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1.
Chem Biol Interact ; 314: 108848, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610156

RESUMO

Cardiomyocyte injury induced by acute myocardial infarction contributes to myocardial dysfunction. Accumulating evidence has demonstrated that pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a cytoprotective protein that protects against various adverse injuries. However, whether PHLPP2 participates in regulating myocardial-infarction-induced cardiomyocyte injury remains unknown. In the present study, we aimed to investigate the biological role and molecular mechanism of PHLPP2 in regulating hypoxia-induced cardiomyocyte injury. Cardiomyocytes were cultured in an anaerobic chamber for 24 h to induce hypoxic injury in vitro. The expression of PHLPP2 was determined by real-time quantitative PCR and Western blot analysis. Cell viability was measured by MTT assay. Cell apoptosis was assessed by TUNEL and caspase-3 activity assays. Intracellular reactive oxygen species (ROS) levels were measured by DCFH-DA probe. PHLPP2 expression was highly upregulated in hypoxia-injured cardiomyocytes. Inhibition of PHLPP2 by small interfering RNA (siRNA)-mediated gene silencing significantly improved the viability of hypoxia-injured cardiomyocytes and attenuated hypoxia-induced apoptosis and ROS production. In contrast, PHLPP2 overexpression exacerbated hypoxia-induced apoptosis and ROS production in cardiomyocytes. Mechanism research revealed that PHLPP2 silencing increased the phosphorylation of glycogen synthase kinase (GSK)-3ß and promoted the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, PHLPP2 inhibition promoted Nrf2/antioxidant response element (ARE) transcriptional activity. However, Nrf2 silencing markedly reversed PHLPP2-inhibition-mediated cardioprotection, while GSK-3ß inhibition partially blocked the PHLPP2-overexpression-induced adverse effect. Taken together, these findings demonstrate that PHLPP2 inhibition alleviates hypoxia-induced cardiomyocyte injury by reinforcing Nrf2/ARE antioxidant signaling via inactivating GSK-3ß, a pathway that highlights the importance of the PHLPP2/GSK-3ß/Nrf2/ARE signaling axis in regulation of cardiomyocyte injury. Our study suggests a potential relevance for PHLPP2 in acute myocardial infarction, and this protein may serve as a promising target for cardioprotection.


Assuntos
Elementos de Resposta Antioxidante/genética , Hipóxia Celular , Fator 2 Relacionado a NF-E2/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/genética , Fosforilação , Pirimidinas/farmacologia , Pirróis/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Lett Appl Microbiol ; 69(4): 294-301, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31424588

RESUMO

Saccharothrix algeriensis NRRL B-24137 is an actinobacterium isolated from Algerian Saharan soil. It produces bioactive compounds belonging to the dithiolopyrrolone class of antibiotics, which are characterized by the possession of a unique pyrrolinonodithiole nucleus. Dithiolopyrrolones are known for their strong antibacterial and antifungal activities. This class of antibiotics generated great interest after the discovery of their anticancer properties. In this study, an antibiotic named PR11, produced after a long bacterial fermentation (11 days) in sorbic acid-containing culture broth, was characterized as a new dithiolopyrrolone derivative. After HPLC analysis and purification, the chemical structure of this antibiotic was determined by 1 H- and 13 C-nuclear magnetic resonance, mass and UV-visible data. PR11 was thus characterized as an iso-hexanoyl-pyrrothine, a novel dithiolopyrrolone derivative. The minimum inhibitory concentrations of the new induced antibiotic were determined against several pathogenic micro-organisms. A moderate to strong activity was noted against all Gram-positive bacteria, filamentous fungi and yeasts tested. SIGNIFICANCE AND IMPACT OF THE STUDY: Given the strong activities of dithiolopyrrolones against diverse prokaryotic and eukaryotic micro-organisms including potent selective-anticancer activity, the discovery of new-related derivatives draw continuous attention for therapeutic research. Depending on nature and concentration of added precursor, Saccharothrix algeriensis NRRL B-24137 produce several dithiolopyrrolone coumpounds. In this study, sorbic acid addition combined to long fermentation duration was shown to induce the biosynthesis of a novel dithiolopyrrolone derivative. After purification and full spectroscopic and spectrometric study, the compound was characterized as iso-hexanoyl-pyrrothine. In the future investigation for novel dithiolopyrrolone discovery, fermentation duration should be regarded as a key parameter as well.


