Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
J Org Chem ; 89(1): 565-575, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38115769

RESUMO

An array of biologically interesting tri/difluoromethylated chromones and their heteroatom analogues were conveniently synthesized from the reaction of chromones and their heteroatom analogues with CF3SO2Na or HCF2SO2Na in the presence of tert-butyl hydroperoxide under mild conditions. A mechanistic pathway involving the generation of the electrophilic tri/difluoromethyl radical, followed with the radical substitution of chromones and their heteroatom analogues, was postulated.

2.
Int J Mol Sci ; 25(13)2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-39000585

RESUMO

Plant flowering time is affected by endogenous and exogenous factors, but its variation patterns among different populations of a species has not been fully established. In this study, 27 Arabidopsis thaliana accessions were used to investigate the relationship between autonomous pathway gene methylation, gene expression and flowering time variation. DNA methylation analysis, RT-qPCR and transgenic verification showed that variation in the flowering time among the Arabidopsis populations ranged from 19 to 55 days and was significantly correlated with methylation of the coding regions of six upstream genes in the autonomous pathway, FLOWERING LOCUS VE (FVE), FLOWERING LOCUS Y (FY), FLOWERING LOCUS D (FLD), PEPPER (PEP), HISTONE DEACETYLASE 5 (HAD5) and Pre-mRNA Processing Protein 39-1 (PRP39-1), as well as their relative expression levels. The expression of FVE and FVE(CS) was modified separately through degenerate codon substitution of cytosine and led to earlier flowering of transgenic plants by 8 days and 25 days, respectively. An accurate determination of methylated sites in FVE and FVE(CS) among those transgenic plants and the recipient Col-0 verified the close relationship between the number of methylation sites, expression and flowering time. Our findings suggest that the methylation variation of these six key upstream transcription factors was associated with the gene expression level of the autonomous pathway and flowering time in Arabidopsis. The FVE(CS) and FVE genes in transgenic plants tended to be hypermethylated, which could be a protective mechanism for plants. However, modification of gene sequences through degenerate codon substitution to reduce cytosine can avoid hypermethylated transferred genes in transgenic plants. It may be possible to partially regulate the flowering of plants by modified trans-epigenetic technology.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Metilação de DNA , Flores , Regulação da Expressão Gênica de Plantas , Arabidopsis/genética , Flores/genética , Flores/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Plantas Geneticamente Modificadas/genética , Epigênese Genética
3.
J Asian Nat Prod Res ; 25(11): 1029-1037, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37010929

RESUMO

Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,2'-diol) is a biologically active natural product derived from Magnolia and has been shown to have excellent biological activities. This paper discusses research progress on the use of honokiol in the treatment of lung cancer, as studies have confirmed that honokiol can exert anti-lung-cancer effects through multiple pathways and multiple signaling pathways, such as inhibiting angiogenesis, affecting mitochondrial function and apoptosis, regulating of autophagy and epithelial-mesenchymal transition (EMT). In addition, honokiol combined with other chemotherapy drugs is also a way in which it can be applied.


Assuntos
Lignanas , Neoplasias Pulmonares , Neoplasias Pulmonares/tratamento farmacológico , Lignanas/farmacologia , Compostos de Bifenilo/farmacologia , Transdução de Sinais , Apoptose , Linhagem Celular Tumoral
4.
Mol Pharm ; 19(7): 2456-2470, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35621695

RESUMO

The abnormal expression of aromatase is associated with the occurrence and development of a variety of neurological diseases and tumors. A series of 18F-labeled and 68Ga-labeled potential aromatase-binding candidate compounds were designed and synthesized based on the structures of aromatase inhibitors. Competitive inhibition experiments in vitro and molecular docking showed that BIBD-069 and BIBD-071 have high affinity for aromatase. The radiolabeling conditions of [18F]BIBD-069 and [18F]BIBD-071 were simple, and the yields were high. Biodistribution and in vivo inhibition experiments confirmed that [18F]BIBD-069 and [18F]BIBD-071 specifically bind to aromatase. [18F]BIBD-069 and [18F]BIBD-071 selectively imaged the amygdala and nucleus of the stria terminalis, which is similar to the imaging result of [11C]vorozole. Radiometabolites of [18F]BIBD-069 and [18F]BIBD-071 did not bind to aromatase and interfered with brain imaging. MicroPET-CT imaging further confirmed that [18F]BIBD-069 and [18F]BIBD-071 can specifically bind to aromatase and were not defluorinated in vivo. Given that [18F]BIBD-069 and [18F]BIBD-071 exhibit excellent aromatase binding affinities, mild radiolabeling conditions, and good pharmacokinetics, they can be important tools for the diagnosis and treatment of aromatase-related diseases.


