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1.
Life Sci ; 234: 116792, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465733

RESUMO

AIMS: Assisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. MATERIALS AND METHODS: Human umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. KEY FINDINGS: In IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SIGNIFICANCE: The hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.


Assuntos
Angiotensina II/metabolismo , Metilação de DNA , Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Receptor Tipo 1 de Angiotensina/genética , Cordão Umbilical/irrigação sanguínea , Vasoconstrição , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Transferência Embrionária/efeitos adversos , Feminino , Fertilização In Vitro/efeitos adversos , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Gravidez , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 545-551, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292059

RESUMO

Objective To illuminate whether IL-17 regulates receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) expression in human periodontal ligament fibroblasts (HPDLFs) via p38MAPK signaling pathway. Methods HPDLFs were incubated in the presence of 20 ng/mL IL-17 for 0, 20, 40, 60 and 80 minutes. HPDLFs were divided randomly into 6 groups: control group, dimethyl sulfoxide (DMSO) group, p38MAPK pathway inhibitor SB203580 group, IL-17 group, IL-17 combined with DMSO group and IL-17 combined with SB203580 group. SB203580 (10 µmol/L) and IL-17 (20 ng/mL) were added to the corresponding groups. Real-time quantitative PCR was used to detect the expression of RANKL and OPG mRNAs in HPDLFs. The levels of phospho-p38MAPK (p-p38MAPK) and RANKL protein were measured using Western blot analysis. The protein level of OPG was detected by ELISA. Results After IL-17 stimulation, the expression level of p-p38MAPK protein gradually increased starting from 0 minute and reached its highest level at 60 minutes. It started to decline at 80 minutes. Stimulation with IL-17 could increase the mRNA and protein expression level of RANKL but decrease the mRNA and protein expression level of OPG. Nevertheless, unlike the IL-17 group, IL-17 combined with inhibitor SB203580 decreased the expression of RANKL mRNA and protein and increased OPG mRNA. Conclusion IL-17 can enhance the expression of RANKL in human periodontal fibroblasts and inhibit the expression of OPG mRNA through the p38MAPK signal transduction pathways.


Assuntos
Fibroblastos/citologia , Interleucina-17/farmacologia , Sistema de Sinalização das MAP Quinases , Osteoprotegerina/metabolismo , Ligamento Periodontal/citologia , Ligante RANK/metabolismo , Células Cultivadas , Dimetil Sulfóxido/farmacologia , Humanos , Imidazóis/farmacologia , Piridinas/farmacologia , Distribuição Aleatória , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Eur J Med Chem ; 179: 470-482, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271959

RESUMO

A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Receptor trkB/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Glicoproteínas de Membrana/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Receptor trkB/metabolismo , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
4.
Anticancer Res ; 39(7): 3803-3808, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262907

RESUMO

BACKGROUND: Platinum-based therapy represents the main pharmacological treatment for ovarian carcinoma. Since molecular targeting of receptor tyrosine kinases (RTK) affects factors that may modulate drug response, the aim of this study was to examine whether downstream targets of AXL RTK could be exploited to improve cell response to cisplatin. MATERIALS AND METHODS: Inhibitors of p38 (SB203580) and of signal transducer and activator of transcription 3 (stattic) were employed in combination with cisplatin in ovarian carcinoma cell lines. Apoptosis assay and western blot analysis were performed to evaluate cell response after treatment. RESULTS: SB203580 produced a synergistic effect in combination with cisplatin in cisplatin-resistant IGROV-1/Pt1 cells. In addition, a favorable drug interaction was observed in A2780 cells when pre-incubated with cisplatin prior to stattic. The analysis of cell response after combined treatment showed down-regulation of the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). CONCLUSION: Our results support the notion that downstream targets of AXL in ovarian carcinoma cells can be exploited to increase cisplatin activity in ovarian carcinoma models.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Imidazóis/farmacologia , Neoplasias Ovarianas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3
5.
Int J Nanomedicine ; 14: 3955-3966, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239665

