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1.
Aquat Toxicol ; 218: 105354, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734615

RESUMO

Increasing microplastics pollution of marine and terrestrial water is a concerning issue for ecosystems and human health. Nevertheless, the interaction of microplastics with freshwater biota is still a poorly explored field. In order to achieve information concerning the uptake, distribution and effect of microplastics in planarians, Dugesia japonica specimens have been fed with mixtures of food and differently shaped and sized plastic particles. Feeding activity and food intake were non-altered by the presence of high concentrations of different types of plastic particles. However, the persistence of microplastic within the planarian body was a function of size/shape, being small spheres (<10 µm in diameter) and short fibers (14 µm large and 5/6 µm length) more persisting than larger spheres and longer fibers which were eliminated almost entirely by ejection in a few hours. Transmission electron microscopy analysis demonstrated that at least part of microplastics was phagocytized by the enterocytes. Chronic exposure to small plastic did not alter the regenerative ability but caused a significant reduction of the gut epithelium thickness and lipid content of enterocytes, together with the induction of apoptotic cell death, modulation of Djgata 4/5/6 expression and reduced growth rate. The ability of microplastic to perturb planarian homeostasis is concerning being them extremely resilient against mechanical and chemical insults and suggests possible harmful effects upon other more susceptible species in freshwater ecosystems.


Assuntos
Monitoramento Ambiental/métodos , Homeostase/efeitos dos fármacos , Planárias/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Apoptose/efeitos dos fármacos , Biota/efeitos dos fármacos , Ecossistema , Enterócitos/efeitos dos fármacos , Enterócitos/ultraestrutura , Comportamento Alimentar/efeitos dos fármacos , Água Doce/análise , Humanos , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Planárias/fisiologia , Planárias/ultraestrutura
2.
Vet Res ; 50(1): 110, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856906

RESUMO

Intestinal epithelium functions as a barrier to protect multicellular organisms from the outside world. It consists of epithelial cells closely connected by intercellular junctions, selective gates which control paracellular diffusion of solutes, ions and macromolecules across the epithelium and keep out pathogens. Rotavirus is one of the major enteric viruses causing severe diarrhea in humans and animals. It specifically infects the enterocytes on villi of small intestines. The polarity of rotavirus replication in their target enterocytes and the role of intestinal epithelial integrity were examined in the present study. Treatment with EGTA, a drug that chelates calcium and disrupts the intercellular junctions, (i) significantly enhanced the infection of rotavirus in primary enterocytes, (ii) increased the binding of rotavirus to enterocytes, but (iii) considerably blocked internalization of rotavirus. After internalization, rotavirus was resistant to EGTA treatment. To investigate the polarity of rotavirus infection, the primary enterocytes were cultured in a transwell system and infected with rotavirus at either the apical or the basolateral surface. Rotavirus preferentially infected enterocytes at the basolateral surface. Restriction of infection through apical inoculation was overcome by EGTA treatment. Overall, our findings demonstrate that integrity of the intestinal epithelium is crucial in the host's innate defense against rotavirus infection. In addition, the intercellular receptor is located basolaterally and disruption of intercellular junctions facilitates the binding of rotavirus to their receptor at the basolateral surface.


Assuntos
Enterócitos/virologia , Células Epiteliais/virologia , Mucosa Intestinal/citologia , Rotavirus/classificação , Rotavirus/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura/veterinária , Ácido Egtázico/farmacologia , Enterócitos/efeitos dos fármacos , Miofibroblastos/fisiologia , Suínos , Internalização do Vírus , Replicação Viral
3.
Biomed Pharmacother ; 118: 109338, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545238

RESUMO

Dyslipidemia is a key risk factor for cardiovascular diseases, which are a major cause of morbidity and mortality worldwide. However, despite the advancement of the treatment and prevention of dyslipidemia, medications used to treat dyslipidemia are limited to chemical drugs. Herbal medicine, as an alternative treatment, has a long history of usage and provides more treatment options, and related studies have revealed intervention targets for dyslipidemia. Four lipid-lowering mechanisms of herbal medicines have been proposed and are discussed in this paper. These mechanisms are the inhibition of cholesterol absorption in enterocytes, reduction of cholesterol synthesis, elevation of reverse cholesterol transport, and promotion of cholesterol excretion in the liver. This review elaborates on the underlying molecular pathways involved in plasma lipid balance via bioactive compounds from herbal medicines.