Assuntos
Aromatase , Tomografia por Emissão de Pósitrons , Aromatase/metabolismo , Inibidores da Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Radioisótopos de Flúor/química , Simulação de Acoplamento Molecular , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual
5.
Mol Pharm ; 19(7): 2351-2366, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35671264

RESUMO

[11C]ER176 has adequate sensitivity to image the human brain translocator protein (TSPO) in all three genotypes by positron emission tomography (PET). However, its clinical application is limited by the short half-life of 11C (20.38 min). To overcome the deficiency of [11C]ER176 and keep the pharmacophore features of ER176 to the maximum extent, we designed four fluorine-labeled ER176 derivatives using the deuterium method. In vitro competition binding confirmed that the designed compounds had high affinity for TSPO. Biodistribution experiments showed that tissues with high expression of TSPO had high uptake of these compounds, as well as that the compound showed high brain penetration and mild defluorination in vivo. Therefore, [18F]BIBD-239 with simple synthesis conditions was selected for further biological evaluation. Theoretical simulations showed that BIBD-239 and ER176 have similar binding modes and sites to Ala147-TSPO and Thr147-TSPO, which indicated that the tracers may have consistent sensitivity to the three affinity genotypes. In vitro autoradiography and in vivo PET studies of the ischemic rat brain showed dramatically higher uptake of [18F]BIBD-239 on the lesion site compared to the contralateral side with good brain kinetics. Additionally, [18F]BIBD-239 provided clear tumor PET images in a GL261 glioma model. Importantly, PET imaging and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) results showed that in vivo defluorination and other metabolites of [18F]BIBD-239 did not interfere with brain imaging. Conclusively, [18F]BIBD-239, similar to ER176 with low polymorphism sensitivity, has simple labeling conditions, high labeling yield, high affinity, and high specificity for TSPO, and it is planned for further evaluation in higher species.


Assuntos
Radioisótopos de Flúor , Glioma , Animais , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Fluoretos/metabolismo , Radioisótopos de Flúor/química , Glioma/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Ratos , Receptores de GABA/genética , Receptores de GABA/metabolismo , Distribuição Tecidual
6.
J Org Chem ; 87(12): 7747-7762, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35678138

RESUMO

Chiral dinuclear rare-earth metal complexes RE2Ln2 (n = 1, RE = Y(1), Eu(2), Nd(3), La(4), Gd(5); n = 2, RE = Eu(6), Gd(7)) stabilized by the corresponding Trost ligands H3L1 or H3L2 (H3L1 = (S,S)-2,6-bis[2-(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-methylphenol, H3L2 = (S,S)-2,6-bis[2-(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-chlorophenol) were prepared and three unknown complexes 5-7 were characterized by X-ray diffraction analysis. The chiral rare-earth metal complexes 1-7 displayed high reactivity in the asymmetric hydrophosphonylation of α,ß-unsaturated ketones, and 5 mol % of complex 7 together with 10 mol % of chiral diamine (1S,2S)-1,2-cyclohexanediamine were proved to be the optimal catalyst combination. Various hydrophosphonylation products with excellent yields and high to excellent enantiomeric excess (ee) values were obtained in toluene (up to 99% yield, >99% ee).

