RESUMEN
Docetaxel is the preferred chemotherapeutic agent in patients with castrate-resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance and in the absence of effective treatment options. Consequently, it is essential to investigate the mechanisms generating docetaxel resistance and develop novel alternative therapeutic targets. RNA sequencing was undertaken on docetaxel-sensitive and docetaxel-resistant prostate cancer (PCa) cells. Subsequently, chemoresistance, cancer stemness, and lipid metabolism were investigated. To obtain insight into the precise activities and action mechanisms of NOTCH3 in docetaxel-resistant PCa, immunoprecipitation, mass spectrometry, ChIP, luciferase reporter assay, cell metabolism, and animal experiments were performed. Through RNA sequencing analysis, we found that NOTCH3 expression was markedly higher in docetaxel-resistant cells relative to parental cells, and that this trend was continued in docetaxel-resistant PCa tissues. Experiments in vitro and in vivo revealed that NOTCH3 enhanced stemness, lipid metabolism, and docetaxel resistance in PCa. Mechanistically, NOTCH3 is bound to TUBB3 and activates the MAPK signaling pathway. Moreover, NOTCH3 was directly regulated by MEF2A in docetaxel-resistant cells. Notably, targeting NOTCH3 and the MEF2A/TUBB3 signaling axis was related to docetaxel chemoresistance in PCa. Overall, these results demonstrated that NOTCH3 fostered stemness, lipid metabolism, and docetaxel resistance in PCa via the TUBB3 and MAPK signaling pathways. Therefore, NOTCH3 may be employed as a prognostic biomarker in PCa patients. NOTCH3 could be a therapeutic target for PCa patients, particularly those who have developed docetaxel resistance.
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Resistencia a Antineoplásicos , Neoplasias de la Próstata , Masculino , Animales , Humanos , Docetaxel/farmacología , Docetaxel/uso terapéutico , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Transducción de Señal/genética , Tubulina (Proteína)/metabolismo , Receptor Notch3/genéticaRESUMEN
Dysregulation of deubiquitination contributes to various diseases, including cancer, and aberrant expression of deubiquitinating enzymes is involved in carcinoma progression. As a member of the ovarian tumor (OTU) deubiquitinases, OTUD4 is considered a tumor suppressor in many kinds of malignancies. The biological characteristics and mechanisms of OTUD4 in clear cell renal cell carcinoma (ccRCC) remain unclear. The downregulation of OTUD4 in ccRCC was confirmed based on the TCGA database and a validation cohort of 30-paired ccRCC and para-carcinoma samples. Moreover, OTUD4 expression was detected by immunohistochemistry in 50 cases of ccRCC tissues, and patients with lower levels of OTUD4 showed larger tumor size (p = 0.015). TCGA data revealed that patients with high expression of OTUD4 had a longer overall survival rate. In vitro and in vivo studies revealed that downregulation of OTUD4 was essential for tumor cell growth and metastasis in ccRCC, and OTUD4 overexpression inhibited these malignant phenotypes. We further found that OTUD4 sensitized ccRCC cells to Erastin-induced ferroptosis, and ferrostain-1 inhibited OTUD4-induced ferroptotic cell death. Mechanistic studies indicated that OTUD4 functioned as an anti-proliferative and anti-metastasic factor through the regulation of RNA-binding protein 47 (RBM47)-mediated activating transcription factor 3 (ATF3). OTUD4 directly interacted with RBM47 and promoted its stability via deubiquitination events. RBM47 was critical in ccRCC progression by regulating ATF3 mRNA stability, thereby promoting ATF3-mediated ferroptosis. RBM47 interference abolished the suppressive role of OTUD4 overexpression in ccRCC. Our findings provide mechanistic insight into OTUD4 of ccRCC progression and indicate a novel critical pathway OTUD4/RBM47/ATF3 may serve as a potential therapeutic pathway for ccRCC.
