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1.
Toxicol Appl Pharmacol ; 412: 115389, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385404

RESUMO

Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.


Assuntos
Variação Biológica da População , Sistema Enzimático do Citocromo P-450/genética , Fígado/enzimologia , MicroRNAs/genética , Fatores de Transcrição/genética , Fatores Etários , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Heterogeneidade Genética , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Isoenzimas , Masculino , MicroRNAs/metabolismo , Fenótipo , Fumar/genética , Fumar/metabolismo , Fatores de Transcrição/metabolismo
2.
Neuroscience ; 452: 280-294, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33246060

RESUMO

Retinitis pigmentosa (RP) is a heterogeneous group of retinal degenerative diseases in which the final pathological feature is photoreceptor cell apoptosis. Currently, the pathogenesis of RP remains poorly understood and therapeutics are ineffective. 17ß-Oestradiol (ßE2) is universally acknowledged as a neuroprotective factor in neurodegenerative diseases and has manifested neuroprotective effects in a light-induced retinal degeneration model. Recently, we identified N-myc downstream regulated gene 2 (NDRG2) suppression as a molecular marker of mouse retinal photoreceptor-specific cell death. ßE2 has also been reported to regulate NDRG2 in salivary acinar cells. Therefore, in this study, we investigated whether ßE2 plays a protective role in RP and regulates NDRG2 in photoreceptor cells. To this end, we generated RP models and observed that ßE2 not only reduced the apoptosis of photoreceptor cells, but also restored the level of NDRG2 expression in RP models. Then, we showed that siNDRG2 inhibits the anti-apoptotic effect of ßE2 on photoreceptor cells in a cellular RP model. Subsequently, we used a classic oestrogen receptor (ER) antagonist to attenuate the effects of ßE2, suggesting that ßE2 exerted its effects on RP models via the classic ERs. In addition, we performed a bioinformatics analysis, and the results indicated that the reported oestrogen response element (ERE) sequence is present in the promoter region of the mouse NDRG2 gene. Overall, our results suggest that ßE2 attenuated the apoptosis of photoreceptor cells in RP models by maintaining NDRG2 expression via a classic ER-mediated mechanism.


Assuntos
Degeneração Retiniana , Retinose Pigmentar , Animais , Apoptose , Modelos Animais de Doenças , Estradiol/farmacologia , Camundongos , Células Fotorreceptoras , Células Fotorreceptoras de Vertebrados , Retinose Pigmentar/tratamento farmacológico
3.
Carbohydr Polym ; 241: 116326, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32507202

RESUMO

Two polysaccharides, named DOP-1 and DOP-2, with molecular weights of 6.8 kDa and 14.3 kDa, respectively, were isolated and purified from the stems of Dendrobium officinale. Monosaccharide composition, Fourier-transform infrared spectroscopy, methylation, and nuclear magnetic resonance analyses indicated that DOP-1 and DOP-2 may have a backbone consisted of →4)-ß-d-Glcp-(1→, →4)-ß-d-Manp-(1→, →4)-2-O-acetyl-ß-d-Manp-(1→ and →4)-3-O-acetyl-ß-d-Manp-(1→. In vivo assays showed that D. officinale polysaccharides (DOPs) exerted significant hypoglycemic effects accompanying increased serum insulin and glucagon-like peptide-1 (GLP-1) levels in streptozotocin-induced diabetic rats. Further in vitro experiments showed that DOP-induced GLP-1 secretion was inhibited by an intracellular calcium chelator, a Ca2+/calmodulin-dependent protein kinase (CaMK) II inhibitor, a specific calcium-sensing receptor antagonist, and a p38-mitogen-activated protein kinases (MAPK) inhibitor. These results indicated that DOPs may decrease fasting blood sugar levels by stimulating GLP-1 secretion and that intracellular DOP-induced GLP-1 secretion involved the Ca2+/calmodulin/CaMKII and MAPK pathways.


Assuntos
Dendrobium/química , Diabetes Mellitus Experimental/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes , Extratos Vegetais , Polissacarídeos , Animais , Linhagem Celular , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Secreção de Insulina , Masculino , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Bioorg Med Chem ; 27(17): 3846-3852, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31324565

RESUMO

The stems of Dryopteris crassirhizoma, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin ABBA is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin ABBA and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 µM), it was very exciting that dryocrassin ABBA and its analogues (b5 and e2) showed better NAs inhibitory activity against Anhui H7N9 with IC50 values of 3.6 µM, 2.5 µM and 1.6 µM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin ABBA and its analogues especially AB, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.


Assuntos
Antivirais/farmacologia , Compostos de Benzilideno/farmacologia , Cicloexanonas/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Subtipo H7N9 do Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Cicloexanonas/síntese química , Cicloexanonas/química , Relação Dose-Resposta a Droga , Dryopteris/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Subtipo H7N9 do Vírus da Influenza A/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-Atividade
5.
Fitoterapia ; 129: 241-248, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30055233

RESUMO

Ten previously undescribed stilbenoids, including six bibenzyls (bleochrins A-F, 1-6), three phenanthrenes derivatives (bleochrins G-J, 7-10) along with eleven known compounds were isolated from the rhizomes of Bletilla ochracea Schltr. The structural characterizations of 1-21 were accomplished by spectroscopic data, while the absolute stereostructure of 6 was confirmed by electronic circular dichroism (ECD) data analyses. All isolated metabolites except 7 were evaluated for cytotoxic activity against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480). Four isolates exhibited significant inhibitory ability against HL-60, SMMC-7721, and MCF-7 cell lines, with IC50 values ranging from 0.79 to 6.57 µM. The isolates were tested further for inhibitory effects on the NO production of the liposaccharide (LPS)-induced RAW264.7 macrophages and showed activity with IC50 values at 15.29-24.02 µM.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Bibenzilas/farmacologia , Orchidaceae/química , Fenantrenos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Bibenzilas/isolamento & purificação , Linhagem Celular Tumoral , China , Humanos , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Fenantrenos/isolamento & purificação , Células RAW 264.7 , Rizoma/química
6.
Int J Mol Sci ; 13(11): 15162-76, 2012 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-23203117

RESUMO

Proteinase inhibitors play an important role in plant resistance of insects and pathogens. In this study, we characterized the serine proteinase inhibitor SaPIN2b, which is constitutively expressed in Solanum americanum trichomes and contains two conserved motifs of the proteinase inhibitor II (PIN2) family. The recombinant SaPIN2b (rSaPIN2b), which was expressed in Escherichia coli, was demonstrated to be a potent proteinase inhibitor against a panel of serine proteinases, including subtilisin A, chymotrypsin and trypsin. Moreover, rSaPIN2b also effectively inhibited the proteinase activities of midgut trypsin-like proteinases that were extracted from the devastating pest Helicoverpa armigera. Furthermore, the overexpression of SaPIN2b in transgenic tobacco plants resulted in enhanced resistance against H. armigera. Taken together, our results demonstrated that SaPIN2b is a potent serine proteinase inhibitor that may act as a protective protein in plant defense against insect attacks.


Assuntos
Proteínas de Plantas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Solanum/química , Tricomas/química , Sequência de Aminoácidos , Animais , Relação Dose-Resposta a Droga , Expressão Gênica , Dados de Sequência Molecular , Mariposas/enzimologia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/isolamento & purificação , Plantas Geneticamente Modificadas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Alinhamento de Sequência , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/isolamento & purificação , Nicotiana/genética , Nicotiana/parasitologia
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