7.
Br J Nutr ; : 1-33, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36047051

RESUMO

Previously, we provided an evidence that L-leucine supplementation facilitates growth performance in suckling piglets with normal birth weight. However, it remains hitherto obscure weather breast-fed piglets displaying intrauterine growth restriction (IUGR) show a similar effect in response to L-leucine provision. In this study, seven-day-old sow-reared IUGR piglets were orally administrated with L-leucine (0, 0.7 1.4, 2.1 g/kg BW) twice daily for two weeks. Increasing leucine levels hampered the growth performance of suckling IUGR piglets. The average daily gain of IUGR piglets was significantly reduced in 1.4 g/kg BW and 2.1 g/kg BW L-leucine supplementation groups (P < 0.05). Except for ornithine and glutamine, the plasma concentrations of other amino acids were abated as L-leucine levels increased (P < 0.05). Leucine supplementation led to reduction in the levels of urea, blood ammonia, blood glucose, triglyceride, and total cholesterol, as well as an elevation in the level of low density lipoprotein cholesterol in suckling IUGR piglets (P < 0.05). In addition, 1.4g/kg BW of L-leucine enhanced the mRNA expression of ATB 0,+ , whereas decreased the mRNA abundances of CAT1, y+LAT1, ASCT2 and b 0,+ AT in the jejunum (P < 0.05). Concomitantly, the jejunum of IUGR piglets in L-leucine group contains more ATB0,+ and less SNAT2 protein than in the control (P < 0.05). Collectively, L-leucine supplementation impairs growth performance in breast-fed IUGR piglets, which may be associated with depressed nutritional conditions and alterations in the uptake of amino acids and the expression of amino acid transporters in the small intestine.

8.
J Labelled Comp Radiopharm ; 65(14): 354-360, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36261868

RESUMO

Diabetes mellitus (DM) and insulinoma are mainly affected by the status of pancreatic ß-cell mass (BCM). Development of imaging agents for BCM allows to study pancreatic ß cells and the relationship between ß cells and DM or insulinoma. In this study, we investigated the density of dopamine D1 receptor on the ß cells and measured BCM by statistical image processing. The pancreatic uptakes of [125 I]I-R-(+)-7-chloro-8-hydroxy-1-(3'-iodopheny1)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine ([125 I]I-R-(+)-TISCH), dopamine D1 receptor tracer, in normal and diabetic rats displayed significant differences at 30 min (1.11 ± 0.08% ID/g vs. 0.63 ± 0.09% ID/g, p < 0.0001). In the presence of SCH23390, the pancreatic uptake of [125 I]I-R-(+)-TISCH at 30 min in normal rats was lower (1.01 ± 0.04% ID/g, p < 0.05). Although the blocking was not complete, [125 I]I-R-(+)-TISCH showed specific binding signals to the pancreas. Furthermore, the uptakes of [125 I]I-R-(+)-TISCH in INS-1 cells were reduced in the presence of SCH23390 at different concentrations. [125 I]I-R-(+)-TISCH displayed a respectable uptake in insulinoma. Overall, [125 I]I-R-(+)-TISCH provided specific binding signals to pancreatic ß cells. Although the specific signal may not be sufficient for imaging in vivo, the dopamine D1 receptor can still be considered as a potential target for studying BCM. Further investigation will be required to optimize the ligand.


Assuntos
Diabetes Mellitus Experimental , Células Secretoras de Insulina , Insulinoma , Neoplasias Pancreáticas , Animais , Ratos , Dopamina , Receptores de Dopamina D1/metabolismo , Ligantes , Células Secretoras de Insulina/metabolismo , Benzazepinas/metabolismo
9.
Bioorg Med Chem Lett ; 34: 127776, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33418064

RESUMO

Estrogen receptor is an attractive target for the diagnosis and treatment of breast cancer. This article reports for the first time a dual-modality imaging agent targeting estrogen receptor that can use PET imaging to diagnose breast cancer and utilize fluorescence imaging to achieve intraoperative navigation. Fluorescence experiments show that [natGa] 1 has typical aggregate induced emission characteristics. Above the critical concentration, [natGa] 1 can form biocompatible nanomicelles. [natGa] 1 can quickly light up estrogen receptor positive MCF-7 cells. Cell uptake experiments show that [68Ga] 1 is mediated by estrogen receptor. Therefore, [nat/68Ga] 1 shows the characteristics of highly sensitive diagnosis and visualization of breast cancer, and can be used as a lead compound for the development of a novel PET-FI bimodal imaging agent targeting the estrogen receptor.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Receptores de Estrogênio/análise , Feminino , Germânio/química , Humanos , Marcação por Isótopo , Células MCF-7 , Conformação Molecular , Imagem Óptica , Compostos Radiofarmacêuticos/síntese química
10.
Angew Chem Int Ed Engl ; 60(19): 10833-10841, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33624345