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Factor de Transcripción Activador 3 , Carcinoma de Células Renales , Neoplasias Renales , Proteínas de Unión al ARN , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Enzimas Desubicuitinizantes/genética , Enzimas Desubicuitinizantes/metabolismo , Ferroptosis/genética , Ferroptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones Desnudos , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismoRESUMEN
Neptunium-237, owing to its long half-life (t1/2 = 2.14 × 106 year) and similar conservatism to 137Cs, has the potential to replace 137Cs for water mass circulation studies on decades and even longer time scales. A new method for the determination of 137Cs, 237Np, and Pu isotopes in seawater samples was proposed to solve the difficulty of 237Np analysis in seawater. The developed method includes the separation technique of ammonium phosphomolybdate (AMP) adsorption for 137Cs and anion exchange chromatography for 237Np and Pu, a measurement technique of gamma spectrometry for 137Cs and SF-ICP-MS for 237Np and Pu isotopes. 242Pu as a pseudo isotope dilution tracer for Np, the negligible chemical fractionation between 237Np and 242Pu of 1.02 ± 0.06 (k = 2) was obtained by implementing sophisticated control of the redox system and chromatographic elution optimization. The analytical results for the International Atomic Energy Agency Certified Reference Materials (IAEA-443) agreed with the reference values, showing chemical yields of 65-88%, U decontamination factor above 106 level, and improved sample throughput (5 days for 12 samples). Meanwhile, the lower method detection limits (MDLs) of 237Np, 239Pu, and 240Pu were 1.3 × 10-3, 0.065, and 0.15 µBq L-1 for 15 L seawater, respectively. Results obtained by the developed method can be used to evaluate the impact on the marine ecological system of the planned marine discharge of Fukushima decontaminated wastewater. Working toward that purpose, we are the first to report the 237Np activity concentration in Pacific Ocean seawater sampled near the station site, and we obtained the value of 0.122-0.154 µBq L-1.
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The synthesis of dicyclic spiropyridazine oxoindole derivatives by using [3+3]-cycloaddition of N-unsubstituted isatin N,N'-cyclic azomethine imine 1,3-dipoles was reported. The products bearing two consecutive stereocenters, including spiroquaternary stereocenters in one ring structure, can be effectively obtained in moderate to excellent yields (20-93%) and low to moderate diastereoselectivities (1:9-10:1 dr). The synthesized compounds (>35 examples) were characterized by single-crystal XRD, FTIR, NMR, and mass spectral analysis.
RESUMEN
Allylation of N-unsubstituted isatin N,N'-cyclic azomethine imines with Morita-Baylis-Hillman carbonates in the presence of 1-10 mol% DABCO in DCM at room temperature, rapidly gave N-allylated and N, ß-diallylated isatin N,N'-cyclic azomethine imine 1,3-dipoles in moderate to high yields. The reaction features mild reaction conditions, easily practical operation, and short reaction times in most cases. Furthermore, the alkylated products were transformed into novel bicyclic spiropyrrolidine oxoindole derivatives through the [3+2] or [3+3]-cycloaddition with maleimides or Knoevenagel adducts.
RESUMEN
A meta-analysis study to assess the effect of honey dressing (HD) in the management of diabetic foot ulcer (DFU). A comprehensive literature examination till January 2023 was implemented and 1794 linked studies were appraised. The picked studies contained 882 subjects with DFUs were in the picked studies' baseline, 424 of them were using HD, and 458 were using a control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of HD in the management of DFUs after DFU by the dichotomous and continuous styles and a fixed or random model. The HD applied to DFUs caused a significantly higher wound healing rate (OR, 2.06; 95% CI, 1.45-2.93, P < .001) and lower wound healing time (MD, -10.42; 95% CI, -16.27- -4.58, P < .001) compared with the control. The HD applied to DFUs caused a significantly higher wound healing rate and lower wound healing time compared with the control. Although precautions should be taken when commerce with the consequences since most of the picked studies for this meta-analysis was with low sample sizes.
