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1.
Mol Pharm ; 21(6): 2828-2837, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38723178

RESUMO

Nefecon, a targeted-release capsule formulation of budesonide approved for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy, targets overproduction of galactose-deficient immunoglobulin A type 1 in the Peyer's patches at the gut mucosal level. To investigate whether the commercial formulation of Nefecon capsules reliably releases budesonide to the distal ileum, a human study was conducted with test capsules reproducing the delayed-release function of Nefecon capsules. Caffeine was included in the test capsules as a marker for capsule opening in the gut since it appears rapidly in saliva after release from orally administered dosage forms. Magnetic resonance imaging with black iron oxide was used to determine the capsule's position in the gut at the time caffeine was first measured in saliva and additionally to directly visualize dispersion of the capsule contents in the gut. In vitro dissolution results confirmed that the test capsules had the same delayed-release characteristics as Nefecon capsules. In 10 of 12 human volunteers, the capsule was demonstrated to open in the distal ileum; in the other two subjects, it opened just past the ileocecal junction. These results compared favorably with the high degree of variability seen in other published imaging studies of delayed-release formulations targeting the gut. The test capsules were shown to reliably deliver their contents to the distal ileum, the region with the highest concentration of Peyer's patches.


Assuntos
Budesonida , Cápsulas , Sistemas de Liberação de Medicamentos , Íleo , Humanos , Íleo/metabolismo , Íleo/efeitos dos fármacos , Adulto , Sistemas de Liberação de Medicamentos/métodos , Masculino , Budesonida/administração & dosagem , Budesonida/farmacocinética , Budesonida/química , Feminino , Cápsulas/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Imageamento por Ressonância Magnética/métodos , Administração Oral , Pessoa de Meia-Idade , Cafeína/química , Cafeína/administração & dosagem , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/efeitos dos fármacos , Adulto Jovem
2.
Biol Pharm Bull ; 47(8): 1429-1436, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39135238

RESUMO

Farnesoid X receptor (FXR) is a nuclear receptor that regulates the synthesis and enterohepatic circulation of bile acids (BAs). It also regulates lipid and carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized a series of FXR antagonists and showed that oral administration of FLG249 reduced the expression of several FXR target genes in the mouse ileum. Here, we investigated the effects of FLG249 on lipid metabolism in mice fed a high-fat diet (HFD). When FLG249 was administered for 4 weeks to HFD-induced obese mice, it altered the expression of genes related to BA metabolism, ceramide synthesis and fatty acid ß-oxidation, improving lipid metabolism in the liver and ileum without decreasing body weight. These findings suggest that FLG249 has the potential to be a low toxicity pharmaceutical compound and likely acts as a nonsteroidal FXR antagonist to improve lipid metabolism disorders.


Assuntos
Colesterol , Dieta Hiperlipídica , Fígado , Camundongos Endogâmicos C57BL , Obesidade , Receptores Citoplasmáticos e Nucleares , Triglicerídeos , Animais , Dieta Hiperlipídica/efeitos adversos , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/sangue , Colesterol/sangue , Triglicerídeos/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Camundongos , Camundongos Obesos , Íleo/metabolismo , Íleo/efeitos dos fármacos
3.
J Appl Toxicol ; 44(6): 863-873, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38311468

RESUMO

Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL-induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5 mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL-induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down-regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down-regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice.


Assuntos
Ácidos e Sais Biliares , Colchicina , Circulação Êntero-Hepática , Homeostase , Fígado , Animais , Ácidos e Sais Biliares/metabolismo , Circulação Êntero-Hepática/efeitos dos fármacos , Colchicina/toxicidade , Homeostase/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Masculino , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Íleo/efeitos dos fármacos , Íleo/metabolismo , Diarreia/induzido quimicamente
4.
Ecotoxicol Environ Saf ; 284: 116901, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39178762