Assuntos
Dislipidemias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Animais , Colesterol/sangue , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Humanos , Modelos Biológicos , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/farmacologia , Fitoterapia
4.
Food Funct ; 10(9): 5333-5338, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31389458

RESUMO

This study investigates, for the first time, the ability of punicalagin to modulate intestinal glutamate uptake by upregulation of the expression of one of its transporters present on the enterocyte membrane. The use of an Ussing chamber revealed an increase in glutamate transport in differentiated Caco-2 cells after punicalagin treatment for 24 h. This cell line constitutively expresses two glutamate transporters: EAAT1 and EAAT3. In response to punicalagin, the expression of EAAT3 was increased, at both mRNA and protein levels, but not that of EAAT1. Transfection with EAAT3-targeting siRNA specifically altered basal and induced EAAT3 gene expression, decreasing the positive effect of punicalagin on glutamate uptake. These data confirmed the involvement of EAAT3 in increasing glutamate uptake by enterocytes after punicalagin treatment.


Assuntos
Transportador 3 de Aminoácido Excitatório/genética , Ácido Glutâmico/metabolismo , Taninos Hidrolisáveis/farmacologia , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Diferenciação Celular , Enterócitos/citologia , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 3 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos
5.
Nihon Yakurigaku Zasshi ; 154(2): 72-77, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406046

RESUMO

In drug disposition, the liver and small intestine are very important as tissues involving in drug metabolism, absorption, and excretion. Thus, in drug development studies, it is necessary to evaluate the pharmacokinetics in these tissues accurately including the contributions of drug-metabolizing enzymes and drug transporters. Currently, all kinds of evaluation systems have been used for the pharmacokinetic prediction; however, there are some issues in these systems. Therefore, the researches for the development of human induced pluripotent stem (iPS) cell-derived hepatocytes and enterocytes, as novel systems besides existing ones, are being advanced. Because human iPS cells have abilities of pluripotency and almost infinite proliferation, it is thought to be possible to stably provide the high-quality cells that have similar characteristics to human normal tissue cells by using human iPS cells. In this review, we describe current status of differentiation studies of human iPS cell-derived hepatocytes and enterocytes and the functional characteristics of these cells centered on pharmacokinetic functions.


Assuntos
Enterócitos/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Diferenciação Celular , Avaliação Pré-Clínica de Medicamentos , Enterócitos/citologia , Hepatócitos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Intestino Delgado , Fígado , Farmacocinética
6.
J Dairy Sci ; 102(9): 7684-7696, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255276

RESUMO

Oxidative stress is the basic reason for aging and age-related diseases. In this study, we investigated the protective effect of 2 strains of lactic acid bacteria (LAB), Lactobacillus rhamnosus GG and L. plantarum J26, against oxidative stress in Caco-2 cells, and gave an overview of the mechanisms of lactic acid bacteria antioxidant activity using digital gene expression profiling. The 2 LAB strains provided significant protection against hydrogen peroxide (H2O2)-induced reduction in superoxide dismutase activity and increase in glutathione peroxidase activity in Caco-2 cells. However, inactive bacteria had little effect on alleviating oxidation stress in Caco-2 cells. Eight genes related to oxidative stress-FOSB, TNF, PPP1R15A, NUAK2, ATF3, TNFAIP3, EGR2, and FBN2-were significantly upregulated in H2O2-induced Caco-2 cells compared with untreated Caco-2 cells. After incubation of the H2O2-induced Caco-2 cells with L. rhamnosus GG and L. plantarum J26, 5 genes (TNF, EGR2, NUAK2, FBN2, and TNFAIP3) and 2 genes (NUAK2 and FBN2) were downregulated, respectively. In addition, the Kyoto Encyclopedia of Genes and Genomes indicated that some signaling pathways associated with inflammation, immune response, and apoptosis, such as Janus kinase/signal transducers and activators of transcription (Jak-STAT), mitogen-activated protein kinase (MAPK), nuclear factor-κB, and tumor necrosis factor, were all negatively modulated by the 2 strains, especially L. rhamnosus GG. In this paper, we reveal the mechanism of LAB in relieving oxidative stress and provide a theoretical basis for the rapid screening and evaluation of new LAB resources.


