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1.
J Cell Sci ; 136(18)2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37622462

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive and poorly treated subtype of breast cancer. Identifying novel drivers and mechanisms for tumor progression is essential for precise targeted therapy of TNBC. Immunoglobulin-like transcript 4 (ILT4; also known as LILRB2) is a classic myeloid suppressor for their activation and immune response. Our recent results found that ILT4 is also highly expressed in lung cancer cells, where it has a role in promoting immune evasion and thus tumor formation. However, the expression and function of ILT4 in breast cancer remains elusive. Here, using our patient cohort and public database analysis, we found that TNBC displayed the most abundant ILT4 expression among all breast cancer subtypes. Functionally, enriched ILT4 promoted TNBC cell proliferation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Further mechanistic analysis revealed that ILT4 reprogrammed aerobic glycolysis of tumor cells via AKT-mTOR signaling-mediated glucose transporter 3 (GLUT3; also known as SLC2A3) and pyruvate kinase muscle 2 (PKM2, an isoform encoded by PKM) overexpression. ILT4 inhibition in TNBC reduced tumor progression and GLUT3 and PKM2 expression in vivo. Our study identified a novel driver for TNBC progression and proposed a promising strategy to combat TNBC by targeting ILT4.


Assuntos
Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Transportador de Glucose Tipo 3 , Proliferação de Células/genética , Glucose
2.
Med Phys ; 50(3): 1635-1646, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36303466

RESUMO

BACKGROUND: Automatic segmentation of lesion, organ, and tissue from the medical image is an important part of medical image analysis, which are useful for improving the accuracy of disease diagnosis and clinical analysis. For skin melanomas lesions, the contrast ratio between lesions and surrounding skin is low and there are many irregular shapes, uneven distribution, and local and boundary features. Moreover, some hair covering the lesions destroys the local context. Polyp characteristics such as shape, size, and appearance vary at different development stages. Early polyps with small sizes have no distinctive features and could be easily mistaken for other intestinal structures, such as wrinkles and folds. Imaging positions and illumination conditions would alter polyps' appearance and lead to no visible transitions between polyps and surrounding tissue. It remains a challenging task to accurately segment the skin lesions and polyps due to the high variability in the location, shape, size, color, and texture of the target object. Developing a robust and accurate segmentation method for medical images is necessary. PURPOSE: To achieve better segmentation performance while dealing with the difficulties above, a U-shape network based on the encoder and decoder structure is proposed to enhance the segmentation performance in target regions. METHODS: In this paper, a novel deep network of the encoder-decoder model that combines HarDNet, dual attention (DA), and reverse attention (RA) is proposed. First, HarDNet68 is employed to extract the backbone features while improving the inference speed and computational efficiency. Second, the DA block is adopted to capture the global feature dependency in spatial and channel dimensions, and enrich the contextual information on local features. At last, three RA blocks are exploited to fuse and refine the boundary features to obtain the final segmentation results. RESULTS: Extensive experiments are conducted on a skin lesion dataset which consists of ISIC2016, ISIC2017, and ISIC 2018, and a polyp dataset which consists of several public datasets, that is, Kvasir, CVC-ClinicDB, CVC-ColonDB, ETIS, Endosece. The proposed method outperforms some state-of-art segmentation models on the ISIC2018, ISIC2017, and ISIC2016 datasets, with Jaccard's indexes of 0.846, 0.881, and 0.894, mean Dice coefficients of 0.907, 0.929, and 03939, precisions of 0.908, 0.977, and 0.968, and accuracies of 0.953, 0.975, and 0.972. Additionally, the proposed method also performs better than some state-of-art segmentation models on the Kvasir, CVC-ClinicDB, CVC-ColonDB, ETIS, and Endosece datasets, with mean Dice coefficients of 0.907, 0.935, 0.716, 0.667, and 0.887, mean intersection over union coefficients of 0.850, 0.885, 0.644, 0.595, and 0.821, structural similarity measures of 0.918, 0.953, 0.823, 0.807, and 0.933, enhanced alignment measures of 0.952, 0.983, 0.850, 0.817, and 0.957, mean absolute errors of 0.026, 0.007, 0.037, 0.030, and 0.009. CONCLUSIONS: The proposed deep network could improve lesion segmentation performance in polyp and skin lesion images. The quantitative and qualitative results show that the proposed method can effectively handle the challenging task of segmentation while revealing the great potential for clinical application.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Processamento de Imagem Assistida por Computador , Iluminação , Pele , Neoplasias Cutâneas/diagnóstico por imagem
3.
Cell Host Microbe ; 30(7): 944-960.e8, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35654045