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Diabetes Mellitus , Pie Diabético , Miel , Humanos , Pie Diabético/terapia , Pie Diabético/diagnóstico , Vendas Hidrocoloidales , Cicatrización de HeridasRESUMEN
BACKGROUND: Biomarkers of DNA damage repair deficiency provide opportunities for personalized treatment with immunotherapy. However, there is limited research on the immune microenvironment of adeno-neuroendocrine prostate cancer (NEPC). In this study, we aimed to assess and describe the comprehensive clinicopathological manifestations of NEPC to improve diagnosis and predict prognosis. METHODS: A retrospective medical record review of 66 patients with prostate cancer (PCa) was performed. PCa samples from the 66 patients were analyzed using immunohistochemical staining for the detection of chromogranin, neural cell adhesion molecule 1, and synaptophysin. For tumor-associated immune microenvironment analysis, PD-L1, CD3, and CD8 were labeled in tissue slides. The effect of clinicopathological factors on the survival of patients with Adeno-NEPC was analyzed. RESULTS: Twenty patients presented with adeno-NEPC, whereas 46 presented with adeno-PCa. The median age of patients at PCa diagnosis was 67.86 ± 7.05 years (68.65 ± 7.23 years, adeno-NEPC; 67.52 ± 7.02 years, adeno-PCa). Eleven patients with adeno-NEPC underwent prostatectomy, whereas nine received primary androgen deprivation therapy (ADT). Additionally, 30 patients with adeno-PCa underwent prostatectomy, whereas 16 (34.8%) received primary ADT. There was a significant difference in overall survival between patients with adeno-NEPC and those with adeno-PCa (46.0 months vs. 65.0 months). There was also a significant difference in time from prostatectomy to biochemical recurrence between the groups of patients who underwent prostatectomy. Prostatectomy and normal lactate dehydrogenase levels were clinical factors that were significantly associated with better outcomes in patients with adeno-NEPC. Metastatic adeno-NEPC was associated with a higher programmed death ligand 1 (PD-L1) score (2-4) than localized PCa. The data showed that PD-L1 expression in adeno-NEPC may be negatively associated with that in CD8+ T cells. CONCLUSIONS: Our study revealed clinicopathological manifestations of adeno-NEPC and some possible predictive factors significantly associated with better outcomes in patients with adeno-NEPC. These findings might be beneficial in the development of diagnostic strategies and customized treatment plans.
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Adenocarcinoma , Neoplasias de la Próstata , Masculino , Humanos , Persona de Mediana Edad , Anciano , Neoplasias de la Próstata/patología , Antígeno B7-H1 , Estudios Retrospectivos , Antagonistas de Andrógenos/uso terapéutico , Linfocitos T CD8-positivos/patología , Próstata/patología , Adenocarcinoma/genética , Microambiente TumoralRESUMEN
Soil and road dust are important receptors of heavy metals in the environment. Meanwhile, heavy metal could transfer to the atmosphere through resuspension. Due to the serious consequences and atmospheric haze in Jing-Jin-Ji area, it's important to evaluate the pollution level, particle size distribution and sources of heavy metals. For heavy metals in soil samples, similar concentrations to the background values and no obvious pollution or low-level pollution was presented. Higher concentration of Cu (78.9 mg/kg) and Zn (261 mg/kg) were found in road dust. The source appointment results showed that Mn, Co, Cr, Ni, Zn and Pb in soils and Cr, Co and Mn in road dust were mainly from the natural sources, while traffic source contributed to most of Cu, Zn and Pb in road dust. Different particle size distribution patterns were found in soils and road dusts, and the finest particles presented the highest heavy metal concentrations.
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Metales Pesados , Contaminantes del Suelo , China , Ciudades , Polvo/análisis , Monitoreo del Ambiente/métodos , Plomo , Metales Pesados/análisis , Medición de Riesgo , Suelo , Contaminantes del Suelo/análisisRESUMEN
BACKGROUND: We aimed to establish a novel method, using the weighted Procrustes analysis (WPA) algorithm, which assigns weight to facial anatomical landmarks, to construct a three-dimensional facial symmetry reference plane (SRP) for mandibular deviation patients. METHODS: Three-dimensional facial SRPs were independently extracted from 15 mandibular deviation patients using both our WPA algorithm and the standard PA algorithm. A reference plane was defined to serve as the ground truth. To determine whether the WPA SRP or the PA SRP was closer to the ground truth, we measured the position error of mirrored landmarks, the facial asymmetry index (FAI) error, and the angle error for the global face and each facial third partition. RESULTS: The average angle error between the WPA SRP and the ground truth was 1.66 ± 0.81°, which was smaller than that between the PA SRP and the ground truth. The position error of the mirrored landmarks constructed using the WPA algorithm in the global face (3.64 ± 1.53 mm) and each facial partition was lower than that constructed using the PA algorithm. The average FAI error of the WPA SRP was - 7.77 ± 17.02 mm, which was smaller than that of the PA SRP. CONCLUSIONS: This novel automatic algorithm, based on weighted anatomic landmarks, can provide a more adaptable SRP than the standard PA algorithm when applied to severe mandibular deviation patients and can better simulate the diagnosis strategies of clinical experts.
