RESUMO
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.
Assuntos
Injúria Renal Aguda , Peptídeos , Insuficiência Renal Crônica , Traumatismo por Reperfusão , Humanos , Ratos , Animais , Laxantes/metabolismo , Laxantes/farmacologia , Laxantes/uso terapêutico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Rim/patologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Insuficiência Renal Crônica/patologia , Isquemia/patologia , Reperfusão , Fator de Crescimento Transformador beta/metabolismo , FibroseRESUMO
The non-absorbable disaccharide lactulose is mostly used in the treatment of various gastrointestinal disorders such as chronic constipation and hepatic encephalopathy. The mechanism of action of lactulose remains unclear, but it elicits more than osmotic laxative effects. As a prebiotic, lactulose may act as a bifidogenic factor with positive effects in preventing and controlling diabetes. In this review, we summarized the current evidence for the effect of lactulose on gut metabolism and type 2 diabetes (T2D) prevention. Similar to acarbose, lactulose can also increase the abundance of the short-chain fatty acid (SCFA)-producing bacteria Lactobacillus and Bifidobacterium as well as suppress the potentially pathogenic bacteria Escherichia coli. These bacterial activities have anti-inflammatory effects, nourishing the gut epithelial cells and providing a protective barrier from microorganism infection. Activation of peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP1) can influence secondary bile acids and reduce lipopolysaccharide (LPS) endotoxins. A low dose of lactulose with food delayed gastric emptying and increased the whole gut transit times, attenuating the hyperglycemic response without adverse gastrointestinal events. These findings suggest that lactulose may have a role as a pharmacotherapeutic agent in the management and prevention of type 2 diabetes via actions on the gut microbiota.
Assuntos
Diabetes Mellitus Tipo 2 , Lactulose , Acarbose , Anti-Inflamatórios/metabolismo , Bactérias , Ácidos e Sais Biliares , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos Voláteis , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Lactulose/metabolismo , Lactulose/uso terapêutico , Laxantes/metabolismo , Lipopolissacarídeos , Peptídeos/metabolismo , Tirosina/metabolismoRESUMO
Inulin (IN), a fructan-type plant polysaccharide, is widely found in nature. The major plant sources of IN include chicory, Jerusalem artichoke, dahlia etc. Studies have found that IN possessed a wide array of biological activities, e.g. as a prebiotic to improve the intestinal microbe environment, regulating blood sugar, regulating blood lipids, antioxidant, anticancer, immune regulation and so on. Currently, IN is widely used in the food and pharmaceutical industries. IN can be used as thickener, fat replacer, sweetener and water retaining agent in the food industry. IN also can be applied in the pharmaceutics as stabilizer, drug carrier, and auxiliary therapeutic agent for certain diseases such as constipation and diabetes. This paper reviews the physiological functions of IN and its applications in the field of pharmaceutics, analyzes its present research status and future research direction. This review will serve as a one-in-all resource for the researchers who are interested to work on IN.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Fatores Imunológicos/farmacologia , Inulina/farmacologia , Laxantes/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/metabolismo , Glicemia/metabolismo , Cichorium intybus/química , Dahlia/química , Portadores de Fármacos/química , Excipientes/química , Excipientes/isolamento & purificação , Helianthus/química , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/metabolismo , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/metabolismo , Inulina/química , Inulina/isolamento & purificação , Inulina/metabolismo , Laxantes/química , Laxantes/isolamento & purificação , Laxantes/metabolismo , Lipídeos/sangue , Prebióticos/administração & dosagem , Edulcorantes/química , Edulcorantes/isolamento & purificaçãoRESUMO
Three new flavonoids, quercetin-3-O-6-[methyl-(S)-3-hydroxy-3-methylglutaroyl(1â6]-ß-d-glucopyranoside (1), kaempferol-3-O-[methyl-(S)-3-hydroxy-3-methylglutaroyl(1â6)]-ß-d-glucopyranoside (2), and quercetin-3-O-6-[(E)-4-methoxy-5-methylhexa-2,4-dienoatyl(1â6)]-ß-d-glucopyranoside (3), and two new alkaloids, 5-dehydroxymethyl-pyrrolemarumine 4â³-O-α-l-rhamnopyranoside (4) and N1-methyl-N2-((4-O-α-l-rhamnopyranoside)benzyl) oxalamide (5), together with 45 known compounds (6-50) were isolated from the leaves of Moringa oleifera Lam. Among those compounds, 1-octacosanol (50), a straight-chain 28-carbon alcohol, exhibited good activity against diphenoxylate-induced constipation in mice, which is obtained as a laxative constituent from the plant for the first time. In order to have an accurate understanding of the content of compound 50, a quantification with gas chromatography-tandem mass spectrometry (GC-MS/MS) was carried out. The anti-inflammatory and α-glucosidase inhibitory activity of some compounds also was assessed.