RESUMO

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.


Assuntos
Bacteriófagos , Disfunção Cognitiva , Microbioma Gastrointestinal , Aminas , Animais , Bactérias , Bacteriófagos/genética , Humanos , Camundongos , Microglia , Proteína Supressora de Tumor p53
4.
Medicine (Baltimore) ; 99(33): e21085, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32871979

RESUMO

The lymph nodal invasion diagnosis is critical for therapeutic-decision and follows up in gastric cancer. However, the number of nodes to be examined for nodal invasion diagnosis is still under controversy, and the model for quantifying risk of missing positive node is currently not reported yet. We analyzed the nodal invasion status of 13,857 gastric cancer samples with records of primary tumor stage, the number of examined and positive lymph nodes in the surveillance, epidemiology, and end results (SEER) database, fitting a beta-binomial model. The nodes need to be examined with different primary tumor stage were determined based on the model. Overall, examining 11 lymph nodes reduces the probability of missing positive nodes to <10%, and the currently median nodes dissected is adequate (12 nodes). While the number of nodes demands to be dissected for T1, T2, T3, and T4 subgroups are 6, 19, 40, and 66, respectively. The currently implemented median value for these samples was 12, 12, 13, and 16, separately. It implies that the number of nodes to be examined is sufficient for early gastric cancer (T1), but it is inadequate for middle and advanced gastric cancer (T2-T3). The clinical significance of nodal staging score was validated with survival information. In summary, we first quantified the lymph nodes to be examined during surgery using a beta-binomial model, and validated with survival information.


Assuntos
Linfonodos/patologia , Metástase Linfática/diagnóstico , Metástase Linfática/patologia , Estadiamento de Neoplasias/métodos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Reações Falso-Negativas , Feminino , Humanos , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Probabilidade , Estudos Retrospectivos , Programa de SEER , Sensibilidade e Especificidade , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/cirurgia , Análise de Sobrevida
5.
World J Gastroenterol ; 24(30): 3448-3461, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30122883

RESUMO

AIM: To elucidate tongue coating microbiota and metabolic differences in chronic hepatitis B (CHB) patients with yellow or white tongue coatings. METHODS: Tongue coating samples were collected from 53 CHB patients (28 CHB yellow tongue coating patients and 25 CHB white tongue coating patients) and 22 healthy controls. Microbial DNA was extracted from the tongue samples, and the bacterial 16S ribosomal RNA gene V3 region was amplified from all samples and sequenced with the Ion Torrent PGM™ sequencing platform according to the standard protocols. The metabolites in the tongue coatings were evaluated using a liquid chromatography-mass spectrometry (LC-MS) platform. Statistical analyses were then performed. RESULTS: The relative compositions of the tongue coating microbiotas and metabolites in the CHB patients were significantly different from those of the healthy controls, but the tongue coating microbiota abundances and diversity levels were not significantly different. Compared with the CHB white tongue coating patients, the CHB yellow tongue coating patients had higher hepatitis B viral DNA (HBV-DNA) titers (median 21210 vs 500, respectively, P = 0.03) and a significantly lower level of Bacteroidetes (20.14% vs 27.93%, respectively, P = 0.013) and higher level of Proteobacteria (25.99% vs 18.17%, respectively, P = 0.045) in the microbial compositions at the phylum level. The inferred metagenomic pathways enriched in the CHB yellow tongue coating patients were mainly those involved in amino acid metabolism, which was consistent with the metabolic disorder. The abundances of bacteria from Bacteroidales at the order level were higher in the CHB white tongue coating patients (19.2% vs 27.22%, respectively, P = 0.011), whereas Neisseriales were enriched in the yellow tongue coating patients (21.85% vs 13.83%, respectively, P = 0.029). At the family level, the abundance of Neisseriaceae in the yellow tongue patients was positively correlated with the HBV-DNA level but negatively correlated with the S-adenosyl-L-methionine level. CONCLUSION: This research illustrates specific clinical features and bacterial structures in CHB patients with different tongue coatings, which facilitates understanding of the traditional tongue diagnosis.