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Asimetría Facial , Imagenología Tridimensional , Algoritmos , Puntos Anatómicos de Referencia , Cefalometría , HumanosRESUMEN
BACKGROUND: Docetaxel was used to treat metastatic CRPC patients. However, Doc resistance in prostate cancer (PCa) hinders its clinical application. OBJECTIVE: To understand the underlying mechanisms by which Doc resistance is developed and to find novel therapeutic target to cure Doc resistant PCa has clinical importance. METHODS: We established Doc resistant cell lines and explored the role of Ezh2 in the development of Doc resistance by overexpressing its cDNA or using its inhibitor. RESULTS: We found that Ezh2 was induced in our established Doc resistant (DocR) cells, which was attributable to the silenced expression of miR-101-3p and miR-138-5p. Blockage of Ezh2 activity by either inhibitor or miRNA mimics could overcome Doc resistance by suppressing Doc-induced cancer stem cells populations. Mechanistically, Ezh2 activity was required for the induced expression of Nanog, Sox2 and CD44 upon Doc treatment. CONCLUSIONS: Targeting Ezh2 could overcome Doc resistance.
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Proteína Potenciadora del Homólogo Zeste 2/genética , MicroARNs/genética , Neoplasias de la Próstata/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Docetaxel/efectos adversos , Docetaxel/farmacología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. METHODS: Purified recombinant human inhibitor of κB kinase subunit ß (IKKß) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. RESULTS: We showed that hydrogen sulfide (H2S) inhibited IKKß activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKß activity directly via sulfhydrating IKKß at cysteinyl residue 179 (C179) in purified recombinant IKKß protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKß inactivation. Furthermore, to demonstrate the significance of IKKß sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKß. In purified IKKß protein, C179S mutation of IKKß abolished H2S-induced IKKß sulfhydration and the subsequent IKKß inactivation. In human PAECs, C179S mutation of IKKß blocked H2S-inhibited IKKß activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKß abolished the inhibitory effect of H2S on IKKß activation and pulmonary vascular inflammation and remodeling. CONCLUSION: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKß via sulfhydrating IKKß at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.
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Cisteína/metabolismo , Sulfuro de Hidrógeno/metabolismo , Hipertensión Pulmonar/metabolismo , Quinasa I-kappa B/metabolismo , Inflamación/metabolismo , Arteria Pulmonar/metabolismo , Animales , Células Cultivadas , Cisteína/deficiencia , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Sulfuro de Hidrógeno/antagonistas & inhibidores , Hipertensión Pulmonar/patología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Monocrotalina/análogos & derivados , Monocrotalina/farmacología , FN-kappa B/metabolismo , Arteria Pulmonar/citología , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Aroma plays an important role in fruit quality and varies among different fruit cultivars. In this study, a sensitive and accurate method based on headspace solid-phase microextraction (HS-SPME) coupled with comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS) was developed to comprehensively compare aroma components of five pear cultivars. In total, 241 volatile compounds were identified and the predominant volatile compounds were esters (101 compounds), followed by alcohols (20 compounds) and aldehydes (28 compounds). The longyuanyangli has the highest relative concentration (838.12 ng/g), while the Packham has the lowest (208.45 ng/g). This study provides a practical method for pear aroma analysis using SPME and GC×GC-TOFMS.
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Cromatografía de Gases y Espectrometría de Masas/métodos , Pyrus/química , Microextracción en Fase Sólida/métodos , Compuestos Orgánicos Volátiles/análisis , Análisis por Conglomerados , Odorantes/análisisRESUMEN
While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression levels via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help to develop a new therapy to better suppress the ccRCC metastasis.