Assuntos
Enterócitos/metabolismo , Lactobacillus plantarum/fisiologia , Lactobacillus rhamnosus/fisiologia , Estresse Oxidativo/genética , Transcriptoma/genética , Animais , Apoptose/genética , Células CACO-2 , Enterócitos/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imunidade/genética , Inflamação/genética , Probióticos/farmacologia
7.
Int Immunopharmacol ; 74: 105665, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254957

RESUMO

Neonatal necrotizing enterocolitis (NEC) is a life-threatening disease with severe inflammation and intestinal cell apoptosis. Tauroursodeoxycholic acid (TUDCA) is a recognized endoplasmic reticulum stress (ERS) inhibitor which can inhibit cell apoptosis. Recently, intestinal cell apoptosis has been demonstrated to be vital for the pathogenesis of NEC. The purpose of the present study was to investigate the potential of TUDCA in the treatment of NEC and the possible mechanisms in vivo and in vitro. Our results showed that TUDCA reduced mortality rates, prolonged survival times, significantly diminished intestinal damage, and inhibited intestinal inflammation in the mouse model of NEC. The protective effect of TUDCA on the NEC mouse model was realized through inhibiting the expression levels of ERS markers and inhibiting the apoptosis of intestinal cells. In addition, TUDCA increased the expression of phospho-Akt (p-Akt). Furthermore, we confirmed that TUDCA inhibited the apoptosis of intestinal cells by modulating the PERK-eIF2α ERS pathway and the Akt pathway in vitro studies. Besides, TUDCA effects were impaired by AKT specific inhibitor MK2206 in vitro studies. Therefore, these results indicated that TUDCA alleviated intestinal injury in a mouse model of NEC and inhibited ERS-mediated intestinal cell apoptosis by activating the Akt pathway.


Assuntos
Enterocolite Necrosante/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Ácido Tauroquenodesoxicólico/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/sangue , Citocinas/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/patologia , Enterócitos/efeitos dos fármacos , Enterócitos/patologia , Feminino , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Ácido Tauroquenodesoxicólico/farmacologia
8.
J Dairy Sci ; 102(8): 6863-6875, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178173

RESUMO

Some Lactobacillus strains have been reported to have antioxidative activity. In our previous work, we screened Lactobacillus plantarum Y44 for its antioxidative activity. In this study, we further studied the antioxidative activities of L. plantarum Y44 using chemical antioxidant methods, including the 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) free radical scavenging assays, the ferric reducing antioxidant power test, and oxygen radical absorbance capacity test, and we assessed damage caused by 2,2'-azobis(2-methylpropionamidine) dihydrochloride (ABAP) in a Caco-2 cell model. The results of the chemical antioxidant assays confirmed the antioxidative activity of L. plantarum Y44, which was consistent with the protection of Caco-2 cells against ABAP injury by L. plantarum Y44. We also found that L. plantarum Y44 significantly promoted expression of Nrf2 pathway-associated proteins, downregulated expression of inflammatory-related cytokines IL-8 and tumor necrosis factor-α in ABAP-damaged Caco-2 cells, and enhanced expression of the tight junction proteins ß-catenin and E-cadherin. We determined that L. plantarum Y44 exerted antioxidative effects by quenching oxygen free radicals and activating the Nrf2 signaling pathway in Caco-2 cells.


Assuntos
Amidinas/farmacologia , Antioxidantes/fisiologia , Enterócitos/efeitos dos fármacos , Lactobacillus plantarum/fisiologia , Animais , Células CACO-2 , Enterócitos/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/química , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Biol Pharm Bull ; 42(6): 989-995, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155596

RESUMO

An Intact form of lactoferrin (LF) is known to be absorbed from the small intestine and transported into the blood circulation. We reevaluated the cellular uptake and release of LF using an enterocyte model of human small intestinal cells derived from the Caco-2 cell line. In contrast to a previous report, we observed that intact bovine LF was taken up into seven and 21 d-cultured Caco-2 cells and successfully released back into the culture medium, even though the human intestinal LF receptor, intelectin-1, was not immunochemically detectable. Similar observations were made for human LF and its derivatives (the N-terminal half of LF designated N-lobe and Fc fusions). These observations regarding the uptake and release of intact LF in Caco-2 cells were consistent with in vivo observations. Therefore, we propose that the uptake and release of intact LF by Caco-2 cells should be assessed as a potential in vitro model of in vivo LF absorption in human intestines.