RESUMO

Glyphosate is the active ingredient in the herbicide (i.e., Roundup, Touchdown and Erasure), the safety of which has become a social concern. Hawthorn-leaf flavonoid (HF) possesses various biological functions, including antioxidant, regulating lipid metabolism and intestinal microbiota. Whether HF could reduce the health risk of pure glyphosate to birds remain unknown. The experiment aimed to evaluate the effects of pure glyphosate (25 mg/kg added to water) on the intestinal health and microbiota of chicks and the protective roles of HF (60 mg/kg added to the diet). Exposure to glyphosate decreased growth performance, ileal morphology structure, and antioxidant capacity, and increased the serum level of lipid and pro-inflammatory factors. 16S rRNA sequencing indicated that glyphosate decreased bacterial richness and the abundance of Lactobacillus, and increased proportions of pathogens in the ileum. Metabolomic results revealed that glyphosate increased the level of the cholic acid and fatty acids in the ileac digesta. Meanwhile, glyphosate down-regulated the protein expression associated with lipid transport, antioxidant and tight junction in the ileal mucosal tissue, and up-regulated the pro-inflammatory, oxidative stress proteins. However, dietary HF supplementation effectively mitigated the adverse effects of glyphosate and improved intestinal health of chicks. Therefore, dietary HF can ameliorate the harmful effects of glyphosate on birds, which highlights the potential application of HF in reducing the health risks.


Assuntos
Galinhas , Crataegus , Disbiose , Flavonoides , Microbioma Gastrointestinal , Glicina , Glifosato , Herbicidas , Animais , Glicina/análogos & derivados , Glicina/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Disbiose/induzido quimicamente , Herbicidas/toxicidade , Flavonoides/farmacologia , Folhas de Planta , Masculino , Antioxidantes/farmacologia , Íleo/efeitos dos fármacos , Íleo/patologia
5.
An Acad Bras Cienc ; 96(suppl 1): e20230244, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39140520

RESUMO

This study aimed to investigate the antioxidant and anti-inflammatory properties of quercetin on the cellular components of the Enteric Nervous System in the ileum of rats with arthritis. Rats were distributed into five groups: control (C), arthritic (AIA), arthritic treated with ibuprofen (AI), arthritic treated with quercetin (AQ) and arthritic treated with both ibuprofen and quercetin (AIQ). The ileum was processed for immunohistochemical techniques for HuC/D, calcitonin gene-related peptide, and vasoactive intestinal polypeptide. Measurements in histological sections, chemiluminescence assays, and total antioxidant capacity were also performed. Rheumatoid arthritis resulted in a decrease in neuronal density, yet neuroplasticity mechanisms were evident through observed changes in varicosities size and neuronal area compared to the control group. Reduced paw edema and neuroprotective effects were predominantly noted in both plexuses, as evidenced by the increased density preservation of HuC/D-IR neurons in the AIQ group. The increase of lipoperoxidation levels and paw edema volume in the AQ group was observed compared to the arthritic, whereas the AIQ group mainly showed similar results to those observed in the control. The enteropathy associated with arthritis proved to be significant in the field of gastroenterology, and the combination of quercetin and ibuprofen demonstrated promising anti-inflammatory and neuroprotective effects.


Assuntos
Anti-Inflamatórios , Antioxidantes , Ibuprofeno , Quercetina , Ratos Wistar , Animais , Quercetina/farmacologia , Quercetina/uso terapêutico , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Ratos , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/patologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/patologia , Imuno-Histoquímica , Íleo/efeitos dos fármacos , Íleo/patologia
6.
Int J Mol Sci ; 25(14)2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39063219

RESUMO

This article follows-up on our recently published work, which evaluated the impact of the addition of an alfalfa leaf-derived adsorbent in the aflatoxin B1 (AFB1)-contaminated diet in regard to the production parameters, blood cell count, serum biochemistry, liver enzymes, and liver histology of turkey poults. This paper presents complementary results on microbial community, ileal morphology, barrier function, and immunity. For this purpose, 350 1-day-old female turkey poults were randomly distributed into five groups: (1) Control, AFB1-free diet; (2) AF, AFB1-contaminated diet at 250 ng/g; (3) alfalfa, AFB1-free diet + 0.5% (w/w) adsorbent; (4) alfalfa + AF, AFB1-contaminated diet at 250 ng/g + 0.5% (w/w) adsorbent; and (5) YCW + AF, AFB1-contaminated diet at 250 ng/g + 0.5% (w/w) commercial yeast cell wall-based adsorbent (reference group). In general, in the AF group, the growth of opportunistic pathogens was promoted, which lead to gut dysbacteriosis, mainly influenced by Streptococcus lutetiensis. Conversely, a significant increase in beneficial bacteria (Faecalibacterium and Coprococcus catus) was promoted by the addition of the plant-based adsorbent. Moreover, the AF group had the lowest villus height and a compromised barrier function, as evidenced by a significant (p < 0.05) increase in fluorescein isothiocyanate dextran (FITC-d), but these negative effects were almost reversed by the addition of the alfalfa adsorbent. Furthermore, the AF + YCW and alfalfa + AF groups exhibited a significant increase in the cutaneous basophil hypersensitivity response compared to the rest of the experimental groups. Taken together, these results pointed out that the alfalfa counteracts the adverse effects of AFB1 in poults, facilitating the colonization of beneficial bacteria and improving the barrier function of the turkey poults.