RESUMO

The m-pyridine urea (mPU) oligomer was constructed by using the intramolecular hydrogen bond formed by the pyridine nitrogen atom and the NH of urea and the intermolecular hydrogen bond of the terminal carbonyl group and the NH of urea. Due to the synergistic effect of hydrogen bonds, mPU oligomer folds and exhibits strong self-assembly behaviour. Affected by folding, mPU oligomer generates a twisted plane, and one of its important features is that the carbonyl group of the urea group orientates outwards from the twisted plane, while the NHs tend to direct inward. This feature is beneficial to NH attraction for electron-rich species. Among them, the trimer self-assembles into helical nanotubes, and can efficiently transport chloride ions. This study provides a novel and efficient strategy for constructing self-assembled biomimetic materials for electron-rich species transmission.


Assuntos
Materiais Biomiméticos/química , Canais de Cloreto/química , Piridinas/química , Ureia/química , Tamanho da Partícula , Propriedades de Superfície
11.
J Org Chem ; 85(16): 10504-10513, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32589850

RESUMO

Four chiral dinuclear rare-earth metal complexes [REL1]2 (RE = Y(1), Eu(2), Nd(3), La (4)) stabilized by Trost proligand H3L1 (H3L1 = (S,S)-2,6-bis[2-(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-methylphenol) were first prepared, and all were characterized by X-ray diffraction. Complex 4 was employed as the catalyst for enantioselective hydroboration reaction of substituted ketones, and the corresponding secondary alcohols with excellent yields and high ee values were obtained using reductant HBpin. The same result was also achieved using the combination of lanthanium amides La[N(SiMe3)2]3 with Trost proligand H3L1 in a 1:1 molar ratio. The experimental findings and DFT calculation revealed the possible mechanism of the enantioselective hydroboration reaction and defined the origin of the enantioselectivity in the current system.

12.
Plant Cell Physiol ; 60(1): 152-165, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295898

RESUMO

Cold stress is a major abiotic factor plants face during their life cycle. Although plants often exhibit phenotypic variation in cold tolerance, the underlying mechanism remains poorly understood. In the present study, the 50% lethal temperature (LT50) values of 37 Arabidopsis thaliana accessions at latitudes from 15° to 58° ranged from -13.2°C to -4.9°C and were closely correlated with the cold climates of the collection sites. According to a methylation analysis of all C-repeat (CRT)-binding factor (CBF) pathway genes, the coding and promoter regions of AtICE1, a regulator of CBF genes, exhibited the greatest variability in methylation levels among the accessions and included 5-122 methylated cytosine residues. In contrast, unmethylated or only slightly methylated genes in the CBF pathway showed little variation among the accessions. According to a gene expression analysis of four selected A. thaliana populations with distinct methylation patterns, except for the down-regulated gene AtCBF2, the expression levels of all members of the CBF pathway were negatively correlated with AtICE1 gene methylation levels. Treatment of the four A. thaliana populations with the DNA methylation inhibitory reagent 5-azacytidine resulted in a 30.0-78.3% enhancement of freezing tolerance and decreases in LT50 values of approximately 1.9-3.6°C. Similar effects were observed in drm2 mutants, including 30.0-48.3% increases in freezing tolerance and decreases in LT50 values of approximately 0.7-3.4°C. Thus, the AtICE1 methylation-regulated transcription of CBF pathway genes is responsible for the phenotypic variation in the freezing tolerance observed in A. thaliana.


Assuntos
Adaptação Fisiológica/genética , Arabidopsis/genética , Arabidopsis/fisiologia , Variação Biológica da População , Metilação de DNA/genética , Congelamento , Variação Genética , Fatores de Transcrição/genética , Azacitidina/farmacologia , Ecossistema , Ecótipo , Eletrólitos/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genes de Plantas , Genótipo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo
13.
Angew Chem Int Ed Engl ; 58(20): 6747-6751, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-30912227

RESUMO

A palladium-catalyzed enantioselective intramolecular σ-bond cross-exchange between C-I and C-C bonds is realized, providing chiral indanones bearing an alkyl iodide group and an all-carbon quaternary stereocenter. Pd/TADDOL-derived phosphoramidite is found to be an efficient catalytic system for both C-C bond cleavage and alkyl iodide reductive elimination. In addition to aryl iodides, aryl bromides can also be used for this transformation in the presence of KI. Density-functional theory (DFT) calculation studies support the ring-opening of cyclobutanones occuring through an oxidative addition/reductive elimination process involving PdIV species.

