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Journal of Molecular Biology Aug 2020G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins responsible for cellular signal transductions. Identification of therapeutic...
G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins responsible for cellular signal transductions. Identification of therapeutic compounds to regulate physiological processes is an important first step of drug discovery. We proposed MAGELLAN, a novel hierarchical virtual-screening (VS) pipeline, which starts with low-resolution protein structure prediction and structure-based binding-site identification, followed by homologous GPCR detections through structure and orthosteric binding-site comparisons. Ligand profiles constructed from the homologous ligand-GPCR complexes are then used to thread through compound databases for VS. The pipeline was first tested in a large-scale retrospective screening experiment against 224 human Class A GPCRs, where MAGELLAN achieved a median enrichment factor (EF) of 14.38, significantly higher than that using individual ligand profiles. Next, MAGELLAN was examined on 5 and 20 GPCRs from two public VS databases (DUD-E and GPCR-Bench) and resulted in an average EF of 9.75 and 13.70, respectively, which compare favorably with other state-of-the-art docking- and ligand-based methods, including AutoDock Vina (with EF = 1.48/3.16 in DUD-E and GPCR-Bench), DOCK 6 (2.12/3.47 in DUD-E and GPCR-Bench), PoLi (2.2 in DUD-E), and FINDSITECcomb2.0 (2.90 in DUD-E). Detailed data analyses show that the major advantage of MAGELLAN is attributed to the power of ligand profiling, which integrates complementary methods for ligand-GPCR interaction recognition and thus significantly improves the coverage and sensitivity of VS models. Finally, cases studies on opioid and motilin receptors show that new connections between functionally related GPCRs can be visualized in the minimum spanning tree built on the similarities of predicted ligand-binding ensembles, suggesting a novel use of MAGELLAN for GPCR deorphanization.
Topics: Binding Sites; Drug Evaluation, Preclinical; Humans; Ligands; Molecular Docking Simulation; Protein Binding; Protein Conformation; Receptors, G-Protein-Coupled; Structure-Activity Relationship
PubMed: 32652079
DOI: 10.1016/j.jmb.2020.07.003 -
Nutrients Jun 2022Constipation is a common problem in sows and women during late pregnancy. Dietary fiber has potential in the regulation of intestinal microbiota, thereby promoting...
Constipation is a common problem in sows and women during late pregnancy. Dietary fiber has potential in the regulation of intestinal microbiota, thereby promoting intestinal motility and reducing constipation. However, the effects of fibers with different physicochemical properties on intestinal microbe and constipation during late pregnancy have not been fully explored. In this study, a total of 80 sows were randomly allocated to control and one of three dietary fiber treatments from day 85 of gestation to delivery: LIG (lignocellulose), PRS (resistant starch), and KON (konjaku flour). Results showed that the defecation frequency and fecal consistency scores were highest in PRS. PRS and KON significantly increased the level of gut motility regulatory factors, 5-hydroxytryptamine (5-HT), motilin (MTL), and acetylcholinesterase (AChE) in serum. Moreover, PRS and KON promoted the IL-10 level and reduced the TNF-α level in serum. Furthermore, maternal PRS and KON supplementation significantly reduced the number of stillborn piglets. Microbial sequencing analysis showed that PRS and KON increased short-chain fatty acids (SCFAs)-producing genera and and decreased the abundance of endotoxin-producing bacteria and in feces. Moreover, the relative abundance of and the fecal butyrate concentration in PRS were the highest. Correlation analysis further revealed that the defecation frequency and serum 5-HT were positively correlated with and butyrate. In conclusion, PRS is the best fiber source for promoting gut motility, which was associated with increased levels of 5-HT under specific bacteria and butyrate stimulation, thereby relieving constipation. Our findings provide a reference for dietary fiber selection to improve intestinal motility in late pregnant mothers.