RESUMO

Background: Sulconazole (SCZ) is a broad-spectrum transdermally administered anti-fungicidal agent. However, the therapeutic effect of SCZ is generally limited by its poor water solubility. This present study aimed to develop and evaluate sulconazole-loaded nanoemulsions (SCZ-NEs) for enhancement of the transdermal permeation and antifungal activity. Methods: A spontaneous titration method was applied to prepare the SCZ-NEs. And the optimized formulation of SCZ-NEs was screened by central composite design (CCD). In addition, the characteristics of the SCZ-NEs were evaluated, including particle size, zeta potential, drug loading (DL%) and encapsulation efficiency (EE%). The morphology of SCZ-NEs was observed by transmission electron microscopy (TEM). Franz diffusion cells were used to evaluate the transdermal permeability of the SCZ-NEs. The antifungal activity of the SCZ-NEs was measured by a zone of inhibition (ZOI) test. Results: The optimized SCZ-NEs possessed a moderate particle size of 52.3±3.8 nm, zeta potential of 23.3±1.2 mV, DL% of 0.47±0.05% and EE% of 87.1±3.2%. The ex vivo skin permeation study verified that the cumulative permeability (Qn) and penetration rate (Js) of the optimized SCZ-NEs were about 1.7-fold higher than that of a commercial reference, miconazole (MCZ) cream and 3-fold higher than that of SCZ-DMSO solution. The optimized SCZ-NEs exhibited zone of inhibition (ZOI) values of 23.5±2.4 and 20.4±2.5 mm against C. albicans and T. rubrum, which were larger compared with these of the MCZ cream and SCZ-DMSO solution. Conclusion: SCZ-NEs were effectively developed to overcome the poor solubility of SCZ, promote SCZ permeation through the skin and improve its antifungal activity. Thus, the SCZ-NEs are a promising percutaneous administration for skin fungal infections induced by C. albicans and T. rubrum.


Assuntos
Antifúngicos/farmacologia , Emulsões/química , Imidazóis/farmacologia , Nanopartículas/química , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Análise de Variância , Animais , Candida albicans/efeitos dos fármacos , Fungos/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura , Óleos/química , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Transição de Fase , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
6.
Eur J Med Chem ; 178: 39-47, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176094

RESUMO

Tuberculosis (TB) has recently become the leading killer among infectious diseases. Multidrug and extensively drug-resistant Mycobacterium tuberculosis strains urge the need to develop anti-TB drugs with a novel mechanism of action. We describe synthesis of 22 novel imidazo[1,2-b][1,2,4,5]tetrazine derivatives with different substituents at C(3) and C(6) positions, and their antimycobacterial activity in vitro. 8 compounds show activity as potential serine/threonine protein kinase (STPK) inhibitors in M. smegmatis aphVIII+ test-system, which is characteristic for this class. 3 compounds out of 5 most active STPK inhibitors have a prominent minimal inhibitory concentration on M. tuberculosis H37Rv of 1 µg/ml. We were able to obtain M. smegmatis mc2 155 mutants resistant to 4 compounds and show that they do not have cross resistance with other drugs, but have a common mechanism of resistance among these 4 imidazo[1,2-b][1,2,4,5]tetrazines. Compound 3h seems the most promising, combining a predicted STPK inhibitor activity, the lowest MIC on M. tuberculosis and a low frequency of drug resistant mutants' emergence.


Assuntos
Antituberculosos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Imidazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Eritromicina/farmacologia , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Imidazóis/síntese química , Imidazóis/química , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Ofloxacino/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Rifampina/farmacologia
7.
Life Sci ; 231: 116559, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200001

RESUMO

AIM: Previously, we reported that mice deficient in most of the Zfp521 coding region (Zfp521Δ/Δ mice) displayed abnormal behaviors, including hyperlocomotion and lower anxiety. In this study, we aimed to elucidate the involvement and mechanisms of monoamine variation. MAIN METHODS: First, we compared the levels of dopamine (DA), noradrenaline (NA), and serotonin in the brains of Zfp521Δ/Δ and Zfp521+/+ mice using enzyme-linked immunosorbent assay. Next, we elucidated the mechanisms using quantitative PCR and Western Blotting. Additionally, we administered inhibitory drug to the mice and performed behavioral tests. KEY FINDINGS: Our results showed that the DA level decreased and the NA level increased in Zfp521Δ/Δ mice. We found that ZFP521 suppresses the expression of dopamine ß-hydroxylase (DBH), which converts DA into NA. We also demonstrated that paired homeodomain transcription factor 2 and early growth response protein-1, which are the transcription factors for Dbh, were involved in the upregulation of Dbh by ZFP521. The administration of nepicastat, a specific inhibitor of DBH, attenuated the abnormal behaviors of Zfp521Δ/Δ mice. SIGNIFICANCE: These results suggest that the lack of ZFP521 upregulates the expression of DBH, which leads to a decrease in the DA level and an increase in the NA level in the brain, resulting in abnormal behaviors.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Fatores de Transcrição/deficiência , Animais , Encéfalo/enzimologia , Linhagem Celular Tumoral , Dopamina/metabolismo , Imidazóis/farmacologia , Locomoção/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Norepinefrina/metabolismo , Serotonina/metabolismo , Tionas/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Dedos de Zinco
8.
Eur J Med Chem ; 178: 715-725, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229874

RESUMO

A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.