Assuntos
Enterócitos/efeitos dos fármacos , Intestinos/citologia , Lactoferrina/farmacologia , Animais , Células CHO , Células CACO-2 , Cricetulus , Enterócitos/metabolismo , Humanos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes/metabolismo
10.
J Pharm Pharmacol ; 71(8): 1231-1242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155721

RESUMO

OBJECTIVE: According to the regulatory guidelines, one of the critical steps in using in-vitro permeability methods for permeability classification is to demonstrate the suitability of the method. Here, suitability of the permeability method by using a monolayer of cultured epithelial cells was verified with different criteria. METHODS: Imaging with a transmission electron microscope was used for characterisation of the cells. Monolayer integrity was confirmed by transepithelial electrical resistance measurements and permeability of zero permeability marker compounds. Real-time polymerase chain reaction was employed to evaluate expression levels of 84 known transporters. Samples for bidirectional permeability determination were quantified by ultra-performance liquid chromatography. KEY FINDINGS: The Caco-2 cells grow in an intact monolayer and morphologically resemble enterocytes. Genes of 84 known transporters were expressed at different levels; furthermore, expression was time depended. Functional expression of efflux transporter P-glycoprotein was confirmed. We established a correlation between permeability coefficients of 21 tested drug substances ranging from low, moderate and high absorption with human fraction absorbed literature data (R2  = 0.84). CONCLUSIONS: Assay standardisation assures the consistency of experimental data. Only such fully characterised model has the ability to accurately predict drug's intestinal permeability at the early stage of research or for the BCS-based biowaiver application.


Assuntos
Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Biofarmácia/métodos , Células CACO-2 , Linhagem Celular Tumoral , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Absorção Intestinal/fisiologia , Permeabilidade , Estados Unidos , United States Food and Drug Administration
11.
PLoS One ; 14(6): e0218734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238335

RESUMO

Ceterach officinarum Willd is a plant widespread throughout Europe and used in southern Italy as a diuretic. Beliefs in the benefits of C. officinarum aqueous extract in the treatment of calcium oxalate kidney stones are widely held. Little is known, however, about the actual mechanism of its antilithiatic action. Our results in this in vitro study corroborate C. officinarum aqueous extract as a good source of antioxidants with a high antioxidant effects. Our results also demonstrate a major impact of C. officinarum aqueous extract on in vitro induced calcium oxalate crystallization kinetics and crystal morphology, showing its critical role in kidney stone formation and/or elimination. We show that progressively increasing doses of C. officinarum aqueous extract cause a sequence of effects. A powerful inhibitory action on calcium oxalate monohydrate (COM) growth and aggregation is first observed. C. officinarum aqueous extract also appears highly effective in stimulating nucleation increasing the number and reducing the size of COM crystals, which become progressively thinner, rounded and concave in a dose-dependent manner. These shape-modified COM crystals are known to be less adherent to renal tubular cells and more easily excreted through the urinary tract preventing kidney stone formation. Further, C. officinarum aqueous extract promotes the formation of calcium oxalate dihydrate (COD) rather than the monohydrate so that, at the highest concentrations used, only COD crystals are observed, in significant greater numbers with a clear reduction in their size, in a dose-dependent manner. Furthermore, AFM analyses allowed us to reveal the presence of C. officinarum component(s) on the surfaces of COD and modified COM crystals. The crystal surface adsorbed component(s) are shown to be similarly active as the total aqueous extract, suggesting a trigger factor which may direct crystal modification towards COD forms. In urolithiasis pathogenesis COD crystals are less dangerous than the COM forms due to their lower affinity for renal tubular cells. Our results are important in understanding the mechanisms which guide the modification induced by C. officinarum on the crystallization process. Based on these data, together with no adverse toxic effect being observed on the in vitro model of human intestinal enterocytes, C. officinarum aqueous extract could represent an attractive natural therapy for the treatment of urolithiasis.


Assuntos
Oxalato de Cálcio/química , Gleiquênias , Cálculos Renais/química , Cálculos Renais/tratamento farmacológico , Plantas Medicinais , Antioxidantes/farmacologia , Células CACO-2 , Cristalização , Diuréticos/farmacologia , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Gleiquênias/química , Humanos , Técnicas In Vitro , Itália , Cinética , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Modelos Químicos , Extratos Vegetais/farmacologia , Plantas Medicinais/química
12.
Animal ; 13(12): 2773-2781, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31113501

RESUMO

Gut microbiota have been shown to play a critical role in the maintenance of host health. Probiotics, which regulate gut microbiota balance, could serve as an effective alternative to antibiotic growth promoters. Since changes in the gastrointestinal tract, caused by a variety of different strains, groups and amounts of microorganisms, may be reflected in its histological structure, the aim of the present study was to examine the effects of rising doses of a mixed probiotic preparation on the structure and development of the small intestine of female turkeys. Eighty, three-day-old, healthy, female turkeys (Big-6 breed) were used in the current (16-week) study. The turkeys were randomly allocated to four weight-matched (59.70 ± 0.83 g) groups (n = 20), according to probiotic treatment dose (0, 107 cfu•g-1, 108 cfu•g-1 or 109 cfu•g-1, in 500 g•1000 kg-1) (cfu - a colony-forming unit). Three, non-genetically modified strains of probiotic cultures obtained from poultry, four bacterial and one yeast culture, were used. Histomorphometric analysis of the structure of the small intestinal wall of the duodenum and jejunum was performed. All probiotic doses used in the current study exerted a beneficial effect on the histological structure of the small intestine; however, the observed effect was dose and region dependent. Significant increases in villi height, crypt depth, villi and crypt width, mucosa thickness, epithelial height, enterocyte number, absorption surface and intestinal ganglia geometric indices were observed, specifically in the duodenum of birds receiving an intermediate dose of probiotic (108 cfu•g-1). The probiotic doses used in the current study differed significantly in their effect on the small intestine (P < 0.01), with the intermediate dose (108 cfu•g-1) significantly improving 58% of the parameters assessed, compared to the control. The duodenum was more susceptible to the favourable effects of the probiotic than the jejunum (56% v. 31% improvement in the parameters assessed) (P < 0.01). The weakest favourable effect was observed in the group that received the highest dose of probiotic.


Assuntos
Suplementos Nutricionais/análise , Microbioma Gastrointestinal/efeitos dos fármacos , Probióticos/administração & dosagem , Perus/anatomia & histologia , Ração Animal/análise , Animais , Peso Corporal , Dieta/veterinária , Enterócitos/efeitos dos fármacos , Feminino , Trato Gastrointestinal/anatomia & histologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Intestino Delgado/anatomia & histologia , Intestino Delgado/efeitos dos fármacos , Distribuição Aleatória
13.
Molecules ; 24(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072069

RESUMO

Nandina domestica (Berberidaceae) has been used in traditional medicine for the treatment of cough. This plant is distributed in Korea, Japan, China, and India This study aimed to investigate the anti-inflammatory phytochemicals obtained from the N. domestica fruits. We isolated a biflavonoid-type phytochemical, robustaflavone (R), from N. domestica fruits through bioactivity-guided fractionation based on its capacity to inhibit inflammation. The anti-inflammatory mechanism of R isolated from N. domestica has not yet been studied. In the present study, we evaluated the anti-inflammatory activities of R using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We have shown that R reduces the production of nitric oxide (NO), pro-inflammatory cytokine interleukin-1 beta (IL-1ß), and IL-6. Western blot analysis showed that R suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and downregulates the expression of LPS-induced nuclear factor-kappa B (NF-κB) and the phosphorylation of extracellular-regulated kinases (pERK 1/2). Moreover, R inhibited IL-8 release in LPS-induced human colonic epithelial cells (HT-29). These results suggest that R could be a potential therapeutic candidate for inflammatory bowel disease (IBD).


Assuntos
Berberidaceae/química , Biflavonoides/isolamento & purificação , Biflavonoides/farmacologia , Regulação para Baixo , Mediadores da Inflamação/metabolismo , Animais , Biflavonoides/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HT29 , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/biossíntese , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Células RAW 264.7
14.
Methodist Debakey Cardiovasc J ; 15(1): 70-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049152

RESUMO

Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through which cholesterol is disposed from the body. In the process of TICE, cholesterol is taken up from lipoprotein particles at the basolateral side of the enterocyte and translocates towards the apical side of the enterocyte. At the apical side, the ATP-binding cassette transporters G5 and G8 form a heterodimer that transports cholesterol into the intestinal lumen. A substantial amount of the secreted cholesterol is likely reabsorbed by the cholesterol influx transporter Niemann-Pick C1-Like 1 (NPC1L1) since recent data indicate that inhibition of NPC1L1 increases the efficacy of TICE for disposal of cholesterol via the feces. The pathways and proteins involved in intracellular cholesterol trafficking in the enterocyte have not yet been identified. Therefore, in addition to discussing known mediators of TICE, this review will also examine potential candidates involved in cholesterol translocation in the enterocyte. Both the cholesterol reuptake and efflux pathways can be influenced by pharmaceutical means; thus, the TICE pathway is a very attractive target to increase cholesterol excretion from the body and prevent or mitigate atherosclerotic cardiovascular disease.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Enterócitos/efeitos dos fármacos , Eliminação Intestinal/efeitos dos fármacos , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Animais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Enterócitos/metabolismo , Fezes/química , Humanos , Proteínas de Membrana Transportadoras/metabolismo
15.
Cancer Chemother Pharmacol ; 83(5): 893-904, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30815720

RESUMO

Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175 mg/kg of irinotecan intraperitoneally and 0.01 mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120 h after treatment. Jejunum and colon samples were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test, and nonlinear regression. Total goblet cells decreased at 72 h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120 h in the colon. The number of S-100-positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), on comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24 h and 96 h. Irinotecan-induced mucositis is associated with increases in mucus secretion and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.


Assuntos
Adenocarcinoma/tratamento farmacológico , Enterócitos/efeitos dos fármacos , Irinotecano/efeitos adversos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Mucina-2/metabolismo , Mucina-4/metabolismo , Mucosite/induzido quimicamente , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Enterócitos/metabolismo , Enterócitos/patologia , Feminino , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Irinotecano/uso terapêutico , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/patologia , Mucina-2/genética , Mucina-4/genética , Mucosite/metabolismo , Mucosite/patologia , Ratos Endogâmicos
16.
Am J Physiol Gastrointest Liver Physiol ; 316(5): G585-G597, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30817180

RESUMO

We investigated the migration of intestinal immune cells to the liver and their contribution to alcoholic liver disease. In mice fed ethanol, we found that an increased number of invariant natural killer T (iNKT) cells, which respond to the antigen presented by CD1d, migrated from mesenteric lymph nodes to the liver. iNKT cells react to lipid antigens, so we studied their activities in mice with intestinal epithelial cell-specific deletion of Pparg (PpargΔIEC) as a model for altering intestinal lipidomic profiles. Levels of CD1d increased in intestines of ethanol-fed PpargΔIEC mice, and in cell-tracking experiments, more iNKT cells migrated to the liver, compared with mice without disruption of Pparg. Livers of PpargΔIEC mice had increased markers of apoptosis and liver injury after ethanol feeding. iNKT cells isolated from livers of ethanol-fed PpargΔIEC mice induced apoptosis of cultured hepatocytes. An inhibitor of iNKT cells reduced ethanol-induced liver injury in PpargΔIEC mice. Duodenal tissues from patients with alcohol-use disorder have been found to have increased levels of CD1d compared with tissues from patients without alcohol overuse. Ethanol use, therefore, activates iNKT cells in the intestine to migrate to liver, where they-along with the resident hepatic iNKT cells-contribute to hepatocyte death and injury. NEW & NOTEWORTHY In this article, we studied migration of intestinal immune cells into the liver in response to ethanol-induced liver disease. We found that chronic ethanol feeding induces expression of CD1d by enterocytes, which activate invariant natural killer T (iNKT) cells in mesenteric lymph nodes; activation is further increased with loss of peroxisome proliferator-activated receptor gamma gene and altered lipid profiles. The activated iNKT cells migrate into the liver, where they promote hepatocyte apoptosis. Patients with alcohol use disorder have increased expression of CD1d in the small intestine. Strategies to block these processes might be developed to treat alcoholic liver disease.


Assuntos
Enterócitos , Etanol/farmacologia , Hepatócitos , Hepatopatias Alcoólicas , Células T Matadoras Naturais , Animais , Antígenos CD1d/metabolismo , Apoptose , Ensaios de Migração de Leucócitos/métodos , Movimento Celular , Depressores do Sistema Nervoso Central/farmacologia , Enterócitos/efeitos dos fármacos , Enterócitos/imunologia , Enterócitos/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Ativação Linfocitária , Camundongos , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/metabolismo
17.
Int J Mol Sci ; 20(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917504

RESUMO

Na-amino acid co-transporters (NaAAcT) are uniquely affected in rabbit intestinal villus cell brush border membrane (BBM) during chronic intestinal inflammation. Specifically, Na-alanine co-transport (ASCT1) is inhibited secondary to a reduction in the affinity of the co-transporter for alanine, whereas Na-glutamine co-transport (B0AT1) is inhibited secondary to a reduction in BBM co-transporter numbers. During chronic intestinal inflammation, there is abundant production of the potent oxidant peroxynitrite (OONO). However, whether OONO mediates the unique alteration in NaAAcT in intestinal epithelial cells during chronic intestinal inflammation is unknown. In this study, ASCT1 and B0AT1 were inhibited by OONO in vitro. The mechanism of inhibition of ASCT1 by OONO was secondary to a reduction in the affinity of the co-transporter for alanine, and secondary to a reduction in the number of co-transporters for B0AT1, which were further confirmed by Western blot analyses. In conclusion, peroxynitrite inhibited both BBM ASCT1 and B0AT1 in intestinal epithelial cells but by different mechanisms. These alterations in the villus cells are similar to those seen in the rabbit model of chronic enteritis. Therefore, this study indicates that peroxynitrite may mediate the inhibition of ASCT1 and B0AT1 during inflammation, when OONO levels are known to be elevated in the mucosa.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Enterócitos/metabolismo , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Microvilosidades/metabolismo , Simportadores/metabolismo , Animais , Linhagem Celular , Enterócitos/efeitos dos fármacos , Enterócitos/patologia , Inflamação/metabolismo , Ácido Peroxinitroso/toxicidade , Ratos
18.
Fish Physiol Biochem ; 45(2): 539-549, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729411

RESUMO

Dietary arginine (Arg) could improve the intestinal structure and absorption of grass carp (Ctenopharyngodon idellus); however, the mechanism of Arg on intestinal morphology improvement was unclear. The present study aimed to explain the possible mechanism of the positive effect of Arg on intestinal epithelial cells of grass carp. An in vitro study was conducted through a primary culture model to assess the growth, cell viability, mRNA expressions of TOR signal pathway, and tight junction proteins of enterocytes after culture in the medium with 6 levels of Arg (0, 0.1, 0.2, 0.5, 1.0, and 2.0 mmol/L). The results showed that 0.5 mmol/L Arg improved the cell number and decreased the lactate dehydrogenase and creatine kinase activities in culture medium (P < 0.05). The alkaline phosphatase activity in cell lysis buffer was depressed by 1 and 2 mmol/L Arg (P < 0.05). The nitric oxide (NO) content showed an increasing trend with the Arg content (P < 0.05), whereas the NO synthase activity showed an opposite trend to NO. TOR expression was higher in 0.2 and 0.5 mmol/L groups, whereas S6K1 expression in 1.0 mmol/L and 2.0 mmol/L groups were lower (P < 0.05). The mRNA expressions of occludin, claudin 3, and claudin c in 0.5 mmol/L group were the highest, while ZO-1 and claudin b expressions were higher in 0.2 and 0.5 mmol/L groups (P < 0.05). This study indicated that Arg enhanced the growth and integrity of intestinal epithelial cells of grass carp through upregulation of mRNA expression of TOR signal pathway and tight junction proteins at an optimal Arg content of 0.2-0.5 mmol/L.