Assuntos
Bactérias/isolamento & purificação , Microbioma Gastrointestinal/fisiologia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/microbiologia , Língua/microbiologia , Adulto , Bactérias/genética , Bactérias/metabolismo , Estudos de Casos e Controles , DNA Viral/isolamento & purificação , Feminino , Voluntários Saudáveis , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/metabolismo , Humanos , Masculino , Medicina Tradicional Chinesa/métodos , Metagenômica , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética
6.
Eur J Med Chem ; 157: 161-176, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30096650

RESUMO

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC50, 0.075 µM for eeAChE and 0.75 µM for hAChE) and Monoamine oxidase B (MAO-B) inhibition (IC50, 7.4 µM for hMAO-B), excellent antioxidant activity (71.7 µM of IC50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, hAChE-induced Aß aggregation. Moreover, 7d possessed neuroprotective potency against H2O2-induced oxidative damage on PC12 cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Hidroxitolueno Butilado/química , Hidroxitolueno Butilado/farmacologia , Linhagem Celular , Colinérgicos/síntese química , Colinérgicos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Donepezila , Relação Dose-Resposta a Droga , Indanos/química , Indanos/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Piperidinas/química , Piperidinas/farmacologia , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 26(12): 3191-3201, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29729985

RESUMO

A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced Aß1-42 aggregation and potential antioxidant properties especially compound 5b (IC50 = 5.64 µM for self-induced Aß aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu2+/Zn2+-induced Aß1-42 aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H2O2 and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood-brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000 mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Quelantes/química , Metais/química , Estresse Oxidativo , Oxiquinolina/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Antioxidantes/química , Barreira Hematoencefálica/metabolismo , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Concentração Inibidora 50 , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Oxiquinolina/farmacologia , Oxiquinolina/uso terapêutico , Células PC12 , Permeabilidade/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem ; 25(21): 5917-5928, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28988627

RESUMO

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Iminas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Salicilatos/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/farmacologia , Iminas/síntese química , Iminas/química , Ligantes , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Salicilatos/síntese química , Salicilatos/química , Relação Estrutura-Atividade
9.
ACS Chem Neurosci ; 8(11): 2496-2511, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28806057

RESUMO

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/uso terapêutico , Fármacos do Sistema Nervoso Central/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Cromanos/uso terapêutico , Indanos/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Piperidinas/uso terapêutico , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Barreira Hematoencefálica , Linhagem Celular , Fármacos do Sistema Nervoso Central/farmacologia , Fármacos do Sistema Nervoso Central/toxicidade , Quelantes/farmacologia , Quelantes/uso terapêutico , Quelantes/toxicidade , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Cromanos/farmacologia , Cromanos/toxicidade , Cobre , Donepezila , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Indanos/farmacologia , Indanos/toxicidade , Masculino , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/toxicidade , Neurotoxinas/toxicidade , Oxidantes/toxicidade , Células PC12 , Fragmentos de Peptídeos/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/toxicidade , Agregação Patológica de Proteínas/tratamento farmacológico , Ratos , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 138: 715-728, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28728104

RESUMO

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-ß (Aß) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 µM for MAO-B; 3.275 ± 0.040 µM for MAO-A) and Aß1-42 aggregation (54.0 ± 1.1%, 25 µM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Pargilina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Células PC12 , Pargilina/química , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
11.
Bioorg Med Chem ; 25(14): 3815-3826, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28549891

RESUMO

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12µM for hMAO-A and 0.816µM for hMAO-B), moderate inhibition of Aß aggregation (75.1% at 20µM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.


