RESUMEN
Acute lung injury (ALI) is a serious pulmonary inflammatory disease resulting from excessive reactive oxygen species (ROS) which could cause the damage of the alveolar epithelial cells and capillary endothelial cells. Peroxynitrite, as one of short-lived reactive oxygen species, is closely related to the process of ALI. Thus, it is important to monitor the fluctuation of peroxynitrite in living system for understanding the process of ALI. Herein, the novel mitochondria-targeted fluorescent probe BHMT was designed to respond to peroxynitrite and pH with distinct fluorescence properties respectively. The absorption spectrum of the probe BHMT exhibited a notable red shift as the pH value declined from 8.8 to 2.6. Upon reaction with peroxynitrite, BHMT had a significant increase of fluorescence intensity (63-fold) with maintaining a detection limit of only 43.7 nM. Furthermore, BHMT could detect the levels of endogenous peroxynitrite and image the intracellular pH in ratiometric channels utilizing cell imaging. In addition, BHMT was successfully applied to revealing the relationship between the peroxynitrite and the extent of ALI. Thus, these results indicated the probe BHMT could be a potential tool for diagnosing the early stage of ALI and revealed the peroxynitrite was likely to be a crucial therapeutic target in ALI treatment.
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Phospholipase A2(PLA2) superfamily is recognized as being involved in the pathogenesis of schizophrenia by affecting lipid homeostasis in cell membranes. We hypothesized that PLA2 gene copy number variation (CNV) may affect PLA2 enzyme expression and be associated with schizophrenia risk. This study indicated that in the discovery stage, an increased copy number of PLA2G6 and the deletion of PLA2G3, PLA2G4A, PLA2G4F and PLA2G12F was associated with increased risk of schizophrenia. CNV segments involving six PLA2 genes were detected in publicly available datasets, including two deletion segments specific to the PLA2G4A gene. The relationship between the deletion of PLA2G4A and susceptibility to schizophrenia was then reaffirmed in the validation group of 806 individuals. There was a significant correlation between PLA2G4A deletion and the symptoms of poverty of thought in male patients and erotomanic delusion in females. Furthermore, ELISA results demonstrate a significant decrease in peripheral blood cytosolic PLA2(cPLA2) levels in patients with the PLA2G4A deletion genotype compared to those with normal and copy number duplicate genotypes. These data suggest that the functional copy number deletion in the PLA2G4A gene is associated with the risk of schizophrenia and clinical phenotypes by reducing the expression of cPLA2, which may be an indicator of susceptibility to schizophrenia.
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Background: With the rapid growth of global aging, frailty has become a serious public health burden, affecting the life quality of older adults. Depressive symptoms (depression hereafter) and sleep quality are associated with frailty, but the pathways in which sleep quality and depression affect frailty remain unclear. Method: This cross-sectional study included 1866 community-dwelling older adults. Demographic characteristics and health-related data of them was collected, and we also assessed frailty, depression, and sleep quality. Descriptive statistics were carried out and ordinal logistic regression analysis was used to identify the factors correlated with frailty. Spearman correlation analysis and mediation analysis were employed to assess associations between sleep quality, depression and frailty. Two-sided p < 0.05 was considered as significant. Results: The results showed that 4.1% older adults were frail and 31.0% were pre-frail. Ordinal logistic regression showed that age, consumptions of vegetables, exercise, sleep quality, depression, number of chronic diseases, chronic pain, and self-rated health were correlated with frailty. Spearman correlation analysis revealed that frailty was associated with depression and sleep quality. There was a mediation effect that sleep quality was a significant and positive predictor of frailty (total effect = 0.0545, 95% boot CI = 0.0449-0.0641), and depression was a mediator between sleep quality and frailty (mediation effect = 60.4%). Conclusion: Depression and poor sleep quality may be early indicators of frailty in older adults. Improving the sleep quality and psychological state of older adults can improve frailty, which is beneficial for healthy aging.
Asunto(s)
Depresión , Fragilidad , Calidad del Sueño , Humanos , Estudios Transversales , Masculino , Femenino , Anciano , China/epidemiología , Depresión/epidemiología , Anciano de 80 o más Años , Anciano Frágil/estadística & datos numéricos , Anciano Frágil/psicología , Vida Independiente , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti-tumor treatment. In addition, central nervous system neoplasm-targeted nanoplatforms are urgently required. To address these issues, a new multi-functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP-TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione-responsive disulfide bond. Mechanistically, ODP-TH crosses the blood-brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down-regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia-inducible factor-1-α (HIF-1α). The results reveal that ODP-TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP-TH achieves a more efficient tumor-inhibiting effect. This study not only overcomes the hypoxia-related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi-functional targeted and intensive anti-tumor nanoplatform.