Assuntos
Arginina/farmacologia , Carpas/fisiologia , Enterócitos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Arginina/administração & dosagem , Células Cultivadas , Dieta/veterinária , Relação Dose-Resposta a Droga , Enterócitos/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais , Proteínas de Junções Íntimas/genética
19.
Cell Mol Gastroenterol Hepatol ; 7(2): 255-274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30686779

RESUMO

BACKGROUND & AIMS: Epithelial regeneration is essential for homeostasis and repair of the mucosal barrier. In the context of infectious and immune-mediated intestinal disease, interleukin (IL) 22 is thought to augment these processes. We sought to define the mechanisms by which IL22 promotes mucosal healing. METHODS: Intestinal stem cell cultures and mice were treated with recombinant IL22. Cell proliferation, death, and differentiation were assessed in vitro and in vivo by morphometric analysis, quantitative reverse transcriptase polymerase chain reaction, and immunohistochemistry. RESULTS: IL22 increased the size and number of proliferating cells within enteroids but decreased the total number of enteroids. Enteroid size increases required IL22-dependent up-regulation of the tight junction cation and water channel claudin-2, indicating that enteroid enlargement reflected paracellular flux-induced swelling. However, claudin-2 did not contribute to IL22-dependent enteroid loss, depletion of Lgr5+ stem cells, or increased epithelial proliferation. IL22 induced stem cell apoptosis but, conversely, enhanced proliferation within and expanded numbers of transit-amplifying cells. These changes were associated with reduced wnt and notch signaling, both in vitro and in vivo, as well as skewing of epithelial differentiation, with increases in Paneth cells and reduced numbers of enteroendocrine cells. CONCLUSIONS: IL22 promotes transit-amplifying cell proliferation but reduces Lgr5+ stem cell survival by inhibiting notch and wnt signaling. IL22 can therefore promote or inhibit mucosal repair, depending on whether effects on transit-amplifying or stem cells predominate. These data may explain why mucosal healing is difficult to achieve in some inflammatory bowel disease patients despite markedly elevated IL22 production.


Assuntos
Interleucinas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Notch/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Claudina-2/metabolismo , Enterócitos/citologia , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Intestinos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Organoides/metabolismo , Células-Tronco/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
J Agric Food Chem ; 67(7): 1955-1962, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30629420

RESUMO

We hypothesized that Lactobacillus casei BL23 and milk work synergistically to prevent damage to epithelial barrier integrity induced by pro-inflammatory cytokines. To test this, barrier disruption was induced in polarized Caco-2 monolayers by sequential, basolateral treatment with IFN-γ and TNF-α. Apical application of either 25% v/v reconstituted skim milk (RSM) or ultra high temperature (UHT) milk (2% fat) prior to cytokine exposure reduced losses to transepithelial electrical resistance (TER). Permeability to fluorescein isothiocyanate-dextran (FD-4; 4 kDa) was also significantly reduced in the presence of 25% v/v UHT milk ( P < 0.05) but not RSM. Protection against increases in paracellular permeability was even greater when cell-free preparations of L. casei BL23 fermented UHT milk or fermented RSM were applied. The permeability coefficients of cells incubated with BL23 fermented UHT milk were equivalent to the untreated controls ( P = 0.12) and those cells also produced 247.6 ± 35.5 pg/mL IL-8, quantities significantly lower than found for cytokine-treated controls (353.9 ± 40.0 pg/mL). The benefits of the fermented milk were also confirmed by the reduced expression of TNF receptor 2 (TNFR2), myosin light-chain kinase (MLCK), and claudin-encoding genes relative to the controls. By comparison, apical application of viable L. casei onto the Caco-2 cells did not result in protection from the barrier-disruptive actions of IFN-γ and TNF-α. These results indicate that milk can maintain intestinal barrier integrity during pro-inflammatory cytokine exposure and that this is enhanced by modifications to milk matrix caused by prior incubation with L. casei BL23.


Assuntos
Enterócitos/fisiologia , Lactobacillus casei/fisiologia , Leite/fisiologia , Probióticos/farmacologia , Animais , Anti-Inflamatórios , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Claudinas/genética , Produtos Fermentados do Leite , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Interferon gama/farmacologia , Quinase de Cadeia Leve de Miosina/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/farmacologia
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