Assuntos
Aflatoxina B1 , Ração Animal , Íleo , Medicago sativa , Folhas de Planta , Perus , Animais , Medicago sativa/química , Perus/microbiologia , Folhas de Planta/química , Íleo/efeitos dos fármacos , Íleo/microbiologia , Íleo/patologia , Íleo/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Adsorção
7.
Int J Mol Sci ; 25(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38928404

RESUMO

Phytochemicals and tryptophan (Trp) metabolites have been found to modulate gut function and health. However, whether these metabolites modulate gut ion transport and serotonin (5-HT) metabolism and signaling requires further investigation. The aim of this study was to investigate the effects of selected phytochemicals and Trp metabolites on the ion transport and 5-HT metabolism and signaling in the ileum of mice in vitro using the Ussing chamber technique. During the in vitro incubation, vanillylmandelic acid (VMA) reduced (p < 0.05) the short-circuit current, and 100 µM chlorogenic acid (CGA) (p = 0.12) and perillic acid (PA) (p = 0.14) had a tendency to reduce the short-circuit current of the ileum. Compared with the control, PA and N-acetylserotonin treatment upregulated the expression of tryptophan hydroxylase 1 (Tph1), while 100 µM cinnamic acid, indolelactic acid (ILA), and 10 µM CGA or indoleacetaldehyde (IAld) treatments downregulated (p < 0.05) the mRNA levels of Tph1. In addition, 10 µM IAld or 100 µM ILA upregulated (p < 0.05) the expression of monoamine oxidase A (Maoa). However, 10 µM CGA or 100 µM PA downregulated (p < 0.05) Maoa expression. All selected phytochemicals and Trp metabolites upregulated (p < 0.05) the expression of Htr4 and Htr7 compared to that of the control group. VMA and CGA reduced (p < 0.05) the ratios of Htr1a/Htr7 and Htr4/Htr7. These findings may help to elucidate the effects of phytochemicals and Trp metabolites on the regulation of gut ion transport and 5-HT signaling-related gut homeostasis in health and disease.


Assuntos
Cinamatos , Íleo , Serotonina , Transdução de Sinais , Triptofano , Animais , Serotonina/metabolismo , Camundongos , Íleo/metabolismo , Íleo/efeitos dos fármacos , Triptofano/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cinamatos/farmacologia , Cinamatos/metabolismo , Transporte de Íons/efeitos dos fármacos , Masculino , Triptofano Hidroxilase/metabolismo , Triptofano Hidroxilase/genética , Ácido Clorogênico/farmacologia , Ácido Clorogênico/metabolismo
8.
Int J Mol Sci ; 25(14)2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39063026

RESUMO

Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and ß-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/ß, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.


Assuntos
Ácidos e Sais Biliares , Colo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Liraglutida , Serotonina , Animais , Liraglutida/farmacologia , Serotonina/metabolismo , Ácidos e Sais Biliares/metabolismo , Camundongos , Colo/metabolismo , Colo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Triptofano/metabolismo , Triptofano/farmacologia , Triptofano/análogos & derivados , Camundongos Endogâmicos C57BL , Íleo/metabolismo , Íleo/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Ácidos Cólicos , Proteínas de Membrana Transportadoras , Simportadores
9.
Bull Exp Biol Med ; 177(1): 47-50, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38955852

RESUMO

Ectonucleotidases play an important role in regulating the level of extracellular nucleotides and nucleosides and are an important part of the regulation of the effects of adenosine and ATP on adenosine and P2 receptors, respectively. We have previously established the ambiguous effect of P2 receptor agonists on the contractile activity of smooth muscle tissue in rats with the valproate model of autism. In this work, HPLC was used to evaluate the activity of ectonucleotidases in the smooth muscle tissues of the internal organs of rats with a valproate model of autism. The activity of ectonucleotidases was significantly higher in the smooth muscle tissues of the duodenum, vas deferens, and bladder, but lower in the ileum and uterus. The results obtained make it possible to compare the activity of ectonucleotidases identified here with changes in P2 receptor-mediated contractility of smooth muscle tissues revealed in our previous experiments.


