RESUMO
Cervical human papillomavirus (HPV) infection is believed to increase the risks of pregnancy failure and abortion, however, whether the uterine cavity HPV infection reduces pregnancy rate or increases miscarriage rate remains unclarified in infertile women undergoing assisted reproductive technology (ART) treatment. Therefore, we aimed to assess ART outcomes in the presence of intrauterine HPV. This was a hospital-based multicenter (five reproductive medicine centers) matched cohort study. This study involved 4153 infertile women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection treatment in five reproductive medicine centers between October 2018 and 2020. The spent embryo transfer media sample with endometrium tissue were collected and performed with flow-through hybridization and gene chips to detect HPV DNA. According to basic characteristics, HPV-positive and negative patients were matched in a ratio of 1:4 by age, body mass index transfer timing, transfer type, and number of embryos transferred. The primary outcome was pregnancy and clinical miscarriage rates in the transfer cycle underwent HPV detection. 92 HPV-positive and 368 HPV-negative patients were screened and analyzed statistically. Univariate analysis showed uterine cavity HPV infection resulted in lower rates of ongoing pregnancy (31.5% vs. 44.6%; p = 0.023), implantation (32.3% vs. 43.1%; p = 0.026), biochemical pregnancy (47.8% vs. 62.5%; p = 0.010), and clinical pregnancy (40.2% vs. 54.3%; p = 0.015) compared with HPV negative group. The infertile female with positive HPV also had a slightly higher frequency of biochemical miscarriage (15.9% vs. 13.0%; p = 0.610) and clinical miscarriage (24.3% vs. 15.5%; p = 0.188). These findings suggest that HPV infection in the uterine cavity is a high risk for ART failure. HPV screening is recommended before ART treatment, which may be benefit to improving pregnancy outcome.
Assuntos
Aborto Espontâneo , Infertilidade Feminina , Infecções por Papillomavirus , Gravidez , Humanos , Masculino , Feminino , Infecções por Papillomavirus/diagnóstico , Infertilidade Feminina/terapia , Papillomavirus Humano , Estudos de Coortes , Sêmen , Transferência Embrionária/métodos , Técnicas de Reprodução Assistida , Fertilização in vitro , Falha de TratamentoRESUMO
Accurate detection and timely treatment of component defects in substations is an important measure to ensure the safe operation of power systems. In this study, taking substation meters as an example, a dataset of common meter defects, such as a fuzzy or damaged dial on the meter and broken meter housing, is constructed from the images of manual inspection in power systems. There are several challenges involved in accurately detecting defects in substation meter images, such as the complex background, different meter sizes and large differences in the shapes of meter defects. Therefore, this paper proposes the PHAM-YOLO (Parallel Hybrid Attention Mechanism You Only Look Once) network for automatic detection of substation meter defects. In order to make the network pay attention to the key areas against the complex background of the meter defect images and the differences between different defect features, a Parallel Hybrid Attention Mechanism (PHAM) module is designed and added to the backbone of YOLOv5. PHAM integration of local and non-local correlation information can highlight these differences while remaining focused on the meter defect features. To improve the expressive ability of the feature map, a Spatial Pyramid Pooling Fast (SPPF) module is introduced, which pools the input feature map using a continuous fixed convolution kernel, fusing the feature maps of different receptive fields. Bounding box regression (BBR) is the key way to determine object positioning performance in defect detection. EIOU (Efficient Intersection over Union) is, therefore, introduced as a boundary loss function to solve the ambiguity of the CIOU (Complete Intersection Over Union) loss function, making the BBR regression more accurate. The experimental results show that the Average Precision Mean (mAP), Precision (P) and Recall (R) of the proposed PHAM-YOLO network in the dataset are 78.3%, 78.3%, and 79.9%, respectively, with mAP being improved by 2.7% compared to the original model and higher than SSD, Fast R-CNN, etc.