Assuntos
Antituberculosos/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Relação Estrutura-Atividade
9.
J Appl Microbiol ; 127(3): 670-682, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165532

RESUMO

AIMS: Experiments were designed to determine the effects of different chemical inhibitors of lysozyme and peptidases on rumen protozoa and the associated prokaryotes, and in vitro fermentation using Entodinium caudatum as a model protozoan species. METHODS AND RESULTS: Imidazole (a lysozyme inhibitor), phenylmethylsulphonyl fluoride (PMSF, a serine peptidase inhibitor) and iodoacetamide (IOD, a cysteine peptidase inhibitor) were evaluated in vitro both individually and in two- and three-way combinations using E. caudatum monocultures with respect to their ability to inhibit the protozoan and their effect on feed digestion, fermentation and the microbiota. All the three inhibitors, both individually and in combination, decreased E. caudatum counts (P < 0·001), and IOD and its combinations with the other inhibitors significantly (P < 0·01) decreased ammonia concentration, with the two- and three-way combinations showing additive effective. Feed digestion was not affected, but fermentation and microbial diversity were affected mostly by PMSF, IOD and their combinatorial treatments potentially due to the overgrowth of Streptococcus luteciae accompanying with the disappearance of host ciliates. CONCLUSIONS: Entodinium caudatum depends on lysozyme and peptidase for digestion and utilization of the engulfed microbes and specific inhibition of these enzymes can inhibition E. caudatum without adversely affecting feed digestion or fermentation even though they changed the microbiota composition in the cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: The peptidase inhibitors may have the potential to be used in controlling rumen protozoa to improve ruminal nitrogen utilization efficiency.


Assuntos
Cilióforos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Muramidase/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Amônia/metabolismo , Animais , Cilióforos/enzimologia , Cilióforos/crescimento & desenvolvimento , Cilióforos/microbiologia , Digestão/efeitos dos fármacos , Fermentação/efeitos dos fármacos , Imidazóis/farmacologia , Iodoacetamida/farmacologia , Microbiota/efeitos dos fármacos , Fluoreto de Fenilmetilsulfonil/farmacologia , Rúmen/parasitologia
10.
Eur J Med Chem ; 179: 1-15, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31229883

RESUMO

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT6R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT6R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT6R and very high selectivity over 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Desenho de Drogas , Imidazóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Células Cultivadas , Disfunção Cognitiva/induzido quimicamente , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Escopolamina/administração & dosagem , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 179: 109-122, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247373

RESUMO

Toll-like receptors (TLRs) are promising targets for treatment of viral infections, autoimmune diseases, and cancers. Here, two new series of selective small-molecule TLR7 agonists with novel scaffolds and good selectivity over TLR8 are described, some with potencies in the low micromolar range. 8-Hydroxy-1-isobutylchromeno[3,4-d]imidazol-4(1H)-one (26) from the first series was designed and synthesized on the basis of previously described TLR7 antagonist 2, and is shown to be a selective TLR7 agonist (EC50, 1.8 µM). The second series was based on 2-(trifluoromethyl)quinolin-4-amine and 2-(trifluoromethyl)quinazolin-4-amine scaffolds, which were defined according to our in-house ligand-based virtual screening protocol. Further synthesis of a focused library of analogs, biological evaluation, and docking studies provided systematic exploration of the structure-activity relationships, which indicate that a secondary or tertiary amine with smaller flexible alkyl substituents up to three carbon atoms in length, or bulkier rigid aliphatic rings is required at position 4 on 2-(trifluoromethyl)quinoline/quinazoline scaffold for potent TLR7 agonist activity. The influence of selected TLR7 agonists on cytokine production is also reported showing that N-cyclopropyl-2-(trifluoromethyl)quinazolin-4-amine (46) is able to induce increased levels of IL-6 and IL-8. These data demonstrate successful in-silico definition of novel TLR7 versus TLR8-selective compounds as promising chemical probes for further development of potent small-molecule immunomodulators.


