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1.
Eur J Pharm Biopharm ; 144: 132-138, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31521716

RESUMO

Novel treatment methods for obesity are urgently needed due to the increasing global severity of the problem. Gastrointestinal hormones, such as GLP-1 and PYY, are secreted by the enteroendocrine cells, playing a critical role in regulating food intake. Digested nutrients trigger the secretion of these hormones, which have a very short half-life. α-Linolenic acid (αLA) has been shown to stimulate GLP-1 secretion, however, chemical instability and fast uptake in the small intestine hinder its use in body weight management. We developed a novel delivery system based on inorganic mesoporous particles for αLA to increase secretion of gastrointestinal peptides. αLA was loaded to thermally hydrocarbonized porous silicon particles (THCPSi). 47.9 ±â€¯3.84% and 30.7 ±â€¯2.86% of αLA was released during 6 h from 3.0% and 9.2% loading degree (w/w) samples in vitro, respectively. Native αLA (50 µM) significantly increased GLP-1 secretion from enteroendocrine STC-1 and GLUTag cell lines. αLA loaded THCPSi significantly and dose dependently stimulated GLP-1 secretion from STC-1 cells, whereas empty particles did not. We demonstrated in vitro that THCPSi particles have the potential to be used as a controlled delivery system for nutrients such as αLA, increasing GLP-1 secretion. Our results justify further in vivo investigations.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Intestino Delgado/metabolismo , Ácido alfa-Linoleico/administração & dosagem , Animais , Linhagem Celular , Sistemas de Liberação de Medicamentos/métodos , Camundongos , Peptídeos/metabolismo , Silício/química
2.
Clin Nucl Med ; 44(9): e526-e528, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274556

RESUMO

An FDG PET with diagnostic CT was performed on a 52-year-old man for investigation of lymphocytosis and the clinical suspicion of lymphoma. The PET/CT demonstrated diffuse small bowel uptake, prominent mesenteric lymph nodes without significant FDG uptake, and other features suggestive of celiac disease. Subsequently, the patient was found to have markedly elevated celiac disease antibodies (deamidated gliadin IgG and tissue transglutaminase IgA) and to be HLA DQ2 and DQ8 allele positive on genotyping for celiac disease. Gastroscopy and duodenal biopsy also confirmed the diagnosed.


Assuntos
Doença Celíaca/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Transporte Biológico , Biópsia , Doença Celíaca/genética , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Fluordesoxiglucose F18/metabolismo , Técnicas de Genotipagem , Humanos , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Pessoa de Meia-Idade
3.
Eur J Pharm Biopharm ; 142: 307-314, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288077

RESUMO

The influence of physiological factors on the solubility of drug compounds has been thoroughly investigated in humans. However, as these factors vary between species and since many in vivo studies are carried out in rats or mice, it has been difficult to establish sufficient in vitro in vivo relations. The aim of this study was to develop a physiologically relevant in vitro dissolution model simulating the gastrointestinal (GI) fluids of fasted rats and compare it to previously published in vitro and in vivo data. To develop the in vitro model, the pH was measured in situ in six segments of the GI tract of anesthetised rats, then the fluids from the stomach, the proximal and the distal small intestine were collected and characterized with regard to osmolality, and bile acid and phospholipid concentration. The pH and osmolality were found to increase throughout the GI tract. The bile acids and phospholipids were present in high concentrations in the proximal small intestine, and the bile acid concentration doubled in the distal part, where the phospholipid concentration decreased. Matrix-assisted laser desorption ionisation mass spectrometry imaging was applied on a cross section of the small intestine, to study which bile acids and phospholipid classes were present in the small intestine of rats. Both cholic acid, taurocholic acid and glycocholic acid were detected, and phosphatidylcholine (34:2) was found to be mainly present in the intestinal wall or mucus, whereas lysophosphatidylcholine (16:0) was also detected in the lumen. Based on these observations, biorelevant media were developed to simulate fluids in the stomach and the proximal part of the small intestine in fasted rats. The media were implemented in a two-step in vitro dissolution model, which was found to better predict the in vivo performance of furosemide, when compared to previously published in vitro and in vivo data.


Assuntos
Líquidos Corporais/metabolismo , Líquidos Corporais/fisiologia , Mucosa Gástrica/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/fisiologia , Preparações Farmacêuticas/metabolismo , Estômago/fisiologia , Animais , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Solubilidade
4.
J Sci Food Agric ; 99(13): 6108-6113, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177538

RESUMO

BACKGROUND: Nucleotides are key constituents of milk, where they are utilized in cell replication, although there are limited studies for weaned piglets. This study evaluated the effects of uridine monophosphate (UMP) with uridine (UR) feed supplementation on the intestinal development and nucleotide transport in weaned piglets. RESULTS: Supplementation with UMP significantly increased (P < 0.05) plasma glucose, and UR supplementation significantly reduced (0.05 < P < 0.10) the plasma total cholesterol (TC) of piglets when compared with that of the control group, although non-significant difference (P > 0.05) in growth performance was observed among three groups. Piglets fed supplementary UR exhibited greater (P < 0.05) crypt depth in the duodenum and ileum when compared with those in the supplementary UMP and control groups. Real-time quantitative polymerase chain reaction (RT-qPCR) results revealed that UR supplementation increased (P < 0.05) the relative mRNA levels of genes encoding the transmembrane proteins ZO-1 and occludin in the duodenum mucosa, and ZO-1 in the jejunum mucosa (P < 0.05). Similarly, UR supplementation increased (P < 0.05) expression of solute carriers SLC28A1 and SLC29A1 in the duodenum mucosa. Conversely, claudin-1 expression in the duodenum mucosa was inhibited (P < 0.05) by dietary supplementation with UMP or UR. CONCLUSION: Collectively, our data indicated that dietary supplementation with UMP or UR was conducive to stimulating intestinal development and promoting nucleotide transport in weaned piglets. © 2019 Society of Chemical Industry.


Assuntos
Intestino Delgado/crescimento & desenvolvimento , Nucleotídeos/metabolismo , Suínos/crescimento & desenvolvimento , Uridina Monofosfato/metabolismo , Uridina/metabolismo , Animais , Transporte Biológico , Claudina-1/genética , Claudina-1/metabolismo , Suplementos Nutricionais/análise , Feminino , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Masculino , Suínos/genética , Suínos/metabolismo , Desmame
5.
Life Sci ; 231: 116581, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220524

RESUMO

AIMS: The aims of this study were to investigate the effect of colonic electrical stimulation (CES) on delayed colonic transit in Parkinson's disease (PD) model induced by rotenone and its possible mechanisms. MAIN METHODS: Sprague-Dawley male rats were implanted with a pair of electrodes on the serosa at the proximal colon and rotenone was subcutaneously injected for 6 weeks to induce the PD model. Behavior activity, stool volume and open-field test were recorded during the injection. Colonic propulsion rate was measured 6 weeks after rotenone injection. Colon samples of all rats were collected for the measurement of phosphorylated alpha-synuclein, choline acetyltransferase (CHAT), neuronal nitric oxide synthase (nNOS), and tyrosine hydroxylase (TH). The protocols of control rats were the same as the PD rats except that no electrodes were implanted and no rotenone was injected. KEY FINDINGS: (1) Rotenone-induced PD rats demonstrated weight loss, significant decrease of the dopaminergic neurons in substantia nigra, and impairment of colon movement. (2) CES significantly accelerated the delayed colonic transmit (91.67 ±â€¯5.58% vs 51.33 ±â€¯4.18%), superior to Macrogol-4000. (3) CES significantly upregulated the expression of CHAT, nNOS and TH protein in colon of PD rats. (4) In colon of PD rats, the phosphorylated alpha-synuclein was significantly upregulated, but CES had no significant effect on phosphorylated alpha-synuclein. SIGNIFICANCE: Our data show that CES can normalize the delayed colonic transit and this normalization may attribute to affecting enteric excitatory and inhibitory neurons.


Assuntos
Colo/metabolismo , Sistema Nervoso Entérico/efeitos dos fármacos , Doença de Parkinson/fisiopatologia , Animais , Colina O-Acetiltransferase/metabolismo , Colo/fisiopatologia , Constipação Intestinal/fisiopatologia , Modelos Animais de Doenças , Estimulação Elétrica , Motilidade Gastrointestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Sprague-Dawley , Rotenona/metabolismo , Rotenona/farmacologia , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
6.
Mol Biol (Mosk) ; 53(3): 485-496, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184614

RESUMO

Human apolipoprotein A-I (ApoA-I) is a major structural and functional protein component of high-density lipoprotein (HDL). ApoA-I constitutes ~75% of the protein content of HDL. The main sites of ApoA-I synthesis in humans are the liver and the small intestine. The mechanisms that govern tissue-specific apoA-I transcription in tissues and organs other than the liver and the small intestine are poorly understood. It is known that the human apoA-I has two additional promoters, the proximal and the distal one. In this work these two alternative apoA-I promoters are characterized, their transcription start sites are mapped and their competition for apoA-Itranscription is demonstrated; the role of the alternative promoters in apoA-I expression in human cells and tissues other than hepatocytes and enterocytes is discussed.


Assuntos
Apolipoproteína A-I/genética , Regiões Promotoras Genéticas/genética , Sítio de Iniciação de Transcrição , Transcrição Genética/genética , Humanos , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Lipoproteínas HDL/química , Lipoproteínas HDL/metabolismo , Fígado/citologia , Fígado/metabolismo , Especificidade de Órgãos/genética
7.
Eur J Pharm Biopharm ; 142: 8-19, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195131

RESUMO

In-vitro dissolution testing of pharmaceutical formulations has been used as a quality control test for many years. At early drug product development, in vivo predictive dissolution testing can be used for guidance in the rational selection of candidate formulations that best fit the desired in vivo dissolution characteristics. At present, the most widely applied dissolution media are phosphate-based buffers and, in some cases, the result of dissolution tests performed in such media have demonstrated reasonable/acceptable IVIVCs. However, the presence of phosphates in human GI luminal fluids is insignificant, which makes the use of such media poorly representative of the in vivo environment. The gastrointestinal lumen has long been shown to be buffered by bicarbonate. Hence, much interest in the development of suitable biorelevant in vitro dissolution media based on bicarbonate buffer systems has evolved. However, there are inherent difficulties associated with these buffers, such as maintaining the pH throughout the dissolution test, as CO2 tends to leave the system. Various mathematical models have been proposed to analyze bicarbonate buffers and they are discussed in this review. Approaches such as using simpler buffer systems instead of bicarbonate have been proposed as surrogate buffers to produce an equivalent buffer effect on drug dissolution on a case-by-case basis. There are many drawbacks related to simpler buffers systems including their poor in vivo predictability. Considerable discrepancies between phosphate and bicarbonate buffer dissolution results have been reported for certain dosage forms, e.g. enteric coated formulations. The role and need of bicarbonate-based buffers in quality control testing requires scientific analysis. This review also encompasses on the use of bicarbonate-based buffers as a potentially in vivo predictive dissolution medium for enteric coated dosage forms.


Assuntos
Bicarbonatos/química , Tampões (Química) , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Intestino Delgado/metabolismo , Fosfatos/química , Solubilidade/efeitos dos fármacos , Tecnologia Farmacêutica/métodos
8.
J Dairy Sci ; 102(8): 7038-7048, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178190

RESUMO

Circular RNA (circRNA) have been suggested to contribute to regulating gene expression in various tissues and cells of eukaryotes. However, little is known regarding the expression pattern of circRNA and their potential function in the small intestine of neonatal calves that receive colostrum. In the current study, jejunum tissue samples were collected from control calves (2 h after birth; CT; n = 3) and neonatal calves that ingested colostrum (24 h after birth; CO; n = 3) or milk (24 h after birth; MK; n = 3) to compare the circRNA expression patterns using a high-throughput RNA sequencing approach. A total of 21,213, 17,861, and 21,737 circRNA were identified in the CT, CO, and MK groups, respectively. Only 13,254 of these circRNA were common to the 3 groups, suggesting high specificity of circRNA expression depending on nutrient type. In total, 243, 249, and 283 circRNA were differentially expressed in the CO versus CT, CO versus MK, and MK versus CT comparisons, respectively. Gene ontology analysis showed that the differentially expressed circRNA and their predicted or known target genes from the CO and MK groups were mainly involved in macromolecule metabolic process, response to stress, and vesicle-mediated transport. Moreover, pathway analysis showed that the Rap1 signaling pathway, focal adhesion, ubiquitin-mediated proteolysis, and extracellular matrix-receptor interaction were the most significantly enriched pathways. These data collectively indicate that circRNA are abundant and dynamically expressed when calves receive colostrum and act as microRNA sponges to regulate their target genes for jejunum function during the early development of newborn calves.