Assuntos
Algoritmos , Registros , Coluna VertebralRESUMO
BACKGROUND: Microwave ablation (MWA) is a potentially curative treatment for unresectable patients with hepatocellular carcinoma (HCC) ≤ 3 cm, while its therapeutic efficacy decreases significantly for HCC > 3cm. Previous studies have demonstrated that conventional transarterial chemoembolization (cTACE) combined with MWA (cTACE-MWA) may improve local tumor control rate and reduce the recurrence rate for HCC > 3cm. However, there have been few study designs to analyze the clinical efficacy of cTACE-MWA for medium-sized HCC (3-5cm). Therefore, this study aims to compare the clinical efficacy and safety of cTACE-MWA with cTACE alone for a single medium-sized HCC of 3-5 cm in diameter. METHODS: We retrospectively investigate the data of 90 patients with a single medium-sized HCC who were referred to our hospital and underwent cTACE-MWA or cTACE alone from December 2017 to March 2020. Then, patients were identified with propensity score-matched (1:1). The local tumor response to treatment and time to progression (TTP) were compared using mRECIST criteria between the cTACE-MWA group and the cTACE group. RESULTS: A total of 42 patients were included after matching (cTACE-MWA: 21; cTACE: 21). Comparing with cTACE, cTACE-MWA demonstrate significantly better local tumor control (ORR: 95.2% vs 61.9%, p = 0.02; DCR: 95.2% vs 66.7%, p = 0.045) and TTP (median 19.8 months vs 6.8 months, p < 0.001). The 1- and 2-year cumulative probabilities of OS were 100% and 95% in the cTACE-MWA group, which were significantly higher than those in the cTACE group (95% and 76%) (p = 0.032). Multivariate Cox regression analysis illustrates that cTACE-MWA was associated with better TTP (hazard ratio, 0.28; 95% CI: 0.1, 0.76; p = 0.012), but tumor size was associated with worse TTP (hazard ratio, 1.71; 95% CI: 1.01, 2.89; p = 0.045). CONCLUSIONS: cTACE followed by MWA improved TTP and OS in patients with a single medium-sized HCC, and no major complication was observed in this study.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Terapia Combinada , Humanos , Neoplasias Hepáticas/cirurgia , Micro-Ondas/uso terapêutico , Pontuação de Propensão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Lung adenocarcinoma (LAC) is the predominant histologic subtype of lung cancer and has a complicated pathogenesis with high mortality. The purpose of this study was to identify differentially expressed genes (DEGs) with prognostic value and determine their underlying mechanisms. METHODS: Gene expression data of GSE27262 and GSE118370 were acquired from the Gene Expression Omnibus database, enrolling 31 LAC and 31 normal tissues. Common DEGs between LAC and normal tissues were identified using the GEO2R tool and Venn diagram software. Next, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to analyze the Gene Ontology and Kyoto Encyclopedia of Gene and Genome (KEGG) pathways. Then, protein-protein interaction (PPI) network of DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes and central genes were identified via Molecular Complex Detection. Furthermore, the expression and prognostic information of central genes were validated via Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier analysis, respectively. Finally, DAVID, real-time PCR and immunohistochemistry were applied to re-analyze the identified genes, which were also further validated in two additional datasets from ArrayExpress database. RESULTS: First, 189 common DEGs were identified among the two datasets, including 162 downregulated and 27 upregulated genes. Next, Gene Ontology and KEGG pathway analysis of the DEGs were conducted through DAVID. Then, PPI network of DEGs was constructed and 17 downregulated central genes were identified. Furthermore, the 17 downregulated central genes were validated via GEPIA and datasets from ArrayExpress, and 12 of them showed a significantly better prognosis. Finally, six genes were identified significantly enriched in neuroactive ligand-receptor interactions (EDNRB, RXFP1, P2RY1, CALCRL) and Rap1 signaling pathway (TEK, P2RY1, ANGPT1) via DAVID, which were further validated to be weakly expressed in LAC tissues via RNA quantification and immunohistochemistry analysis. CONCLUSIONS: The low expression pattern and relation to prognosis indicated that the six genes were potential tumor suppressor genes in LAC. In conclusion, we identified six significantly downregulated DEGs as prognostic markers and potential tumor suppressor genes in LAC based on integrated bioinformatics methods, which could act as potential molecular markers and therapeutic targets for LAC patients.
Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/mortalidade , Biologia Computacional , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Análise em Microsséries , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genéticaRESUMO
Bisphenol A (BPA) is a substance ubiquitously present in the environment, and its toxicity on reproductive function has been well characterised in animal models. However, it is still controversy about the effects of BPA exposure on human female reproduction. Therefore, in the present study, the associations of urinary BPA concentration with the outcomes of in vitro fertilisation (IVF) and embryo transfer from fresh and frozen cycles were analysed in the same cohort. 351 women who underwent IVF treatment from September 2013 to October 2016, at the Centre of Reproductive Medicine in the Women's Hospital School of Medicine at Zhejiang University were recruited. Single-spot urine samples were collected on the day of oocyte retrieval to detect BPA using solid-phase extraction and liquid chromatography coupled with tandem mass spectrometry. A multivariable generalised linear mixed model was used to evaluate the association between the urinary BPA concentration and IVF outcomes. After adjustment for age, body mass index, baseline follicle-stimulating hormone level, baseline oestradiol level, and antral follicle count, a significant decrease in the number of retrieved oocytes and in the rates of clinical pregnancy and implantation was observed in the patients with a high urinary BPA concentration. We concluded that BPA exposure exert negative effects on oocyte retrieval and embryo implantation in women undergoing IVF.
Assuntos
Compostos Benzidrílicos/urina , Implantação do Embrião/efeitos dos fármacos , Exposição Ambiental/análise , Poluentes Ambientais/urina , Fertilização in vitro , Infertilidade Feminina/urina , Recuperação de Oócitos , Fenóis/urina , Adulto , Compostos Benzidrílicos/toxicidade , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Feminino , Humanos , Fenóis/toxicidade , GravidezRESUMO
Three Legionella-like strains, designed km488T, km489 and km521, were isolated from freshwater samples in China. Cells were Gram-stain-negative, rod-shaped and non-spore-forming. Growth was observed on BCYEα agar, but not on BCYEα agar without l-cysteine, chocolate agar with PolyViteX or Columbia blood agar. The major fatty acids (>5â%) of strains km488T, km489 and km521 were C16â:â0, anteiso-C15â:â0, iso-C16â:â0 and anteiso-C17â:â0. The mip gene sequences (574 nt) showed the isolates were almost identical with more than 99.7â% sequence similarities, and closely matched to L. gormanii ATCC 33297T with 95.4-95.6â% sequence similarities. Phylogenetic analyses based on concatenated gene (16S rRNA, mip, rpoB and rnpB) sequences indicated that the isolates formed a distinct cluster along with L. gormanii within the genus Legionella. Matrix-assisted laser desorption ionization time-of-flight analyses also demonstrated a clear separation between the isolates and other closely and distantly related Legionella species. DNA-DNA hybridization studies demonstrated that the isolates were closely related (92.0â-95.0â% DNA-DNA relatedness) but differentiated from their phylogenetic neighbours (<70â% DNA-DNA relatedness). The whole genome of km488T was sequenced, and showed a G+C content of 37.8âmol%. Based on the findings from this polyphasic taxonomic study, the isolates are considered to represent a single novel species, for which the name Legionella qingyii sp. nov. is proposed. The type strain is km488T (KCTC 15636T=CCTCC AB 2018025T=NRBC 113223T).
Assuntos
Água Doce/microbiologia , Legionella/classificação , Filogenia , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Genes Bacterianos , Legionella/isolamento & purificação , Hibridização de Ácido Nucleico , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Piperazinas/farmacologia , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
For the development of potential anti-prostate cancer agents, 24 kinds of novel naftopidil-based arylpiperazine derivatives have been synthesized and characterized by spectroscopic methods. Their antitumor activities were evaluated against several classical prostate cancer cell lines including PC-3, LNCaP, and DU145. Among all the compounds, 9, 13, 17, 21 and 27 showed strong cytotoxic activities against DU145 cells (IC50â¯<â¯1⯵M). Further testing confirmed that compound 17 inhibited the growth of DU145 cells by inducing cell cycle arrest at G0/G1 phase. Besides, antagonistic activities of compounds (9, 13, 17, 21 and 27) towards a1-ARs (α1A, α1B, and α1D) were further evaluated using dual-luciferase reporter assays, and the compounds 13 and 17 exhibited better a1-ARs subtype selectivity. The structure-activity relationship (SAR) of these developed arylpiperazine derivatives was rationally discussed. Taken together, these results suggested that further development of such compounds may be of great interest.
Assuntos
Antineoplásicos/farmacologia , Naftalenos/farmacologia , Piperazina/farmacologia , Piperazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftalenos/química , Piperazina/síntese química , Piperazina/química , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Naftalenos/farmacologia , Fenilacetatos/farmacologia , Piperazinas/farmacologia , Vasodilatadores/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/síntese química , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animais , Aorta/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Naftalenos/síntese química , Naftalenos/química , Fenilacetatos/síntese química , Fenilacetatos/química , Piperazinas/síntese química , Piperazinas/química , Prazosina/análogos & derivados , Prazosina/farmacologia , Coelhos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Estereoisomerismo , Ducto Deferente/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/químicaRESUMO
Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC50) < 2 µM). The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data. This work provides a potential lead compound for anticancer agent development focusing on prostate cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sacarina/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Subtype-selective α1-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α1-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA2 7.13) with a poor selectivity for α1A and α1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α1D subtype (pA2 7.06) and excellent selectivity for α1D over α1B (α1D/α1B ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α1 receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α1D-selective antagonists.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Carbazóis/farmacologia , Desenho de Fármacos , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas Adrenérgicos/química , Carbazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
Homoharringtonine (HHT), a natural plant alkaloid derived from Cephalotaxus, has demonstrated to have a broad antitumor activity and efficacy in treating human chronic myeloid leukemia. An alternative source is required to substitute for the slow-growing and scarce Cephalotaxus to meet the increasing demand of the drug market. The objective of this study was to screen HHT-producing endophytic fungi from Cephalotaxus hainanensis Li. By screening 213 fungal isolates obtained from the bark parts of Cephalotaxus hainanensis Li, one isolate was found to be capable of biosynthesizing HHT. The fungus was identified as Alternaria tenuissima by morphological characteristics and internal transcribed spacer (ITS) sequence analysis and was named as CH1307. HHT obtained from CH1307 was analyzed through the HPLC and LC-MS/MS and NMR spectroscopy. The extract of the fermentation broth of CH1307 showed antiproliferative activities against K562 (chronic myelocytic leukemia), NB4 (acute promyelocytic leukemia), and HL-60 (promyelocytic leukemia) human cancer cell lines with IC50 values of 67.25 ± 4.26, 65.02 ± 4.75, and 99.23 ± 4.26 µg/mL, respectively. The findings suggest that HHT-producing endophytic fungus, Alternaria tenuissima CH1307 might provide a promising source for the research and application of HHT.
Assuntos
Cephalotaxus/microbiologia , Endófitos/isolamento & purificação , Endófitos/metabolismo , Harringtoninas/biossíntese , Alcaloides/biossíntese , Alcaloides/química , Alternaria/genética , Alternaria/crescimento & desenvolvimento , Alternaria/isolamento & purificação , Alternaria/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Endófitos/genética , Endófitos/crescimento & desenvolvimento , Fermentação , Células HL-60 , Harringtoninas/química , Harringtoninas/metabolismo , Harringtoninas/farmacologia , Mepesuccinato de Omacetaxina , Humanos , Células K562 , Leucemia Promielocítica Aguda/tratamento farmacológicoRESUMO
A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were evaluated by a CCK-8 assay. Compounds 10, 24 and 29 exhibited strong cytotoxic activities against LNCaP cells (IC50 <3µM). In addition, these compounds exhibited weak cytotoxic effects on human epithelial prostate normal cells RWPE-1. The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of novel arylpiperazine derivatives as α1A/1D-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards α1-ARs (α1A, α1B, and α1D). Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on α1A and/or α1D subtypes over α1B in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest α1A/D-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled α1-ARs (α1A, α1B, and α1D) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of α1A was validated as the key residues for binding ligand. This work provides useful information for finding more new potential drugs in clinic in treating benign prostatic hyperplasia (BPH).
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Relação Estrutura-AtividadeRESUMO
Indole-arylpiperazine derivatives have exhibited good selectivity for the α1A-adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H···π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α1A antagonists with high selectivity.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/química , Cristalografia por Raios X , Modelos Moleculares , Piperazinas/química , Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Piperazina , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Relação Estrutura-AtividadeRESUMO
A method was developed for the determination of 59 glucocorticoids, sex hormones, nonsteroidal anti-inflammatory drugs, antibiotics, and other contaminants in cosmetics simultaneously by ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Acetonitrile was used to extract the sample, and the mixed sorbents were dispersed for purification. With the optimal conditions, the optimized pretreatment processes led to no significant interference on analysis from an extremely complicated sample matrix, and the linear ranges of 59 analytes were 0-480.0 µg/kg with the correlation coefficients above 0.99 and the limits of quantification (S/N≥10) were 5-40 µg/kg. Statistical evaluation revealed that the average recoveries were in the range of 61.2-131.2%, and relative standard deviations were in the range of 2.0-22.8%, meanwhile the interday precision ranged from 3.8 to 21.8%. This method is simple, fast, and credible, and it can be applied to simultaneous screening and determination of various classes of substances under investigations illegally presented in cosmetic products, covering a wide diversity of polarities, and pKa values.