Assuntos
Transtorno Autístico , Contração Muscular , Músculo Liso , Bexiga Urinária , Ácido Valproico , Ducto Deferente , Animais , Ratos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Ácido Valproico/farmacologia , Transtorno Autístico/metabolismo , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Masculino , Feminino , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/enzimologia , Contração Muscular/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/metabolismo , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/enzimologia , Modelos Animais de Doenças , Ratos Wistar , Receptores Purinérgicos P2/metabolismo , Adenosina Trifosfatases/metabolismo
10.
Am J Physiol Gastrointest Liver Physiol ; 320(2): G227-G239, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33236951

RESUMO

Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development. Forty-two preterm pigs were randomized to receive one of three lipid emulsions containing 100% soybean oil (SO), 15% fish oil (MO15), or 100% fish oil (FO100) with enteral feedings over an 8-day protocol. Blood and distal ileum tissue were collected for fatty acid analysis. The distal ileum underwent histologic, proteomic, and metabolomic analyses. Eight pigs [3/14 SO (21%), 3/14 MO15 (21%), and 2/14 FO100 (14%)] developed NEC. No differences in NEC risk were evident between groups despite differences in induced fatty acid profiles in blood and ileal tissue. Metabolomic analysis of NEC versus no NEC tissue revealed differences in tryptophan metabolism and arachidonic acid-containing glycerophospholipids. Proteomic analysis demonstrated no differences by lipid group; however, 15 proteins differentiated NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling. Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC development. Metabolomic and proteomic analyses of NEC versus no NEC intestinal tissue provide mechanistic insights into the pathogenesis of NEC in preterm infants.NEW & NOTEWORTHY Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC risk in preterm pigs. Metabolomic and proteomic analyses provide mechanistic insights into NEC pathogenesis. Compared with healthy ileal tissue, metabolites in tryptophan metabolism and arachidonic acid-containing glycerophospholipids are increased in NEC tissue. Proteomic analysis differentiates NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling.


Assuntos
Enterocolite Necrosante/veterinária , Emulsões Gordurosas Intravenosas/farmacologia , Ácidos Graxos/metabolismo , Íleo/efeitos dos fármacos , Metaboloma , Animais , Enterocolite Necrosante/induzido quimicamente , Humanos , Íleo/metabolismo , Nutrição Parenteral/efeitos adversos , Nascimento Prematuro , Fatores de Risco , Suínos , Doenças dos Suínos/induzido quimicamente
11.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G521-G530, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33085904

RESUMO

Infants born under 1,500 g have an increased incidence of necrotizing enterocolitis in the ileum and the colon, which is a life-threatening intestinal necrosis. This is in part due to excessive inflammation in the immature intestine to colonizing bacteria because of an immature innate immune response. Breastmilk complex carbohydrates create metabolites of colonizing bacteria in the form of short-chain fatty acids (SCFAs). We studied the effect of breastmilk metabolites, SCFAs, on immature intestine with regard to anti-inflammatory effects. This showed that acetate, propionate, and butyrate were all anti-inflammatory to an IL-1ß inflammatory stimulus. In this study, to further define the mechanism of anti-inflammation, we created transcription profiles of RNA from immature human enterocytes after exposure to butyrate with and without an IL-1ß inflammatory stimulus. We demonstrated that butyrate stimulates an increase in tight-junction and mucus genes and if we inhibit these genes, the anti-inflammatory effect is partially lost. SCFAs, products of microbial metabolism of complex carbohydrates of breastmilk oligosaccharides, have been found with this study to induce an anti-IL-1ß response that is associated with an upregulation of tight junctions and mucus genes in epithelial cells (H4 cells). These studies suggest that breastmilk in conjunction with probiotics can reduce excessive inflammation with metabolites that are anti-inflammatory and stimulate an increase in the mucosal barrier.NEW & NOTEWORTHY This study extends previous observations to define the anti-inflammatory properties of butyrate, a short-chain fatty acid produced by the metabolism of breastmilk oligosaccharides by colonizing bacteria. Using transcription profiling of immature enterocyte genes, after exposure to butyrate and an IL-1ß stimulus, we showed that tight-junction genes and mucus genes were increased, which contributed to the anti-inflammatory effect.


Assuntos
Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , Colo/efeitos dos fármacos , Enterocolite Necrosante/prevenção & controle , Enterócitos/efeitos dos fármacos , Íleo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Leite Humano/metabolismo , Animais , Animais Recém-Nascidos , Butiratos/metabolismo , Linhagem Celular , Colo/metabolismo , Enterocolite Necrosante/metabolismo , Enterócitos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Íleo/metabolismo , Interleucina-1beta/farmacologia , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Muco/metabolismo , Permeabilidade , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Técnicas de Cultura de Tecidos , Transcriptoma
12.
Drug Metab Dispos ; 49(3): 276-286, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33376148

RESUMO

Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was determined. The results revealed that BBR (150 mg/kg) and M1 (50 mg/kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids, and purine. BBR showed a stronger modulatory effect on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.


