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1.
Nutrients ; 13(4)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923589

RESUMO

Bitter substances are contained in many plants, are often toxic and can be present in spoiled food. Thus, the capacity to detect bitter taste has classically been viewed to have evolved primarily to signal the presence of toxins and thereby avoid their consumption. The recognition, based on preclinical studies (i.e., studies in cell cultures or experimental animals), that bitter substances may have potent effects to stimulate the secretion of gastrointestinal (GI) hormones and modulate gut motility, via activation of bitter taste receptors located in the GI tract, reduce food intake and lower postprandial blood glucose, has sparked considerable interest in their potential use in the management or prevention of obesity and/or type 2 diabetes. However, it remains to be established whether findings from preclinical studies can be translated to health outcomes, including weight loss and improved long-term glycaemic control. This review examines information relating to the effects of bitter substances on the secretion of key gut hormones, gastric motility, food intake and blood glucose in preclinical studies, as well as the evidence from clinical studies, as to whether findings from animal studies translate to humans. Finally, the evidence that bitter substances have the capacity to reduce body weight and/or improve glycaemic control in obesity and/or type 2 diabetes, and potentially represent a novel strategy for the management, or prevention, of obesity and type 2 diabetes, is explored.


Assuntos
Agentes Aversivos/farmacologia , Glicemia/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Paladar/fisiologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Digestão/efeitos dos fármacos , Hormônios Gastrointestinais/metabolismo , Trato Gastrointestinal/metabolismo , Humanos , Obesidade/metabolismo , Período Pós-Prandial , Pesquisa Médica Translacional , Perda de Peso/efeitos dos fármacos
2.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760185

RESUMO

Intestinal inflammation frequently occurs alongside dysmotility, which is characterized by altered myosin light chain phosphorylation levels. Curcumin, an active component from the ginger family, is reported to confer anti­inflammatory effects. However, the effects of curcumin on both diarrhea and constipation associated inflammation remains to be elucidated. The present study was designed to investigate the effects of curcumin on diarrhea and constipation and to determine the related mechanisms. Sprague­Dawley rats were used to establish diarrhea and constipation models via intracolonic acetic acid (4%) instillation or cold water gavage for 2 weeks, respectively. Blood samples were collected to measure the serum levels of the cytokines TNF­α and IL­1ß using ELISA kits. Western blotting was performed to measure NF­κB, RhoA, Rho­related kinase 2, phosphorylated MLC20, phosphorylated myosin phosphorylated target subunit 1, 130k Da­MLC kinase (MLCK), c­kit tyrosine kinase protein expression, and reverse transcription­quantitative PCR was conducted to measure MLCK expression levels. The results indicated that curcumin reversed the elevations in the pro­inflammatory cytokines IL­1ß and TNF­α by inhibiting the NF­κB pathway in rats with diarrhea and constipation. The results also indicated that myosin light chain (MLC) phosphorylation in intestinal smooth muscle was positively and negatively associated with the motility of inflammation­related diarrhea and constipation in rats, respectively. Curcumin significantly reversed the increased MLC phosphorylation in the jejunum of the rats with diarrhea, significantly enhanced the reductions in inflammatory mediators, including TNF­α and IL­1ß, of rats with constipation and significantly ameliorated the related hyper­motility and hypo­motility in rats with both diarrhea and constipation. In conclusion, the potential roles of the MLC kinase, c­kit tyrosine and Rho A/Rho­associated kinase 2 pathways, which are involved in curcumin­induced amelioration of inflammation­related diarrhea and constipation, were explored in the present study. Results from the present study suggested that curcumin has potential therapeutic value for treating intestinal inflammation and inflammation­related motility disorders.


Assuntos
Curcumina/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Animais , Motilidade Gastrointestinal/genética , Humanos , Inflamação/genética , Inflamação/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Quinase de Cadeia Leve de Miosina/genética , NF-kappa B/genética , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina B/genética , Fator de Necrose Tumoral alfa/genética , Proteína rhoA de Ligação ao GTP/genética
3.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760155

RESUMO

Interstitial cells of Cajal (ICCs) are pacemaker cells that control smooth muscle contraction in the gastrointestinal (GI) tract. The present study investigated the effects of Salvia miltiorrhiza (SM) on the pacemaker potentials of ICCs from the mouse small intestine in vitro and on GI motility in vivo. The whole­cell patch­clamp configuration was used to record pacemaker potential in ICCs in vitro, and GI motility was investigated in vivo by recording intestinal transit rate (ITR). Using the whole­cell patch­clamp configuration, SM depolarized the pacemaker potentials of ICCs in a dose­dependent manner. Fulvestrant blocked SM­induced effects but 1,3­dihydro­3,3­bis(4­hydroxyphenyl)-7-methyl­2H­indol­2­one did not. Additionally, 4­[2­phenyl-5,7­bis(trifluoromethyl) pyrazolo[1,5­a]pyrimidin­3­yl] phenol blocked SM­induced effects. Intracellular guanosine 5'­O­(2­thiodiphosphate), and pretreatment with extracellular Ca2+­ and Na+­free solutions also blocked SM­induced effects. Furthermore, ITR values were increased by SM in vivo and SM elevated the levels of motilin (MTL). The SM­induced increase in ITR was associated with increased protein expression levels of c­kit and the transmembrane protein 16A (TMEM16A) channel. In addition, SM induced pacemaker potential depolarization through estrogen receptor ß in a G protein­dependent manner via extracellular Ca2+ and Na+ regulation in the murine small intestine in vitro. Moreover, SM increased the ITR in vivo through the MTL hormone via c­kit and TMEM16A­dependent pathways. Taken together, these results suggested that SM may have the ability to control GI motility and could be used as a GI motility regulator.