Assuntos
Animais Recém-Nascidos/metabolismo , Bovinos/metabolismo , Colostro/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/metabolismo , RNA/metabolismo , Animais , Animais Recém-Nascidos/genética , Animais Recém-Nascidos/crescimento & desenvolvimento , Bovinos/genética , Bovinos/crescimento & desenvolvimento , Feminino , Intestino Delgado/metabolismo , Jejuno/metabolismo , MicroRNAs/genética , Leite/metabolismo , Gravidez , RNA/genética , Transdução de Sinais
9.
Nat Commun ; 10(1): 2631, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201301

RESUMO

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/metabolismo , Aterosclerose/genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Cromossomo X/fisiologia , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Fatores Sexuais , Proteína da Região Y Determinante do Sexo/genética , Testículo/metabolismo
10.
J BUON ; 24(2): 779-790, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31128036

RESUMO

PURPOSE: Gastroenteropancreatic tumors (GEPNETs) is a heterogeneous disease with variable clinical course. While promising therapeutic options exist for other adult cancers, there are no new molecular-based treatments developed for GEPNETs. One of the main targets of cancer immunotherapy is the Programmed Cell Death Ligand-1 (PD-L1) pathway. Our purpose was to investigate the profile of PD-L1 expression in different organs of GEPNETs and compare the conventional immunohistochemistry (IHC) with the RNA expression analysis via real time polymerase chain reaction (RT-PCR) in order to determine which patients might be appropriate for immune check point-targeted therapy. METHODS: A total of 59 surgically or endoscopically resected GEPNET tissues were retrospectively collected. The expression of PD-L1 and mRNA was evaluated with IHC. RESULTS: The expression of PD-L1 was significantly associated with the high-grade classification (p=0.012). PD-L1 mRNA expression in tumor samples appeared to be higher compared to the corresponding normal tissues. In appendix, stomach and small intestine, the expression of PD-L1 mRNA was higher in the tumor tissues compared to the respective controls. In pancreas and colon, control tissues tend to have a higher PD-L1 mRNA expression compared to tumor tissues. PD-L1 mRNA expression was higher in GEP carcinomas (p=0.0031). CONCLUSION: RT-PCR was found to be more sensitive in detecting PD-L1 expression than conventional IHC. This study may provide an important starting point and useful background information for future research about immunotherapy for appendix, stomach and small intestine neuroendocrine carcinomas.


Assuntos
Antígeno B7-H1/genética , Carcinoma Neuroendócrino/genética , Imuno-Histoquímica , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Colo/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia , Neoplasias Intestinais/imunologia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/terapia , Intestino Delgado/metabolismo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Pâncreas/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , RNA Mensageiro/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adulto Jovem
11.
Adv Colloid Interface Sci ; 269: 219-235, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31096075

RESUMO

This article focuses on the relevance of amorphous calcium (and magnesium) phosphates in living organisms. Although crystalline calcium phosphate (CaP)-based materials are known to constitute the major inorganic constituents of human hard tissues, amorphous CaP-based structures, often in combination with magnesium, are frequently employed by Nature to build up components of our body and guarantee their proper functioning. After a brief description of amorphous calcium phosphate (ACP) formation mechanism and structure, this paper is focused on the stabilization strategies that can be used to enhance the lifetime of the poorly stable amorphous phase. The various locations of our body in which ACP (pure or in combination with Mg2+) can be found (i.e. bone, enamel, small intestine, calciprotein particles and casein micelles) are highlighted, showing how the amorphous nature of ACP is often of paramount importance for the achievement of a specific physiological function. The last section is devoted to ACP-based biomaterials, focusing on how these materials differ from their crystalline counterparts in terms of biological response.


Assuntos
Fosfatos de Cálcio/metabolismo , Materiais Dentários/química , Compostos de Magnésio/metabolismo , Fosfatos/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Osso e Ossos/química , Osso e Ossos/metabolismo , Fosfatos de Cálcio/análise , Fosfatos de Cálcio/química , Caseínas/química , Esmalte Dentário/química , Esmalte Dentário/metabolismo , Humanos , Intestino Delgado/química , Intestino Delgado/metabolismo , Micelas , Leite Humano/química
12.
Gastroenterology ; 157(3): 731-743, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31103627

RESUMO

BACKGROUND & AIMS: Paneth cells secrete antimicrobial proteins including lysozyme via secretory autophagy as part of the mucosal protective response. The ELAV like RNA-binding protein 1 (ELAVL1, also called HuR) regulates stability and translation of messenger RNAs (mRNAs) and many aspects of mucosal physiology. We studied the posttranscriptional mechanisms by which HuR regulates Paneth cell function. METHODS: Intestinal mucosal tissues were collected from mice with intestinal epithelium (IE)-specific disruption of HuR (IE-HuR-/-), HuRfl/fl-Cre- mice (controls), and patients with inflammatory bowel diseases and analyzed by histology and immunohistochemistry. Paneth cell functions were determined by lysozyme-immunostaining assays. We isolated primary enterocytes from IE-HuR-/- and control mice and derived intestinal organoids. HuR and the chaperone CNPY3 were overexpressed from transgenes in intestinal epithelial cells (IECs) or knocked down with small interfering RNAs. We performed RNA pulldown assays to investigate interactions between HuR and its target mRNAs. RESULTS: Intestinal tissues from IE-HuR-/- mice had reduced numbers of Paneth cells, and Paneth cells had fewer lysozyme granules per cell, compared with tissues from control mice, but there were no effects on Goblet cells or enterocytes. Intestinal mucosa from patients with inflammatory bowel diseases had reduced levels of HuR and fewer Paneth cells. IE-HuR-/- mice did not have the apical distribution of TLR2 in the intestinal mucosa as observed in control mice. IECs from IE-HuR-/- mice expressed lower levels of CNPY3. Intestinal organoids from IE-HuR-/- mice were smaller and contained fewer buds compared with those generated from controls, and had fewer lysozyme-positive cells. In IECs, knockdown of HuR decreased levels of the autophagy proteins LC3-I and LC3-II, compared with control cells, and prevented rapamycin-induced autophagy. We found HuR to interact directly with the Cnpy3 mRNA coding region and increase levels of CNPY3 by increasing the stability and translation of Cnpy3 mRNA. CNPY3 bound TLR2, and cells with knockdown of CNPY3 or HuR lost membrane localization of TLR2, but increased cytoplasmic levels of TLR2. CONCLUSIONS: In studies of mice, IECs, and human tissues, we found HuR to increase expression of CNPY3 at the posttranscriptional level. CNPY3 is required for membrane localization of TLR2 and Paneth cell function.


Assuntos
Membrana Celular/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Intestino Delgado/metabolismo , Chaperonas Moleculares/metabolismo , Celulas de Paneth/metabolismo , Processamento Pós-Transcricional do RNA , Receptor 2 Toll-Like/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Proteína Semelhante a ELAV 1/deficiência , Proteína Semelhante a ELAV 1/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Intestino Delgado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Celulas de Paneth/patologia , Transporte Proteico , Transdução de Sinais , Regulação para Cima
13.
Sci Total Environ ; 659: 1546-1554, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096364

RESUMO

In this study, we investigated the levels of 12 priority polycyclic aromatic hydrocarbons (PAH12) pollutants, bioaccessible PAH12, and sorption sink for PAH12 by a silicone sheet of indoor dust samples, which were collected from teachers' offices (n = 17), students' offices (n = 17), laboratory (n = 11), and experimental center (n = 9), using an in vitro digestive model. In PAH12, bioaccessible PAH12, and sorption sink PAH12, benzo[b]fluoranthene (BbF), phenanthrenes (Phe), and fluoranthene (FLA) were labeled respectively the most significant PAHs (6.61 ±â€¯4.42 µg/g, 0.16 ±â€¯0.11 µg/g, and 0.08 ±â€¯0.06 µg/g) after indoor dust ingestion, whereas the proportions of anthracene (Ant), benzo(g,h,i)perylene (BghiP), and BghiP (0.34 ±â€¯0.17, 0.03 ±â€¯0.03 and 0.01 ±â€¯0.01 µg/g) were low. Based on benzo[a]pyrene- equivalent carcinogenic concentrations, the mean daily exposure of bioaccessible PAH12 and sorption sink for PAH12 by indoor dust ingestion was 4.07 × 10-3 ±â€¯1.73 × 10-3 and 3.23 × 10-3 ±â€¯1.36 × 10-3 µg/day in the experimental center; 4.01 × 10-3 ±â€¯2.05 × 10-3 and 1.46 × 10-3 ±â€¯6.72 × 10-4 µg/day in students' offices; 8.25 × 10-4 ±â€¯2.33 × 10-4 and 5.15 × 10-4 ±â€¯1.37 × 10-4 µg/day in laboratory; and 7.05 × 10-4 ±â€¯4.12 × 10-5 and 2.82 × 10-4 ±â€¯4.36 × 10-5 µg/day in teachers' offices, respectively. Our results indicated that the passive transfer fraction of PAH12 (44.07%-67.36% in this case) is therefore large and needs to be considered in exposure and risk assessments.


Assuntos
Poluentes Atmosféricos/metabolismo , Poluição do Ar em Ambientes Fechados/análise , Exposição Dietética/análise , Poeira/análise , Intestino Delgado/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Benzo(a)pireno , Carcinógenos , Exposição Dietética/estatística & dados numéricos , Digestão , Ingestão de Alimentos , Monitoramento Ambiental , Fluorenos , Humanos , Fenantrenos , Hidrocarbonetos Policíclicos Aromáticos/análise , Medição de Risco
14.
Nat Commun ; 10(1): 2012, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043597

RESUMO

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.


Assuntos
Disbiose/microbiologia , Gastroenteropatias/microbiologia , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , Intestino Delgado/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos , DNA Bacteriano/isolamento & purificação , Fibras na Dieta/administração & dosagem , Açúcares da Dieta/efeitos adversos , Disbiose/dietoterapia , Disbiose/tratamento farmacológico , Disbiose/fisiopatologia , Feminino , Gastroenteropatias/dietoterapia , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/fisiopatologia , Voluntários Saudáveis , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Permeabilidade , Projetos Piloto , Adulto Jovem
15.
BMC Bioinformatics ; 20(Suppl 7): 201, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074378

RESUMO

BACKGROUND: A key problem in systems biology is the determination of the regulatory mechanism corresponding to a phenotype. An empirical approach in this regard is to compare the expression profiles of cells under two conditions or tissues from two phenotypes and to unravel the underlying transcriptional regulation. We have proposed the method BASE to statistically infer the effective regulatory factors that are responsible for the gene expression differentiation with the help from the binding data between factors and genes. Usually the protein-DNA binding data are obtained by ChIP-seq experiments, which could be costly and are condition-specific. RESULTS: Here we report a definition of binding strength based on a probability model. Using this condition-free definition, the BASE method needs only the frequencies of cis-motifs in regulatory regions, thereby the inferences can be carried out in silico. The directional regulation can be inferred by considering down- and up-regulation separately. We showed the effectiveness of the approach by one case study. In the study of the effects of polyunsaturated fatty acids (PUFA), namely, docosahexaenoic (DHA) and eicosapentaenoic (EPA) diets on mouse small intestine cells, the inferences of regulations are consistent with those reported in the literature, including PPARα and NFκB, respectively corresponding to enhanced adipogenesis and reduced inflammation. Moreover, we discovered enhanced RORA regulation of circadian rhythm, and reduced ETS1 regulation of angiogenesis. CONCLUSIONS: With the probabilistic definition of cis-trans binding affinity, the BASE method could obtain the significances of TF regulation changes corresponding to a gene expression differentiation profile between treatment and control samples. The landscape of the inferred cis-trans regulations is helpful for revealing the underlying molecular mechanisms. Particularly we reported a more comprehensive regulation induced by EPA&DHA diet.


Assuntos
Indutores da Angiogênese/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Regulação da Expressão Gênica , Hiperlipidemias/genética , Motivos de Nucleotídeos , Transcrição Genética , Adipogenia/efeitos dos fármacos , Animais , Hiperlipidemias/tratamento farmacológico , Intestino Delgado/metabolismo , Camundongos , Regiões Promotoras Genéticas
16.
Pancreas ; 48(4): 514-518, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946234