Assuntos
Actinobacteria/metabolismo , Anti-Infecciosos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pirróis/farmacologia , Fermentação , Testes de Sensibilidade Microbiana , Ácido Sórbico/metabolismo
3.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
4.
Life Sci ; 235: 116791, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31465732

RESUMO

AIMS: Prostate cancer (PCa) incidence rates are rising in China currently. Cancer-associated fibroblasts (CAFs), as a major component of tumor microenvironment, are crucial for tumor progression. This study was aimed to explore the promotion effect of patient-derived CAFs on the proliferation and migration of prostate cancer cells. MAIN METHODS: CAFs were isolated from tumor tissues of PCa patients. The promotion effect of CAFs on the proliferation and migration of PC-3 and LNCaP cells were evaluated in vitro and in vivo. The concentration of TGF-ß1 was measured by Luminex assay. The blocking activity of LY2109761 on the promotion effect of CAFs was also evaluated. KEY FINDINGS: CAFs could significantly promote the proliferation and migration of PC-3 and LNCaP cells both in vitro and in vivo. TGF-ß1 was identified as a highly increased factor in CAFs-CM compared with the normal culture medium of these two cancer cell lines. TGF-ß receptor inhibitor LY2109761 could suppress the CAFs-induced cellular proliferation and migration of PC-3 cells but not LNCaP cells. SIGNIFICANCE: Our study suggested a crucial role for CAFs and TGF-ß signaling in the progression of PCa. Zebrafish xenograft model was an ideal animal model for the study of CAFs and cancer cell interaction.


Assuntos
Fibroblastos Associados a Câncer , Movimento Celular , Proliferação de Células , Embrião não Mamífero/patologia , Neoplasias da Próstata/patologia , Pirazóis/farmacologia , Pirróis/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
5.
Pestic Biochem Physiol ; 158: 18-24, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378355

RESUMO

Outbreaks of bitter rot were observed in three commercial apple orchards in Illinois despite best management efforts during the 2018 production season. Three isolates from symptomatic fruit from these orchards and two isolates from an orchard in South Carolina were identified to the species level using morphological tools and calmodulin, glyceraldehyde-3-phosphate dehydrogenase, and beta-tubulin gene sequences. The isolates from Illinois were identified as Colletotrichum siamense of the Colletotrichum gloeosporioides species complex and the ones from South Carolina as Colletotrichum fioriniae and Colletotrichum fructicola of the Colletotrichum acutatum and the C. gloeosporioides species complex, respectively. Two of the three C. siamense isolates from Illinois were resistant to azoxystrobin and thiophanate-methyl as determined in mycelial growth tests in vitro. EC50 values were >100 µg/ml for both fungicides. One isolate was only resistant to azoxystrobin. None of the isolates from South Carolina was resistant to either of the two compounds. All five isolates were sensitive to fludioxonil (EC50 values <0.1 µg/ml), propiconazole (EC50 values ranged from 0.15 to 0.36 µg/ml), and benzovindiflupyr (EC50 values ranged from <0.1 to 0.33 µg/ml). Resistance in C. siamense to azoxystrobin and thiophanate-methyl was confirmed in detached fruit studies using apples treated with label rates of registered product. Resistance to thiophanate-methyl in C. siamense was based on E198A mutation in b-tubulin gene, whereas resistance to azoxystrobin was based on G143A in cytochrome b (CYTB). One isolate resistant to azoxystrobin possessed no amino acid variation in CYTB. This study shows that quinone outside inhibitor fungicide resistance in Colletotrichum from apple has emerged and is being selected for in Illinois apple orchards by current spray strategies. Resistance monitoring may alert growers to potential threats, but the employment of molecular tools based on current knowledge of resistance mechanisms will provide incomplete results.