Assuntos
Laxantes/química , Moringa oleifera/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Laxantes/metabolismo , Moringa oleifera/química , Extratos Vegetais/metabolismoRESUMO
BACKGROUND: Constipation, a common health problem, causes discomfort and affects the quality of life. This study intended to evaluate the potential laxative effect of triple fermented barley (Hordeum vulgare L.) extract (FBe), produced by saccharification, Saccharomyces cerevisiae, and Weissella cibaria, on loperamide (LP)-induced constipation in Sprague-Dawley (SD) rats, a well-established animal model of spastic constipation. METHODS: Spastic constipation was induced via oral treatment with LP (3 mg/kg) for 6 days 1 h before the administration of each test compound. Similarly, FBe (100, 200 and 300 mg/kg) was orally administered to rats once a day for 6 days. The changes in number, weight, and water content of fecal, motility ratio, colonic mucosa histology, and fecal mucous contents were recorded. The laxative properties of FBe were compared with those of a cathartic stimulant, sodium picosulfate. A total of 48 (8 rats in 6 groups) healthy male rats were selected and following 10 days of acclimatization. Fecal pellets were collected one day before administration of the first dose and starting from immediately after the fourth administration for a duration of 24 h. Charcoal transfer was conducted after the sixth and final administration of the test compounds. RESULTS: In the present study, oral administration of 100-300 mg/kg of FBe exhibited promising laxative properties including intestinal charcoal transit ratio, thicknesses and mucous producing goblet cells of colonic mucosa with decreases of fecal pellet numbers and mean diameters remained in the lumen of colon, mediated by increases in gastrointestinal motility. CONCLUSION: Therefore, FBe might act as a promising laxative agent and functional food ingredient to cure spastic constipation, with less toxicity observed at a dose of 100 mg/kg.
Assuntos
Constipação Intestinal/dietoterapia , Alimentos Fermentados/análise , Hordeum/microbiologia , Laxantes/metabolismo , Extratos Vegetais/metabolismo , Animais , Constipação Intestinal/induzido quimicamente , Alimentos Fermentados/microbiologia , Hordeum/química , Hordeum/metabolismo , Humanos , Laxantes/química , Loperamida/efeitos adversos , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Saccharomyces cerevisiae/metabolismo , Weissella/metabolismoRESUMO
The gastrointestinal phenotype of cystic fibrosis (CF) features intestinal bile acid (BA) malabsorption, impaired intestinal farnesoid X receptor (FXR) activation, and consequently reduced fibroblast growth factor 19 (FGF19, FGF15 in mice) production. The osmotic laxative polyethylene glycol (PEG) has been shown to decrease intestinal mucus accumulation in CF mice and could, by doing so, improve BA reabsorption. Here we determined the effect of PEG on BA excretion and FXR-FGF15 signaling in CF mice. Male Cftr-/-tm1Unc (CF) and wild-type (WT) littermates were administered PEG 4000 in drinking water and fed either chow or a semisynthetic diet. PEG was withdrawn for 3 days before termination. Fecal BA excretion was measured at PEG dosages of 37 g/l (100%) and 0 g/l (0%). Ileal FXR activation was assessed by gene expression of its downstream targets Fgf15 and small heterodimer partner ( Shp). In CF mice, PEG withdrawal increased fecal BA excretion on either diet compared with full PEG dosage (chow, 2-fold, P = 0.06; semisynthetic, 4.4-fold, P = 0.007). PEG withdrawal did not affect fecal BA excretion in WT mice on either diet. After PEG withdrawal, gene expression levels of intestinal FXR target genes Fgf15 and Shp were decreased in CF mice but unaffected in WT littermates. PEG did not affect the gene expression of the main intestinal BA transporter apical sodium-dependent bile acid transporter (ASBT). PEG treatment ameliorates intestinal BA malabsorption in CF mice and restores intestinal FXR-FGF15 signaling, independent from Asbt gene expression. These findings highlight the potential of PEG in the prevention and treatment of the gastrointestinal phenotype of CF. NEW & NOTEWORTHY A gastrointestinal feature of cystic fibrosis is bile acid malabsorption and consequent impairment of farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling. FXR-FGF15 signaling regulates various metabolic processes and could be implicated in metabolic and gastrointestinal complications of cystic fibrosis, such as diabetes and liver disease. In cystic fibrosis mice, treatment with the osmotic laxative polyethylene glycol is associated with decreased fecal bile acid loss and restoration of FXR-FGF15 signaling.
Assuntos
Fibrose Cística/metabolismo , Homeostase/fisiologia , Laxantes/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Animais , Ácidos e Sais Biliares/metabolismo , Fibrose Cística/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Íleo/metabolismo , Intestinos/fisiologia , Fígado/metabolismo , Masculino , Camundongos Transgênicos , Receptores Citoplasmáticos e Nucleares/genéticaRESUMO
Litter moisture contents vary greatly between and within practical poultry barns. The current experiment was designed to measure the effects of 8 different dietary characteristics on litter and excreta moisture content. Additionally, free water content and water activity of the excreta and litter were evaluated as additional quality measures. The dietary treatments consisted of nonstarch polysaccharide content (NSP; corn vs. wheat), particle size of insoluble fiber (coarse vs. finely ground oat hulls), viscosity of a nonfermentable fiber (low- and high-viscosity carboxymethyl cellulose), inclusion of a clay mineral (sepiolite), and inclusion of a laxative electrolyte (MgSO4). The 8 treatments were randomly assigned to cages within blocks, resulting in 12 replicates per treatment with 6 birds per replicate. Limited effects of the dietary treatments were noted on excreta and litter water activity, and indications were observed that this measurement is limited in high-moisture samples. Increasing dietary NSP content by feeding a corn-based diet (low NSP) compared with a wheat-based diet (high NSP) increased water intake, excreta moisture and free water, and litter moisture content. Adding insoluble fibers to the wheat-based diet reduced excreta and litter moisture content, as well as litter water activity. Fine grinding of the oat hulls diminished the effect on litter moisture and water activity. However, excreta moisture and free water content were similar when fed finely or coarsely ground oat hulls. The effects of changing viscosity and adding a clay mineral or laxative deviated from results observed in previous studies. Findings of the current experiment indicate a potential for excreta free water measurement as an additional parameter to assess excreta quality besides total moisture. The exact implication of this parameter warrants further investigation.
Assuntos
Ração Animal/análise , Galinhas/fisiologia , Dieta/veterinária , Fezes/química , Água/análise , Criação de Animais Domésticos , Animais , Avena/química , Fibras na Dieta/análise , Ingestão de Líquidos , Laxantes/metabolismo , Silicatos de Magnésio/metabolismo , Sulfato de Magnésio/metabolismo , Tamanho da Partícula , Polissacarídeos/administração & dosagem , Polissacarídeos/metabolismo , Distribuição Aleatória , Triticum/química , Viscosidade , Água/metabolismo , Zea mays/químicaRESUMO
Rhein (4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid, cassic acid) is a pharmacological active component found in Rheum palmatum L. the major herb of San-Huang-Xie-Xin-Tang (SHXXT), a medicinal herbal product used as a remedy for constipation. Here we have determined multiple bioactive components in SHXXT and investigated the comparative pharmacokinetics of rhein in rats. A sensitive and specific method combining liquid chromatography with electrospray ionization tandem mass spectrometry has been developed and validated to simultaneously quantify six active compounds in the pharmaceutical herbal product SHXXT to further study their pharmacokinetics in rats. Multiple reaction monitoring (MRM) was employed for quantification with switching electrospray ion source polarity between positive and negative modes in a single run. There were no significant matrix effects in the quantitative analysis and the mean recovery for rhein in rat plasma was 91.6%±3.4%. The pharmacokinetic data of rhein demonstrate that the herbal formulae or the single herbal extract provide significantly higher absorption rate than the pure compound. This phenomenon suggests that the other herbal ingredients of SHXXT and rhubarb extract significantly enhance the absorption of rhein in rats. In conclusion, the herbal formulae (SHXXT) are more efficient than the single herb (rhubarb) or the pure compound (rhein) in rhein absorption.
Assuntos
Antraquinonas/isolamento & purificação , Medicamentos de Ervas Chinesas/química , Inibidores Enzimáticos/isolamento & purificação , Laxantes/isolamento & purificação , Rheum/química , Animais , Antraquinonas/sangue , Antraquinonas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Absorção Intestinal , Laxantes/metabolismo , Laxantes/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Linaclotide is a first-in-class, orally administered 14-amino acid peptide that is in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. We have characterized the solution structure of linaclotide, the in vitro binding and agonist activity to guanylate cyclase C receptors, the stability of linaclotide under conditions mimicking the gastric environment, oral bioavailability, and the pharmacodynamic effects in rat models of gastrointestinal transit and intestinal secretion. Nuclear magnetic resonance spectroscopy analysis determined that the molecular structure of linaclotide is stabilized by three intramolecular disulfide bridges. Linaclotide exhibited high affinity and pH-independent binding (K(i): 1.23-1.64 nM) to guanylate cyclase C receptors on human colon carcinoma T84 cells and concomitantly, linaclotide binding resulted in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP) (EC50:99 nM). Linaclotide was stable after 3 h incubation in simulated gastric fluid (pH 1) and similarly, was completely resistant to hydrolysis by pepsin. Pharmacokinetic analysis of linaclotide showed very low oral bioavailability (0.1%). Orally administered linaclotide elicited a significant, dose-dependent increase in gastrointestinal transit rates in rats at doses of ≥5 µg/kg. Exposure of surgically ligated small intestinal loops to linaclotide induced a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels. These results suggest that the guanylate cyclase C agonist linaclotide elicits potent pharmacological responses locally in the gastrointestinal tract, and that orally administered guanylate cyclase C agonists may be capable of improving bowel habits in patients suffering from irritable bowel syndrome with constipation and chronic constipation.
Assuntos
Trânsito Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Laxantes/farmacologia , Peptídeos/farmacologia , Receptores Acoplados a Guanilato Ciclase/agonistas , Receptores de Peptídeos/agonistas , Animais , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular , Células Cultivadas , Constipação Intestinal/tratamento farmacológico , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Mucosa Intestinal/citologia , Secreções Intestinais/metabolismo , Síndrome do Intestino Irritável/tratamento farmacológico , Laxantes/química , Laxantes/metabolismo , Laxantes/farmacocinética , Masculino , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacocinética , Conformação Proteica , Estabilidade Proteica , Ratos , Receptores de EnterotoxinaRESUMO
OBJECTIVE: This randomized, double-blind crossover trial evaluated the effects of a type 3 novel resistant starch (RS) versus wheat bran (WB) on faecal weight, frequency, and consistency in healthy adults. METHODS: Following a 14-day baseline period during which subjects (n=14) consumed low-fibre (<2 g) test products, participants were assigned to receive 25 g RS or WB fibre daily for 14 days, then crossed over to the opposite treatment after a 7-day washout. RESULTS: Daily faecal output increased from 128.8+/-68.7 g at baseline to 164.2+/-88.4 g with RS and 194.5+/-92.0 g with WB (both P<0.02 versus baseline). No significant differences among the three conditions were observed for bowel movement frequency. Faecal consistency ratings were increased with WB (P=0.001), but unchanged with RS. CONCLUSIONS: Dietary RS and WB increase faecal output in healthy adults.