RESUMO

OBJECTIVE: Neuroendocrine tumors (NETs) comprise 41.8% of small intestine malignancies. The NET nomogram is a 15-item prognostic tool that includes relevant factors for guiding management decisions. This is the first external validation of this tool among American patients at a tertiary treatment center. METHODS: Patients who underwent surgical intervention from 2005 to 2017 were screened by retrospective chart review. Nomogram scores were calculated following the methods outlined by Modlin et al (Neuroendocrinology. 2010;92:143-157). Validation assessed the association between nomogram scores and survival using Wilcoxon test and Cox regression. RESULTS: Among the 121 patients selected, the NET nomogram significantly predicted survival as a continuous variable (P < 0.01) and when dichotomized using 83 points to distinguish low-risk versus high-risk groups (P < 0.01). However, the nomogram was not universally applicable as even at our specialty center, variables such as chromogranin A and urinary 5-hydroxyindoleacetic acid are not routinely collected, whereas others, like tumor grade, do not reflect the most recently updated classifications. CONCLUSION: The NET nomogram accurately identified patients at low and high risk of death. However, revision to update prognosticators could improve its usefulness for predicting survival of small intestine NETs.


Assuntos
Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Tumores Neuroendócrinos/patologia , Nomogramas , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromogranina A/metabolismo , Feminino , Humanos , Neoplasias Intestinais/cirurgia , Intestino Delgado/metabolismo , Intestino Delgado/cirurgia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/cirurgia , Prognóstico , Encaminhamento e Consulta , Estudos Retrospectivos , Adulto Jovem
17.
Int J Mol Sci ; 20(7)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987291

RESUMO

Diabetic autonomic peripheral neuropathy (PN) involves a broad spectrum of organs. One of them is the gastrointestinal (GI) tract. The molecular mechanisms underlying the pathogenesis of digestive complications are not yet fully understood. Digestion is controlled by the central nervous system (CNS) and the enteric nervous system (ENS) within the wall of the GI tract. Enteric neurons exert regulatory effects due to the many biologically active substances secreted and released by enteric nervous system (ENS) structures. These include nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS). It is a very important inhibitory factor, necessary for smooth muscle relaxation. Moreover, it was noted that nitrergic innervation can undergo adaptive changes during pathological processes. Additionally, nitrergic neurons function may be regulated through the synthesis of other active neuropeptides. Therefore, in the present study, using the immunofluorescence technique, we first examined the influence of hyperglycemia on the NOS- containing neurons in the porcine small intestine and secondly the co-localization of nNOS with vasoactive intestinal polypeptide (VIP), galanin (GAL) and substance P (SP) in all plexuses studied. Following chronic hyperglycaemia, we observed a reduction in the number of the NOS-positive neurons in all intestinal segments studied, as well as an increased in investigated substances in nNOS positive neurons. This observation confirmed that diabetic hyperglycaemia can cause changes in the neurochemical characteristics of enteric neurons, which can lead to numerous disturbances in gastrointestinal tract functions. Moreover, can be the basis of an elaboration of these peptides analogues utilized as therapeutic agents in the treatment of GI complications.


Assuntos
Intestino Delgado/citologia , Intestino Delgado/metabolismo , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/metabolismo , Feminino , Galanina/metabolismo , Hiperglicemia/metabolismo , Substância P/metabolismo , Suínos , Peptídeo Intestinal Vasoativo/metabolismo
18.
BMC Vet Res ; 15(1): 117, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992015

RESUMO

BACKGROUND: Porcine deltacoronavirus (PDCoV) is a novel coronavirus that can cause diarrhea in nursing piglets. This study was aimed to investigate the roles of host differentially expressed genes on metabolic pathways in PDCoV infections. RESULTS: Twenty thousand six hundred seventy-four differentially expressed mRNAs were identified in 5-day-old piglets responded to PDCoV experimental infections. Many of these genes were correlated to the basic metabolism, such as the peroxisome proliferator-activated receptor (PPAR) signaling pathway which plays a critical role in digestion. At the same time, in the PPAR pathway genes of fatty acid-binding protein (FABP) family members were observed with remarkably differential expressions. The differential expressed genes were associated with appetite decrease and weight loss of PDCoV- affected piglets. DISCUSSION: Fatty acid-binding protein 1 (FABP1) and fatty acid-binding protein 3 (FABP3) were found to be regulated by PDCoV. These two genes not only mediate fatty acid transportation to different cell organelles such as mitochondria, peroxisome, endoplasmic reticulum and nucleus, but also modulate fatty acid metabolism and storage as a signaling molecule outside the cell. Therefore, it can be preliminarily concluded that PPAR differential expression caused by PDCoV was mostly associated with weight loss and death from emaciation. CONCLUSIONS: The host differentially expressed genes were associated with infection response, metabolism signaling and organismal systems signaling pathways. The genes of FABP family members in the PPAR signaling pathway were the most highly altered and played important roles in metabolism. Alteration of these genes were most likely the reason of weight loss and other clinical symptoms. Our results provided new insights into the metabolic mechanisms and pathogenesis of PDCoV infection. METHODS: Animal experiment, Determination of viral growth by real-time RT-PCR, Histopathology, Immunohistochemical staining, Microarray analysis.


Assuntos
Animais Recém-Nascidos/virologia , Infecções por Coronavirus/veterinária , Coronavirus , Doenças dos Suínos/virologia , Animais , Animais Recém-Nascidos/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Intestino Delgado/virologia , Jejuno/metabolismo , Jejuno/patologia , Jejuno/virologia , Redes e Vias Metabólicas/genética , Análise de Sequência com Séries de Oligonucleotídeos/veterinária , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Suínos , Doenças dos Suínos/metabolismo , Transcriptoma
19.
Food Chem ; 289: 694-700, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30955667

RESUMO

The major allergen of chum salmon (Oncorhynchus keta) roe is the ß'-component (Onc k 5, ß'-c), which is a yolk protein and a fragment of vitellogenin. When yolk content containing ß'-c was orally administered to mice, ß'-c passed through the gastrointestinal tract and was excreted in feces without marked degradation. The direct administration of ß'-c to ligated jejunal and ileal loops showed that ß'-c was absorbed through the small intestine and transferred into the blood. Immunohistochemical staining showed that orally administered ß'-c was distributed from the apical side to the basal side of intestinal epithelial cells, suggesting that endocytosis may be involved in the intestinal absorption of ß'-c. In conclusion, ß'-c is absorbed along a large portion of the small intestine and circulates in the blood stream without significant digestion. The resistance of ß'-c to gastrointestinal digestion seems to contribute to its strong allergenicity.


Assuntos
Alérgenos/metabolismo , Proteínas de Peixes/metabolismo , Galectina 3/metabolismo , Trato Gastrointestinal/metabolismo , Salmão , Animais , Culinária , Digestão , Proteínas do Ovo/metabolismo , Células Epiteliais/metabolismo , Hipersensibilidade Alimentar , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR
20.
Protein Pept Lett ; 26(9): 676-683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30950341

RESUMO

BACKGROUND: The number of oral vaccines is still limited due to many difficulties suffered in the intestinal environment, such as mucosal clearance, vast area, harsh conditions, deteriorative enzymes, impermeability, tolerance, etc. Numerous strategies have focused on directing antigen to the receptors of M cells, which is the main gateway to acquire and initiate specific responses to antigens in intestine. FimHrb is a receptor binding domain of type 1 of fimbriae from E. coli and Salmonella that can bind to GP2 receptor expressed exclusively on M cells. OBJECTIVE: In this study, we evaluated the potential of FimHrb for oral vaccine development via its ability to adhere M cells. METHODS: The coding gene of FimHrb fused Green Fluorescent Protein (GFP) was cloned and expressed intracellularly in E. coli host strain. The recombinant protein FimHrb-GFP was then purified by IMAC method through 6x His tag designed downstream of GFP. Finally, the purified protein was monitored its binding on murine M cells in Payer Patch region. RESULTS: Following the methods mentioned above, the coding gene FimHrb-GFP was successfully cloned into vector pET22b and intracellularly expressed in soluble form at low temperature induction. The purity and the recovered yield of this protein were 90% and 20%, respectively. After that, the adhesion of FimHrb-GFP was monitored in murine small intestine, which showed that the protein bound to Peyer Patch region and did not restrict on M cells. CONCLUSION: With the present data, we revealed a candidate protein FimHrb targeted receptor on M cells for oral vaccine development and other factors in E. coli would supplement FimH to provide the specific invasion of these bacteria via M cells.


Assuntos
Adesinas de Escherichia coli/química , Proteínas de Fímbrias/química , Proteínas de Fluorescência Verde/química , Proteínas Recombinantes de Fusão/química , Adesinas de Escherichia coli/genética , Animais , Linhagem Celular , Escherichia coli/genética , Proteínas de Fímbrias/genética , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Camundongos , Ligação Proteica , Domínios Proteicos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
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