RESUMO
Accumulating evidence indicates that microRNAs (miRNAs) can control and coordinate various biological processes. Consequently, abnormal expressions of miRNAs have been linked to various complex diseases. Recognizable proof of miRNA-disease associations (MDAs) will contribute to the diagnosis and treatment of human diseases. Nevertheless, traditional experimental verification of MDAs is laborious and limited to small-scale. Therefore, it is necessary to develop reliable and effective computational methods to predict novel MDAs. In this work, a multi-kernel graph attention deep autoencoder (MGADAE) method is proposed to predict potential MDAs. In detail, MGADAE first employs the multiple kernel learning (MKL) algorithm to construct an integrated miRNA similarity and disease similarity, providing more biological information for further feature learning. Second, MGADAE combines the known MDAs, disease similarity, and miRNA similarity into a heterogeneous network, then learns the representations of miRNAs and diseases through graph convolution operation. After that, an attention mechanism is introduced into MGADAE to integrate the representations from multiple graph convolutional network (GCN) layers. Lastly, the integrated representations of miRNAs and diseases are input into the bilinear decoder to obtain the final predicted association scores. Corresponding experiments prove that the proposed method outperforms existing advanced approaches in MDA prediction. Furthermore, case studies related to two human cancers provide further confirmation of the reliability of MGADAE in practice.
Assuntos
MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , Reprodutibilidade dos Testes , Biologia Computacional/métodos , Neoplasias/genética , AlgoritmosRESUMO
Bendamustine hydrochloride is an alkylating agent that was developed for the treatment of various human cancers. The stable isotope-labeled bendamustine was required to support clinic studies. An effective and operationally simple method for the synthesis of [D6 ] bendamustine hydrochloride was developed using DCl as a catalyst and D2 O as a deuterium source. Under the present condition, regioselectively deuterated bendamustine hydrochloride with high deuterium incorporation is achieved.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Cloridrato de Bendamustina/química , Cloridrato de Bendamustina/síntese química , Deutério/química , Técnicas de Química Sintética , Marcação por IsótopoRESUMO
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, 12k, was considered to be the most promising for in-depth study. 12k possessed high potency (EC50 = 57.9 ± 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. 12k also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells. However, 12k did not have any effects on CYP3A4 activity or P-gp expression. In particular, 12k had a good half-life and oral bioavailability and displayed no influence on DOX metabolism to obviate the side effects closely related to increased plasma concentrations of cytotoxic agents in vivo.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Adenosina Trifosfatases/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Humanos , Células K562 , Masculino , Quinazolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Rodamina 123/metabolismo , Análise Espectral/métodosRESUMO
A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50>100µM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Benzamidas/farmacologia , Química Click , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células K562 , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese químicaRESUMO
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)benzamide (compound 7 h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 =127.5 ± 9.1 nM), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Benzamidas/química , Tetra-Hidroisoquinolinas/química , Triazóis/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/metabolismo , Daunorrubicina/metabolismo , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células K562 , Paclitaxel/farmacologia , Ligação Proteica , Rodamina 123/química , Rodamina 123/metabolismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Vincristina/farmacologiaRESUMO
The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L(-1)) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacocinética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Animais , Humanos , Células K562 , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The purpose of this study was to screen genetic variations in plakophilin-2 (PKP2) gene in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and investigate the differences in clinical features between mutation and no-mutation groups. METHODS: Thirty unrelated Chinese patients clinically diagnosed with ARVC/D and 50 healthy controls were included. Genomic DNA was isolated from peripheral blood samples. PCR and direct sequencing were used to detect variations in PKP2 gene. RESULTS: Eight PKP2 mutant variants were identified in 10 ARVC/D patients (8 men, 2 women). Among the eight mutation, three (c.2194C>T, c. 1170+ 1G>A and c. 810_813delGGTC) were novel mutation. Clinical features of the PKP2 mutation group were similar to those of the non-mutation group. CONCLUSIONS: The rate of PKP2 mutation is 33.3% (10/30) in ARVC/D patients. The penetrance of PKP2 mutation for ARVC/D tends to be higher in man patients. No significant differences could be detected in phenotype characteristics between patients with and without PKP2 mutation.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Povo Asiático/genética , Placofilinas/genética , Displasia Arritmogênica Ventricular Direita/diagnóstico , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Mutação , FenótipoRESUMO
A novel series of triazol-N-ethyl-tetrahydroisoquinoline based compounds were designed and synthesized via click chemistry. Most of the synthesized compounds showed P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal activities. Among them, compound 7 with little cytotoxicity towards GES-1 cells (IC50 >80µM) and K562/A02 cells (IC50 >80µM) exhibited more potency than verapamil (VRP) on increasing anticancer drug accumulation in K562/A02 cells. Moreover, compound 7 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 7 in reversing MDR revealed that it could remarkably increase the intracellular accumulation of both rhodamine-123 (Rh123) and adriamycin (ADM) in K562/A02 cells as well as inhibit their efflux from the cells. These results suggested that compound 7 showed more potency than the classical P-gp inhibitor VRP under the same conditions, which may be a promising P-gp-mediated MDR modulator for further development.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/síntese química , Benzamidas/química , Benzamidas/farmacologia , Desenho de Fármacos , Isoquinolinas/química , Isoquinolinas/farmacologia , Triazóis/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Click , Doxorrubicina/química , Doxorrubicina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Células K562 , Rodamina 123/química , Rodamina 123/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazol-phenethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 5 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity (IC50s > 100 µm). Compared with VRP, compound 5 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 5 persisted longer chemo-sensitizing effect (>24 h) than VRP (<6 h) with reversibility. Given the low intrinsic cytotoxicity and the potent reversal activity, compound 5 may represent a promising candidate for developing P-gp-mediated MDR inhibitor.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacologia , Benzamidas/química , Benzamidas/farmacocinética , Química Click , Doxorrubicina/farmacologia , Humanos , Células K562 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)- tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC50 values at 0.66, 0.65 and 0.96µM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Concentração Inibidora 50 , Células K562 , Estrutura Molecular , Tetra-Hidroisoquinolinas/químicaRESUMO
An automatic gas-phase molecular absorption spectrometric (GPMAS) system was developed and applied to determine nitrite and total nitrate in water samples. The GPMAS system was coupled with a UV-light emitting diode photodiode (UV-LED-PD) based photometric detector, including a 255 nm UV-LED as the light source, a polyvinyl chloride (PVC) tube of 14 cm as the gas flow cell, and an integrated photodiode amplifier to measure the transmitted light intensity. The UV-LED-PD detector was compact, robust, simple and of low heat production, comparing with detectors used in other GPMAS works. For nitrite measurement, citric acid was used to acidify the sample, and ethanol to catalyze the quantitative formation of NO(2). The produced NO(2) was purged with air flow into the UV-LED-PD detector, and the gaseous absorbance value was measured. The total nitrate could be determined after being reduced to nitrite with a cadmium column. Limits of detection for nitrite and nitrate were 7 µmol/L and 12 µmol/L, respectively; and linear ranges of 0.021-5 mmol/L for nitrite and 0.036-4 mmol/L for nitrate were obtained. Related standard deviations were 1.81% and 1.08% for nitrite and nitrate, respectively, both at 2 mmol/L. The proposed method has been applied to determine nitrite and total nitrate in some environmental water samples.
RESUMO
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart muscle disease associated with increased risks of sudden death, particularly in young, otherwise healthy, patients. The pathologic features are progressive myocardial atrophy and fibrofatty replacement. Plakophilin-2 (PKP2) is reported as the most common ARVD/C-causing gene in Western countries. In this study we aimed to determine the prevalence of PKP2 mutations in Chinese patients with ARVD/C and their phenotype characteristics. Genotype and phenotype were investigated in a cohort of 18 unrelated Chinese patients with a clinical diagnosis of ARVD/C. Direct sequencing of PKP2 led to the identification of 5 novel heterozygous mutations (R158K, Q211X, L419S, A793D, and N852fsX930) in 39% of patients (7 of 18) with ARVD/C. Among them, N852fsX930 was found in 3 unrelated young patients who presented with symptomatic ventricular tachyarrhythmia. Nevertheless, no significant difference could be detected between patients with ARVD/C with (n = 7) and without (n = 11) PKP2 mutations with regard to the phenotype characteristics and clinical outcomes. Decreased penetrance was prominent in family members. In conclusion, 5 novel PKP2 mutations were identified in a cohort of symptomatic Chinese patients with ARVD/C. N852fsX930 appeared to be a hot-spot mutation in which patients presented with a severe ARVD/C phenotype, and 2/3 had early onset of arrhythmic events. No significant difference was found in phenotype characteristics between patients with ARVD/C with and without PKP2 mutations. The decreased penetrance indicated that an ARVD/C diagnosis cannot solely rely on genotyping results.