14.
Angew Chem Int Ed Engl ; 58(3): 897-901, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30456924

RESUMO

A palladium-catalyzed enantioselective sequential ring-opening/cross-coupling of cyclobutanones is disclosed that provides chiral indanones bearing C3-quaternary stereocenters. The reaction process involves palladium-catalyzed nucleophilic addition of cyclobutanones and aryl halides, enantioselective ß-carbon elimination, and intermolecular trapping of a transient σ-alkylpalladium complex with boronic acids. Alternatively, an intramolecular cyclopropanation is realized through C-H bond functionalization in the absence of external coupling reagents, affording chiral cyclopropane-fused-indanones in good yields and enantioselectivity.

15.
Int J Colorectal Dis ; 33(2): 131-139, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29282495

RESUMO

PURPOSE: The purpose of this study is to estimate the detection rates of adenomas and serrated polyps and to identify proximalization and associate risk factors in patients from Southern China. METHODS: Consecutive patients undergoing colonoscopy from 2004 to 2013 in Guangzhou were included. The proportions of proximal adenomas to advanced adenomas and serrated polyps were compared and potential predictors were evaluated. RESULTS: Colonoscopies (n = 62,560) were performed, and 11,427 patients were diagnosed with polyps. Detection rates for adenomas, hyperplastic polyps, and serrated adenomas were 12.0, 2.5, and 0.2 patients per 100 colonoscopies. When comparing the 1st (2004-2008) to the 2nd period (2009-2013), adenoma and serrated polyp detection in proximal and distal colon both increased significantly (proximal colon [adenoma 3.9 vs. 6.1 patients/100 colonoscopies, P < 0.001; serrated polyp 0.4 vs. 1.1 patients/100 colonoscopies, P < 0.001]; distal colon [adenoma 6.6 vs. 7.2 patients/100 colonoscopies, P = 0.003; serrated polyp 1.2 vs. 2.4 patients/100 colonoscopies, P < 0.001]). Advanced adenoma detection increased over these two periods only in proximal colon (1st vs. 2nd period: 1.5 vs. 2.4 patients/100 colonoscopies, P < 0.001), not the distal colon (P = 0.114). Multivariate analyses showed that diagnostic period was an independent predictor for adenoma proximalization (OR = 1.36, 95% CI 1.25-1.48, P < 0.001), but not for advanced adenomas (P = 0.117) or serrated polyps (P = 0.928). CONCLUSIONS: Adenomas and serrated polyps were increasingly detected throughout the colon, whereas advanced adenomas were only in proximal colon. A proximal shift tendency detected by colonoscopy was observed for adenomas, but not advanced adenomas or serrated polyps, in Southern China. The screening for proximal polyps should be emphasized and colonoscopy might be a preferred initial screening tool.


Assuntos
Adenoma/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscopia , Adenoma/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Pólipos do Colo/patologia , Demografia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Adulto Jovem
16.
J Nutr ; 145(1): 25-31, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25527658

RESUMO

BACKGROUND: Dysfunction of tight junction integrity is associated with decreased nutrient absorption and numerous gastrointestinal diseases in humans and piglets. Although l-glutamine has been reported to enhance intestinal-mucosal mass and barrier function under stressful conditions, in vivo data to support a functional role for l-glutamine on intestinal tight junction protein (TJP) expression in weanling mammals are limited. OBJECTIVE: This study tested the hypothesis that glutamine regulates expression of TJPs and stress-related corticotropin-releasing factor (CRF) signaling in the jejunum of weanling piglets. METHODS: Piglets were reared by sows or weaned at 21 d of age to a corn and soybean meal-based diet that was or was not supplemented with 1% l-glutamine for 7 d. Growth performance, intestinal permeability, TJP abundance, and CRF expression were examined. RESULTS: Weaning caused increases (P < 0.05) in intestinal permeability by 40% and in CRF concentrations by 4.7 times in association with villus atrophy (P < 0.05). Western blot analysis showed reductions (P < 0.05) in jejunal expression of occludin, claudin-1, zonula occludens (ZO) 2, and ZO-3, but no changes in the abundance of claudin-3, claudin-4, or ZO-1 in weanling piglets compared with age-matched suckling controls. Glutamine supplementation improved (P < 0.05) intestinal permeability and villus height, while reducing (P < 0.05) jejunal mRNA and protein levels for CRF and attenuating (P < 0.05) weanling-induced decreases in occludin, claudin-1, ZO-2, and ZO-3 protein abundances. CONCLUSION: Collectively, our results support an important role for l-glutamine in regulating expression of TJPs and CRF in the jejunum of weanling piglets.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Glutamina/administração & dosagem , Jejuno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/análise , Animais , Claudinas/análise , Hormônio Liberador da Corticotropina/análise , Hormônio Liberador da Corticotropina/genética , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Jejuno/anatomia & histologia , Jejuno/química , Sus scrofa , Desmame , Proteínas da Zônula de Oclusão/análise
17.
J Nutr ; 145(6): 1156-62, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25878205