Assuntos
Imidazóis/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Citocinas/análise , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
12.
Eur J Med Chem ; 176: 476-491, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31128449

RESUMO

Tumor suppressor protein p53 is important to the regulation of many cellular processes and the prevention of cancer development. In some cancer cells, the function of p53 is inhibited by murine double minute 2 protein (MDM2). To restore the function of p53, the inhibition or depletion of MDM2 has become a potential therapeutic treatment. We have successfully developed a series of small molecule MDM2 degraders that can promote the proteolysis of MDM2 oncoprotein, thus reactivating tumor suppressor p53. The superior degrader features a nutlin-based MDM2 ligand and a lenalidomide-based cereblon E3 ubiquitin ligase ligand with a short linker between the two ligands. At low nanomolar concentrations in RS4; 11 leukemia cells, this degrader promotes efficient degradation of MDM2. It also inhibits the proliferation of leukemia cells with an IC50 value of 3.2 nM and induces apoptosis effectively. All of these data indicate that MDM2 degraders are promising therapeutics for the treatment of cancers, such as leukemia.


Assuntos
Imidazóis/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/metabolismo , Ligação Proteica , Estereoisomerismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
13.
Environ Toxicol ; 34(8): 928-940, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31067004

RESUMO

Bioactive components of dietary phytochemicals have been reported to possess antitumor activities. Evidences suggested key role of stress responsive p38MAPK in the induction of nutraceuticals mediated apoptosis in hepatocellular carcinoma (HCC). Current study demonstrated detailed molecular bagatelle associated with p38 MAPK mediated effective suppression of cell growth both in HepG2 and chemically induced liver carcinoma after S-allyl cysteine (SAC) treatment. SAC promoted p38MAPK activity responsible for p53 phosphorylation, its stabilization followed by nuclear translocation leading to induction in expression and oligomerization of Fas protein. Distinctive p38MAPK-p53 axis dependent Fas-FasL-FADD mediated caspase activities along with perturbed cell cycling became normalized with continuation of SAC treatment for another month to diethylnitrosamine induced liver carcinoma. Co-treatment with SB203580, the p38MAPK inhibitor, prevented pro-apoptotic effect of SAC by altering p53 phosphorylation and death inducing signaling complex conformation in HepG2 and induced HCC. Collectively study suggested significant contribution of p38MAPK-p53-DISC-Caspase pathway in the regulation of anti-neoplastic activity of SAC against HCC.


Assuntos
Antineoplásicos/farmacologia , Cisteína/análogos & derivados , Neoplasias Hepáticas Experimentais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antineoplásicos/uso terapêutico , Caspases/metabolismo , Cisteína/farmacologia , Cisteína/uso terapêutico , Proteína Ligante Fas/metabolismo , Células Hep G2 , Humanos , Imidazóis/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Receptor fas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
14.
Mol Med Rep ; 19(6): 4553-4560, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059021

RESUMO

Cardiac fibrosis secondary to long­term hypertension is known to promote cardiac dysfunction; however, few therapeutic agents are available for the treatment of this condition in clinical practice. The heptapeptide alamandine (Ala) has recently been identified as a component of the renin­angiotensin system (RAS), which exerts a protective effect against cardiac hypertrophy; however, it is unknown whether Ala may also be useful for the treatment of cardiac fibrosis. In the present study, the potential therapeutic effects of Ala on long­term hypertension­induced cardiac fibrosis were investigated in an aged, spontaneous hypertensive rat model. Weekly blood pressure (BP) measurements revealed that daily Ala treatment significantly decreased the systolic, diastolic and mean arterial BP compared with the control. Of note, the observed reduction in BP in Ala­treated animals markedly differed to that observed in rats treated with hydralazine (Hyd). Echocardiography further demonstrated that Ala treatment decreased the ratio of left ventricle mass to body weight, and alleviated structural and functional parameters associated with cardiac fibrosis, including left ventricular volume, ejection fraction and fractional shortening compared with the control and Hyd­treated groups. Furthermore, Ala deceased the density of cardiac fibrosis, as assessed by Masson and Sirius red staining; reduced expression of fibrotic proteins, including connective tissue growth factor, collagen I (COL1A1) and matrix metalloproteinase 9, was also observed. In addition, Ala treatment further decreased the expression of angiotensin II­induced fibrotic markers at the mRNA and protein levels in cultured cardiac fibroblasts; Ala­mediated inhibition of COL1A1 expression and Akt phosphorylation was inhibited via the Mas­related G protein receptor antagonist, PD123319. Collectively, the findings of the present study suggest that Ala is an effective anti­hypertensive peptide that can attenuate cardiac dysfunction and fibrosis induced by chronic hypertension, independent of BP.