Topics: Animals; Female; Pregnancy; Acetylcholinesterase; Bacteria; Butyrates; Constipation; Dietary Fiber; Feces; Gastrointestinal Microbiome; Serotonin; Swine
PubMed: 35745241
DOI: 10.3390/nu14122511 -
Pharmaceutical Biology Dec 2022Hedysari Radix Praeparata Cum Melle (HRPCM) and Astragali Radix Praeparata Cum Melle (ARPCM) are used interchangeably in clinics to treat spleen-qi deficiency (SQD)...
Comparative study on the gastrointestinal- and immune- regulation functions of Hedysari Radix Paeparata Cum Melle and Astragali Radix Praeparata cum Melle in rats with spleen-qi deficiency, based on fuzzy matter-element analysis.
CONTEXT
Hedysari Radix Praeparata Cum Melle (HRPCM) and Astragali Radix Praeparata Cum Melle (ARPCM) are used interchangeably in clinics to treat spleen-qi deficiency (SQD) symptom mainly including gastrointestinal dysfunction and decreased immunity, which has unknown differences in efficacy.
OBJECTIVE
To investigate the differences between HRPCM and ARPCM on intervening gastrointestinal- and immune-function with SQD syndrome.
MATERIALS AND METHODS
After the SQD model was established, the Sprague-Dawley (SD) rats were randomly divided into nine groups ( = 10): normal; model; Bu-Zhong-Yi-Qi Pills; 18.9, 12.6 and 6.3 g/kg dose groups of HRPCM and ARPCM. Gastrointestinal function including d-xylose, gastrin, amylase vasoactive intestinal peptide, motilin, pepsin, H/K-ATPase, Na/K-ATPase, sodium-glucose cotransporter 1 (SGLT1), glucose transporter 2 (GLUT2) and immune function including spleen and thymus index, blood routine, interleukin (IL)-2, IL-6, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), immunoglobulin (Ig) M, IgA, IgG and delayed-type hypersensitivity (DTH) were detected. Finally, the efficacy differences were analysed comprehensively by the fuzzy matter-element method.
RESULTS
In regulating immune, the doses differences in efficacy between HRPCM and ARPCM showed in the high-dose (18.9 g/kg), but there were no differences in the middle- and low- dose (12.6 and 6.37 g/kg); the efficacy differences were primarily reflected in levels of IL-6, IFN-γ, TNF-α and IgM in serum, and the mRNA expression of IL-6 and IFN-γ in the spleen. In regulating gastrointestinal, the efficacy differences were primarily reflected in the levels of D-xylose, MTL, and GAS in serum, and the mRNA and protein expression of SGLT1 and GLUT2 in jejunum and ileum.
DISCUSSION AND CONCLUSIONS
HRPCM is more effective than ARPCM on regulating gastrointestinal function and immune function with SQD syndrome. Therefore, we propose that HRPCM should be mainly used to treat SQD syndrome in the future.
Topics: Adenosine Triphosphatases; Animals; Astragalus Plant; Drugs, Chinese Herbal; Interleukin-6; RNA, Messenger; Rats; Rats, Sprague-Dawley; Spleen; Tumor Necrosis Factor-alpha; Xylose
PubMed: 35763552
DOI: 10.1080/13880209.2022.2086990 -
Frontiers in Microbiology 2022The aim of this study was to investigate the effects of subsp VHProbi YB11 (YB11) on attenuating sucralfate-induced constipation in BALB/c mice. The strain of YB11...
INTRODUCTION
The aim of this study was to investigate the effects of subsp VHProbi YB11 (YB11) on attenuating sucralfate-induced constipation in BALB/c mice. The strain of YB11 exhibited favorable tolerance of simulated gastrointestinal (GI) juice. Only 0.42 Log value declined when the live cells of YB11 were co-incubated with simulated GI juice. Meanwhile, this strain also displayed perfect ability to adhere the intestinal epithelium Caco-2 cells with adhesion index of 18.5. 24 of female mice were randomized into four groups.
METHODS
The normal group (NOR) was fed with a normal diet, whereas the placebo group (PLA), positive group (POS), and probiotic group (PRO) were fed with sucralfate to induce constipation. After first successfully establishing the constipation model, groups NOR and PLA received the oral administration of saline solutions. Meanwhile, the POS and PRO groups were orally administered phenolphthalein and YB11 suspensions, respectively. Several indices, including fecal water content, GI transit time, short-chain fatty acids (SCFAs), intestinal neuropeptides level, and histopathology of colonic tissues, were investigated.
RESULTS AND DISCUSSION
Compared with PLA, YB11 had a positive effect in increasing the fecal water content and intestinal peristalsis. Some positive trends, including the acetic and total acids level of fecal samples, and the colonic tissue histopathology, were also observed. Furthermore, YB11 had an ability to upregulate the levels of gut excitatory neuropeptides including motilin, gastrin, and substance P, whereas it downregulated the levels of inhibitory neuropeptides including endothelin-1, somatostatin, and vasoactive intestinal peptide. We conclude that the strain YB11 has a positive impact on improving gastrointestinal mobility and reducing the severity of constipation.
PubMed: 36532450
DOI: 10.3389/fmicb.2022.1040371 -
American Journal of Physiology.... Jul 2021Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks... (Randomized Controlled Trial)
Randomized Controlled Trial
Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill." However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: ) the site of administration: intragastrically (IG) or intraduodenally (ID), ) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and ) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1 µmol/kg), QHCl (10 µmol/kg), or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min before administration and every 10 min after administration for a period of 2 h. Hunger was rated at the same time points on a visual analogue scale. ID bitter administration did not affect hunger sensations, motilin, or acyl-ghrelin release compared with its placebo infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50 and 70 min after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 min before food intake. Bitter tastants are a potential new weight-loss treatment. This is a noninvasive, easy approach, which should be received with considerable enthusiasm by the public. However, literature about bitter administration lacks consistency in methods and findings. We summarize how the compound should be given based on: the site of administration, the best bitter compound to use, and at what timing in respect to the meal. This paper is therefore a fundamental step to continue research toward the further development of the "bitter pill."
Topics: Cholecystokinin; Cross-Over Studies; Duodenum; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Intubation, Gastrointestinal; Motilin; Peptide Hormones; Placebos; Quaternary Ammonium Compounds; Quinine; Single-Blind Method; Stomach; Taste; Weight Loss; Young Adult
PubMed: 34029163
DOI: 10.1152/ajpendo.00636.2020 -
Journal of Exercise Nutrition &... Dec 2019In this study, we examined the in vitro antioxidant activities and laxative effects of taurine-xylose (T-X), a synthetic taurine-carbohydrate derivative, in a rat model...
PURPOSE
In this study, we examined the in vitro antioxidant activities and laxative effects of taurine-xylose (T-X), a synthetic taurine-carbohydrate derivative, in a rat model of constipation induced by loperamide.
METHODS
The animals were divided into four treatment groups: normal untreated rats (NOR group), loperamide-treated control rats (CON group), loperamide and taurine-xylose (15 mg/kg)-treated rats (T-X group), and loperamide and commercial Dulcolax S (5.5 mg/kg)-treated rats (DS group).
RESULTS
In the present study, T-X exhibited potent reducing power and free radical scavenging activities for DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS+ (2,2'-azino-bis (3-ethylbenzothiazoline 6-sulfonic acid ammonium salt) radicals. The laxative effects of T-X were dependent on food, body weight, fecal properties, gastrointestinal transit (GIT) ratio, and serum metabolic parameters. In the T-X group, the number, wet weight, and water content of fecal pellets were noticeably increased compared to those in the loperamide-induced group. T-X treatment significantly increased the activities of hepatic antioxidant enzymes, including those of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), relative to those in loperamide-induced constipated rats. Furthermore, the GIT ratio and loperamide-induced metabolic parameters in serum, including gastrin (GAS), motilin (MTL), and somatostatin (SS) levels, were significantly improved by T-X treatment.
CONCLUSION
These results suggest that taurine-xylose exerts antioxidant activities and laxative effects on loperamide-induced constipation by promoting gastrointestinal motility.
PubMed: 32018340
DOI: 10.20463/jenb.2019.0025 -
Frontiers in Pharmacology 2023The demand for complementary and alternative medicine for the management of functional dyspepsia (FD) is increasing due to the insufficient efficacy of conventional...
The demand for complementary and alternative medicine for the management of functional dyspepsia (FD) is increasing due to the insufficient efficacy of conventional treatment options. In Asia, the Chinese herbal medicine formula (BXT) has been used to treat FD. We searched 11 digital medical databases on 1 September 2021. Randomized controlled trials (RCTs) that investigated the efficacy of BXT or combination therapy (BXT plus Western medicines) for FD were selected. The outcome parameters were total clinical efficacy rate (TCE), motilin level, symptom checklist-90-revised (SCL-90-R), and visual analog scale (VAS) for dyspepsia and adverse events. Cochrane risk of bias tool 2.0 (RoB 2) was used for the quality assessment of included studies. The meta-analysis comprised 57 RCTs with 5,525 participants. BXT was more efficacious, with a higher TCE than Western medicine. Combination therapy (BXT plus Western medicine) also resulted in a higher TCE than Western medicine. Combination therapy improved motilin levels and psychological symptoms to a greater extent than Western medicine, evidenced by a higher SCL-90-R score. However, no significant difference in VAS scores was observed between the BXT and placebo groups. BXT and combination therapy were associated with fewer adverse events than Western medicine or placebo. Our findings suggest that BXT and its combination therapy may be an effective and safe alternative treatment for FD. More RCTs with better methodologies are required to strengthen this evidence. [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019123285], identifier [CRD42019123285].
PubMed: 37274096
DOI: 10.3389/fphar.2023.1130257 -
Journal of Inflammation Research 2021To investigate the effects of Chinese herbal medicine in tonifying qi and attaining hemostasis caused by the metabolism of the drug clopidogrel and as a result of...
BACKGROUND
To investigate the effects of Chinese herbal medicine in tonifying qi and attaining hemostasis caused by the metabolism of the drug clopidogrel and as a result of platelet and gastric mucosa injury in an ischemia-reperfusion rat model.
METHODS
A pharmacokinetic model was established to record the drug metabolism parameters of clopidogrel metabolites. Then, absorption of the drug was compared with approaches using the traditional Chinese medicine (TCM) approach of tonifying qi and establishing hemostasis, to using the drug pantoprazole and applying these approaches in combination with clopidogrel. Intragastric administration was performed, and all indicators were tested.
RESULTS
The area under the curve (AUC; 0-T, 300.342 ± 35.832 mg/L* h; AUC 0-∞, 320.462 ± 40.213 mg/L* h), the plasma peak concentration (30.622 ± 9.917 mg/L*), and the peak time and half-life (7.954 ± 1.121 h) in the clopidogrel and the TCM groups were higher than those in the clopidogrel and pantoprazole groups. In terms of antiplatelet aggregation, compared with model group, the platelet aggregation rate induced by arachidonic acid (AA) and adenosine diphosphate (ADP) was significantly decreased by the TCM approach of tonifying qi and stopping bleeding (p < 0.05). The ADP, thromboxane A2, GPII B/Pa-A, CD62P and platelet factor 4 content in the TCM yiqi decoction and hemostasis approach were significantly decreased (p < 0.01). Compared with the clopidogrel group, the gastrin and motilin in the serum, the cyclooxygenase (COX)-1 and prostaglandin E2 in gastric tissue, and expression of vascular endothelial growth factor messenger ribonucleic acid in the serum were all significantly increased using TCM approach to protect against gastric mucosal injury (p < 0.05).
CONCLUSION
TCM invigorating qi and hemostasis has an inhibitory effect on platelet activation. It can reduce the local inflammatory reaction at the same time as protecting gastric mucosa.