RESUMO

BACKGROUND: Besides serving as a substrate for protein synthesis, L-tryptophan (L-Trp) is used via serotonin-, kynurenine-, and niacin-synthetic pathways to produce bioactive compounds crucial for whole-body homeostasis. It is unknown whether L-Trp itself can regulate metabolic pathways in animal cells. OBJECTIVE: This study tested the hypothesis that L-Trp may activate mammalian target of rapamycin (mTOR) complex 1 and enhance expression of tight junction (TJ) proteins in intestinal porcine epithelial cells. METHODS: Jejunal enterocytes, intestinal porcine epithelial cell line 1 (IPEC-1) isolated from newborn pigs, were cultured in customized Dulbecco's modified Eagle medium (DMEM) supplemented with or without L-Trp for the indicated time periods. Cell proliferation, L-Trp metabolism, protein turnover, mRNA abundance for L-Trp transporters [solute carrier family 3 member 1 (SLC3A1), solute carrier family 6 member 14 (SLC6A14), solute carrier family 6 member 19 (SLC6A19), and Na(+)/K(+) ATPase subunit-α1 (ATP1A1)], abundance of proteins involved in mTOR signaling, and TJ proteins were determined. RESULTS: L-Trp was not degraded in IPEC-1 cells. Compared with basal medium containing 0.04 mmol/L L-Trp, 0.4 and 0.8 mmol/L L-Trp enhanced (P < 0.05) protein synthesis by 45-52% and cell growth by 17% and 25% on day 1 and 72% and 51% on day 2, respectively, while reducing (P < 0.05) protein degradation by 12% and 22%, respectively. These effects of L-Trp were associated with mTOR activation and increased (P < 0.05) mRNA abundance for L-Trp transporters (SLC6A19, SLC6A14, and SLC3A1) by 1.5-2.7 fold and ATP1A1 by 3 fold. L-Trp also upregulated (P < 0.05) the abundance of occludin, claudin-4, zonula occludens (ZO) 1 and 2 by 0.5-2 fold but did not affect expression of claudin-1 or ZO-3 in IPEC-1 cells. CONCLUSION: L-Trp is not catabolized by pig small intestinal epithelial cells but can regulate intracellular protein turnover and expression of TJ proteins in these cells.


Assuntos
Enterócitos/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Junções Íntimas/metabolismo , Triptofano/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Claudina-1/genética , Claudina-1/metabolismo , Claudina-4/genética , Claudina-4/metabolismo , Enterócitos/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestinos/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/genética , Ocludina/genética , Ocludina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Suínos , Serina-Treonina Quinases TOR/genética , Proteínas de Junções Íntimas/genética , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Regulação para Cima
18.
Amino Acids ; 47(10): 2177-84, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25287255