Assuntos
Células Intersticiais de Cajal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Salvia miltiorrhiza/química , Animais , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Intestino Delgado/fisiologia , Camundongos , Motilina , Contração Muscular/fisiologia , Miócitos de Músculo Liso/efeitos dos fármacos , Marca-Passo Artificial , Técnicas de Patch-Clamp
4.
Medicine (Baltimore) ; 100(4): e24361, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530231

RESUMO

BACKGROUND: While irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal diseases in clinical practice, it has diverse pathogenesis. Because of its sudden and lingering intractable symptoms, it seriously affects patients work and life. Opioid receptors are G protein-coupled receptors distributed across the brain, spinal cord, skin, and gastrointestinal tract, and each of the subtypes has a unique role and specific distribution. They play a role in regulating gastrointestinal motility, secretion, and visceral sensations in the gastrointestinal tract. Therefore, this meta-analysis aims to evaluate the effects of opioid receptor modulators on improving the symptoms of IBS. METHODS: Searching the key words (Irritable Bowel Syndromes or Syndrome, Irritable Bowel OR Syndromes, Irritable Bowel OR Colon, Irritable OR Irritable Colon OR Colitis, Mucous OR Colitides, Mucous OR Mucous Colitides OR Mucous Colitis) AND (opioid receptor modulators OR eluxadoline OR Viberzi OR asimadoline OR loperamide), a preliminary search on PubMed (English), EMBASE (English), Cochrane Library (English), China National Knowledge Infrastructure Database (CNKI, Chinese), WanFang (Chinese), VIP citation databases (Chinese) and SinoMed (Chinese) databases yielded 1023 papers published in English and Chinese from inception to July 1, 2019. Nine studies were included in the final meta-analysis. Because this is a systematic review and meta-analysis, ethical approval is not necessary. RESULTS: The random-effects meta-analysis based on these 9 studies and their 4156 patients found that opioid receptor modulators have a statistically significant beneficial effect on IBS global symptoms (RR = 0.85, 95%CI = 0.79-0.92, P < .01) and bowel movement frequency (SMD = -1.26, 95%CI = -2.49--0.04, P < .05), and while there was an improvement trend in stool consistency and quality of life, these findings were not statistically significant. CONCLUSIONS: This is the first meta-analysis to examine the use of opioid receptor modulators in IBS, and few adverse events were reported in the available trials. Compared with the control group, eluxadolin has a better effect in improving IBS global symptoms and abdominal pain and has statistical significance and showed a low rate of constipation development in IBS patients in comparison with known effects of other opioid receptor modulators. However, current findings are based on a considerably limited evidence base with marked heterogeneity. Future studies should aim to identify subpopulations of patients with IBS and need to evaluate the long-term safety of these therapies.PROSPERO registration number: CRD42020141597.


Assuntos
Fármacos Gastrointestinais/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Antagonistas de Entorpecentes/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
5.
PLoS Biol ; 19(1): e3001070, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481771

RESUMO

Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions.


Assuntos
Bactérias/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Indóis/metabolismo , Indóis/farmacologia , 5-Hidroxitriptofano/metabolismo , Adulto , Animais , Canais de Cálcio Tipo L/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Motilidade Gastrointestinal/fisiologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Ratos , Adulto Jovem
6.
J Pharmacol Sci ; 145(1): 122-129, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357770

RESUMO

Functional dyspepsia (FD) is thought to be mainly based on gastric motility dysfunction and chronic hypersensitivity, yet FD animal models has been reported a few. We studied to establish the mouse model of impaired gastric motility induced by a pungent ingredient of wasabi allyl isothiocyanate (AITC), which is reliable to evaluate prokinetic agents. Male ddY mice were used. Gastric motility was measured by 13C-acetic acid breath test in conscious mice. AITC (80 mM) was given 60 min before the measurement of motility. Prokinetic agents including itopride (30, 100 mg/kg), mosapride (0.1-1 mg/kg), neostigmine (30 µg/kg), acotiamide (10-100 mg/kg), and daikenchuto (100-1000 mg/kg) were given 40 min before the measurement. AITC impaired gastric motility without mucosal damages, which reverted 24 h after AITC treatment. The decreased motility induced by AITC was restored by prokinetic agents such as itopride, mosapride, neostigmine, and acotiamide. In separate experiment, daikenchuto recovered the decreased motility induced by AITC, although daikenchuto had no effect on motility in normal condition. In conclusion, it is considered that the AITC-induced impaired gastric motility mouse model is useful to develop new prokinetic agents for treatment of FD, and to re-evaluate traditional Japanese herbal medicines.


