerated the defecation frequency of mice, while it did not significantly alter the levels of short-chain organic acids in the cecum. The 16S rRNA sequencing showed that DHC elevated the abundance of Akkermansia, Bifidobacterium and Flavonifractor, while it reduced the level of pathogens (such as Helicobacter and Vibrio). Furthermore, a transcriptomics analysis revealed 736 differentially expressed genes (DEGs) after DHC treatment, which are mainly enriched in the olfactory transduction pathway. The integration of transcriptomes and network pharmacology revealed seven overlapping targets (Alb, Drd2, Igf2, Pon1, Tshr, Mc2r and Nalcn). A qPCR analysis further showed that DHC reduced the expression of Alb, Pon1 and Cnr1 in the colon of constipated mice. Our findings provide a novel insight into the anti-constipation effects of DHC.

Potential Targets in Constipation Research: A Review.

BACKGROUND: Constipation is one of the most frequent abnormalities of the gastrointestinal system that affects the patient's quality of life. Constipation is more common in women and affects them more frequently as they get older. Many constipated patients take over-the-counter drugs for treatment, but some do not respond to these medicines and need newer, more expensive drugs. Still, many patients are not completely satisfied with these medicines. Unlike other areas, constipation research is not given much importance. OBJECTIVE: This review discusses targets such as ClC-2, CFTR, opioid receptors, and 5HT-4 receptors, which are important in constipation therapy. The recent focus is also on the gut microbiome with the help of various randomized controlled trials. Pharmacological advances have also added novel targets such as IBAT, PAR-2, and intestinal NHE-3 for constipation treatment. METHODS: This review summarises the research on these targets collected from various databases. ClC-2 and CFTR are involved in intestinal chloride secretion followed by sodium or water, which increases stool passage. Non-cancer pain treatment with opioids targeting opiate receptors is considered in 40-90% of patients, which causes constipation as a side effect. On activation, 5HT-4 receptors increase gastrointestinal motility. IBAT is responsible for transporting bile acid into the liver. Bile acid will reach the colon by inhibiting IBAT, stimulating colonic motility, and providing a laxative effect. Activation of the ghrelin receptor results in prokinetic activity in both animals and humans. Intestinal NHE-3 mediates the absorption of Na+ and the secretion of hydrogen into the intestine. Many reports show that PAR-2 is involved in the pathogenesis of gastrointestinal diseases. The gut microbiota influences the peristaltic action of the intestine. CONCLUSION: Drugs working on these targets positively impact the treatment of constipation, as do the drugs that are currently in clinical trials acting on these targets. The results from the ongoing clinical trials will also provide some valuable information regarding whether these medications will meet the patients' needs in the future.

Extraction and Fractionation of Prokinetic Phytochemicals from Chrozophora tinctoria and Their Bioactivities.

Chrozophora tinctoria is an annual plant of the family Euphorbiaceae, traditionally used as a laxative, a cathartic and an emetic. A methanolic extract of Chrozophora tinctoria (MEC) whole plant and an n-butanol fraction of Chrozophora tinctoria (NBFC) were analyzed by gas chromatography-mass spectrometry (GC-MS) to detect the phytochemicals. MEC and NBFC were tested for in vitro anti acetylcholinesterase (AChE) potential. The effect of both samples on intestinal propulsive movement and spasmolytic activity in the gastrointestinal tract (GIT) was also studied. About twelve compounds in MEC and three compounds in NBFC were tentatively identified through GC-MS. Some of them are compounds with known therapeutic activity, such as toluene; imipramine; undecane; 14-methyl-pentadecanoic acid methyl ester; and hexadecanoic acid. Both NBFC and MEC samples were checked for acute toxicity and were found to be highly toxic in a dose-dependent manner, causing diarrhea and emesis at 1 g/kg concentration in pigeons, with the highest lethargy and mortality above 3 g/kg. Both the samples of Chrozophora tinctoria revealed significant (p ≤ 0.01) laxative activity against metronidazole (7 mg/kg) and loperamide hydrochloride (4 mg/kg)-induced constipation. NBFC (81.18 ± 2.5%) and MEC (68.28 ± 2.4%) significantly increased charcoal meal intestinal transit compared to distal water (41.15 ± 4.3%). NBFC exhibited a significant relaxant effect (EC50 = 3.40 ± 0.20 mg/mL) in spontaneous rabbit jejunum as compared to MEC (EC50 = 4.34 ± 0.68 mg/kg). Similarly, the impact of NBFC on KCl-induced contraction was more significant than that of MEC (EC50 values of 7.22 ± 0.06 mg/mL and 7.47 ± 0.57 mg/mL, respectively). The present study scientifically validates the folk use of Chrozophora tinctoria in the management of gastrointestinal diseases such as constipation. Further work is needed to isolate the phytochemicals that act as diarrheal agents in Chrozophora tinctoria.

Prokinetic and Laxative Effects of Chrozophora tinctoria Whole Plant Extract.

Chrozophora tinctoria (Euphorbiaceae) has been used as an emetic, anthelminthic, and cathartic agent in traditional medicine. We used gas chromatography-mass spectrometry (GC-MS) to characterize the composition of ethyl acetate (EAC) and dichloromethane (DCMC) fractions from the whole Chrozophora tinctoria plant. EAC and DCMC fractions were evaluated for acetylcholinesterase (AChE) inhibitory activity and acute toxicity. Their effects on intestinal propulsive movement and spasmogenic activity of the gastrointestinal tract (GIT) muscle were also assessed. The compounds detected in both fractions were mostly fatty acids, with about seven compounds in EAC and 10 in DCMC. These included pharmacologically active compounds such as imipramine, used to treat depression, or hexadecanoic acid methyl ester, an antioxidant. Both EAC and DCMC fractions inhibited acetylcholinesterase (AChE) activity with IC50 values of 10 µg and 130 µg, respectively. Both the fractions were found to be toxic in a dose-dependent manner, inducing emesis at 0.5 g or higher and lethargy and mortality from 3-5 g upwards. Similarly, both of the fractions showed laxative activity in metronidazole- and loperamide-induced constipation models. EAC relaxed the intestinal muscle at a lower dose (1 mg/mL) than DCMC. Similarly, the EAC extract showed a significant relaxation effect (EC50 = 0.67 ± 0.15 mg/mL) on KCL-induced contraction in rabbit jejunum as compared to DCMC (EC50 = 5.04 ± 0.05 mg/kg). The present study strongly supports the folklore that this valuable plant is a cathartic agent. Further work is required to isolate and validate the bioactive compounds that act as diarrheal agents in Chrozophora tinctoria.

Targeting intestinal flora and its metabolism to explore the laxative effects of rhubarb.

Rhubarb, a traditional herb, has been used in clinical practice for hundreds of years to cure constipation, but its mechanism is still not clear enough. Currently, growing evidence suggests that intestinal flora might be a potential target for the treatment of constipation. Thus, the aim of this study was to clarify the laxative effect of rhubarb via systematically analyzing the metagenome and metabolome of the gut microbiota. In this study, the laxative effects of rhubarb were investigated by loperamide-induced constipation in rats. The gut microbiota was determined by high-throughput sequencing of 16S rRNA gene. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used for fecal metabolomics analysis. The data showed that rhubarb could significantly shorten gastrointestinal transit time, increase fecal water content and defecation frequency, improve gastrointestinal hormone disruption, and protect the colon mucus layer. Analysis of 16S rRNA gene sequencing indicated that rhubarb could improve the disorder of intestinal microbiota in constipated rats. For example, beneficial bacteria such as Ligilactobacillus, Limosilalactobacillus, and Prevotellaceae UCG-001 were remarkably increased, and pathogens such as Escherichia-Shigella were significantly decreased after rhubarb treatment. Additionally, the fecal metabolic profiles of constipated rats were improved by rhubarb. After rhubarb treatment, metabolites such as chenodeoxycholic acid, cholic acid, prostaglandin F2α, and α-linolenic acid were markedly increased in constipation rats; in contrast, the metabolites such as lithocholic acid, calcidiol, and 10-hydroxystearic acid were notably reduced in constipation rats. Moreover, correlation analysis indicated a close relationship between intestinal flora, fecal metabolites, and biochemical indices associated with constipation. In conclusion, the amelioration of rhubarb in constipation might modulate the intestinal microflora and its metabolism. Moreover, the application of fecal metabolomics could provide a new strategy to uncover the mechanism of herbal medicines.Key points• Rhubarb could significantly improve gut microbiota disorder in constipation rats.• Rhubarb could markedly modulate the fecal metabolite profile of constipated rats.

Herbal Medicine for the Management of Laxative Activity.

Constipation is one of the most common and prevalent chronic gastrointestinal conditions across the globe that is treated or managed through various methods. Laxatives are used for the treatment or management of chronic/acute constipation. But due to the adverse effects associated with these laxatives, herbal foods should be considered as alternative therapies for constipation. In this review, the laxative potential of plant-based medicines used for constipation is discussed. Constipation may be caused by various factors such as lifestyle, particular food habits, pregnancy and even due to some medication. Chronic constipation is responsible for different health issues. Pharmacological and non-pharmacological paradigms are applied for the treatment or management of constipation. In the pharmacological way of treatment, medicinal plants have a key role because of their fibrous nature. Numerous plants such as Prunus persica (Rosaceae), Cyamopsis tetragonolobus (Leguminosae), Citrus sinensis (Rutaceae), Planta goovata (Plantaginaceae), Rheum emodi (Polygonaceae), Cassia auriculata (Caesalpinacea), Ricinus communis (Euphorbiaceae), Croton tiglium (Euphorbiaceae), Aloe barbadensis (Liliaceae), Mareya micrantha (Euphorbiaceae), Euphorbia thymifolia (Euphorbiaceae), Cascara sagrada (Rhamnaceae), Cassia angustifolia (Fabaceae) have laxative activity. Medicinal plants possess a significant laxative potential and support their folklore; therefore, further, well-designed clinical-based studies are required to prove and improve the efficacy of herbal medicine for constipation. The present review showed that herbs laxative effect in various in vivo/ in vitro models.

Therapeutic effect of Moringa oleifera leaves on constipation mice based on pharmacodynamics and serum metabonomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera is native to India, and has been introduced to China in recent years. Moringa oleifera leaves (MOL), as Ayurvedic medicine, has efficacy of Pachana karma (digestive) and Virechana karma (purgative). Folium Sennae (FS), Rhubarb (RB), Aloe vera (AV), Hemp seed (HS) are commonly used as laxatives in Traditional Chinese Medicine (TCM), which have different characteristics. However, the intensity of the diarrheal effect of MOL and its mechanism of action are unclear. AIM OF THE STUDY: The methods of pharmacology and omics were used to compare the purgative effects of MOL and FS, RB, AV, HS, and their effects on metabolomics, to analyze the purgative characteristics and related mechanisms of MOL. MATERIALS AND METHODS: C57BL/6J mouse model of constipation was established by feeding low-fiber food. Feces parameters and colon pathology were used to evaluate the effect of FS, RB, AV, HS and MOL. And mass spectrometry-based serum metabolomics was performed. The differential metabolites of these herbs in the treatment of constipation were obtained by OPLS-DA analysis. Furthermore, pathway analysis was conducted based on different metabolites. RESULTS: Moringa leaves can adjust the stool number, wet fecal weight and fecal water content to varying degrees to achieve laxative effects, and recover colon muscle thickness and mucus. Analysis of metabolomics results showed that 71 metabolites from LC-MS datasets between model group and control group were obtained. 29, 12, 44, 29 and 20 metabolites were significantly reversed by FS, RB, AV, HS, MOL compared with model group respectively. According to the metabolic pathways, RB and AV may be clustered into a similar category, and MOL, FS and HS showed similarity of metabolic characteristics. CONCLUSION: The purgative effect of MOL is inferior to that of FS, and stronger than that of AV, RB and HS. The metabolic pathway for constipation is more similar to that of FS. MOL has a long-lasting and mild effect of laxative, increasing defecation volume and water content of feces, and may become a fewer side effects medicine to treat constipation.

In vivo acute toxicity, laxative and antiulcer effect of the extract of Dryopteris Ramose.