Assuntos
Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Cardiomegalia/etiologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrose/etiologia , Ventrículos do Coração/metabolismo , Hipertensão/complicações , Imidazóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina
15.
J Immunol Res ; 2019: 1749803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093508

RESUMO

Plasmacytoid dendritic cells (pDCs) express high levels of the toll-like receptors (TLRs) TLR7 and TLR9. In response to TLR7 and TLR9 ligands, pDCs are primary producers of type I interferons. Our previous study demonstrated that pDCs activated by the TLR7 ligand imiquimod (IMQ) and the TLR9 ligand CpG A can kill breast cancer cells in vitro and inhibit tumor growth in vivo. Moreover, we observed a distinctive morphological, phenotypic change in pDCs after activation by IMQ and CpG A. However, the effect of other TLR7 and TLR9 ligands on pDCs remains less understood. In this study, we treat pDCs with the TLR7 ligand IMQ, TLR7/8 ligands (CL097 and CL075), and three TLR9 ligands (different types of CpGs). The size of pDCs increased significantly after activation by TLR7, or TLR7/8 ligands. TLR7, TLR7/8, and TLR9 ligands similarly modulated cytokine release, as well as protein expression of pDC markers, costimulatory molecules, and cytotoxic molecules. Interestingly, TLR7/8 ligands, especially CL097, induced stronger responses. These results are relevant to the further study of the role and mechanism of pDC-induced antitumor effects and may aid in the development of a new strategy for future tumor immunotherapy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Imiquimode/farmacologia , Glicoproteínas de Membrana/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Animais , Feminino , Imidazóis/farmacologia , Indutores de Interferon/farmacologia , Interferon Tipo I/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/farmacologia , Tiazóis/farmacologia
16.
Analyst ; 144(13): 3959-3966, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31134974

RESUMO

MDM2 can mediate the degradation of tumor suppressor p53 through an autoregulatory feedback loop, in which MDM2 abolishes wild-type p53 function and accelerates malignant transformation. However, the incorporation of MDM2 antagonist Nutlin-3 could reactivate the transcriptional activity of p53, up-regulate caspase-3, and induce apoptosis. In this work, the simultaneous and label-free monitoring of p53-MDM2 complex and caspase-3 levels in cancer cells before and after Nutlin-3 treatment was conducted using dual-channel surface plasmon resonance (SPR). The p53-MDM2 complex was captured in one fluidic channel covered with consensus double-stranded (ds)-DNA, while the other channel was pre-immobilized with caspase-3-specific biotinylated DEVD-containing peptides. To amplify the SPR signals, the attachment of streptavidin (SA)-conjugated anti-MDM2 antibody in both channels was achieved. The signal diversity before and after Nutlin-3 treatment is indicative of the difference in the levels of the intracellular p53-MDM2 complex and caspase-3. The limit of detection for p53-MDM2 and caspase-3 down to 4.54 pM and 0.03 ng mL-1, respectively, was attained. Upon treatment with Nutlin-3, MCF-7 cancer cells with wild-type p53 showed decreased expression of the p53-MDM2 complex and an increased caspase-3 level, while MDA-MB-231 cancer cells with mutant p53 exhibited an elevated caspase-3 level and unchanged p53-MDM2 complex expression. The apoptosis of MCF-7 and MDA-MB-231 cancer cells upon Nutlin-3 treatment follows a p53-dependent and a p53-independent pathway, respectively. The proposed method is sensitive, selective and label-free, holding great promise for assaying intracellular p53-MDM2 complex and caspase-3 levels and differentiating Nutlin-3-mediated p53-dependent or p53-independent apoptotic pathways.


Assuntos
Caspase 3/análise , Imidazóis/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/análise , Ressonância de Plasmônio de Superfície/métodos , Proteína Supressora de Tumor p53/análise , Apoptose/efeitos dos fármacos , Biotina/química , Caspase 3/química , Caspase 3/metabolismo , Linhagem Celular Tumoral , DNA/química , Relação Dose-Resposta a Droga , Humanos , Limite de Detecção , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptavidina/química , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo
17.
Eur J Med Chem ; 175: 309-329, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096153

RESUMO

Compounds simultaneously inhibiting two targets that are involved in the progression of the same complex disease may exhibit additive or even synergistic therapeutic effects. Here we unveil 2,4,5-trisubstituted imidazoles as dual inhibitors of p38α mitogen-activated protein kinase and glycogen synthase kinase 3ß (GSK3ß). Both enzymes are potential therapeutic targets for neurodegenerative disorders, like Alzheimer's disease. A set of 39 compounds was synthesized and evaluated in kinase activity assays for their ability to inhibit both target kinases. Among the synthesized compounds, potent dual-target-directed inhibitors showing IC50 values down to the low double-digit nanomolar range, were identified. One of the best balanced dual inhibitors presented in here is N-(4-(2-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (20c) (p38α, IC50 = 16 nM; GSK3ß, IC50 = 35 nM) featuring an excellent metabolic stability and an appreciable isoform selectivity over the closely related GSK3α. Our findings were rationalized by computational docking studies based on previously published X-ray structures.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Sequência de Aminoácidos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Imidazóis/química , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Piridinas/química , Homologia de Sequência de Aminoácidos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
18.
Int J Oncol ; 54(6): 2189-2199, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081046

RESUMO

Glioblastoma (GB) is the most common and aggressive malignant tumor of the central nervous system. Despite current intensive treatment regimens, consisting of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ) chemotherapy, the prognosis of patients with GB remains extremely poor. Considering that alterations of the p53 tumor suppressor pathway have a key role in both GB development and resistance to TMZ treatment, the re­activation of p53 could be an effective therapeutic approach against GB. In this study, we challenged p53 wild­type and mutant GB cell lines with RITA, a molecule originally identified for its ability to restore p53 functions, although it was subsequently shown to act also through p53­independent mechanisms. We examined the effects of RITA on GB cell viability, through MTS and clonogenic assays, and analyzed cell death through cytoflourimetric analyses. In all the tested GB cell lines, RITA significantly reduced the cell proliferative and clonogenic potential and induced cell accumulation in the S and/or G2/M cell cycle phases and massive p53­dependent apoptosis. Moreover, RITA was more effective than the well­known p53 re­activating molecule, nutlin­3, and did not affect the viability of normal astrocytes. In addition, RITA decreased survivin expression and induced DNA damage, two mechanisms that likely contribute to its anti­tumor effects. Furthermore, RITA synergized with TMZ and was able to decrease the expression of MGMT, which is a crucial player in TMZ resistance. Thus, although further studies are warranted to clarify the exact mechanisms of action of RITA, the data of this study suggest the potential of such an approach for GB therapy, which may also help to overcome resistance to TMZ.


Assuntos
Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Glioblastoma/metabolismo , Temozolomida/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Imidazóis/farmacologia , Mutação , Piperazinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética
19.
Nat Commun ; 10(1): 2177, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097709

RESUMO

Air filtration has become an essential need for passive pollution control. However, most of the commercial air purifiers rely on dense fibrous filters, which have good particulate matter (PM) removal capability but poor biocidal effect. Here we present the photocatalytic bactericidal properties of a series of metal-organic frameworks (MOFs) and their potentials in air pollution control and personal protection. Specifically, a zinc-imidazolate MOF (ZIF-8) exhibits almost complete inactivation of Escherichia coli (E. coli) (>99.9999% inactivation efficiency) in saline within 2 h of simulated solar irradiation. Mechanistic studies indicate that photoelectrons trapped at Zn+ centers within ZIF-8 via ligand to metal charge transfer (LMCT) are responsible for oxygen-reduction related reactive oxygen species (ROS) production, which is the dominant disinfection mechanism. Air filters fabricated from ZIF-8 show remarkable performance for integrated pollution control, with >99.99% photocatalytic killing efficiency against airborne bacteria in 30 min and 97% PM removal. This work may shed light on designing new porous solids with photocatalytic antibiotic capability for public health protection.


Assuntos
Filtros de Ar , Desinfecção/métodos , Escherichia coli/efeitos dos fármacos , Estruturas Metalorgânicas/farmacologia , Microbiologia do Ar , Catálise/efeitos da radiação , Imidazóis/química , Imidazóis/farmacologia , Luz , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/efeitos da radiação , Testes de Sensibilidade Microbiana , Oxigênio/metabolismo , Porosidade , Espécies Reativas de Oxigênio/farmacologia , Difração de Raios X , Zinco/química , Zinco/farmacologia
20.
Molecules ; 24(7)2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959969

RESUMO

Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on hepatocellular carcinoma cells have not been previously explored. In the present study, we investigated its effects on hepatocellular carcinoma cell growth and the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated protein (MAP) kinase pathway, the phosphorylation of Src on both negative and positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it also activates the PDK1, the protein kinase B (Akt), and the mechanistic target of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
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