Assuntos
Colletotrichum/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Malus/microbiologia , Benzimidazóis/farmacologia , Colletotrichum/genética , Citocromos b/genética , Citocromos b/metabolismo , Dioxóis/farmacologia , Farmacorresistência Fúngica/genética , Frutas/microbiologia , Malus/genética , Norbornanos/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Estrobilurinas/farmacologia , Tiofanato/farmacologia , Triazóis/farmacologia
6.
Gene ; 717: 144047, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31421190

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways play important roles in the formation of the blood vascular system and nervous system across animal phyla. We have earlier reported VEGF and FGF from Hydra vulgaris Ind-Pune, a cnidarian with a defined body axis, an organized nervous system and a remarkable ability of regeneration. We have now identified three more components of VEGF and FGF signaling pathways from hydra. These include FGF-1, FGF receptor 1 (FGFR-1) and VEGF receptor 2 (VEGFR-2) with a view to deciphering their possible roles in regeneration. METHODS: In silico analysis of proteins was performed using Clustal omega, Swiss model, MEGA 7.0, etc. Gene expression was studied by whole mount in situ hybridization. VEGF and FGF signaling was inhibited using specific pharmacological inhibitors and their effects on head regeneration were studied. RESULTS: Expression patterns of the genes indicate a possible interaction between FGF-1 and FGFR-1 and also VEGF and VEGFR-2. Upon treatment of decapitated hydra with pharmacological inhibitor of FGFR-1 or VEGFR-2 for 48 h, head regeneration was delayed in treated as compared to untreated, control regenerates. When we studied the expression of head specific genes HyBra1 and HyKs1 and tentacle specific gene HyAlx in control and treated regenerates using whole mount in situ hybridization, expression of all the three genes was found to be adversely affected in treated regenerates. CONCLUSIONS: The results suggest that VEGF and FGF signaling play important roles in regeneration of hypostome and tentacles in hydra.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Cabeça/fisiologia , Hydra/fisiologia , Regeneração/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Simulação por Computador , Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Hydra/efeitos dos fármacos , Indóis/farmacologia , Domínios Proteicos , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais , Homologia Estrutural de Proteína , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Eur J Med Chem ; 179: 591-607, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279293

RESUMO

Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. ß-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a ß-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on ß-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous ß-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.


Assuntos
Benzodiazepinas/farmacologia , Dipeptídeos/farmacologia , Glucuronídeos/farmacologia , Imunoconjugados/farmacologia , Pirróis/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Glucuronídeos/química , Humanos , Imunoconjugados/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 307-312, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167689

RESUMO

Objective To explore the effect of pexidartinib on the recruitment of monocytes into the tumor microenvironment and the polarization of M2 macrophages. Methods The colon cancer mouse model was established with the subcutaneous rejection of MC38 cells. After the tumor-bearing mice were treated with pexidartinib, we observed the effects of pexidartinib on the tumor growth, the survival of tumor-bearing mouse and the number of intratumoral tumor-associated macrophages (TAMs). Peripheral blood mononuclear cells were isolated from the enhanced green fluorescent protein (EGFPTg/+) transgenic mice and then transferred into the tumor-bearing mice via tail vein. After the tumor-bearing mice were treated with pexidartinib, the monocyte recruitment and the proportions of F4/80 and CD206-positive cells were detected by the immunofluorescence and flow cytometry. Results Pexidartinib alleviated the growth of MC38 cells in vivo and improved the survival rate in tumor-bearing mice. Pexidartinib reduced the number of TAMs and the formation of M2 TAMs in the tumor microenvironment, and inhibited the recruitment of monocytes from peripheral blood to the tumor microenvironment. Conclusion Pexidartinib can inhibit the tumor growth by suppressing the aggregation of macrophages and the number of M2 TAMs in the tumor microenvironment.


Assuntos
Aminopiridinas/farmacologia , Neoplasias do Colo/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Pirróis/farmacologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Citometria de Fluxo , Leucócitos Mononucleares , Camundongos
10.
Cell Prolif ; 52(4): e12637, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168899

RESUMO

OBJECTIVES: Chondrocyte proliferation and differentiation are crucial for endochondral ossification, but their regulatory mechanism remains unclear. The present study aimed to determine the physiological function of TGFß1 signalling in the proliferation and differentiation of antler chondrocytes and explore its relationship with Notch, Shh signalling and Foxa. MATERIALS AND METHODS: Immunofluorescence, Western blot, MTS assay, flow cytometry, RNA interference and real-time PCR were used to analyse the function and regulatory mechanisms of TGFß1 signalling in antler chondrocyte proliferation and differentiation. RESULTS: TGFß1, TGFBR1 and TGFBR2 were highly expressed in antler cartilage. TGFß1 promoted chondrocyte proliferation, increased the proportion of S-phase cells and induced the expression of hypertrophic chondrocyte markers Col X, Runx2 and Alpl. However, this induction was weakened by TGFß receptor inhibitor SB431542 and Smad3 inhibitor SIS3. Simultaneously, TGFß1 activated Notch and Shh signalling whose blockage attenuated the above effects of rTGFß1, whereas addition of rShh rescued the defects in chondrocyte proliferation and differentiation elicited by SB431542 and SIS3. Further analysis revealed that inhibition of Notch signalling impeded TGFß1 activation of the Shh pathway. Knockdown of Foxa1, Foxa2 and Foxa3 abrogated the effects of TGFß1 on chondrocyte differentiation. Notch and Shh signalling mediated the regulation of Foxa transcription factors by TGFß1. CONCLUSIONS: TGFß1 signalling could induce the proliferation and differentiation of antler chondrocytes through Notch-Shh-Foxa pathway.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Chifres de Veado , Benzamidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Dioxóis/farmacologia , Proteínas Hedgehog/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Isoquinolinas/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Notch/metabolismo , Fase S/efeitos dos fármacos , Fase S/fisiologia , Transdução de Sinais/efeitos dos fármacos
11.
Eur J Med Chem ; 178: 329-340, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200235

RESUMO

A novel series of 6-substituted pyrrolo[2,3-d]pyrimidines with reversed amide moieties from the lead compound 1a were designed and synthesized as nonclassical antifolates and as potential antitumor agents. Target compounds 1-9 were successfully obtained through two sequential condensation reactions from the key intermediate 2-amino-6-(2-aminoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. In preliminary antiproliferation assay, all compounds demonstrated submicromolar to nanomolar inhibitory effects against KB tumor cells, whereas compounds 1-3 also exhibited nanomolar antiproliferative activities toward SW620 and A549 cells. In particular, compounds 1-3 were significantly more potent than the positive control methotrexate (MTX) and pemetrexed (PMX) to A549 cells. The growth inhibition induced cell cycle arrest at G1-phase with S-phase suppression. Along with the results of nucleoside protection assays, inhibition assays of dihydrofolate reductase (DHFR) clearly elucidated that the intracellular target of the designed compounds was DHFR. Molecular modeling studies suggested two binding modes of the target compounds with DHFR.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Humanos , Células KB , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 178: 500-514, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202995

RESUMO

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pirróis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197089

RESUMO

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.


Assuntos
Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptor PAR-1/metabolismo , Transdução de Sinais , Trombina/farmacologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Quinazolinas/farmacologia , Receptor PAR-1/agonistas , Receptor PAR-1/antagonistas & inibidores , Proteínas de Transporte Vesicular/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo
14.
Drug Discov Today Technol ; 31: 109-123, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31200854

RESUMO

The Ubiquitin/Proteasome System comprises an essential cellular mechanism for regulated protein degradation. Ubiquitination may also promote the assembly of protein complexes that initiate intracellular signaling cascades. Thus, proper regulation of substrate protein ubiquitination is essential for maintaining normal cellular physiology. Deubiquitinases are the class of enzymes responsible for removing ubiquitin modifications from target proteins and have been implicated in regulating human disease. As such, deubiquitinases are now recognized as emerging drug targets. Small molecule deubiquitinase inhibitors have been developed; among those, inhibitors for the deubiquitinases USP7 and USP14 are the best-characterized given that they are structurally validated. In this review we discuss the normal physiological roles of the USP7 and USP14 deubiquitinases as well as the pathological conditions associated with their dysfunction, with a focus on oncology and neurodegenerative diseases. We also review structural biology of USP7 and USP14 enzymes and the characterization of their respective inhibitors, highlighting the various molecular mechanisms by which these deubiquitinases may be functionally inhibited. Finally, we summarize the cellular and in vivo studies performed using the structurally-validated USP7 and USP14 inhibitors.


Assuntos
Pirróis/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Pirróis/química , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/metabolismo
15.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
16.
Mater Sci Eng C Mater Biol Appl ; 102: 164-170, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146987

RESUMO

Antimicrobial textiles can contribute to the fighting against antibiotic resistance pathogenic microorganisms. Polypyrrole is a conjugated polymer that exerts a biocidal action thanks to positive charges on its backbone chain produced during it synthesis. In this work, dispersions of stable polypyrrole nanoparticles were produced by chemical oxidative polymerization at room temperature in water. An ultrasound-assisted coating process was then used to effectively treat a polyester fabric with the nanoparticles to obtain an optimal antibacterial coating which efficiently eradicates the bacteria. The results showed that the treated fabric with about 4 g/m2 of polypyrrole had log bacteria reductions of 6.0 against Staphylococcus aureus and 7.5 against Escherichia coli. The combination of a polypyrrole synthesis in the form of water nanoparticles dispersions and a continuous coating of fabrics supported by ultrasound overcomes some issues of upscaling of the traditional in-situ chemical deposition used until now for the production of polypyrrole-coated textiles.


Assuntos
Antibacterianos/farmacologia , Polímeros/farmacologia , Pirróis/farmacologia , Têxteis , Ultrassom , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanopartículas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Termogravimetria , Viscosidade
17.
J Nat Med ; 73(4): 769-776, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31209724

RESUMO

Six new pyrrole 2-carbaldehyde derived alkaloids, dahurines A-F (1-6), along with five known ones (7-11) and butyl 2-pyrrolidone-5-carboxylate (12) were isolated from the roots of Angelica dahurica. Their structures were determined by extensive spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) methods. Although compounds 7 and 8 have been chemically synthesized, they were obtained from natural materials for the first time. Compounds 2, 3, 4, 10, and 11 exhibited acetylcholinesterase inhibitory activity with IC50 values in the range of 47.5-52.5 µM. Pyrrole 2-carbaldehyde derived alkaloids from the roots of Angelica dahurica.


Assuntos
Alcaloides/química , Angelica/química , Inibidores da Colinesterase/farmacologia , Raízes de Plantas/química , Pirróis/farmacologia , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/isolamento & purificação , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirróis/isolamento & purificação
18.
Crit Rev Oncol Hematol ; 140: 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154235

RESUMO

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


Assuntos
Anoikis , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/fisiopatologia , Berberina/farmacologia , Berberina/uso terapêutico , Clorobenzoatos/farmacologia , Clorobenzoatos/uso terapêutico , Feminino , Humanos , Piranos/farmacologia , Piranos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Saponinas/farmacologia , Saponinas/uso terapêutico , Estirenos/farmacologia , Estirenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
19.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
20.
J Exp Clin Cancer Res ; 38(1): 220, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126320

RESUMO

BACKGROUND: Androgen receptor (AR) is expressed in approximately 70% of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer. The current study aims to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with USP14 inhibition on breast cancer cells. METHODS: The combining effects of enzalutamide and USP14 inhibition on breast cancer cell proliferation and apoptosis and associated cell signaling were evaluated in vitro and in vivo. RESULTS: USP14 inhibition via administration of IU1 or USP14-specific siRNA/shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo. Additionally, the combination of enzalutamide with USP14 inhibition/knockdown induced significant downregulation of AR proteins and suppression of AR-related signaling pathways, including Wnt/ß-catenin and PI3K/AKT pathways. Moreover, AKT inhibition via MK2206 increased the antiproliferative and proapoptotic effects of enzalutamide+IU1 combined treatment. CONCLUSION: Collectively, our data suggest that USP14 inhibition in combination with enzalutamide represents a potentially new therapeutic strategy for breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Pirróis/administração & dosagem , Pirrolidinas/administração & dosagem , Ubiquitina Tiolesterase/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Células MCF-7 , Camundongos , Feniltioidantoína/administração & dosagem , Feniltioidantoína/farmacologia , Pirróis/farmacologia , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina Tiolesterase/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
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