Assuntos
Cromonas/química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Cromonas/farmacologia , Cromonas/uso terapêutico , Cobre/química , Cobre/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Estrutura Terciária de Proteína , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
12.
Gene ; 533(1): 57-66, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24120393

RESUMO

Dietary cholesterol and aging are major risk factors to accelerate oxidation process for developing hypercholesterolemia. The major aim of this study is to elucidate the effects of rice protein on cholesterol level and oxidative stress in adult rats fed with and without cholesterol. After 2 weeks of feeding, hepatic and plasma contents of cholesterol, reduced glutathione (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA) and protein carbonyl (PCO) were measured. In liver, total antioxidative capacity (T-AOC), activities of antioxidant enzymes (total superoxide dismutase, T-SOD; catalase, CAT), glutathione metabolizing enzyme activities and gene expression levels (γ-glutamylcysteine synthetase, γ-GCS; glutathione reductase, GR; glutathione peroxidase, GPx) were determined. Under cholesterol-free/enriched dietary condition, T-AOC, activities of T-SOD and CAT, glutathione metabolism related enzymes' activities and mRNA levels (γ-GCS, GR and GPx) were effectively stimulated by rice proteins as compared to caseins. Compared with caseins, rice proteins significantly increased hepatic and plasma GSH contents, whereas hepatic and plasma accumulations of MDA, PCO and GSSG were significantly reduced by rice protein-feedings. As a result, the marked reductions of cholesterol in the plasma and in the liver were observed in adult rats fed rice proteins with and without cholesterol. The present study demonstrates that the hypocholesterolemic effect of rice protein is attributable to inducing antioxidative response and depressing oxidative damage in adult rats fed cholesterol-free/enriched diets. Results suggest that the antioxidant capability involved in the hypocholesterolemic action exerted by rice protein is independent of dietary cholesterol during adult period.


Assuntos
Ração Animal , Antioxidantes/metabolismo , Colesterol na Dieta/administração & dosagem , Colesterol/sangue , Oryza , Proteínas de Plantas/administração & dosagem , Animais , Sequência de Bases , Peso Corporal , Colesterol/metabolismo , Primers do DNA , Comportamento Alimentar , Glutationa/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
13.
Mol Carcinog ; 49(1): 44-53, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19623544

RESUMO

The loss of manganese superoxide dismutase function has been associated with increased incidence of Barrett's esophagus and esophageal adenocarcinoma. In previous studies, we have demonstrated that loss of MnSOD resulted in severe esophageal damage by both endogenous and exogenous bile. However, the alterative manner of MnSOD in esophageal epithelium is largely unknown. In this study, we investigated the expression and localization of MnSOD in response to the exposure to bile salts in an esophageal epithelial cell line. Het-1A cells were seeded at 5 x 10(5) and 10(7) and incubated with taurocholate, cholate, glycocholate, deoxycholate, and the mixture of these bile salts. Mitochondria and cytoplasma were separated, and the expression and localization of MnSOD was determined by Western blot and immunocytochemical assay. Proliferation rates were strongly inhibited in the groups with taurocholate and bile salts mixture at 4 h, with 0.367 +/- 0.042 and 0.396 +/- 0.046, respectively, compared to 0.684 +/- 0.054 in untreated groups (P < 0.05). An increased apoptotic rate compared to untreated group (3.65 +/- 0.59) were significantly increased in taurocholate group and in bile salts mixture group were 33.62 +/- 10.25 and 31.52 +/- 8.97 at 4 h, respectively (P < 0.05). The protein level of MnSOD in mitochondria was increased at 4 h, but with a decreased enzymatic activity after bile salts treatment. Cytoplasmic MnSOD was detected in the cells with bile salts treatment. Immunocytochemical staining demonstrated that esophageal epithelial cell underwent morphological alteration and MnSOD relocalization after bile salts treatment. This is the first study to demonstrate cellular cytosolic MnSOD expression and that this relocalization to the cytosol is a cause for decreased MnSOD enzymatic activity. This suggests that bile salts may contribute to the dysfunction of mitochondria, by enzymatically inhibiting of MnSOD localization and thus activation in the mitochondria.


Assuntos
Ácidos e Sais Biliares/farmacologia , Células Epiteliais/efeitos dos fármacos , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citosol/efeitos dos fármacos , Citosol/enzimologia , Células Epiteliais/citologia , Células Epiteliais/enzimologia , Esôfago/citologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Ácido Taurocólico/farmacologia
14.
Ann Surg Oncol ; 16(2): 515-23, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19018598

RESUMO

Previous studies have demonstrated a decrease in manganese superoxide dismutase (MnSOD) in both Barrett's epithelium of patients and columnar esophageal epithelium of rats after esophagoduodenal anastomosis (EDA). Curcuma aromatica, an herbal medicine, has been shown to display anti-carcinogenic properties in a wide variety of cell lines and animals. This study was designed to investigate the ability of Curcuma aromatica oil for the prevention of BE and EAC, possibly through its ability to preserve MnSOD function. EDA was performed on rats and Curcuma aromatica oil was administered by i.p. injection. Histological changes and oxidative damage were determined after EDA of 1, 3, and 6 months. MnSOD protein level and MnSOD enzymatic activity were evaluated. Lipid peroxidation was determined by TBARs assay and 8-hydroxy-deoxyguanosine for DNA oxidative damage was measured by immunohistochemical staining. In addition, the indexes of both apoptosis and proliferation were determined by PCNA staining and TUNEL assay, respectively. Severe esophagitis were seen in EDA rats, and morphological transformation within the esophageal epithelium was observed with intestinal metaplasia and EAC identified after 3 months. The EDA rats treated with Curcuma aromatica oil showed that both MnSOD enzymatic activity and protein level were similar to sham controls. Decreased incidences of intestinal metaplasia and EAC also were observed in the EDA rats with Curcuma aromatica oil treatment. Curcuma aromatica oil prevented loss of MnSOD in EDA rat esophageal epithelium, and this preservation of MnSOD is associated with the potential protective mechanism against transformation of esophageal epithelial to BE to EAC.


Assuntos
Esôfago de Barrett/prevenção & controle , Curcuma/química , Neoplasias Esofágicas/prevenção & controle , Óleos Voláteis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Esôfago de Barrett/patologia , Western Blotting , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Glutationa/metabolismo , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Peroxidação de Lipídeos , Estresse Oxidativo , Ratos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
15.
Clin Cancer Res ; 13(17): 5176-82, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17785574

RESUMO

PURPOSE: Oxidative stress is related to the carcinogenic pathway of reflux esophagitis to Barrett's metaplasia to esophageal adenocarcinoma (EAC). Recent studies have shown that a decreased manganese superoxide dismutase (MnSOD) level is associated with the increased incidences of Barrett's esophagus (BE) and EAC. The aim of this study was to investigate MnSOD supplementation as a chemopreventive agent to prevent oxidative injury and subsequent BE and EAC formation. EXPERIMENTAL DESIGN: Our esophagoduodenal anastomotic (EDA) model was done on rats according to our established procedure and treated with Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP; 10 mg/kg, i.p. every 3 days). Histologic changes were determined after the EDA model at 1, 3, and 6 months. Lipid peroxidation and 8-hydroxy-deoxyguanosine for DNA oxidative damage were determined by thiobarbituric acid-reactive substance assay and immunohistochemical staining. Enzymatic activities of MnSOD and Cu/ZnSOD were evaluated, and the rate of proliferation was determined by proliferating cell nuclear antigen staining. RESULTS: Severe esophagitis was seen in 100% of the EDA rats, and morphologic transformation within the esophageal epithelium was observed with intestinal metaplasia (40% of animals) and cancer (40% of animals) identified after 3 months. Decreased oxidative damage, along with the decreased degree of esophagitis and incidence of BE (20%) and EAC (0%), was found in MnTBAP-treated EDA rats comparing with the saline-treated EDA control. Decreased proliferation (46%) and increased SOD enzymatic activities (25%) were also found in the EDA rats treated with MnTBAP. CONCLUSION: MnTBAP protected rat esophageal epithelium from oxidative injury induced by EDA, and it could prevent the transformation of esophageal epithelial cell to BE to EAC by preservation of antioxidants.


Assuntos
Adenocarcinoma/prevenção & controle , Anticarcinógenos/administração & dosagem , Antioxidantes/uso terapêutico , Neoplasias Esofágicas/prevenção & controle , Metaloporfirinas/uso terapêutico , Superóxido Dismutase/administração & dosagem , 8-Hidroxi-2'-Desoxiguanosina , Animais , Apoptose , Proliferação de Células , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análise , Esôfago/patologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
16.
J Immunol ; 179(1): 313-21, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17579051

RESUMO

Fatty acid-binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. Recent studies have demonstrated the ability of FABPs to simultaneously regulate metabolic and inflammatory pathways. We investigated the role of adipocyte FABP and epithelial FABP in the development of experimental autoimmune encephalomyelitis to test the hypothesis that these FABPs impact adaptive immune responses and contribute to the pathogenesis of autoimmune disease. FABP-deficient mice exhibited a lower incidence of disease, reduced clinical symptoms of experimental autoimmune encephalomyelitis and dramatically lower levels of proinflammatory cytokine mRNA expression in CNS tissue as compared with wild-type mice. In vitro Ag recall responses of myelin oligodendrocyte glycoprotein 35-55-immunized FABP(-/-) mice showed reduced proliferation and impaired IFN-gamma production. Dendritic cells deficient for FABPs were found to be poor producers of proinflammatory cytokines and Ag presentation by FABP(-/-) dendritic cells did not promote proinflammatory T cell responses. This study reveals that metabolic-inflammatory pathway cross-regulation by FABPs contributes to adaptive immune responses and subsequent autoimmune inflammation.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Proteínas de Ligação a Ácido Graxo/deficiência , Sequência de Aminoácidos , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Progressão da Doença , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Proteínas de Ligação a Ácido Graxo/biossíntese , Proteínas de Ligação a Ácido Graxo/genética , Glicoproteínas/administração & dosagem , Glicoproteínas/imunologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
17.
Gene ; 371(1): 7-15, 2006 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-16524674

RESUMO

A novel human gene, named as human CAP10-like protein 46 kDa (hCLP46), was isolated and identified from human acute myeloid leukemia transformed from myelodysplastic syndrome (MDS-AML) CD34(+) cells. hCLP46 (3q13.33) contains 11 exons encoding a putative protein of 392 amino acids, with a highly conserved CAP10 domain, a hydrophobic signal peptide at its N-terminus, and an endoplasmic reticulum (ER) retention signal motif KTEL at the C-terminus. The homologs of hCLP46 exist in different organisms from plants to animal kingdoms. Subcellular localization analysis showed that hCLP46 is an ER-resident protein. hCLP46 expressed in most human adult tissues at different intensities, with lengths of 3.5 kb and 1.9 kb. Transcript of hCLP46 was not detectable in colon, thymus, and small intestine, but was abundant in liver, indicating that hCLP46 may be involved in important physiological functions in the liver. hCLP46 over-expressed U937 cells had higher growth rate than the cells without exogenic hCLP46 protein expression, suggesting that hCLP46 protein possess the ability of promoting cell proliferation.


Assuntos
Antígenos CD34 , Cromossomos Humanos Par 3/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas , Proteínas/genética , Sequência de Aminoácidos , Retículo Endoplasmático/genética , Glucosiltransferases , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Dados de Sequência Molecular , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Proteínas de Neoplasias/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Especificidade de Órgãos/genética , Estrutura Terciária de Proteína/genética , Proteínas/metabolismo , Homologia de Sequência de Aminoácidos , Células U937
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