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Carcinoma de Células Renales/patología , Neoplasias Renales/patología , MicroARNs/genética , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Transducción de Señal , Regulación hacia Arriba , Regiones no Traducidas 3' , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Factor de Crecimiento de Hepatocito/genética , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-met/genética , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Transducción de Señal/efectos de los fármacos , Sunitinib/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Tissue-engineered urethra with autologous cells seeded on biodegradable scaffolds offers an alternative for lower urinary tract reconstruction. Rabbit is most commonly used as an animal model in urethra and bladder tissue repair. The goal of this study is to characterize rabbit urine-derived stem cells (rUSC) and induce these cells to differentiate into urothelial and smooth muscle cells as an autologous cell source for potential use in lower urinary tract tissue regeneration in a rabbit model. We successfully cultured rUSC from 12 urine samples and 13 bladder wash samples of six rabbits. rUSC colonies appeared more in the bladder wash solution (2-4/15 ml) than those in the urine samples (1-2 clones/15 ml urine). The cells displayed rice grain-like in morphology. Mean population doubling of rUSC was 48.5 ± 6.2 and average doubling time was 25.7 ± 8.4 h, indicating that a single of rUSC clone generated about 4 × 1014 cells in 50 days. The rUSC were positive for CD29, CD90 and CD105 but negative for CD31, CD34 and CD45 in flow cytometry. When exposed to PDGF-BB and TGF-ß1, these cells could differentiate into spindle-like cells, expressing smooth muscle-specific proteins, including α-smooth muscle action, desmin and myosin. Urothelially differentiated rUSC expressed urothelial-specific proteins, i.e., AE1/AE3 and E-cadherin when exposed to epidermal growth factor (EGF). Osteogenic-differentiated rUSC expressed osteogenic marker, i.e., alkaline phosphatase when exposed to serum containing DMEM low-glucose medium with osteogenic supplements. In conclusion, rUSC can be isolated from bladder wash or urine samples and cultured in vitro. There stem cells possess strong proliferative ability and are capable of differentiating in urothelial, myogenic and osteogenic lineages. Thus, rUSC are a potential alternative autologous cell source for lower urinary tract repair with tissue engineering technology in a rabbit model.
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Regeneración/fisiología , Células Madre/citología , Vejiga Urinaria/fisiología , Orina/citología , Animales , Biomarcadores/metabolismo , Adhesión Celular , Proliferación Celular , Separación Celular , Forma de la Célula , Células Cultivadas , Humanos , Masculino , Desarrollo de Músculos , Osteogénesis , ConejosRESUMEN
A quick, simple, and reliable method was developed for the simultaneous determination of free and total choline and l-carnitine in infant formula employing a novel hydrophilic interaction liquid chromatography with tandem mass spectrometry method. Microwave-assisted hydrolysis was used to shorten the hydrolysis time to only 15 min. A novel Click XIon zwitterionic stationary phase was chosen because it gave better retention, perfect resolution, and sharper symmetrical peaks compared to traditional columns. The matrix effect under different experimental conditions was evaluated by using the matrix effect factor, which employs stable isotopically labeled internal standards and is more appropriate for evaluating the matrix effect related to endogenous analytes. The accuracy and precision of the method were validated with certified reference materials. The fortified recovery values for choline and l-carnitine were between 85.0 and 104% with relevant standard deviations <5.0%. The established method was applied to the analysis of real infant formulas, demonstrating its applicability and feasibility.
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Carnitina/análisis , Colina/análisis , Fórmulas Infantiles/química , Cromatografía Liquida , Interacciones Hidrofóbicas e Hidrofílicas , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: The mechanism of podocyte apoptosis is not fully understood. In addition, the role of the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (Grp75)/voltage-dependent anion channel 1 (VDAC1)/mitochondrial calcium uniporter (MCU) calcium regulation axis, which is located at sites of endoplasmic reticulum (ER) mitochondria coupling, in the mechanism of podocyte apoptosis is unclear. This study aimed to understand the roles of this axis in podocyte apoptosis and explore potential targets for podocyte protection. METHODS: The expression of IP3R, Grp75, VDAC1, and MCU and mitochondrial Ca2+ were analyzed during Adriamycin- or angiotensin II-induced apoptosis in cultured mouse podocytes. The interaction between IP3R, Grp75, and VDAC1 was investigated using co-immunoprecipitation experiments. The effects of IP3R, Grp75, and MCU agonists and antagonists on mitochondrial Ca2+ and apoptosis were investigated in cultured podocytes. The podocyte-protective effects of an MCU inhibitor were further investigated in rats with Adriamycin-induced nephropathy. RESULTS: Increased expression of IP3R, Grp75, VDAC1 and MCU, enhanced interaction among the IP3R-Grp75-VDAC1 complex, mitochondrial Ca2+ overload, and increased active caspase-3 levels were confirmed during Adriamycin- or angiotensin II-induced mouse podocyte apoptosis. Agonists of this axis facilitated mitochondrial Ca2+ overload and podocyte apoptosis, whereas specific antagonists against IP3R, Grp75, or MCU prevented mitochondrial Ca2+ overload and podocyte apoptosis. A specific MCU inhibitor prevented Adriamycin-induced proteinuria and podocyte foot process effacement in rats. CONCLUSIONS: This study identified a novel pathway in which the IP3R-Grp75-VDAC1-MCU calcium regulation axis mediated podocyte apoptosis by facilitating mitochondrial Ca2+ overload. Antagonists that inhibit Ca2+ transfer from ER to mitochondria protected mouse podocytes from apoptosis. An MCU inhibitor protected podocytes and decreased proteinuria in rats with Adriamycin-induced nephropathy. Therefore, antagonists to this pathway have promise as novel podocyte-protective drugs.
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Calcio/fisiología , Doxorrubicina/toxicidad , Enfermedades Renales/metabolismo , Compuestos Macrocíclicos/farmacología , Oxazoles/farmacología , Podocitos/metabolismo , Proteinuria/metabolismo , Adenosilhomocisteinasa/antagonistas & inhibidores , Adenosilhomocisteinasa/biosíntesis , Animales , Antibióticos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Canales de Calcio/biosíntesis , Células Cultivadas , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/biosíntesis , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Compuestos Macrocíclicos/uso terapéutico , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/biosíntesis , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxazoles/uso terapéutico , Podocitos/efectos de los fármacos , Proteinuria/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Canal Aniónico 1 Dependiente del Voltaje/antagonistas & inhibidores , Canal Aniónico 1 Dependiente del Voltaje/biosíntesisRESUMEN
BACKGROUND: Air pollution constitutes the major threat to human health, whereas their adverse impacts and underlying mechanisms of different particular matters are not clearly defined. SCOPE OF REVIEW: Ultrafine particles (UFPs) are high related to the anthropogenic emission sources, i.e. combustion engines and power plants. Their composition, source, typical characters, oxidative effects, potential exposure routes and health risks were thoroughly reviewed. MAJOR CONCLUSIONS: UFPs play a major role in adverse impacts on human health and require further investigations in future toxicological research of air pollution. GENERAL SIGNIFICANCE: Unlike PM2.5, UFPs may have much more impacts on human health considering loads of evidences emerging from particulate matters and nanotoxicology research fields. The knowledge of nanotoxicology contributes to the understanding of toxicity mechanisms of airborne UFPs in air pollution. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.
Asunto(s)
Encefalopatías/etiología , Enfermedades Cardiovasculares/etiología , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedades Pulmonares/etiología , Material Particulado/toxicidad , Contaminación del Aire/análisis , Encefalopatías/genética , Encefalopatías/metabolismo , Encefalopatías/patología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Humanos , Peroxidación de Lípido/efectos de los fármacos , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Transducción de SeñalRESUMEN
n recent years, photoselective vaporization of the prostate (PVP) has gained a wide clinical application in the treatment of benign prostatic hyperplasia (BPH) for its satisfactory effect, high safety, and low incidence of complications. With the improvement of living conditions, BPH patients are paying more attention to their sexual function, especially erectile function and ejaculatory problems instead of just focusing on the alleviation of lower urinary tract symptoms. Few studies of PVP, however, relate to its association with the sexual function of the patient and there is a certain controversy over the influence of PVP on it in the existing literature. Prevailing views hold that the uprated power in PVP does not affect erectile function or increase the risk of retrograde ejaculation (REj) and that PVP is even better than transurethral resection of the prostate (TURP) in avoiding the risk of REj.