Assuntos
Benzamidas/administração & dosagem , Compostos de Benzil/administração & dosagem , Dispepsia/tratamento farmacológico , Motilidade Gastrointestinal , Isotiocianatos/efeitos adversos , Morfolinas/administração & dosagem , Neostigmina/administração & dosagem , Fitoterapia , Extratos Vegetais/administração & dosagem , Tiazóis/administração & dosagem , Wasabia/química , Animais , Benzamidas/farmacologia , Compostos de Benzil/farmacologia , Modelos Animais de Doenças , Dispepsia/fisiopatologia , Motilidade Gastrointestinal/efeitos dos fármacos , Isotiocianatos/isolamento & purificação , Masculino , Camundongos Endogâmicos , Morfolinas/farmacologia , Neostigmina/farmacologia , Extratos Vegetais/farmacologia , Tiazóis/farmacologia
7.
Gen Comp Endocrinol ; 300: 113649, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33153968

RESUMO

Ghrelin (GHRL) and motilin (MLN), gut peptides isolated from the mucosa of the stomach and duodenum, respectively, stimulate gastrointestinal (GI) motility in mammals and birds. However, the functions of MLN and GHRL in amphibian GI tracts have not been examined in detail. To clarify the regulation of GI motility by the two peptides, the effects of human MLN and rat GHRL on contractility of isolated GI strips from three species of frogs, the black-spotted pond frog (pond frog; Pelophylax nigromaculata), bullfrog (Lithobates catesbeiana) and Western clawed frog (Xenopus; Xenopus tropicalis), were examined in in vitro experiments. The GI tract of each frog was divided into the stomach, upper intestine, middle intestine and lower intestine. Human MLN caused contractions of the stomach in the pond frog and upper intestine in the bullfrog and Xenopus, but other GI regions were insensitive to human MLN. Erythromycin did not cause contraction of the upper intestine of the bullfrog and Xenopus. Rat GHRL did not cause contraction of the stomach and small intestines in the pond frog and bullfrog, but it caused a concentration-dependent contraction in the stomach and upper intestine of Xenopus, while des-acyl rat GHRL did not cause any contraction of them. In conclusion, human MLN caused the contraction of the stomach or upper intestine in the three species of frogs, but GHRL was effective only in the stomach and upper intestine of Xenopus. On the basis of these data, MLN but not GHRL causes the GI region-dependent contractions in the frogs.


Assuntos
Anuros/fisiologia , Trato Gastrointestinal/fisiologia , Grelina/farmacologia , Motilina/farmacologia , Contração Muscular/efeitos dos fármacos , Animais , Motilidade Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Rana catesbeiana , Ratos , Xenopus
8.
Carbohydr Polym ; 253: 117218, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278982

RESUMO

This study was designed to explore the improvement of chitosan oligosaccharides (COS) on constipation through regulation of gut microbiota. Here, we proved that COS treatment profoundly boosted intestinal motility, restrained inflammatory responses, improved water-electrolyte metabolism and prevented gut barrier damage in constipated mice induced by loperamide. By 16S rDNA gene sequencing, the disbalanced gut microbiota was observed in constipated mice, while COS treatment statistically reversed the abundance changes of several intestinal bacteria at either phylum, family and genus levels, which partly led to the balance in production of intestinal metabolites including bile acids, short-chain fatty acids and tryptophan catabolites. In addition, COS failed to relieve the constipation in mice with intestinal flora depletion, confirming the essentiality of gut microbiota in COS-initiated prevention against constipation. In summary, COS can ameliorate the development of loperamide-induced constipation in mice by remodeling the structure of gut microbial community.


Assuntos
Antidiarreicos/efeitos adversos , Quitosana/farmacologia , Constipação Intestinal/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Loperamida/efeitos adversos , Oligossacarídeos/farmacologia , Animais , Sequência de Bases , Ácidos e Sais Biliares/metabolismo , DNA Ribossômico/genética , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência de DNA , Transdução de Sinais/efeitos dos fármacos , Triptofano/metabolismo
9.
PLoS One ; 15(12): e0244680, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382780

RESUMO

OBJECTIVE: We determined the effectiveness of a multi-strain probiotic (Hexbio®) containing microbial cell preparation MCP®BCMC® on constipation symptoms and gut motility in PD patients with constipation. METHODS: PD patients with constipation (ROME III criteria) were randomized to receive a multi-strain probiotic (Lactobacillus sp and Bifidobacterium sp at 30 X 109 CFU) with fructo-oligosaccaride or placebo (fermented milk) twice daily for 8 weeks. Primary outcomes were changes in the presence of constipation symptoms using 9 items of Garrigues Questionnaire (GQ), which included an item on bowel opening frequency. Secondary outcomes were gut transit time (GTT), quality of life (PDQ39-SI), motor (MDS-UPDRS) and non-motor symptoms (NMSS). RESULTS: Of 55 recruited, 48 patients completed the study: 22 received probiotic and 26 received placebo. At 8 weeks, there was a significantly higher mean weekly BOF in the probiotic group compared to placebo [SD 4.18 (1.44) vs SD 2.81(1.06); (mean difference 1.37, 95% CI 0.68, 2.07, uncorrected p<0.001)]. Patients in the probiotic group reported five times higher odds (odds ratio = 5.48, 95% CI 1.57, 19.12, uncorrected p = 0.008) for having higher BOF (< 3 to 3-5 to >5 times/week) compared to the placebo group. The GTT in the probiotic group [77.32 (SD55.35) hours] reduced significantly compared to placebo [113.54 (SD 61.54) hours]; mean difference -36.22, 95% CI -68.90, -3.54, uncorrected p = 0.030). The mean change in GTT was 58.04 (SD59.04) hour vs 20.73 (SD60.48) hours respectively (mean difference 37.32, 95% CI 4.00, 70.63, uncorrected p = 0.028). No between-groups differences were observed in the NMSS, PDQ39-SI, MDS-UPDRS II and MDS-UPDRS III scores. Four patients in the probiotics group experienced mild reversible side effects. CONCLUSION: This study showed that consumption of a multi-strain probiotic (Hexbio®) over 8 weeks improved bowel opening frequency and whole gut transit time in PD patients with constipation.


Assuntos
Constipação Intestinal/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Doença de Parkinson/fisiopatologia , Probióticos/uso terapêutico , Idoso , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Método Duplo-Cego , Feminino , Motilidade Gastrointestinal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Probióticos/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento
10.
Acta Cir Bras ; 35(8): e202000804, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32901681

RESUMO

PURPOSE: To investigate the effect of probiotics on spontaneous contractions of smooth muscle isolated from jejunum and ileum of rat model. METHODS: Four rat groups were created (n=8, in each) including control (Group 1), control+probiotic (Group 2), short bowel (Group 3), and short bowel+probiotic (Group 4). Groups 1 and 2 underwent sham operation, Groups 3 and 4 underwent massive bowel resection. Bifidobacterium Lactis was administered in Groups 2 and 4 daily (P.O.) for three weeks. On postoperative week 3, rats were sacrificed, and jejunum and ileum smooth muscle were isolated for organ bath. Muscle contraction changes were analyzed before and after addition of antagonists. RESULTS: Short bowel group exhibited increased amplitude and frequency of spontaneous contractions. The addition of probiotics significantly decreased enhanced amplitude and frequency of bowel contraction in short bowel group and returned to control values. L-NNA increased amplitude and frequency of contractions in all groups. While indomethacin and nimesulide increased the amplitude in all groups, the frequency was only increased in jejunum. Hexamethonium and tetrodotoxin did not change the contraction characteristics in all groups. CONCLUSION: We suggest that early use of probiotics may significantly regulate bowel motility, and accordingly improve absorption of nutrients in short bowel syndrome.


Assuntos
Motilidade Gastrointestinal , Probióticos , Síndrome do Intestino Curto , Animais , Motilidade Gastrointestinal/efeitos dos fármacos , Jejuno , Músculo Liso , Probióticos/farmacologia , Ratos
11.
Surgery ; 168(5): 793-799, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32682507

RESUMO

BACKGROUND: Postoperative gastrointestinal dysfunction remains a major determinant of the duration of stay after complex abdominal surgery. This study was performed to evaluate the effectiveness of heated fennel therapy in accelerating the recovery of gastrointestinal function. METHODS: This surgeon-blinded, prospective randomized controlled study included 381 patients with hepatobiliary, pancreatic, and gastric tumors who were divided into 2 groups. The patients in the experimental groups received heated fennel therapy, and those in the control groups received heated rice husk therapy. We compared the baseline characteristics, time to first postoperative flatus and defecation, fasting time, duration of postoperative hospital stay, grading of abdominal pain, classification of abdominal distension, inflammatory markers, and nutritional status indicators. RESULTS: The time to first flatus and first defecation and the fasting time were statistically significantly less in the heated fennel therapy group than those in the control groups (P < .05 each); and abdominal distension was also relieved in the experimental groups (P < .001). Heated fennel therapy had no obvious beneficial effect on inflammatory markers but improved the serum albumin (ALB) level of the patients at postop day 9 (P < .001). Among the patients with alimentary tract reconstruction, those in the heated fennel therapy group had a clinically important, lesser hospital stay than those in the control group (9.2 5 ± 5.1 versus 11.1 ± 6.4; P < .023). CONCLUSION: Heated fennel therapy facilitated the gastrointestinal motility function of patients early postoperatively.


Assuntos
Abdome/cirurgia , Recuperação Pós-Cirúrgica Melhorada , Foeniculum , Motilidade Gastrointestinal/efeitos dos fármacos , Fitoterapia , Adulto , Idoso , Feminino , Humanos , Tempo de Internação , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Neoplasias Gástricas/fisiopatologia , Neoplasias Gástricas/cirurgia
12.
J Zoo Wildl Med ; 51(2): 326-333, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32549562

RESUMO

Gastrointestinal (GI) pathology is common in elasmobranchs; however, information regarding normal GI transit time and the effect of therapeutics on GI motility is lacking. The objective of this study was to determine baseline gastric emptying and GI transit times in cownose rays (Rhinoptera bonasus) and whitespotted bamboo sharks (Chiloscyllium plagiosum) via radiographic barium sulfate contrast studies. Additionally, a pilot study was undertaken to determine the effect of metoclopramide on GI transit time in whitespotted bamboo sharks. Eight cownose rays and eight whitespotted bamboo sharks were administered a 98% w/w barium sulfate suspension at 8 ml/kg via orogastric tube. Post-contrast radiographs were obtained at 2 min, 3, 6, 12, and 23 hr for rays; and 2 min, 3, 6, 9, 12, 16, 25, 30, 36, and every 12 hr until complete gastric emptying occurred for sharks. In cownose rays, the mean and standard error were established for time of initial spiral colon filling (3.4 ± 0.4 hr), complete spiral colon opacification (12 ± 0 hr), initial spiral colon emptying (21.6 ± 1.4 hr), and complete gastric emptying (23 ± 0 hr). In bamboo sharks, the mean and standard error were established for time of initial spiral colon filling (5.3 ± 0.5 hr), complete spiral colon opacification (12.4 ± 1.3 hr), initial spiral colon emptying (22.5 ± 2.7 hr), and complete gastric emptying (39.9 ± 3.3 hr). Cownose rays had a significantly shorter time to spiral colon filling and complete gastric emptying compared with bamboo sharks (P < 0.05). Whitespotted bamboo sharks (n = 8) were administered metoclopramide (0.4 mg/kg orally once daily for 10 days) and the barium series was repeated. Complete gastric emptying time was significantly shorter in treated sharks compared with control (P < 0.05), suggesting that metoclopramide may be a useful therapeutic for GI motility disorders in elasmobranchs.


Assuntos
Antieméticos/administração & dosagem , Motilidade Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Metoclopramida/administração & dosagem , Tubarões/fisiologia , Animais , Feminino , Esvaziamento Gástrico , Trato Gastrointestinal/diagnóstico por imagem , Trânsito Gastrointestinal , Masculino , Projetos Piloto , Rajidae/fisiologia , Especificidade da Espécie
13.
J Smooth Muscle Res ; 56(0): 29-45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581184

RESUMO

Gastric motility is controlled by slow waves. In general, the activation of the ATP-sensitive K+ (KATP) channels in the smooth muscle opposes the membrane excitability and produces relaxation. Since metabolic inhibition and/or diabetes mellitus are accompanied by dysfunctions of gastric smooth muscle, we examined the possible roles of KATP channels in human gastric motility. We used human gastric corpus and antrum smooth muscle preparations and recorded the mechanical activities with a conventional contractile measuring system. We also identified the subunits of the KATP channels using Western blot. Pinacidil (10 µM), a KATP channel opener, suppressed contractions to 30% (basal tone to -0.2 g) of the control. The inhibitory effect of pinacidil on contraction was reversed to 59% of the control by glibenclamide (20 µM), a KATP channel blocker. The relaxation by pinacidil was not affected by a pretreatment with L-arginine methyl ester, tetraethylammonium, or 4-aminopyridine. Pinacidil also inhibited the acetylcholine (ACh)-induced tonic and phasic contractions in a glibenclamide-sensitive manner (42% and 6% of the control, respectively). Other KATP channel openers such as diazoxide, cromakalim and nicorandil also inhibited the spontaneous and ACh-induced contractions. Calcitonin gene-related peptide (CGRP), a gastric neuropeptide, induced muscle relaxation by the activation of KATP channels in human gastric smooth muscle. Finally, we have found with Western blot studies, that human gastric smooth muscle expressed KATP channels which were composed of Kir 6.2 and SUR2B subunits.


Assuntos
Canais KATP/metabolismo , Canais KATP/fisiologia , Músculo Liso/fisiologia , Estômago/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Glibureto/farmacologia , Humanos , Técnicas In Vitro , Canais KATP/antagonistas & inibidores , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/química
14.
Surg Today ; 50(11): 1524-1529, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32588153

RESUMO

PURPOSE: To investigate the efficacy and safety of Daikenchuto (DKT) for colorectal cancer patients undergoing surgery with the potential risk of postoperative ileus (POI). METHODS: Colorectal cancer patients with abdominal pain and distention, scheduled for surgery, were randomly assigned to a DKT group or a control group. Patients assigned to the DKT group were given 15 g of DKT per day during the perioperative period. We then compared the perioperative gastrointestinal symptoms between the two groups. RESULTS: The aim for a sample size of 30 patients per group was not reached in time, so we conducted an analysis on 16 patients in each group. The visual Analogue Scale scores for abdominal pain and distention were similar in the two groups. The number of bowel movements per day on postoperative days (PODs) 1, 2, and 6 were significantly lower in the DKT group. The incidence of a sensation of incomplete bowel evacuation on PODs 3 and 28 was also significantly lower in the DKT group. There were no adverse events thought to be related to DKT. CONCLUSIONS: DKT could potentially inhibit diarrhea and reduce the number of bowel movements per day and the sensation of incomplete bowel evacuation after colorectal surgery. Thus, the perioperative use of DKT may be safe for colorectal cancer patients with abdominal pain and distention, who undergo surgery.


Assuntos
Neoplasias Colorretais/cirurgia , Diarreia/prevenção & controle , Extratos Vegetais/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Dor Abdominal/prevenção & controle , Adulto , Idoso , Neoplasias Colorretais/fisiopatologia , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Extratos Vegetais/farmacologia , Estudos Prospectivos , Segurança
15.
J Vasc Interv Radiol ; 31(7): 1143-1147, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32457012

RESUMO

PURPOSE: To determine whether a single 10-mg intravenous dose of the promotility agent metoclopramide reduces the fluoroscopy time, radiation dose, and procedure time required for gastrojejunostomy (GJ) tube placement. METHODS: This prospective, randomized, double-blind, placebo-controlled trial enrolled consecutive patients who underwent primary GJ tube placement at a single institution from April 10, 2018, to October 3, 2019. Exclusion criteria included age less than 18 years, inability to obtain consent, metoclopramide allergy or contraindication, and altered pyloric anatomy. Average fluoroscopy times, radiation doses, and procedure times were compared using t-tests. The full study protocol can be found at www.clinicaltrials.gov (NCT03331965). RESULTS: Of 110 participants randomized 1:1, 45 received metoclopramide and 51 received placebo and underwent GJ tube placement (38 females and 58 males; mean age, 55 ± 18 years). Demographics of the metoclopramide and placebo groups were similar. The fluoroscopy time required to advance a guide wire through the pylorus averaged 1.6 minutes (range, 0.3-10.1 minutes) in the metoclopramide group versus 4.1 minutes (range, 0.2-27.3 minutes) in the placebo group (P = .002). Total procedure fluoroscopy time averaged 5.8 minutes (range, 1.5-16.2 minutes) for the metoclopramide group versus 8.8 minutes (range, 2.8-29.7 minutes) for the placebo group (P = .002). Air kerma averaged 91 mGy (range, 13-354 mGy) for the metoclopramide group versus 130 mGy (range, 24-525 mGy) for the placebo group (P = .04). Total procedure time averaged 16.4 minutes (range, 8-51 minutes) for the metoclopramide group versus 19.9 minutes (range, 6-53 minutes) for the placebo group (P = .04). There were no drug-related adverse events and no significant differences in procedure-related complications. CONCLUSIONS: A single dose of metoclopramide reduced fluoroscopy time by 34%, radiation dose by 30%, and procedure time by 17% during GJ tube placement.


Assuntos
Nutrição Enteral/instrumentação , Derivação Gástrica/instrumentação , Fármacos Gastrointestinais/administração & dosagem , Motilidade Gastrointestinal/efeitos dos fármacos , Metoclopramida/administração & dosagem , Duração da Cirurgia , Radiografia Intervencionista , Administração Intravenosa , Adulto , Idoso , Método Duplo-Cego , Nutrição Enteral/efeitos adversos , Fluoroscopia , Derivação Gástrica/efeitos adversos , Fármacos Gastrointestinais/efeitos adversos , Humanos , Metoclopramida/efeitos adversos , Pessoa de Meia-Idade , North Carolina , Estudos Prospectivos , Doses de Radiação , Exposição à Radiação , Radiografia Intervencionista/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G1042-G1053, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32390463

RESUMO

The period during and immediately after weaning is an important developmental window when marked shifts in gut microbiota can regulate the maturation of the enteric nervous system (ENS). Because microbiota-derived signals that modulate ENS development are poorly understood, we examined the physiological impact of the broad spectrum of antibiotic, vancomycin-administered postweaning on colonic motility, neurochemistry of enteric neurons, and neuronal excitability. The functional impact of vancomycin on enteric neurons was investigated by Ca2+ imaging in Wnt1-Cre;R26R-GCaMP3 reporter mice to characterize alterations in the submucosal and the myenteric plexus, which contains the neuronal circuitry controlling gut motility. 16S rDNA sequencing of fecal specimens after oral vancomycin demonstrated significant deviations in microbiota abundance, diversity, and community composition. Vancomycin significantly increased the relative family rank abundance of Akkermansiaceae, Lactobacillaceae, and Enterobacteriaceae at the expense of Lachnospiraceae and Bacteroidaceae. In sharp contrast to neonatal vancomycin exposure, microbiota compositional shifts in weaned animals were associated with slower colonic migrating motor complexes (CMMCs) without mucosal serotonin biosynthesis being altered. The slowing of CMMCs is linked to disruptions in the neurochemistry of the underlying enteric circuitry. This included significant reductions in cholinergic and calbindin+ myenteric neurons, neuronal nitric oxide synthase+ submucosal neurons, neurofilament M+ enteric neurons, and increased proportions of cholinergic submucosal neurons. The antibiotic treatment also increased transmission and responsiveness in myenteric and submucosal neurons that may enhance inhibitory motor pathways, leading to slower CMMCs. Differential vancomycin responses during neonatal and weaning periods in mice highlight the developmental-specific impact of antibiotics on colonic enteric circuitry and motility.


Assuntos
Colo/inervação , Sistema Nervoso Entérico/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Vancomicina/farmacologia , Animais , Antibacterianos/farmacologia , Sistema Nervoso Entérico/fisiologia , Feminino , Masculino , Camundongos , Serotonina/biossíntese
17.
Aliment Pharmacol Ther ; 51(11): 1130-1138, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32383253

RESUMO

BACKGROUND: Medications can affect gastrointestinal tract motility. However, their effects on oesophageal motility in particular are often not as widely known or may be underestimated. AIM: To review the effect of existing medication use on high-resolution oesophageal manometry (HRM) in a 'real-world' setting. METHODS: Adult patients with upper gut symptoms and normal endoscopy or imaging who had HRM over a 22-month period were analysed. Achalasia and major disorders of peristalsis were excluded. All medications taken within 24 hours of the procedure were prospectively recorded and compared with HRM results, controlling for age, gender and proton pump inhibitor use. RESULTS: A total of 502 patients (323 female, mean age 51) were recruited. Of these, 41.2% had normal oesophageal HRM, while 41.4% had ineffective oesophageal motility (IOM) and 7.6% had oesophagogastric junction outflow obstruction (OGJOO). Serotonin/norepinephrine reuptake inhibitors (SNRI) and opioids were associated with significantly higher resting lower oesophageal sphincter pressure. Benzodiazepines and opioids were associated with elevated integrated relaxation pressure. SNRI and inhaled beta-agonists were associated with increased distal contractile index, whereas calcium channel blockers were associated with a lower distal contractile index. Odds ratio of being on anticholinergics was higher in IOM patients vs normal (3.6, CI 1.2-10.8). Odds ratio for anticholinergics, inhaled beta-agonists, anticonvulsants, SNRIs and opioids (trend) were all > 3 for OGJOO patients vs normal. CONCLUSION: Many medication classes are associated with abnormal HRM variables and diagnoses such as OGJOO and IOM; some of these associations are probably causal. These possible links should be taken into consideration during manometry interpretation.


Assuntos
Antidepressivos/efeitos adversos , Antagonistas Colinérgicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Doenças do Esôfago/induzido quimicamente , Doenças do Esôfago/epidemiologia , Adulto , Idoso , Estudos de Coortes , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Acalasia Esofágica/induzido quimicamente , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/epidemiologia , Doenças do Esôfago/diagnóstico , Transtornos da Motilidade Esofágica/induzido quimicamente , Transtornos da Motilidade Esofágica/diagnóstico , Transtornos da Motilidade Esofágica/epidemiologia , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Manometria/métodos , Pessoa de Meia-Idade , Contração Muscular , Peristaltismo/efeitos dos fármacos , Inibidores da Bomba de Prótons/efeitos adversos , Estudos Retrospectivos
18.
J Pharmacol Exp Ther ; 374(1): 52-61, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32327529

RESUMO

The analgesic potency of morphine-6-glucuronide (M6G) has been shown to be 50-fold higher than morphine after intracerebral injection. However, the brain penetration of M6G is significantly lower than morphine, thus limiting its usefulness in pain management. Here, we created new entities by the conjugation of the angiopep-2 peptide (An2) that crosses the blood-brain barrier (BBB) by low-density lipoprotein receptor-related protein 1 receptor-mediated transcytosis with either morphine or M6G. We demonstrated improvement of BBB permeability of these new entities compared with that of unconjugated M6G and morphine. Intravenous or subcutaneous administration of the An2-M6G conjugate exerted greater and more sustained analgesic activity than equivalent doses of either morphine or M6G. Likewise, subcutaneous An2-morphine induced a delayed but prolonged antinociceptive effect. The effects of these conjugates on the gastrointestinal tract motility were also evaluated. An2-morphine significantly reduced the intestinal transit time, whereas An2-M6G exhibited a reduced constipation profile, as compared with an equimolar dose of morphine. In summary, we have developed new brain-penetrant opioid conjugates exhibiting improved analgesia to side effect ratios. These results thus support the use of An2-carrier peptides as an innovative BBB-targeting technology to deliver effective drugs, such as M6G, for pain management. SIGNIFICANCE STATEMENT: The metabolite morphine-6-glucuronide (M6G) does not efficiently cross the blood-brain barrier. The low-density lipoprotein receptor-related protein 1 peptide ligand angiopep-2 may serve as an effective drug delivery system to the brain. Here, we demonstrated that the coupling of M6G to angiopep-2 peptide (An2) improves its brain penetration and significantly increases its analgesic potency. The An2-M6G conjugate has a favorable side effect profile that includes reduction of developing constipation. An2-M6G exhibits a unique pharmacodynamic profile with a better therapeutic window than morphine.


Assuntos
Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Barreira Hematoencefálica/metabolismo , Derivados da Morfina/química , Derivados da Morfina/metabolismo , Peptídeos/química , Administração Intravenosa , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Transporte Biológico , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Derivados da Morfina/administração & dosagem , Derivados da Morfina/farmacologia , Nociceptividade/efeitos dos fármacos
19.
Med Sci Monit ; 26: e919815, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32248203

RESUMO

BACKGROUND Fructus aurantii is a flavonoid derived from Citrus aurantium (bitter orange) that is used in traditional Chinese medicine (TCM) to treat gastric motility disorders. This study aimed to investigate the effects of low-dose and high-dose decoctions of Fructus aurantii in a rat model of functional dyspepsia (FD). MATERIAL AND METHODS Sprague-Dawley rats (n=90) were divided into nine study groups: the control group, the FD model group, the domperidone-treated (Domp) group, the low-dose raw Fructus aurantii (FA-L) group, the high-dose raw Fructus aurantii (FA-H) group, the low-dose Fructus aurantii with stir-fried wheat bran (Bran-L) group, the high-dose Fructus aurantii with stir-fried wheat bran (Bran-H) group, the low-dose Fructus aurantii with stir-fried wheat bran and honey (Honey-L) group, and the high-dose Fructus aurantii with stir-fried wheat bran and honey (Honey-H) group. The FD rat model was established by semi-starvation, followed by tail damping, stimulation, and forced exercise with fatigue. Change in weight, rate of gastric emptying and intestinal propulsion, and serum levels of leptin, motilin, vasoactive intestinal peptide (VIP), gastrin, calcitonin gene-related peptide (CGRP), ghrelin, and cholecystokinin were compared between the groups. RESULTS In the FD model group, weight, rate of gastric emptying and intestinal propulsion significantly decreased, the expression of leptin, VIP and CGRP increased, and expression of motilin, gastrin, ghrelin, and cholecystokinin significantly decreased. Treatment with low-dose Fructus aurantii with stir-fried wheat bran significantly reversed these effects. CONCLUSIONS In the rat model of FD, low-dose Fructus aurantii with stir-fried wheat bran increased gastrointestinal motility and gastrointestinal hormone levels.


Assuntos
Citrus/química , Dispepsia/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Medicina Tradicional Chinesa , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
20.
Biol Pharm Bull ; 43(4): 707-715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238713

RESUMO

Chaihu-Shugan-San (CSS) has been widely used as an alternative treatment for gastrointestinal (GI) diseases in East Asia. Interstitial cells of Cajal (ICCs) are pacemakers in the GI tract. In the present study, we examined the action of CSS on pacemaker potentials in cultured ICCs from the mouse small intestine in vitro and on GI motility in vivo. We used the electrophysiological methods to measure the pacemaker potentials in ICCs. GI motility was investigated by measuring intestinal transit rates (ITR). CSS inhibited the pacemaker potentials in a dose-dependent manner. The capsazepine did not block the effect of CSS. However, the effects of CSS were blocked by glibenclamide. In addition, NG-nitro-L-arginine methyl ester (L-NAME) also blocked the CSS-induced effects. Pretreatment with SQ-22536 or with KT-5720 did not suppress the effects of CSS; however, pretreatment with ODQ or KT-5823 did. Furthermore, CSS significantly suppressed murine ITR enhancement by neostigmine in vivo. These results suggest that CSS exerts inhibitory effects on the pacemaker potentials of ICCs via nitric oxide (NO)/cGMP and ATP-sensitive K+ channel dependent and transient receptor potential vanilloid 1 (TRPV1) channel independent pathways. Accordingly, CSS could provide the basis for the development of new treatments for GI motility dysfunction.


Assuntos
Células Intersticiais de Cajal/efeitos dos fármacos , Intestino Delgado/citologia , Extratos Vegetais/farmacologia , Animais , Células Cultivadas , Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Guanilato Ciclase/fisiologia , Células Intersticiais de Cajal/fisiologia , Intestino Delgado/fisiologia , Canais KATP/fisiologia , Masculino , Camundongos Endogâmicos ICR , Óxido Nítrico/fisiologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Canais de Cátion TRPV/fisiologia
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