Dryopteris ramosa (D. ramosa) is one of the most traded medicinally important plants of Himalayan region. Apart from other uses, D. ramosa is traditionally also used to treat gastric ulcers and as a laxative. The present study was designed to investigate the role of methanolic crude extract of Dryopteris Ramosa (MEDR) in acute toxicity, against loperamide induced constipated mice model, antiulcer effect of methanolic extract of D. Ramosa and cholinomimetic like effect of methanolic extract of D. Ramosa. The crude extract was investigated for the presence of active compounds (secondary metabolites) such as alkaloids, flavonoids, carbohydrates, glycosides, terpenoids, phenolic compounds, saponins, and tannins following the standard methods. The antiulcer effect was investigated in mice using the ethanol induced ulcer model at various doses i.e. 50 mg/kg, 100 mg/kg and 200 mg/kg doses. Constipation was induced in the mice via loperamide (3mg/kg body weight). The control group received normal saline. Different doses of plant extracts (50, 100, 150 and 200 mg/kg body weight/day) were administered for 7 days. Various parameters like feeding characteristics, gastrointestinal transit ratio, body weight, fecal properties and the possible mechanism of action of D. Ramosa on intestinal motility were monitored. Various Phytochemicals like saponins, glycosides, flavonoids, tannins, phenols, carbohydrate, alkaloids and triterpenes were found in D. Ramosa. The acute toxicity study showed that MEDR was associated with no mortality except mild and moderate sedation at the highest tested doses (1500 and 2000 mg/kg). MEDR also showed significant antiulcer activity against ethanol-induced ulcerogenesis. The extract enhanced the intestinal motility, normalized the body weight of constipated mice and increased the fecal volume which are indications of laxative property of the herb. The 200 mg/kg body weight dose of the extract was found effective. The presence of various Phytochemicals such as flavonoids, glycosides and tannins might be responsible for the antiulcer activity of D. Ramosa. This study provides the scientific background for the folkloric use of D. Ramosa as antiulcer agent. The laxative action of the extract compares positively with Duphalac, (standard laxative drug). These findings have therefore evidence scientific background to the folkloric use of the herb as a laxative agent.

Laxative Effects of a Standardized Extract of Dendropanax morbiferus H. Léveille Leaves on Experimental Constipation in Rats.

Background and Objectives: This study aimed at investigating the laxative effects of a standardized aqueous extract of Dendropanax morbiferus H. Lév. on two different constipation rat models. Materials and Methods: Animal studies were conducted with low-fiber diet-induced and loperamide-induced constipation animal models, and isolated colons were used in ex vivo analysis to determine the changes in colonic motility caused by D. morbiferus H. Lév. leaf extract (DPL). Results: The results showed that DPL administration significantly improved certain reduced fecal parameters (number, weight, and water content of the stools) in a both low-fiber diet and loperamide-induced constipation models without adverse effects of diarrhea. The laxative effect of DPL was confirmed to improve the charcoal excretion time upon DPL treatment in a low-fiber diet or loperamide-induced constipation model through gastrointestinal (GI) motility evaluation using the charcoal meal test. In addition, when DPL was administered to RAW264.7 cells and loperamide-induced constipation model rats, the production of prostaglandin E2 (PGE2) increased significantly in cells and tissue. Furthermore, DPL dose-dependently stimulated the spontaneous contractile amplitude and frequency of the isolated rat colon. Conclusion: Although our study did not provide information on the acute or chronic toxicity of DPL, our results demonstrated that DPL can effectively promote defecation frequency and rat colon contraction, providing scientific evidence to support the use of DPL as a therapeutic application. However, further toxicity studies of DPL are needed prior to the initiation of clinical trials and clinical applications.

Exploration of the profile-effect relationship of Siraitia grosvenorii aqueous extracts related to their laxative effect on the basis of gray correlation analysis.

BACKGROUND: Siraitia grosvenorii (binomial name Siraitia grosvenorii (Swingle) C. Jeffrey ex Lu et Z. Y. Zhang), also called Arhat Fruit or Monk's Fruit, is a dried ripe fruit belonging to the Cucurbitaceae Family. S. grosvenorii has a long history of being used for constipation treatment in folk medicine. However, there are few studies where the laxative effect, related mechanisms, and active constituents of S. grosvenorii were investigated. This research explores the relationship between the common components and the laxative effect of aqueous extracts of S. grosvenorii from different habitats in China. METHODS: The fingerprints of S. grosvenorii aqueous extracts from different habitats were established by HPLC. The constipation mice model was used to investigate the laxative effect of S. grosvenorii aqueous extracts. The motilin (MTL) level in mice serum, and the water content of the large and small intestines in mice were determined. The profile-effect relationship of S. grosvenorii aqueous extracts was preliminarily clarified using gray correlation analysis. RESULTS: Nine common peaks were identified from the fingerprint of aqueous extracts of S. grosvenorii. The aqueous extracts obviously shortened the incubation period of defecation, and significantly increased the number of defecations, and the wet and dry weight of defecation in constipated mice. The profile-effect relationship indicated that seven common peaks were highly correlated with the effect of the incubation period of defecation, the number of defecations, and the wet and dry weight of defecation in mice. CONCLUSION: This work provides a promising method for the fingerprint establishment, pharmacodynamic evaluation, and quality control of S. grosvenorii on the basis of its profile-effect relationship.

Bisacodyl Suppresses TGF-α-Induced MUC5AC Production in NCI-H292 Cells.

MUC5AC overproduction is commonly observed in chronic inflammatory lung diseases and worsens these conditions. Therefore, drugs that inhibit MUC5AC production are urgently needed. To identify novel drugs directly inhibiting MUC5AC production, 640 already approved drugs were screened. We found that the laxative bisacodyl suppressed transforming growth factor (TGF)-α-induced MUC5AC production in a concentration-dependent manner. Additionally, bisacodyl also suppressed TGF-α-induced MUC5AC mRNA expression in the same concentration range. These results suggested that bisacodyl could be a new drug for treating mucin overproduction.

Heat-inactivated Lactobacillus plantarum nF1 promotes intestinal health in Loperamide-induced constipation rats.

Constipation is a common condition that affects individuals of all ages, and prolonged constipation needs to be prevented to avoid potential complications and reduce the additional stress on individuals with pre-medical conditions. This study aimed to evaluate the effects of heat-inactivated Lactobacillus plantarum (HLp-nF1) on loperamide-induced constipation in rats. Constipation-induced male rats were treated orally with low to high doses of HLp-nF1 and an anti-constipation medication Dulcolax for five weeks. Study has 8 groups, control group; loperamide-treated group; Dulcolax-treated group; treatment with 3.2 × 1010, 8 × 1010 and 1.6 × 1011, cells/mL HLp-nF1; Loperamide + Dulcolax treated group. HLp-nF1 treated rats showed improvements in fecal pellet number, weight, water content, intestinal transit length, and contractility compared to the constipation-induced rats. Also, an increase in the intestine mucosal layer thickness and the number of mucin-producing crypt epithelial cells were observed in HLp-nF1-treated groups. Further, the levels of inflammatory cytokines levels were significantly downregulated by treatment with HLp-nF1 and Dulcolax. Notably, the metagenomics sequencing analysis demonstrated a similar genus pattern to the pre-preparation group and control with HLp-nF1 treatment. In conclusion, the administration of >3.2 × 1010 cells/mL HLp-nF1 has a positive impact on the constipated rats overall health.

Improvement of loperamide-induced slow transit constipation by Bifidobacterium bifidum G9-1 is mediated by the correction of butyrate production and neurotransmitter profile due to improvement in dysbiosis.

A treatment option for constipation that improves the quality of life is needed since available laxatives do not effectively improve the quality of life in patients with constipation. A significant association between gut dysbiosis and constipation is recognized, suggesting that probiotics may be an important option for management of constipation. The underlying mechanism by which probiotics improve constipation remains unclear. In this study, we aimed to evaluate the effects of the probiotic Bifidobacterium bifidum G9-1 (BBG9-1) on loperamide-induced delayed colonic transit constipation and to elucidate its mechanism of action. First, the effect of BBG9-1 was evaluated in a rat model of constipation induced by subcutaneous administration of loperamide. BBG9-1 improved constipation parameters (number of feces, fecal water content, and fecal hardness) in constipated rats. Next, the relationship of organic acids and neurotransmitters to gut microbiota was investigated. BBG9-1 improved dysbiosis and prevented a decrease in butyric acid concentration in the gut, increased serum serotonin, and suppressed an increase in dopamine and a decrease in acetylcholine in serum. Further, an increase in the expression level of tryptophan hydroxylase 1, a 5-HT-synthetizing enzyme, was observed. These results suggest that BBG9-1 improves dysbiosis, which results in an increase in organic acids and improvement of neurotransmission. These actions may increase intestinal mobility, finally leading to alleviating constipation. The probiotic BBG9-1 may, therefore, be a potential option for the treatment of constipation.