RESUMO

The integrity of intestinal barrier is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of various gastrointestinal diseases. Aside from serving as substrates for protein biosynthesis, amino acids also maintain the health of intestinal mucosal barrier. However, the underlying mechanisms remain unclear. We aimed to determine the effect and mechanism of non-essential amino acid (NEAA) deprivation on intestinal tight junction permeability using porcine intestinal epithelial cells as a model. We found that NEAA deprivation led to an impairment of barrier function as evidenced by increased permeability, decreased trans-epithelial resistance, and decreased expression of tight junction proteins claudin-1 and ZO-1. Importantly, NEAA deprivation induced both apoptosis and autophagy as shown by caspase-3 activation, and poly ADP-ribose polymerase cleavage; and LC3II lipidation and p62 degradation, hallmarks of apoptosis and autophagy, respectively. Importantly, we showed that the autophagy induced by NEAA deprivation counteracts apoptosis. Abrogation of autophagy by 3-methyladenine enhanced NEAA deprivation-induced barrier dysfunction and apoptosis; whereas, activation of autophagy by rapamycin partially rescued NEAA deprivation-induced barrier dysfunction and apoptosis. Taken together, our results demonstrate a critical role of NEAA on the mucosal integrity by regulating cell death and survival signaling pathways.


Assuntos
Aminoácidos/deficiência , Autofagia , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Permeabilidade/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Transdução de Sinais , Suínos
19.
Amino Acids ; 47(8): 1517-25, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25940921

RESUMO

L-Leucine is a signaling amino acid in animal metabolism. It is unknown whether supplementing L-leucine to breast-fed neonates may enhance their small-intestinal development. This hypothesis was tested with a piglet model. Seven-day-old sow-reared pigs with an average birth weight of 1.45 kg were assigned randomly to the control or leucine group (n = 30/group). Piglets in the leucine group were orally administrated with 1.4 g L-leucine/kg body weight, whereas piglets in the control group received isonitrogenous L-alanine, twice daily for 14 days. The supplemental L-leucine amounted to 200 % of L-leucine intake from sow's milk by 7-day-old pigs. At the end of the 2-week experiment, tissue samples were collected for determining intestinal morphology, expression of genes for intestinal leucine transporters (real-time RT-PCR and western blot analysis), and plasma metabolites and hormones. L-leucine administration increased (P < 0.05) villus height in the duodenum, an elevated ratio of villus height to crypt depth in the duodenum and ileum, plasma concentrations of leucine, glutamine and asparagine, as well as body-weight gains. mRNA levels for L-leucine transporters (SLC6A14, SLC6A19 and SLC7A9) and the abundance of the ATB(0,+) protein were increased (P < 0.05) but those for SLC7A7 mRNA and the LAT2 protein were decreased (P < 0.05) in the jejunum of leucine-supplemented piglets, compared with the control. Plasma concentrations of ammonia, urea, triglycerides, and growth-related hormones did not differ between the control and leucine groups. Collectively, these results indicate that L-leucine supplementation improves intestinal development and whole-body growth in suckling piglets with a normal birth weight.


Assuntos
Intestino Delgado/efeitos dos fármacos , Intestino Delgado/crescimento & desenvolvimento , Leucina/administração & dosagem , Alanina/administração & dosagem , Sistemas de Transporte de Aminoácidos , Aminoácidos/sangue , Ração Animal , Animais , Animais Lactentes , Suplementos Nutricionais , Modelos Animais , Distribuição Aleatória , Sus scrofa , Aumento de Peso/efeitos dos fármacos
20.
Amino Acids ; 47(10): 2143-54, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24965526

RESUMO

The intestinal barrier integrity is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of multiple gastrointestinal diseases. Recent studies highlighted a critical role for glutamine, which had been traditionally considered as a nutritionally non-essential amino acid, in activating the mammalian target of rapamycin cell signaling in enterocytes. In addition, glutamine has been reported to enhance intestinal and whole-body growth, to promote enterocyte proliferation and survival, and to regulate intestinal barrier function in injury, infection, weaning stress, and other catabolic conditions. Mechanistically, these effects were mediated by maintaining the intracellular redox status and regulating expression of genes associated with various signaling pathways. Furthermore, glutamine stimulates growth of the small intestinal mucosa in young animals and also enhances ion transport by the gut in neonates and adults. Growing evidence supports the notion that glutamine is a nutritionally essential amino acid for neonates and a conditionally essential amino acid for adults. Thus, as a functional amino acid with multiple key physiological roles, glutamine holds great promise in protecting the gut from atrophy and injury under various stress conditions in mammals and other animals.


Assuntos
Glutamina/farmacologia , Absorção Intestinal/efeitos dos fármacos , Intestinos/fisiologia , Permeabilidade/efeitos dos fármacos , Adulto , Animais , Humanos , Intestinos/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA