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1.
Stem Cell Res Ther ; 11(1): 113, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32169098

RESUMO

OBJECTIVES: Microvesicles (MVs) derived from human Wharton's jelly mesenchymal stem cells (MSC-MVs) were demonstrated to ameliorate acute lung injury (ALI). We have previously found that MSC-MV-transferred hepatocyte growth factor was partly involved in their therapeutic effects. Since MSC-MVs also contained a substantial quantity of miR-100, which plays an important role in lung cancer and injury, we speculated that miR-100 might similarly account for a part of the therapeutic effects of MSC-MVs. METHODS: MSCs were transfected with miR-100 inhibitor to downregulate miR-100 in MSC-MVs. A rat model of ALI and cell injury in rat type II alveolar epithelial cell line (L2) was induced by bleomycin (BLM). A co-culture model of alveolar epithelial cells and MSC-MVs was utilized to examine the therapeutic role of MSC-MVs and mechanism. RESULTS: MSC-MV treatment attenuated BLM-induced apoptosis and inflammation in BLM-treated L2 cells and ameliorated BLM-induced lung apoptosis, inflammation, and fibrosis in BLM-induced ALI rats. The beneficial effect of MSC-MVs was partly eliminated when miR-100 was knocked down in MSCs. Moreover, MSC-MV-transferred miR-100 mediated the therapeutic effect of MSC-MVs in ALI through enhancing autophagy by targeting mTOR. CONCLUSION: MSC-MVs enhance autophagy and ameliorate ALI partially via delivery of miR-100.


Assuntos
Lesão Pulmonar Aguda , Células-Tronco Mesenquimais , MicroRNAs , Geleia de Wharton , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Animais , Autofagia , Humanos , MicroRNAs/genética , Ratos
2.
Cell Physiol Biochem ; 50(5): 1617-1637, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30384356

RESUMO

BACKGROUND/AIMS: Heat stress could cause huge losses for Lentinula edodes in China and other Asian cultivation areas. Yet our understanding of mechanism how to defend to heat stress is incomplete. METHODS: Using heat-tolerant and heat-sensitive strains of L. edodes, we reported a combined proteome and transcriptome analysis of L. edodes response to 40 °C heat stress for 24 h. Meanwhile, the effect of LeDnaJ on the thermotolerance and IAA (indoleacetic acid) biosynthesis in L. edodes was analyzed via the over-expression method. RESULTS: The proteome results revealed that HSPs (heat shock proteins) such as Hsp40 (DnaJ), Hsp70, Hsp90 and key enzymes involved in tryptophan and IAA metabolism process LeTrpE, LeTrpD, LeTam-1, LeYUCCA were more highly expressed in S606 than in YS3357, demonstrating that HSPs and tryptophan as well as IAA metabolism pathway should play an important role in thermotolerance. Over-expression of LeDnaJ gene in S606 strains showed better tolerance to heat stress. It was also documented that intracellular IAA accumulation of S606 (8-fold up) was more than YS3357 (2-fold up), and exogenous IAA enhanced L. edodes tolerance to heat stress. CONCLUSION: Our data support the interest of LeTrpE, LeDnaJ, tryptophan and IAA could play a pivotal role in enhancing organism thermotolerance.


Assuntos
Agaricales/metabolismo , Proteínas de Choque Térmico/metabolismo , Ácidos Indolacéticos/metabolismo , Proteoma/metabolismo , Termotolerância , Transcriptoma , Agaricales/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Perfilação da Expressão Gênica , Proteínas de Choque Térmico/genética , Temperatura Alta , Micélio/crescimento & desenvolvimento , Micélio/metabolismo , Isoformas de Proteínas/metabolismo , Proteoma/análise , Proteômica , Termotolerância/genética , Triptofano/metabolismo
3.
Pain ; 158(1): 130-139, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27749604

RESUMO

Accumulating evidence has demonstrated that epigenetic modification-mediated changes in pain-related gene expressions play an important role in the development and maintenance of neuropathic pain. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is involved in the development of chronic pain. Moreover, SIRT1 may be a novel therapeutic target for the prevention of type 2 diabetes mellitus (T2DM). But the role of SIRT1 in T2DM-induced neuropathic pain remains unknown. In this study, we found that spinal SIRT1 expression and activity were downregulated significantly in high-fat-fed/low-dose streptozotocin-induced neuropathic pain rats. SIRT1 localized in spinal neurons but not in astrocytes or microglia. Furthermore, the expressions of metabotropic glutamate receptor (mGluR1) and mGluR5, which play a key role in central sensitization and neuropathic pain, and H3 acetylation levels at Grm1/5 (encoding mGluR1/5) promoter regions were increased in diabetic neuropathic pain rats. SIRT1 activator SRT1720 reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal activation in diabetic neuropathic pain rats. Concurrently, increased expressions of mGluR1/5 and H3 acetylation levels at Grm1/5 promoter regions were reversed by SIRT1 activation. In addition, knockdown of SIRT1 by Ad-SIRT1-shRNA induced pain behaviors and spinal neuronal activation in normal rats, which was accompanied by the increased expressions of mGluR1/5 and H3 acetylation levels at Grm1/5 promoter regions. Therefore, we concluded that SIRT1-mediated epigenetic regulation of mGluR1/5 expressions was involved in the development of neuropathic pain in type 2 diabetic rats.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Regulação da Expressão Gênica/genética , Neuralgia/etiologia , Neuralgia/patologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sirtuína 1/metabolismo , Animais , Astrócitos/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Hiperalgesia/diagnóstico , Hiperalgesia/etiologia , Hiperglicemia/etiologia , Hiperglicemia/fisiopatologia , Masculino , Neuralgia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/genética , Receptores de Glutamato Metabotrópico/genética , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Medula Espinal/metabolismo , Medula Espinal/patologia , Estreptozocina/toxicidade
4.
Protein Expr Purif ; 136: 66-72, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26518366

RESUMO

Esterases (EC 3.1.1.X) have been used as biocatalysts due to their good stability, high chemo-, regio- and stereoselectivity. In our previous studies, Bacillus megaterium WZ009 harboring esterase displayed the unique capability to convert (S)-4-Chloro-3-hydroxyethylbutyrate (CHBE) in the racemate to (S)-3-hydroxy-γ-butyrolactone (HL) through stereoselective hydrolysis, dechlorination, and lactonization. The remaining (R)-CHBE and formed (S)-HL could be obtained in a one-pot enzymatic reaction. An esterase from B. megaterium WZ009 was purified and was found to have 466 encoded amino acids and an apparent molecular mass of 55 kDa. The purified esterase exhibited maximal activity at a temperature of 25 °C and at a pH of 11.5 towards 100 mM CHBE. When the stereoselective biocatalysis of rac-CHBE was performed using the recombinant Escherichia coli BL21 (DH3) cells harboring the esterase, the catalytic activity increased by 20-fold compared with the original strain B. megaterium WZ009. With the addition of activated carbon (62 g/L) in the reaction system, the conversion was increased from 39% to 45% at a substrate concentration of 750 mM. Another remarkable advantage is that both of the obtained residual (R)-CHBE and the formed (S)-HL had high optical purities (e.e.s > 99.9%, e.e.p > 99.9%), thereby making this esterase a usable biocatalyst for industrial application.


Assuntos
Bacillus megaterium , Proteínas de Bactérias , Clonagem Molecular , Esterases , Expressão Gênica , Bacillus megaterium/enzimologia , Bacillus megaterium/genética , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Esterases/biossíntese , Esterases/química , Esterases/genética , Esterases/isolamento & purificação , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação
5.
Bioorg Med Chem ; 22(14): 3620-8, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24882676

RESUMO

3-Arylfuran-2(5H)-one, a novel antibacterial pharmacophore targeting tyrosyl-tRNA synthetase (TyrRS), was hybridized with the clinically used fluoroquinolones to give a series of novel multi-target antimicrobial agents. Thus, twenty seven 3-arylfuran-2(5H)-one-fluoroquinolone hybrids were synthesized and evaluated for their antimicrobial activities. Some of the hybrids exhibited merits from both parents, displaying a broad spectrum of activity against resistant strains including both Gram-negative and Gram-positive bacteria. The most potent compound (11) in antibacterial assay shows MIC50 of 0.11µg/mL against Multiple drug resistant Escherichia coli, being about 51-fold more potent than ciprofloxacin. The enzyme assays reveal that 11 is a potent multi-target inhibitor with IC50 of 1.15±0.07µM against DNA gyrase and 0.12±0.04µM against TyrRS, respectively. Its excellent inhibitory activities against isolated enzymes and intact cells strongly suggest that 11 deserves to further research as a novel antibiotic.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Furanos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Fluoroquinolonas/química , Furanos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 80: 92-100, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24769347

RESUMO

Based on a rationally conceived pharmacophore model to build a multi-target bacterial topoisomerase inhibitor, twenty-one fluoroquinolone-flavonoid hybrids were synthesized. Some obtained hybrids show excellent antibacterial activity against drug-resistant microorganisms with narigenin-ciprofloxacin being the most active, showing 8, 43, 23 and 88 times better activity than ciprofloxacin against Escherichia coli ATCC 35218, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25923 and Candida albicans ATCC 90873, respectively. Drug accumulation and DNA supercoiling assays of two active analogues revealed potent inhibition of both the DNA gyrase and efflux pump, confirming the desired dual mode of action. Molecular docking study disclosed that the introduced flavonoid moiety not only provides several additional interactions but also does not disturb the binding mode of the floxacin moiety. Our data also demonstrated that development of antifungals is possible from fluoroquinolones modified at C-7 position.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Flavonoides/química , Fluoroquinolonas/química , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Candida albicans/efeitos dos fármacos , Técnicas de Química Sintética , DNA Girase/química , DNA Girase/metabolismo , DNA Super-Helicoidal/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Conformação Proteica , Relação Estrutura-Atividade
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