Assuntos
Berberina/análogos & derivados , Berberina/farmacologia , Gluconeogênese/fisiologia , Hipoglicemiantes/farmacologia , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gluconeogênese/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Secundária de Proteína , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Toxicol Appl Pharmacol ; 421: 115543, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33872679

RESUMO

Nimodipine is a clinically used dihydropyridine L-type calcium channel antagonist that effectively inhibits transmembrane Ca2+ influx following the depolarization of smooth muscle cells, but the detailed effect on smooth muscle contraction is not fully understood. Ca2+-activated Cl- channels (CaCCs) in vascular smooth muscle cells (VSMCs) may regulate vascular contractility. We found that nimodipine can inhibit transmembrane protein 16A (TMEM16A) activity in a concentration-dependent manner by cell-based fluorescence-quenching assay and short-circuit current analysis, with an IC50 value of ~5 µM. Short-circuit current analysis also showed that nimodipine prevented Ca2+-activated Cl- current in both HT-29 cells and mouse colonic epithelia accompanied by significantly decreased cytoplasmic Ca2+ concentrations. In the absence of extracellular Ca2+, nimodipine still exhibited an inhibitory effect on TMEM16A/CaCCs. Additionally, the application of nimodipine to CFTR-expressing FRT cells and mouse colonic mucosa resulted in mild activation of CFTR-mediated Cl- currents. Nimodipine inhibited basolateral CCh-activated K+ channel activity with no effect on Na+/K+-ATPase activity. Evaluation of intestinal smooth muscle contraction showed that nimodipine inhibits intestinal smooth muscle contractility and frequency, with an activity pattern that was similar to that of non-specific inhibitors of CaCCs. In aortic smooth muscle, the expression of TMEM16A in thoracic aorta is higher than that in abdominal aorta, corresponding to stronger maximum contractility in thoracic aorta smooth muscle stimulated by phenylephrine (PE) and Eact. Nimodipine completely inhibited the contraction of aortic smooth muscle stimulated by Eact, and partially inhibited the contraction stimulated by PE. In summary, the results indicate that nimodipine effectively inhibits TMEM16A/CaCCs by reduction transmembrane Ca2+ influx and directly interacting with TMEM16A, explaining the mechanisms of nimodipine relaxation of intestinal and aortic smooth muscle contraction and providing new targets for pharmacological applications.


Assuntos
Anoctamina-1/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/toxicidade , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso/efeitos dos fármacos , Nimodipina/toxicidade , Vasoconstrição/efeitos dos fármacos , Animais , Anoctamina-1/metabolismo , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células HT29 , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Técnicas In Vitro , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
14.
FASEB J ; 34(10): 13430-13444, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32812278

RESUMO

Transmembrane 16A (TMEM16A), also known as anoctamin 1, is the molecular basis of the calcium-activated chloride channels. TMEM16A is present in interstitial cells of Cajal, which are the pacemaker cells that control smooth muscle contraction. TMEM16A is implicated in gastrointestinal disorders. Activation of TMEM16A is believed to promote the gastrointestinal muscle contraction. Here, we report a highly efficient, nontoxic, and selective activator of TMEM16A, canthaxanthin (CX). The study using molecular docking and site-directed mutation revealed that CX-specific binging site in TMEM16A is K769. CX was also found to promote the contraction of smooth muscle cells in gastrointestinal tract through activation of TMEM16A channels, which provides an excellent basis for development of CX as a chemical tool and potential therapeutic for gastrointestinal dysfunction.


Assuntos
Anoctamina-1/fisiologia , Cantaxantina/farmacologia , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Animais , Gastroenteropatias/metabolismo , Cobaias , Células HEK293 , Humanos , Masculino , Ligação Proteica
15.
FASEB J ; 34(9): 12615-12633, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32729971

RESUMO

Although it is known that zinc has several beneficial roles in the context of gut inflammation, the underlying mechanisms have not been extensively characterized. Zinc (Zn) is known to be the primary physiological inducer of the expression of the metallothionein (MT) superfamily of small stress-responsive proteins. The expression of MTs in various tissues is induced or enhanced (including the gastrointestinal tract (GIT)) by a variety of stimuli, including infection and inflammation. However, the MTs' exact role in inflammation is still subject to debate. In order to establish whether or not MTs are the sole vectors in the Zn-based modulation of intestinal inflammation, we used transcriptomic and metagenomic approaches to assess the potential effect of dietary Zn, the mechanisms underlying the MTs' beneficial effects, and the induction of previously unidentified mediators. We found that the expression of endogenous MTs in the mouse GIT was stimulated by an optimized dietary supplementation with Zn. The protective effects of dietary supplementation with Zn were then evaluated in mouse models of chemically induced colitis. The potential contribution of MTs and other pathways was explored via transcriptomic analyses of the ileum and colon in Zn-treated mice. The microbiota's role was also assessed via fecal 16S rRNA sequencing. We found that high-dose dietary supplementation with Zn induced the expression of MT-encoding genes in the colon of healthy mice. We next demonstrated that the Zn diet significantly protected mice in the two models of induced colitis. When comparing Zn-treated and control mice, various genes were found to be differentially expressed in the colon and the ileum. Finally, we found that Zn supplementation did not modify the overall structure of the fecal microbiota, with the exception of (i) a significant increase in endogenous Clostridiaceae, and (ii) some subtle but specific changes at the family and genus levels. Our results emphasize the beneficial effects of excess dietary Zn on the prevention of colitis and inflammatory events in mouse models. The main underlying mechanisms were driven by the multifaceted roles of MTs and the other potential molecular mediators highlighted by our transcriptomic analyses although we cannot rule out contributions by other factors from the host and/or the microbiota.


Assuntos
Colite , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Metalotioneína/metabolismo , Transcriptoma , Zinco/farmacologia , Animais , Colite/tratamento farmacológico , Colite/metabolismo , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/metabolismo , Suplementos Nutricionais , Fezes/microbiologia , Feminino , Íleo/efeitos dos fármacos , Íleo/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Zinco/administração & dosagem
16.
Amino Acids ; 53(10): 1523-1532, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34596761

RESUMO

Studies using animal models of hypercholesterolemia have established that taurine reduces cholesterol levels; however, the precise mechanism underlying this cholesterol-lowering effect is unclear. This study addressed this issue by investigating whether bile acid/farnesoid X receptor (FXR) signaling is involved in taurine-mediated cholesterol-lowering effect. Fxr-null and wild-type mice were administered 2% (w/v) taurine in their drinking water and fed a control diet or control diet supplemented with 1% (w/w) cholesterol (cholesterol diet) for 10 days. Taurine intake did not significantly alter hepatic and serum total cholesterol (TC) levels and bile acid compositions of the liver and intestinal lumen in Fxr-null and wild-type mice fed the control diet. By changing to a cholesterol diet, taurine intake significantly decreased hepatic and serum cholesterol levels in wild-type mice. In contrast, it significantly decreased hepatic, not serum, cholesterol levels in Fxr-null mice. Taurine intake significantly altered the bile acid composition of the intestinal lumen in wild-type mice fed a cholesterol diet, but not in Fxr-null mice. An increase in FXR antagonistic bile acids was detected in the intestinal lumen of taurine-treated wild-type mice fed a cholesterol diet. Taurine intake reduced the ileal expression of FXR target genes fibroblast growth factor 15 (Fgf15) and small heterodimer partner (Shp). In contrast, it enhanced the hepatic expression of cholesterol 7α-hydroxylase (Cyp7a1) in wild-type mice fed a cholesterol diet, but not in Fxr-null mice. These results suggest that taurine is partially involved in cholesterol lowering by reducing the ileal FXR signaling due to the alteration of ileal bile acid composition.


Assuntos
Anticolesterolemiantes/farmacologia , Ácidos e Sais Biliares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Taurina/farmacologia , Animais , Colesterol/sangue , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos
17.
Neurochem Res ; 46(6): 1514-1539, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33719004

RESUMO

Gut microbial dysbiosis and alteration of gut microbiota composition in Parkinson's disease (PD) have been increasingly reported, no recognized therapies are available to halt or slow progression of PD and more evidence is still needed to illustrate its causative impact on gut microbiota and PD and mechanisms for targeted mitigation. Epidemiological evidence supported an association between milk intake and a higher incidence of Parkinson's disease (PD), questions have been raised about prospective associations between dietary factors and the incidence of PD. Here, we investigated the significance of casein in the development of PD. The mice were given casein (6.75 g/kg i.g.) for 21 days after MPTP (25 mg/kg i.p. × 5 days) treatment, the motor function, dopaminergic neurons, inflammation, gut microbiota and fecal metabolites were observed. The experimental results revealed that the mice with casein gavage after MPTP treatment showed a persisted dyskinesia, the content of dopamine in striatum and the expression of TH in midbrain and ileum were decreased, the expression of Iba-1, CD4, IL-22 in midbrain and ileum increased continuously with persisted intestinal histopathology and intestinal barrier injury. Decreased intestinal bile secretion in addition with abnormal digestion and metabolism of carbohydrate, lipids and proteins were found, whereas these pathological status for the MPTP mice without casein intake had recovered after 24 days, no significant differences were observed with regard to only treated with casein. Our study demonstrates that intestinal pathologic injury, intestinal dysbacteriosis and metabolism changes promoted by casein in MPTP mice ultimately exacerbated the lesions to dopaminergic neurons.


Assuntos
Caseínas/farmacologia , Disbiose/metabolismo , Inflamação/metabolismo , Doença de Parkinson Secundária/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Caseínas/administração & dosagem , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Disbiose/induzido quimicamente , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/enzimologia , Íleo/metabolismo , Íleo/patologia , Inflamação/etiologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/enzimologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Junções Íntimas/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Pediatr Res ; 89(1): 91-101, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32221473

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) develops through exaggerated toll-like receptor 4 (TLR4) signaling in the intestinal epithelium. Breast milk is rich in non-digestible oligosaccharides and prevents NEC through unclear mechanisms. We now hypothesize that the human milk oligosaccharides 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL) can reduce NEC through inhibition of TLR4 signaling. METHODS: NEC was induced in newborn mice and premature piglets and infant formula was supplemented with 2'-FL, 6'-SL, or lactose. Intestinal tissue was obtained at surgical resection. HMO inhibition of TLR4 was assessed in IEC-6 enterocytes, mice, and human tissue explants and via in silico modeling. RESULTS: Supplementation of infant formula with either 2'-FL and/or 6'-SL, but not the parent sugar lactose, reduced NEC in mice and piglets via reduced apoptosis, inflammation, weight loss, and histological appearance. Mechanistically, both 2'-FL and 6'-SL, but not lactose, reduced TLR4-mediated nuclear factor kappa light-chain enhancer of activated B cells (NF-kB) inflammatory signaling in the mouse and human intestine. Strikingly, in silico modeling revealed 2'-FL and 6'-SL, but not lactose, to dock into the binding pocket of the TLR4-MD2 complex, explaining their ability to inhibit TLR4 signaling. CONCLUSIONS: 2'-FL and 6'-SL, but not lactose, prevent NEC in mice and piglet models and attenuate NEC inflammation in the human ileum, in part through TLR4 inhibition. IMPACT: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants that occurs in the setting of bacterial colonization of the gut and administration of formula feeds and activation by the innate immune receptor toll-like receptor 4 (TLR4). Breast milk prevents NEC through unclear mechanisms. We now show that breast milk-enriched human milk oligosaccharides (HMOs) that are derived from lactose prevent NEC through inhibition of TLR4. The human milk oligosaccharides 2'-FL and 6'-SL, but not the backbone sugar lactose, prevent NEC in mice and piglets. 2'-FL and 6'-SL but not lactose inhibited TLR4 signaling in cultured enterocytes, in enteroids derived from mouse intestine, and in human intestinal explants obtained at the time of surgical resection for patients with NEC. In seeking the mechanisms involved, 2'-FL and 6'-SL but not lactose were found to directly bind to TLR4, explaining the inhibition and protection against NEC. These findings may impact clinical practice by suggesting that administration of HMOs could serve as a preventive strategy for premature infants at risk for NEC development.


Assuntos
Enterocolite Necrosante/prevenção & controle , Íleo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lactose/análogos & derivados , Leite Humano/química , Receptor 4 Toll-Like/antagonistas & inibidores , Trissacarídeos/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/patologia , Humanos , Íleo/imunologia , Íleo/metabolismo , Íleo/patologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Lactose/isolamento & purificação , Lactose/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Transdução de Sinais , Sus scrofa , Receptor 4 Toll-Like/metabolismo , Trissacarídeos/isolamento & purificação , Redução de Peso/efeitos dos fármacos
19.
Microb Cell Fact ; 20(1): 122, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182992

RESUMO

BACKGROUND: The development and utilization of probiotics had many environmental benefits for replacing antibiotics in animal production. Bacteria in the intestinal mucosa have better adhesion to the host intestinal epithelial cells compared to bacteria in the intestinal contents. In this study, lactic acid bacteria were isolated from the intestinal mucosa of broiler chickens and investigated as the substitution to antibiotic in broiler production. RESULTS: In addition to acid resistance, high temperature resistance, antimicrobial sensitivity tests, and intestinal epithelial cell adhesion, Enterococcus faecium PNC01 (E. faecium PNC01) was showed to be non-cytotoxic to epithelial cells. Draft genome sequence of E. faecium PNC01 predicted that it synthesized bacteriocin to perform probiotic functions and bacteriocin activity assay showed it inhibited Salmonella typhimurium from invading intestinal epithelial cells. Diet supplemented with E. faecium PNC01 increased the ileal villus height and crypt depth in broiler chickens, reduced the relative length of the cecum at day 21, and reduced the relative length of jejunum and ileum at day 42. Diet supplemented with E. faecium PNC01 increased the relative abundance of Firmicutes and Lactobacillus, decreased the relative abundance of Bacteroides in the cecal microbiota. CONCLUSION: E. faecium PNC01 replaced antibiotics to reduce the feed conversion rate. Furthermore, E. faecium PNC01 improved intestinal morphology and altered the composition of microbiota in the cecum to reduce feed conversion rate. Thus, it can be used as an alternative for antibiotics in broiler production to avoid the adverse impact of antibiotics by altering the gut microbiota.


Assuntos
Antibacterianos/farmacologia , Galinhas/crescimento & desenvolvimento , Galinhas/microbiologia , Enterococcus faecium/fisiologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Probióticos , Ração Animal/análise , Ração Animal/microbiologia , Animais , Bacteriocinas/farmacologia , Ceco/anatomia & histologia , Ceco/efeitos dos fármacos , Suplementos Nutricionais/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Íleo/anatomia & histologia , Íleo/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Jejuno/anatomia & histologia , Jejuno/efeitos dos fármacos , Masculino , RNA Ribossômico 16S
20.
J Gastroenterol Hepatol ; 36(9): 2523-2530, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33783040

RESUMO

BACKGROUND AND AIM: The small intestine plays a central role in gut immunity, and enhanced lymphocyte migration is involved in the pathophysiology of various enteropathy. Bile acid (BA) is closely related to lipid metabolism and gut microbiota and essential for gut homeostasis. However, the effects of BA on gut immunity have not been studied in detail, especially on the small intestine and lymphocyte migration. Therefore, we aimed to investigate the effect of BA on small intestinal lymphocyte microcirculation. METHODS: The effect of deoxycholic acid (DCA), taurocholic acid (tCA), or cholic acid (CA) on the indomethacin (IND)-induced small intestinal enteropathy in mice was investigated. Lymphocyte movements were evaluated after exposure to BA using intravital microscopy. The effects of BA on surface expression of adhesion molecules on the vascular endothelium and lymphocytes through BA receptors were examined in vitro. RESULTS: IND-induced small intestinal enteropathy was histologically aggravated by DCA treatment alone. The expression of adhesion molecules ICAM-1 and VCAM-1 was significantly enhanced by DCA. Exposure to DCA increased lymphocyte adhesion in the microvessels of the ileum, which was partially blocked by anti-α4ß1 integrin antibody in vivo. The expression of ICAM-1 and VCAM-1 was significantly enhanced by DCA in vitro, which was partially suppressed by the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist. The S1PR2 antagonist significantly ameliorated IND-induced and DCA-exaggerated small intestinal injury. CONCLUSION: DCA exacerbated IND-induced small intestinal enteropathy. DCA directly acts on the vascular endothelium and enhances the expression levels of adhesion molecules partially via S1PR2, leading to enhanced small intestinal lymphocyte migration.


Assuntos
Movimento Celular , Ácido Desoxicólico , Endotélio Vascular , Ileíte , Intestino Delgado , Linfócitos , Animais , Ácidos e Sais Biliares/efeitos adversos , Ácidos e Sais Biliares/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Ácidos Cólicos/efeitos adversos , Ácidos Cólicos/farmacologia , Ácido Desoxicólico/efeitos adversos , Ácido Desoxicólico/farmacologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Ileíte/induzido quimicamente , Ileíte/imunologia , Ileíte/fisiopatologia , Íleo/irrigação sanguínea , Íleo/efeitos dos fármacos , Íleo/imunologia , Íleo/fisiopatologia , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/imunologia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/imunologia , Intestino Delgado/fisiopatologia , Microscopia Intravital , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Ratos , Ratos Wistar , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Circulação Esplâncnica/imunologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/imunologia
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