Asunto(s)
Eyaculación , Terapia por Láser/métodos , Próstata/cirugía , Hiperplasia Prostática/cirugía , Anciano , Humanos , Síntomas del Sistema Urinario Inferior/terapia , Masculino , Erección Peniana , Disfunciones Sexuales Psicológicas , Resección Transuretral de la Próstata , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore the feasibility and effectiveness of "one-puncture one-needle" transrectal ultrasound (TRUS)-guided prostate biopsy in the prevention of postoperative infections. METHODS: We retrospectively analyzed the clinical data about "one-puncture one-needle" (the observation group) and "one-person one-needle" (the control group) TRUS-guided prostate biopsy performed in the Second People's Hospital of Guangdong Province from January 2005 to December 2015, and compared the incidence rates of puncture-related infection between the two strategies. By "one-puncture one-needle", one needle was used for one biopsy puncture, while by "one-person one-needle", one needle was used for all biopsy punctures in one patient and the needle was sterilized with iodophor after each puncture. RESULTS: Totally, 120 patients received 6+1-core or 12+1-core "one-person one-needle" and 466 underwent 12+1-core "one-puncture one-needle" TRUS-guided prostate biopsy. There were no statistically significant differences between the two groups of patients in age, the prostate volume, the serum PSA level, or the detection rate of prostate cancer (P >0.05). Compared with the control group, the observation group showed remarkably lower incidence rates of puncture-related urinary tract infection (7.5% vs 0.9%, P <0.05), fever (5.0% vs 1.1%, P <0.05), bacteriuria (2.5% vs 0.2%, P <0.05), and total infections (16.7% vs 2.6%, P<0.05) postoperatively. Two cases of bacteremia or sepsis were found in each of the groups, with no significant difference between the two. CONCLUSIONS: "One-puncture one-needle" TRUS-guided prostate biopsy can effectively prevent puncture-related infections.
Asunto(s)
Biopsia con Aguja Fina/métodos , Próstata/patología , Neoplasias de la Próstata/patología , Infecciones Urinarias/prevención & control , Bacteriemia/etiología , Biopsia con Aguja Fina/efectos adversos , Biopsia con Aguja Fina/instrumentación , Estudios de Casos y Controles , Estudios de Factibilidad , Humanos , Masculino , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Estudios Retrospectivos , Esterilización/métodos , Ultrasonografía IntervencionalRESUMEN
An acidic leaching method using HNO3 is widely employed to release the global fallout Pu from soil samples for further chemical separations in radioecology and toxicology studies and in many applications using Pu as a useful tracer. In the method's sample ash treatment step to decompose organic matter in soil, various ashing temperatures (400-900 °C) are used; however, the effect of ashing temperature on the accurate Pu analysis has not been well investigated. In this study, two standard reference soils (IAEA-soil-6 and IAEA-375) were used to determine the ashing temperature effect (from 375 to 600 °C) on the HNO3 leaching method. The Pu analytical results of both standard reference materials showed that lower (239+240)Pu activity was observed when the ashing temperature exceeded 450 °C, and the (239+240)Pu activity continued to decrease as the ashing temperature was raised. Approximately 40% of the Pu content could not be leached out by concentrated HNO3 after ashing for 4 h at 600 °C. The Pu loss was attributed to the formation of refractory materials, which are insoluble in HNO3 solution. This hypothesis was confirmed by the XRD analysis of soil samples, which revealed that plagioclase-like silicate materials were formed after high-temperature ashing. To ensure Pu release efficiency in HNO3 leaching, we recommend 450 °C as the ideal ashing temperature. This recommendation is also useful for analysis of other important artificial radionuclides (e.g., (137)Cs, (90)Sr, (241)Am) for which an ashing process is needed to decompose the organic content in soil samples.