PubMed: 34262326
DOI: 10.2147/JIR.S316862 -
Evidence-based Complementary and... 2021The root of Willd. (Polygalaceae) (PT) has been listed as a nootropic, anti-inflammatory, and antipsychotic medicine that can cure insomnia. Raw PT (RPT) is toxic and...
The root of Willd. (Polygalaceae) (PT) has been listed as a nootropic, anti-inflammatory, and antipsychotic medicine that can cure insomnia. Raw PT (RPT) is toxic and must be processed before clinical use. Licorice-simmered PT (LPT) is one of the most common processed products. We conducted this study in order to investigate the differences in chemical components and gastrointestinal function between RPT and LPT. We used principal component analysis (PCA) and quantitative analysis to study the differences in the chemical components. Animal experiments were conducted to evaluate the effects of PT on the gastrointestinal function of rats before and after simmering. Pathological sections of gastrointestinal tissues, serum hormone levels, and inflammatory cytokines were observed. The PCA results demonstrated that obvious separation was achieved between the RPT and LPT samples. Tenuifoliside B (TFSB), 3,6'-disinapoyl sucrose (DSS), tenuifoliose A (TFOA), tenuifoliose H (TFOH), onjisaponin B (OJB), onjisaponin Z (OJZ), and total saponins levels were decreased after licorice processing, while glomeratose A (GA) and 3,4,5-trimethoxycinnamic acid (TMCA) levels were markedly increased. Compared to the control group, the RPT groups exhibited dramatically lower levels of gastrin (GAS), motilin (MTL), and substance P (SP) and markedly higher levels of vasoactive intestinal peptide (VIP) and somatostatin (SS), but the LPT groups exhibited no significant differences in the above indexes. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor- (TNF-) in gastrointestinal tissue were markedly increased in the low RPT (L-RPT), high RPT (H-RPT), and H-LPT groups, showing a certain inflammatory effect, but the inflammatory effect in the L-LPT group was relatively weak. Licorice simmering can effectively reduce the inhibitory effect of RPT on gastrointestinal function in rats and reduce damage to gastrointestinal tissue. This study provides a scientific basis for research on the processing mechanism and clinical application of PT.
PubMed: 33505508
DOI: 10.1155/2021/8855536 -
Journal of Oncology 2021To investigate the changes of intestinal flora in elderly patients with Alzheimer's disease and liver cancer and its correlation with abnormal gastrointestinal motility.
OBJECTIVE
To investigate the changes of intestinal flora in elderly patients with Alzheimer's disease and liver cancer and its correlation with abnormal gastrointestinal motility.
METHODS
From January 2018 to December 2020, 102 elderly patients with Alzheimer's disease and liver cancer were selected as the observation group. Eighty-nine healthy patients during the same period were selected as the control group. The two groups of intestinal flora (intestinal microbial diversity) were detected by real-time fluorescent quantitative PCR (RT-qPCR) and high-throughput sequencing. The two groups of serum motilin (MTL) and gastrin (GAS) levels were measured by the Hitachi automatic biochemical analyzer 7600. Pearson correlation analysis software was used to analyze the relationship between changes in the intestinal flora and gastrointestinal motility in elderly patients with Alzheimer's disease and liver cancer.
RESULTS
The contents of and in the observation group were lower than those in the control group, and the contents of , and were higher than those in the control group. The Chaol index and Shannon index in the observation group were higher than those in the control group. The gastrointestinal motility levels MTL and GAS of the observation group were higher than those of the control group. The results of Pearson correlation analysis showed that the Chaol index and Shannon index of elderly patients with Alzheimer's disease and liver cancer were positively correlated with MTL and GAS.
CONCLUSION
Elderly patients with Alzheimer's disease and liver cancer often have changes in the intestinal flora, which are correlated with abnormal gastrointestinal motility. Strengthening the analysis of changes in patients' intestinal flora can enhance clinical medication knowledge and improve gastrointestinal motility in patients.
PubMed: 34422052
DOI: 10.1155/2021/7517379