Assuntos
Antibacterianos/análise , Anti-Inflamatórios não Esteroides/análise , Cosméticos/química , Glucocorticoides/análise , Hormônios Esteroides Gonadais/análise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
A novel online column-switching chiral high-performance liquid chromatography method was developed and validated for the simultaneous determination of naftopidil (NAF) and its O-desmethyl metabolites (DMN) enantiomers in rat feces. Direct and multiple injections of supernatant from rat feces homogenate were allowed through the column-switching system. Analyte extraction was performed on the Capcell Pak mixed-functional column by acetonitrile-phosphate buffer (pH 7.4; 10 mm; 8:92, v/v) flowing at 1 mL/min. Separation of NAF and DMN enantiomers was achieved on the Chiralpak IA column by methanol-acetonitrile-acetate buffer (pH 5.3; 5 mm; 45:33:22, v/v/v) flowing at 0.5 mL/min. The analytes were measured with a fluorescence detector at 290 nm (λ(ex)) and 340 nm (λ(em)). The validated method showed a good linearity [22.5-15,000 ng/mL for (+)-/(-)-NAF; 35-25,000 ng/mL for (+)-/(-)-DMN] and the lowest limits of quantification for NAF and DMN enantiomers were 22.5 and 35 ng/mL, respectively. Both intra- and inter-day variations were <10%. The assay was successfully applied to the fecal excretion of NAF and DMN enantiomers in rat after single oral administration of (±)-NAF. Nonstereoselective excretion of (+)- and (-)-NAF was found in feces, while stereoselective excretion of (+)- and (-)-DMN was observed with higher excretion levels of (+)-DMN, indicating that there may exist stereoselective metabolism for NAF enantiomers.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fezes/química , Naftalenos/análise , Piperazinas/análise , Animais , Modelos Lineares , Naftalenos/química , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , EstereoisomerismoRESUMO
α1-Adrenoceptors (ARs; 1A, 1B, and 1D) have been determined to perform different prominent functions in the physiological responses of the sympathetic nervous system. A high-throughput screening assay (HTS) was set up to detect α1-AR subtype-selective agonists by a dual-luciferase reporter assay in HEK293 cells. Using the HTS assay, two novel compounds, CHE3 and CHK3, were discovered as α1-ARs agonists in α1-ARs expressed in HEK293 cells. These compounds also showed moderate/weak anti-proliferative activities against tested cancer cell lines. The HTS assay proposed in this study represents a potential method for discovering more α1-AR subtype-selective ligands.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/isolamento & purificação , Ensaios de Triagem em Larga Escala , Receptores Adrenérgicos alfa 1/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 1/química , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Humanos , Ligantes , Receptores Adrenérgicos alfa 1/química , Especificidade por SubstratoRESUMO
A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines (PC-3, LNCaP, and DU145) were evaluated by a CCK-8 assay. Compounds 9 and 15 exhibited strong cytotoxic activities against LNCaP cells (IC50<5 µM), and compound 8 (IC50=8.25 µM) possessed the most potent activity against DU145 cells. However, these compounds also exhibited cytotoxicity towards human epithelial prostate normal cells RWPE-1. The structure-activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.
Assuntos
Piperazinas/administração & dosagem , Piperazinas/síntese química , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Piperazina , Piperazinas/química , Neoplasias da Próstata/patologia , Relação Estrutura-AtividadeRESUMO
Autotrophic denitrification (AD) without carbon source is an inevitable choice for denitrification of municipal wastewater under the carbon peaking and carbon neutrality goals. This study first employed sulfur-tourmaline-AD (STAD) as an innovative nitrate removal trial technique in wastewater. STAD demonstrated a 2.23-fold increase in nitratenitrogen (NO3--N) removal rate with reduced nitritenitrogen (NO2--N) accumulation, effectively removing 99 % of nitrogen pollutants compared to sulfur denitrification. Some denitrifiers microorganisms that could secrete tyrosine, tryptophan, and aromatic protein (extracellular polymeric substances (EPS)). Moreover, according to the EPS composition and characteristics analysis, the secretion of loosely bound extracellular polymeric substances (LB-EPS) that bound to the bacterial endogenous respiration and enriched microbial abundance, was produced more in the STAD system, further improving the system stability. Furthermore, the addition of tourmaline (Tm) facilitated the discovery of a new genus (Paracoccus) that enhanced nitrate decomposition. Applying optimal electron donors through metabolic pathways and the microbial community helps to strengthen the AD process and treat low carbon/nitrogen ratio wastewater efficiently.