RESUMEN
Osteoporosis is with porous bones, which refers to a decrease in the bone mineral density and weakens the bones to become brittle. Osteoporosis often progresses without any pain or symptoms until the bone fractures. Monitoring the condition of bone regularly helps to identify the bone that weakens at its earlier stages. In general, radiological techniques have been used to measure bone mineral density, are expensive, and the procedures are complicated. Therefore, researchers are focusing on the alternative method of biomarker quantification to identify bone mineral density. This research work was focused on quantifying the osteoporosis biomarker of C-terminal telopeptide of type I collagen (CTX-I) on an interdigitated electrode (IDE) sensor. Gold nanomaterial-modified anti-CTX-I antibody was attached to silica nanomaterial-decorated IDE and then identified by CTX-I interaction. Higher immobilization of antibodies was recorded on diamond-modified IDE through gold nanoparticles, and detected CTX-I as low as 0.5 pg/mL [y = 1.5507x - 0.9043 R2 = 0.9715], determined on a linear curve at the range 0.5-3.5 ng/mL. Further, specific identification of CTX-I was confirmed by control performances with osteopontin, IL-6, and anti-IgG antibody.
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Nanopartículas del Metal , Osteoporosis , Humanos , Oro , Péptidos , Osteoporosis/diagnóstico , Inmunoensayo , Electrodos , BiomarcadoresRESUMEN
As one of the most common messenger ribonucleic acid modifications in eukaryotic organisms, N6-methyladenosine (m6A) is involved in a wide variety of biological functions. The imbalance of m6A RNA modification may be linked to cancer and other disorders, according to a growing body of studies. Its effects on clear cell renal cell carcinoma (KIRC) have not been well discussed, though. Here, we acquired the expression patterns of 23 important regulators of m6A RNA modification and assess how they might fare in KIRC. We observed that 17 major m6A RNA modification regulatory factors had a substantial predictive influence on KIRC. Using the "ConsensusCluster" program, we defined two groupings (Cluster 1 and Cluster 2) depending on the expression of the aforementioned 17 key m6A RNA methylation regulators. The Cluster 2 has a less favorable outcome and is strongly related with a lesser immune microenvironment, according to the findings. We also developed a strong risk profile for three m6A RNA modifiers (METTL14, YTHDF1, and LRPPRC) using multivariate Cox regression analysis. According to further research, the aforementioned risk profile could serve as an independent predicting factor for KIRC, and the chemotherapy response sensitivity was analyzed between two risk groups. Moreover, to effectively forecast the future outlook of KIRC clients, we established a novel prognostic approach according to gender, age, histopathological level, clinical stage, and risk score. Finally, the function of hub gene METTL14 was validated by cell proliferation and subcutaneous graft tumor in mice. In conclusion, we discovered that m6A RNA modifiers play an important role in controlling KIRC and created a viable risk profile as a marker of prediction for KIRC clients.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Animales , Ratones , Carcinoma de Células Renales/genética , ARN , Neoplasias Renales/genética , Inmunidad , Microambiente TumoralRESUMEN
Metal oxides with oxygen vacancies have a significant impact on catalytic activity for the transformation of organic pollutants in waste-to-energy (WtE) incineration processes. This study aims to investigate the influence of hematite surface oxygen point defects on the formation of environmentally persistent free radicals (EPFRs) from phenolic compounds based on the first-principles calculations. Two oxygen-deficient conditions were considered: oxygen vacancies at the top surface and on the subsurface. Our simulations indicate that the adsorption strength of phenol on the α-Fe2O3(0001) surface is enhanced by the presence of oxygen vacancies. However, the presence of oxygen vacancies has a negative impact on the dissociation of the phenol molecule, particularly for the surface with a defective point at the top layer. Thermo-kinetic parameters were established over a temperature range of 300-1000 K, and lower reaction rate constants were observed for the scission of phenolic O-H bonds over the oxygen-deficient surfaces compared to the pristine surface. The negative effects caused by the oxygen-deficient conditions could be attributed to the local reduction of FeIII to FeII, which lower the oxidizing ability of surface reaction sites. The findings of this study provide us a promising approach to regulate the formation of EPFRs.
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Compuestos Férricos , Oxígeno , Compuestos Férricos/química , Radicales Libres/química , Fenoles , Fenol/químicaRESUMEN
Chlorophenols (CPs) and phenol are abundant in thermal and combustion procedures, such as stack gas production, industrial incinerators, metal reclamation, etc., which are key precursors for the formation of polychlorinated naphthalenes (PCNs). CPs and phenol can react with H or OH radicals to form chlorophenoxy radicals (CPRs) and phenoxy radical (PhR). The self-condensation of CPRs or cross-condensation of PhR with CPRs is the initial and most important step for PCN formation. In this work, detailed thermodynamic and kinetic calculations were carried out to investigate the PCN formation mechanisms from PhR with 2-CPR/3-CPR. Several energetically advantageous formation pathways were obtained. The rate constants of key elementary steps were calculated over 600~1200 K using the canonical variational transition-state theory (CVT) with the small curvature tunneling (SCT) contribution method. The mechanisms were compared with the experimental observations and our previous works on the PCN formation from the self-condensation of 2-CPRs/3-CPRs. This study shows that naphthalene and 1-monochlorinated naphthalene (1-MCN) are the main PCN products from the cross-condensation of PhR with 2-CPR, and naphthalene and 2-monochlorinated naphthalene (2-MCN) are the main PCN products from the cross-condensation of PhR with 3-CPR. Pathways terminated with Cl elimination are preferred over those terminated with H elimination. PCN formation from the cross-condensation of PhR with 3-CPR can occur much easier than that from the cross-condensation of PhR with 2-CPR. This study, along with the study of PCN formation from the self-condensation 2-CPRs/3-CPRs, can provide reasonable explanations for the experimental observations that the formation potential of naphthalene is larger than that of 1-MCN using 2-CP as a precursor, and an almost equal yield of 1-MCN and 2-MCN can be produced with 3-CP as a precursor.
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Clorofenoles , Naftalenos , FenolesRESUMEN
Ovarian carcinoma (OC) is one of the most common gynecological malignancies, with a poor prognosis for patients at advanced stage. Danusertib (Danu) is a pan-inhibitor of the Aurora kinases with unclear anticancer effect and underlying mechanisms in OC treatment. This study aimed to examine the cancer cell killing effect and explore the possible mechanisms with a focus on proliferation, cell cycle progression, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) in human OC cell lines C13 and A2780cp. The results showed that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both cell lines. Danu arrested cells in G2/M phase and led to an accumulation of polyploidy through the regulation of the expression key cell cycle modulators. Danu induced mitochondria-dependent apoptosis and autophagy in dose and time-dependent manners. Danu suppressed PI3K/Akt/mTOR signaling pathway, evident from the marked reduction in the phosphorylation of PI3K/Akt/mTOR, contributing to the autophagy inducing effect of Danu in both cell lines. In addition, Danu inhibited EMT. In aggregate, Danu exerts potent inducing effect on cell cycle arrest, apoptosis, and autophagy, but exhibits a marked inhibitory effect on EMT. PI3K/Akt/mTOR signaling pathway contributes, partially, to the cancer cell killing effect of Danu in C13 and A2780cp cells.
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Antineoplásicos/farmacología , Benzamidas/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fenotipo , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Heterogeneous transformation of organic pollutants into more toxic chemicals poses substantial health risks to humans. Activation energy is an important indicator that help us to understand transformation efficacy of environmental interfacial reactions. However, the determination of activation energies for large numbers of pollutants using either the experimental or high-accuracy theoretical methods is expensive and time-consuming. Alternatively, the machine learning (ML) method shows the strength in predictive performance. In this study, using the formation of a typical montmorillonite-bound phenoxy radical as an example, a generalized ML framework RAPID was proposed for activation energy prediction of environmental interfacial reactions. Accordingly, an explainable ML model was developed to predict the activation energy via easily accessible properties of the cations and organics. The model developed by decision tree (DT) performed best with the lowest root-mean-squared error (RMSE = 0.22) and the highest coefficient of determination values (R2 score = 0.93), the underlying logic of which was well understood by combining model visualization and SHapley Additive exPlanations (SHAP) analysis. The performance and interpretability of the established model suggest that activation energies can be predicted by the well-designed ML strategy, and this would allow us to predict more heterogeneous transformation reactions in the environmental field.
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BACKGROUND: Various nonpharmacological interventions have been applied to alleviate pain and improve sleep quality after percutaneous nephrolithotomy. However, evidence to compare their efficacy is scant. This study aims to evaluate the efficacy of different nonpharmacological interventions on alleviating pain and improving sleep quality in patients after percutaneous nephrolithotomy through a network meta-analysis . METHODS: Randomized controlled trials reporting the efficacy of nonpharmacological interventions on alleviating pain and improving sleep quality in patients after percutaneous nephrolithotomy will be searched in online databases, including the Chinese Scientific Journal Database, China National Knowledge Infrastructure Database, Wanfang, China Biomedical Literature Database, Pubmed, Web of Science, Embase, and Cochrane Library. After quality assessment and date extraction, network meta-analysis will be performed using Stata 14.0 and R software. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSIONS: This study will provide systematic and comprehensive evidence-based support for the effects of nonpharmacological interventions on alleviating pain and improving sleep quality after percutaneous nephrolithotomy. ETHICS AND DISSEMINATION: Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. REGISTRATION NUMBER: DOI 10.17605/OSF.IO/B4DHW.
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Nefrolitotomía Percutánea , Dolor , Calidad del Sueño , Humanos , Metaanálisis como Asunto , Nefrolitotomía Percutánea/efectos adversos , Metaanálisis en Red , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: Serum CA-125 has been used as a biomarker of gynecological tumors. In this study, we investigated the CA-125 levels in cervical and vaginal secretions from Chinese patients with endometrial polyps, hyperplasia and carcinoma in comparison with those in endometrium and serum. MATERIAL/METHODS: An electro-chemiluminescent immunoassay was utilized to determine the levels of CA-125 in 51 healthy Chinese women and 97 patients with polyps, hyperplasia or endometrial cancer. An immunohistochemistry method was used to detect endometrial CA-125 expression in 242 subjects. RESULTS: Our study demonstrated that serum CA-125 levels were much lower than those in cervical and vaginal secretions in healthy and diseased women. The levels of CA-125 in serum, and cervical and vaginal secretions were significantly increased in complex hyperplasia and endometrial cancer. The increase of CA-125 content in serum, cervical and vaginal secretions was lesser significant in grade 3 cancer than that in grade 1 and 2 cancer. Generally, serum CA-125 levels correlated with those in cervical and vaginal secretions and CA-125 content in cervical secretion correlated with that in vaginal secretion. There was only a weak CA-125 expression in normal endometrium and simple endometrial hyperplasia. There was a significant difference in CA-125 expression among patients with pathological grade 1, 2 and 3 of endometrial carcinoma. CONCLUSIONS: Endo.metrial CA-125 expression together with its levels in the serum and cervical and vaginal secretions can be used as a potential biomarker in the diagnosis of precancerous diseases and endometrial carcinoma.
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Antígeno Ca-125/análisis , Antígeno Ca-125/sangre , Carcinoma/diagnóstico , Neoplasias Endometriales/diagnóstico , Lesiones Precancerosas/diagnóstico , Pueblo Asiatico , Biomarcadores de Tumor/metabolismo , Carcinoma/sangre , Carcinoma/metabolismo , Cuello del Útero/metabolismo , Neoplasias Endometriales/sangre , Neoplasias Endometriales/metabolismo , Endometrio/metabolismo , Femenino , Humanos , Inmunoensayo , Inmunohistoquímica , Lesiones Precancerosas/sangre , Lesiones Precancerosas/metabolismo , Vagina/metabolismoRESUMEN
Trichomonas vaginalis is a common protozoan parasite, which causes trichomoniasis associated with severe adverse reproductive outcomes. However, the underlying pathogenesis has not been fully understood. As the first line of defense against invading pathogens, the vaginal epithelial cells are highly responsive to environmental stimuli and contribute to the formation of the optimal luminal fluid microenvironment. The cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel widely distributed at the apical membrane of epithelial cells, plays a crucial role in mediating the secretion of Cl- and HCO3-. In this study, we investigated the effect of T. vaginalis on vaginal epithelial ion transport elicited by prostaglandin E2 (PGE2), a major prostaglandin in the semen. Luminal administration of PGE2 triggered a remarkable and sustained increase of short-circuit current (ISC) in rat vaginal epithelium, which was mainly due to Cl- and HCO3- secretion mediated by the cAMP-activated CFTR. However, T. vaginalis infection significantly abrogated the ISC response evoked by PGE2, indicating impaired transepithelial anion transport via CFTR. Using a primary cell culture system of rat vaginal epithelium and a human vaginal epithelial cell line, we demonstrated that the expression of CFTR was significantly down-regulated after T. vaginalis infection. In addition, defective Cl- transport function of CFTR was observed in T. vaginalis-infected cells by measuring intracellular Cl- signals. Conclusively, T. vaginalis restrained exogenous PGE2-induced anion secretion through down-regulation of CFTR in vaginal epithelium. These results provide novel insights into the intervention of reproductive complications associated with T. vaginalis infection such as infertility and disequilibrium in vaginal fluid microenvironment.
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Aniones/metabolismo , Cloruros/metabolismo , Vaginitis por Trichomonas/tratamiento farmacológico , Vagina/patología , Animales , Aniones/farmacología , Transporte Biológico , Línea Celular , Células Cultivadas , Antiportadores de Cloruro-Bicarbonato/fisiología , AMP Cíclico/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Dinoprostona/metabolismo , Células Epiteliales/efectos de los fármacos , Epitelio/metabolismo , Epitelio/parasitología , Epitelio/patología , Femenino , Humanos , Ratas , Ratas Sprague-Dawley , Vaginitis por Trichomonas/parasitología , Trichomonas vaginalis/metabolismo , Vagina/metabolismo , Vagina/parasitologíaRESUMEN
The placenta is a unique organ that is essential to a healthy and normal pregnancy. A number of phase I and II metabolizing enzymes are expressed at moderate levels in the placenta, and have been proven to have the ability to metabolize certain xenobiotics. Depending on the substrate, this metabolic action may have significant clinical implications on how it affects the fetus. A wide variety of transporters including P-glycoprotein, breast cancer resistance protein, and multidrug resistance associated proteins have also been discovered in the placenta, and while most are found to have mainly physiological substrates, there are a number of xenobiotics which are also able to gain access to the fetus through transport across the placenta. Depending on the xenobiotics and its intended action, drug transport across the placenta may be desired, acceptable or undesirable. Medications administered to the mother but designed to work on the fetus are now being used increasingly, and demonstrates an important clinical implication in which drug transport across the placenta is desirable. However, medications designed to treat the mother but are also able to cross the placenta carry potential risks to damage the developing fetus, and it is therefore essential that the effects of different drugs on the fetus are known before they are administered during pregnancy. There is still much unknown about drug transport and drug metabolism in the placenta, and it is vital that in the future further research is done to discover the clinical implications of these activities in the placenta. This research is often complicated by the fact that it is unethical to run studies in pregnant women, and so research is often carried out in pregnant animals. These results are not always accurate, however, as the human's placental structure is different from the placenta in other animals. Drug metabolism and drug transport across the placenta should continue to be researched, and guidelines need to be developed to ensure that any medications used during pregnancy are safe to both the mother and the fetus, and that successful treatment of the medical condition is carried out.
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Preparaciones Farmacéuticas/metabolismo , Placenta/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/fisiología , Transporte Biológico , Humanos , Proteínas de Transporte de Membrana/fisiología , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/fisiología , Proteínas de Neoplasias/fisiología , Proteínas de Transporte de Catión Orgánico/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/fisiología , Miembro 5 de la Familia 22 de Transportadores de SolutosRESUMEN
OBJECTIVE: To Explore the effect of oblique preputial island flap for the treating of hypospadias. METHODS: Fifty-one patients were performed one-stage urethroplasty with oblique preputial island flap to repair hypospadias. RESULTS: All cases resulted in a good contour of the penis without any redundancy and a normal anatomic position of slit-shaped urethral meatus. The urination was perfect. Six patients occurred complications (3 cases of urinary fistula, 3 cases of meatal stenosis). CONCLUSION: With extensive scope of materials, reliable blood supply of skin flap, satisfactory appearance of shaping penis and few complications, one-stage urethroplasty with oblique preputial island flap is an effective method to repair hypospadias of penile type and penile-scrotal type.
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Hipospadias/cirugía , Colgajos Quirúrgicos , Uretra/cirugía , Adolescente , Niño , Preescolar , Humanos , Masculino , Pene/cirugíaRESUMEN
OBJECTIVE: To assess the clinical efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis. METHODS: Forty-two patients with adenomyosis diagnosed by clinical symptoms, MRI, laparoscopy and/or chromatic colour type-B ultrasound were treated with LNG-IUS, and the menstrual blood volume, severity of dysmenorrhea and uterine volume were observed three months later. RESULTS: After 3 month treatment of LNG-IUS, the menstrual blood volume reduced significantly to (27 +/- 11)% of that before treatment. The uterine volume was decreased from (143 +/- 33) cm(3) to (115 +/- 22) cm(3) (P < 0.05). Dysmenorrhea was completely relieved or significantly alleviated. Hemoglobin recovered to (124 +/- 8) g/L (P < 0.05) in 20 patients with anemia. CONCLUSION: LNG-IUS is an effective and safe method in the short-term treatment of adenomyosis.
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Endometriosis/terapia , Levonorgestrel/uso terapéutico , Útero/metabolismo , Adulto , Femenino , Humanos , Dispositivos Intrauterinos , Dispositivos Intrauterinos Medicados , Levonorgestrel/farmacocinética , Levonorgestrel/farmacología , Resultado del Tratamiento , Útero/efectos de los fármacosRESUMEN
OBJECTIVE: To assess the effect of levonorgestrel-releasing intrauterine system (LNG-IUS) on serum lipids and hepatic function. METHODS: Blood samples of 35 cases receiving LNG-IUS were collected and determined for serum lipids and hepatic functions. RESULTS: Six months after insertions, HDL-C and ApoA were increased significantly, while LDL-C and ApoB decreased significantly. TG and TC levels were decreased at the 6th months and showed significant difference till the end of one year. TG/HDL-C and LDL-C/HDL-C ratios were increased and Apo A/ApoB ratio decreased significantly. The indices of hepatic function varied in the normal ranges, while Glb were decreased significantly after one year. CONCLUSION: LNG-IUS is an effective therapy without obvious adverse effect on lipid metabolism and hepatic function.
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Dispositivos Intrauterinos Medicados/efectos adversos , Levonorgestrel/efectos adversos , Lipoproteínas/sangre , Hígado/fisiología , Adulto , Femenino , Humanos , Levonorgestrel/administración & dosificación , Pruebas de Función HepáticaRESUMEN
The aberrant expression of human microRNA-181a-1 (hsa-miR-181a) has been implicated in the pathogenesis of various cancers, serving as an oncogene or a tumor suppressor. However, the role of hsa-miR-181a in the pathogenesis of endometrial carcinoma (EC) and its clinical significance are unclear. This study aimed to search for the molecular targets of hsa-miR-181a using bioinformatic tools and then determine the expression levels of hsa-miR-181a in normal, hyperplasia, and EC samples from humans. To predict the targets of hsa-miR-181a, ten different algorithms were used, including miRanda-mirSVR, DIANA microT v5.0, miRDB, RNA22 v2, TargetMiner, TargetScan 6.2, PicTar, MicroCosm Targets v5, and miRWALK. Two algorithms, TarBase 6.0 and miRTarBase, were used to identify the validated targets of hsa-miR-181a-5p (a mature product of hsa-miR-181a), and the web-based Database for Annotation, Visualization and Integrated Discovery (DAVID) 6.7 was used to provide biological functional interpretation of the validated targets of hsa-miR-181a-5p. A total of 78 formalin-fixed, paraffin-embedded tissue specimens from 65 patients and 13 healthy subjects were collected and examined, including normal endometrium (n=13), endometrial hyperplasia (n=18), and EC (37 type I and 10 type II EC cases). Our bioinformatic studies have showed that hsa-miR-181a might regulate a large number of target genes that are important in the regulation of critical cell processes, such as cell fate, cell survival, metabolism, and cell death. To date, 313 targets of hsa-miR-181a have been validated, and 22 of these targets are cancer genes. The precision of predictions by all the algorithms for hsa-miR-181a-1's targets was low. Many of these genes are involved in tumorigenesis of various cancers, including EC, based on the DAVID and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In comparison with normal endometrial tissue, the expression level of hsa-miR-181a was significantly increased in type I and type II EC (P<0.05), and type II EC exhibited a significant higher expression level of hsa-miR-181a than that in type I EC (P<0.05). In addition, there was a significant increase in the expression level of hsa-miR-181a in type II EC compared with endometrial hyperplasia (P<0.05). Taken together, these results suggest that hsa-miR-181a may serve as an oncogene in endometrial tumorigenesis and that hsa-miR-181a might be used as a new biomarker in the prediction of prognosis of EC in clinical practice. More functional and mechanistic studies are needed to validate the role of hsa-miR-181a in the development, progression, and metastasis of EC.
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Biomarcadores de Tumor/genética , Biología Computacional , Neoplasias Endometriales/genética , Neoplasias Endometriales/terapia , MicroARNs/genética , Algoritmos , Neoplasias Endometriales/metabolismo , Femenino , HumanosRESUMEN
An on-site active solid-phase microextraction (SPME) sampling technique coupled with gas chromatography-mass spectrometry (GC-MS) for sampling and monitoring 16 polycyclic aromatic hydrocarbons (PAHs) and 8 organochlorine pesticides (OCPs) in seawater was developed. Laboratory experiments demonstrated that the sampling-rate calibration method was practical and could be used for the quantification of on-site sampling. The proposed method was employed for field tests which covered large amounts of water samples in the Pearl River Estuary in rainy and dry seasons. The on-site SPME sampling method can avoid the contamination of sample, the losses of analytes during sample transportation, as well as the usage of solvent and time-consuming sample preparation process. Results indicated that the technique with the designed device can address the requirement of modern environment water analysis. In addition, the sources, bioaccumulation and potential risk to human of the PAHs and OCPs in seawater of the Pearl River Estuary were discussed.
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Monitoreo del Ambiente/métodos , Estuarios , Agua de Mar/química , Microextracción en Fase Sólida , Contaminantes Químicos del Agua/análisis , Cromatografía de Gases y Espectrometría de Masas , Sustancias Peligrosas/análisis , Hidrocarburos Clorados/análisis , Plaguicidas/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Ríos/químicaRESUMEN
Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and ß-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.
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Apoptosis/efectos de los fármacos , Aurora Quinasas/antagonistas & inhibidores , Autofagia/efectos de los fármacos , Benzamidas/farmacología , Neoplasias de la Mama/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Aurora Quinasas/metabolismo , Benzamidas/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células MCF-7 , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Plumbagin (PLB) has shown anti-cancer activity but the mechanism is unclear. This study has found that PLB has a potent pro-apoptotic and pro-autophagic effect on A549 and H23 cells. PLB arrests cells in G2/M phase, and increases the intracellular level of reactive oxygen species in both cell lines. PLB dose-dependently induces autophagy through inhibition of PI3K/Akt/mTOR pathway as indicated by reduced phosphorylation of Akt and mTOR. Inhibition or induction of autophagy enhances PLB-induced apoptosis. There is crosstalk between PLB-induced apoptosis and autophagy. These findings indicate that PLB initiates both apoptosis and autophagy in NSCLC cells through coordinated pathways.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Naftoquinonas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are generally not needed for herbal remedy discovery and development. For the majority of herbal medicines, data on their ADME and pharmacokinetic properties in humans are lacking or scant. An extensive literature search indicates that there are limited data on ADME properties of herbal medicines in humans. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp/MDR1/ABCB1) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are critical determining factors for the in vivo ADME processes of herbal remedies. There are increasing ADME studies of herbal remedies, but these studies are mainly focused on a small number of herbal medicines including St John's wort, milk thistle, curcumin, echinacea, ginseng, ginkgo, and ginger. For an herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and ADME processes of active herbal components in the body govern their target-site concentrations and thus the therapeutic responses. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their ADME profiles. To optimize the use of herbal remedies, further studies to explore their ADME properties in humans are certainly warranted.