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Carcinoma , Fotoquimioterapia , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Carcinoma/tratamiento farmacológico , Carcinoma/terapia , Hipoxia , Oxígeno/farmacología , Oxígeno/uso terapéutico , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/instrumentación , Fotoquimioterapia/métodos , Nanotecnología/instrumentación , Nanotecnología/métodos , Nanomedicina/instrumentación , Nanomedicina/métodosRESUMEN
Theranostic prodrug was highly desirable for precise diagnosis and anti-cancer therapy to decrease side effects. However, it is difficult to conjugate chemo-drug and molecular probe for combined therapy due to the complex pharmacokinetics of different molecules. Here, a novel anticancer theranostic prodrug (BTMP-SS-PTX) had been designed and synthesized by conjugating paclitaxel (PTX) with 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol (BTMP) through a disulphide (-S-S-) linkage, which was redox-sensitive to the high concentration of glutathione in tumors. Upon activation with glutathione in weakly acid media, the BTMP-SS-PTX can be dissociated to release free PTX and visible BTMP, which realized the visual tracking of free drug. The cytotoxicity study demonstrated that soluble prodrug BTMP-SS-PTX displayed more outstanding anticancer activity in HepG2, MCF-7 and HeLa cells, lower toxicity to non-cancer cells (293 T) than free drugs. Furthermore, BTMP-SS-PTX was still able to induce apoptosis of HeLa cells and significantly inhibited tumor growth in HeLa-xenograft mouse model. On the basis of these findings, BTMP-SS-PTX could play a potential role in cancer diagnosis and therapy.
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Antineoplásicos/farmacología , Glutatión/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Glutatión/química , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Imagen Óptica , Profármacos/síntesis química , Profármacos/química , Solubilidad , Relación Estructura-Actividad , Distribución TisularRESUMEN
The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT), mediated by scavenger receptors into HeLa cells. DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT. Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150â¯nm and length of 300-600â¯nm. The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis, as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage. The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512â¯nM) with a viability of 92% as evidence of its biocompatibility for drug delivery. MTT assay showed superior cytotoxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT internalization. The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT), as illustrated in confocal images. Therefore, in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7%) with CPT-DNA-NT (compared to free CPT; 64.4%). CPT-DNA-NT, being poly-anionic, showed enhanced endocytosis via scavenger receptors.
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The study aimed to achieve enhanced targeted cytotoxicity and cell-internalization of cisplatin-loaded deoxyribonucleic acid-nanothread (CPT-DNA-NT),mediated by scavenger receptors into HeLa cells.DNA-NT was developed with stiff-topology utilizing circular-scaffold to encapsulate CPT.Atomic force microscopy (AFM) characterization of the DNA-NT showed uniformity in the structure with a diameter of 50-150 nm and length of 300-600 nm.The successful fabrication of the DNA-NT was confirmed through native-polyacrylamide gel electrophoresis analysis,as large the molecular-weight (polymeric) DNA-NT did not split into constituting strands under applied current and voltage.The results of cell viability confirmed that blank DNA-NT had the least cytotoxicity at the highest concentration (512 nM) with a viability of 92% as evidence of its biocompatibility for drug delivery.MTT assay showed superior cyto-toxicity of CPT-DNA-NT than that of the free CPT due to the depot release of CPT after DNA-NT inter-nalization.The DNA-NT exhibited targeted cell internalizations with the controlled intracellular release of CPT (from DNA-NT),as illustrated in confocal images.Therefore,in vitro cytotoxicity assessment through flow cytometry showed enhanced apoptosis (72.7%) with CPT-DNA-NT (compared to free CPT;64.4%).CPT-DNA-NT,being poly-anionic,showed enhanced endocytosis via scavenger receptors.
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Reporting on brucellosis, a relatively rare infectious disease caused by Brucella, is often delayed or incomplete in traditional disease surveillance systems in China. Internet search engine data related to brucellosis can provide an economical and efficient complement to a conventional surveillance system because people tend to seek brucellosis-related health information from Baidu, the largest search engine in China. In this study, brucellosis incidence data reported by the CDC of China and Baidu index data were gathered to evaluate the relationship between them. We applied an autoregressive integrated moving average (ARIMA) model and an ARIMA model with Baidu search index data as the external variable (ARIMAX) to predict the incidence of brucellosis. The two models based on brucellosis incidence data were then compared, and the ARIMAX model performed better in all the measurements we applied. Our results illustrate that Baidu index data can enhance the traditional surveillance system to monitor and predict brucellosis epidemics in China.
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Brucelosis/epidemiología , Minería de Datos/métodos , Epidemias/prevención & control , Monitoreo Epidemiológico , Motor de Búsqueda/estadística & datos numéricos , Brucelosis/microbiología , China/epidemiología , Epidemias/estadística & datos numéricos , Estudios de Factibilidad , Humanos , Incidencia , Internet/estadística & datos numéricos , Internet/tendencias , Modelos Estadísticos , Prevalencia , Medición de Riesgo/métodos , Motor de Búsqueda/tendencias , Estaciones del AñoRESUMEN
In pastoral parts of China, anthrax still presents a major risk to livestock and threatens the health of local human populations. Currently, whole-genome-based molecular markers, such as single-nucleotide polymorphisms (SNPs) and variable number tandem repeats (VNTRs), are the most effective tools for genotyping Bacillus anthracis. In this study, 191 isolates were selected to assess the diversity of B. anthracis in China. Five isolates were confirmed not to be B. anthracis by clustered regularly interspaced short palindromic repeat analysis, while the remaining 186 isolates were typed using canonical SNP (canSNP) and VNTR analyses. Five sublineages/subgroups, A.Br.001/002, A.Br.Vollum, A.Br.Aust.94, A.Br.Ames, and A.Br.008/009, were detected based on 13 canSNP sites. The 186 isolates were further assigned 114 sequence types based on 27 VNTR loci, with major branches correlating with the canSNP analysis. We then used a simplified multiple-locus variable number tandem repeat analysis (MLVA) protocol (MLVAmin) based on eight high-resolution VNTR sites to analyze the Chinese isolates, with the resulting phylogeny again agreeing with the canSNP analysis. We also developed two schemes, MLVAc and MLVAp, using various numbers of VNTRs to analyze different canSNP sublineages to increase the typing resolution of the canSNP protocol. The results showed a highly imbalanced geographical distribution of the B. anthracis population, with four different sublineages observed in Xinjiang Province, while only one sublineage, A.Br.001/002, was found in the other six provinces, except for three A.Br.Ames strains isolated from Inner Mongolia. Based on the MLVA and canSNP analysis, the spread of B. anthracis appears to have occurred from west to east via three independent routes.
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Carbunco/microbiología , Bacillus anthracis/clasificación , Variación Genética , Repeticiones de Minisatélite , Polimorfismo de Nucleótido Simple , Técnicas de Tipificación Bacteriana , China , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Genotipo , Técnicas de Genotipaje , HumanosRESUMEN
In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50â¯=â¯6.43-10.97⯵M for F10, HeLa, A549 and MCF-7â¯cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50â¯=â¯194.01⯵M vs.celecoxib: IC50â¯=â¯97.87⯵M for 293T cells), and excellent inhibitory activities on COX-2 (IC50â¯=â¯0.17⯵M) and 5-LOX (IC50â¯=â¯0.68⯵M). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10â¯cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.
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Antineoplásicos/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Azoles/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Morfolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Azoles/síntesis química , Azoles/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Relación Estructura-ActividadRESUMEN
A series of novel ferrocene-pyrazole derivatives containing nitric oxide donors as COX-2 inhibitors for cancer therapy were designed, synthesized and biologically evaluated. Among them, compound 7l displayed the most potent inhibitory against COX-2 (IC50â¯=â¯0.82⯵M) and antiproliferative activities against Hela cells (IC50â¯=â¯0.34⯵M) compared with Celecoxib (IC50â¯=â¯0.38 and 7.91⯵M). The further mechanistic studies revealed that 7l could induce apoptosis of Hela cells by mitochondrial depolarization and the antiproliferative activities of 7l were positively correlated with the levels of intracellular NO release in Hela cells. Most notably, 7l could dramatically suppress tumor growth in Hela cells xenografted mouse model. In summary, compound 7l may be promising candidates for cancer therapy.
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Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Diseño de Fármacos , Compuestos Ferrosos/farmacología , Metalocenos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Donantes de Óxido Nítrico/farmacología , Pirazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos Ferrosos/química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Metalocenos/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0.23±0.16µM for COX-2, IC50=0.87±0.07µM for 5-LOX, IC50=4.48±0.57µM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41±0.28µM for COX-2, IC50=7.68±0.55µM against A549) and Zileuton (IC50=1.35±0.24µM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.
Asunto(s)
Cumarinas/química , Cumarinas/farmacología , Ciclooxigenasa 2/metabolismo , Pirazoles/química , Pirazoles/farmacología , Células A549 , Apoptosis/efectos de los fármacos , Araquidonato 5-Lipooxigenasa/química , Araquidonato 5-Lipooxigenasa/metabolismo , Sitios de Unión , Dominio Catalítico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC50 values ranging from 15 to 40nM), especially HeLa cells (with IC50 values of 15nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug.