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The structural, electronic, and magnetic properties of vanadium disulfide VS2 monolayers were investigated using first-principles calculations and Monte Carlo (MC) simulations. The results of molecular dynamics simulations and phonon dispersion showed that the VS2 monolayer has good dynamic and thermodynamic stabilities. Based on the results of the band structure, we also explore the effect of carrier concentrations on the spin gap, spin polarization and the direction of the easy magnetic axis. Our results demonstrated that doping an appropriate amount of holes can cause the reversal of the easy magnetic axis and maintain nearly 100% spin polarization, which greatly improves the application possibility of the VS2 monolayer as a spintronic device. The contribution of different orbits to the spin-orbit coupling (SOC) effect is given in magnetocrystalline anisotropy energy, which provides a theoretical basis for explaining the origin of magnetic crystal anisotropy. Based on the MC simulations, we also showed the influences of different parameters (carrier concentrations, magnetic field and crystal field) on the magnetothermal properties of the VS2 monolayer. It is found that the increase of hole doping concentrations can promote the increase of the Curie temperature, while the increase of electron doping concentrations will greatly weaken the Curie temperature. Furthermore, according to the influences of different parameters on the Curie temperature and spin polarization, we conclude that a suitably enhanced magnetic field and appropriate hole concentrations will not only make the system maintain high spin polarization, but also make the system exhibit ferromagnetic properties above room temperature.
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BACKGROUND: Common bile duct microlithiasis (CBDM) with a diameter of ≤ 3 mm can pass spontaneously without causing any symptoms, but in some cases, it can also cause severe cholangitis and pancreatitis. The optimal strategy for managing CBDM is yet to be determined. METHODS: Data of 154 patients with CBDM were collected and divided into two groups: with endoscopic retrograde cholangiopancreatography (with ERCP, n = 82) and without ERCP (n = 72). Clinical outcomes, including the incidence of unfavorable outcomes (UOs), such as cholangitis and pancreatitis, were observed and compared between the two groups. RESULTS: The incidence of UOs was significantly lower in the ERCP group than in the without ERCP group (3.7% vs. 23.6%, respectively, p < 0.001). Moreover, the total number of readmissions was also lower in the ERCP group than in the without ERCP group (p < 0.001). A multivariate analysis adjusted for age, sex, and the American Society of Anesthesiologists (ASA) class revealed that endoscopic sphincterotomy (EST) and cholecystectomy were associated with a lower risk of UOs. CONCLUSION: The high rate of UOs in CBDM patients without ERCP suggests that its natural clinical course may not be as favorable as previously suggested. This finding implies that efforts should be made to clear the bile ducts.
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To improve the adsorption efficiency of pollutants by biochar, preparing graphene-like biochar (GBC) or nitrogen-doped biochar are two commonly used methods. However, the difference in the nitrogen doping (N-doping) effects upon the adsorption of pollutants by pristine biochar (PBC) and GBC, as well as the underlying mechanisms, are still unclear. Take the tetracycline (TC) as an example, the present study analyzed the characteristics of the adsorption of TCs on biochars (PBC, GBC, N-PBC, N-GBC), and significant differences in the effects of N-doping on the adsorption of TCs by PBC and GBC were consistently observed at different solution properties. Specifically, N-doping had varied effects on the adsorption performance of PBC, whereas it uniformly improved the adsorption performance of GBC. To interpret the phenomenon, the N-doping upon the adsorption was revealed by the QSAR model, which indicated that the pore filling (VM) and the interactions between TCs with biochars (Ead-v) were found to be the most important two factors. Furthermore, the density functional theory (DFT) results demonstrated that N-doping slightly affects biochar's chemical reactivity. The van der Waals (vdWs) and electrostatic interactions are the main forces for TCs-biochars interactions. Moreover, N-doping mostly strengthened the electrostatic interactions of TCs-biochars, but the vdWs interactions of most samples remained largely unaffected. Overall, the revealed mechanism of N-doping on TCs adsorption by biochars will enhance our knowledge of antibiotic pollution remediation.
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Carbón Orgánico , Contaminantes Ambientales , Grafito , Compuestos Heterocíclicos , Adsorción , Tetraciclina , Antibacterianos , Nitrógeno , Factores de TranscripciónRESUMEN
Unlike other members of the VEGF family, the function of VEGF-B in tumor progression remains to be elucidated. Thus, the present study aimed to determine the function of VEGF-B in human choriocarcinoma cells by investigating its detailed effects and molecular mechanisms. VEGF-B and aryl hydrocarbon receptor (AhR) expression were evaluated by reverse transcription-quantitative PCR analysis and western blot analysis in JEG-3 cells and choriocarcinoma stem-like cells (CSLCs) and their proliferation, migration, and invasion after the transfection of short hairpin RNA VEGF-B, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; AhR agonist) treatment or StemRegenin 1 (SR1; AhR antagonist) treatment were examined by cell proliferation assay, wound healing assay and Transwell assay. In addition, luciferase reporter analysis and bioinformatics data mining were used to investigate the association between VEGF-B and AhR. Upregulation of VEGF-B and AhR expression was observed in CSLCs. Following VEGF-B knockdown or SR1 treatment, the proliferative, migratory, and invasive abilities of CSLCs were significantly decreased, contrary to the findings after TCDD treatment. It was also found that AhR enhanced VEGF-B transcriptional activity by binding to the relative promoter region. These observations indicated that VEGF-B may be an oncogene that promotes choriocarcinoma cell migration and invasion targeted by AhR. Therefore, targeting VEGF-B may provide a novel therapeutic opportunity for choriocarcinoma.
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Janus transition metal dichalcogenide monolayers (TMDs) have attracted wide attention due to their unique physical and chemical properties since the successful synthesis of the MoSSe monolayer. However, the related studies of Janus monolayers of transition metal halides (TMHs) with similar structures have rarely been reported. In this article, we systematically investigate the electronic properties, piezoelectric properties, optical properties, and carrier mobility of new Janus TiXY (X ≠ Y, X/Y = Cl, Br, I) monolayers using first principles calculations for the first time. These Janus TiXY monolayers are thermally, dynamically, and mechanically stable, and their energy bands near the Fermi level (EF) are almost entirely contributed by the central Ti atom. Besides, the Janus TiXY monolayers exhibit excellent in-plane and out-of-plane piezoelectric effects, especially with an in-plane piezoelectric coefficient of â¼4.58 pm V-1 for the TiBrI monolayer and an out-of-plane piezoelectric coefficient of â¼1.63 pm V-1 for the TiClI monolayer, suggesting their promising applications in piezoelectric sensors and energy storage applications. The absorption spectra of Janus TiXY monolayers are mainly distributed in the visible and infrared regions, implying that they are fantastic candidates for photoelectric and photovoltaic applications. The obtained carrier mobilities revealed that TiXY monolayers are hole-type semiconductors. Under uniaxial compressive strain, the hole mobilities of these monolayers are gradually improved, indicating that TiXY monolayers have potential applications in the field of flexible electronic devices.
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Bismuth telluride (Bi2Te3) and its derivatives are often focused on as thermoelectric materials around room temperature. In this work, we theoretically predicted two new types of Bi2Te3-based two-dimensional materials Bi2SSe2 and Bi2S2Se using density functional theory (DFT) combined with Boltzmann transport theory. The thermal, dynamic, and mechanical stabilities of Bi2SSe2 and Bi2S2Se monolayers are confirmed using ab initio molecular dynamics (AIMD) simulations, phonon dispersion, and elastic constant calculations. The phonon transport properties, including lattice thermal conductivity, group velocity, Grüneisen parameter, converged scattering rate, and phonon lifetimes contributed by different branches, are systematically investigated. The electronic and thermoelectric properties, including carrier mobility (µ), Seebeck coefficient (S), electrical conductivity (σ), power factors, and figure of merit (zT) along the zigzag and armchair directions as a function of carrier concentration at different temperatures, are also investigated. It is found that the Bi2SSe2 and Bi2S2Se monolayers have moderate indirect band gaps (0.92 eV and 1.08 eV at the PBE level, respectively) and low lattice thermal conductivities (4.35 and 5.37 W m-1 K-1 at 300 K, respectively). The largest zT values of Bi2SSe2 and Bi2S2Se monolayers are 0.50 and 0.28 at 300 K and 1.39 and 0.93 at 700 K for p-doping types, respectively. The Bi2SSe2 and Bi2S2Se monolayers are predicted to show high optical absorption peaks at 8 × 105 cm-1 in the visible and near-UV light region, respectively. Our results indicate that both Bi2SSe2 and Bi2S2Se could be promising candidates in energy conversion, solar cells, and optoelectronic devices.
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STUDY OBJECTIVE: To study the effect of different surgical approaches (laparoscopy and laparotomy) on the oncological outcomes of patients with apparent early-stage uterine clear cell carcinoma (UCCC). DESIGN: Retrospective cohort study. SETTING: Four Chinese teaching hospitals. PATIENTS: A total of 273 women with apparent early-stage UCCC. INTERVENTIONS: All included patients were surgically staged by laparoscopy or laparotomy. MEASUREMENTS AND MAIN RESULTS: The eligible patients were divided into the laparotomy group and the laparoscopy group. Disease-free survival (DFS) and overall survival (OS) were evaluated by the Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazards regression model was used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the effect of surgical approach on DFS and OS. With a median follow-up of 31.0 months, the 3-year DFS rates were 68.82% and 64.27% in the laparotomy group and the laparoscopy group, respectively. The difference in DFS between the 2 groups was not statistically significant (HR, 1.06; 95% CI, 0.72-1.58; p = .758). In addition, the 3-year OS rate (72.76% vs 73.46%; HR, 1.06; 95% CI, 0.65-1.72; p = .823) was not different between the 2 groups. Furthermore, multivariable analysis showed that for patients with apparent early-stage UCCC, the approach of surgical staging was not an independent prognostic factor for OS (adjusted HR, 1.29; 95% CI, 0.78-2.12; p = .321) and DFS (adjusted HR, 1.11; 95% CI, 0.73-1.68; p = .621). CONCLUSION: For clinical early-stage clear cell carcinoma of the uterus, staging by laparoscopy is oncologically safe. This needs to be justified by further prospective studies.
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Carcinoma , Laparoscopía , Supervivencia sin Enfermedad , Femenino , Humanos , Laparoscopía/métodos , Estadificación de Neoplasias , Estudios Prospectivos , Estudios Retrospectivos , ÚteroRESUMEN
The endothelial-mesenchymal transition (EndMT) plays a key role in the development of cardiac fibrosis (CF) after acute myocardial infarction (AMI). The results of our previous study showed that amphiregulin (AR) expression was enhanced after MI. However, the role of AR on EndMT post MI remains unknown. This study aimed to elucidate the impact of AR on EndMT post MI and the associated molecular mechanisms. AR expression was markedly enhanced in infarct border area post MI, and endothelial cells were one of the primary cell sources of AR secretion. Stimulation with AR promoted endothelial cell proliferation, invasion, migration, collagen synthesis and EndMT. In addition, EGFR and downstream gene expression was significantly enhanced. In vivo, EndMT was significantly inhibited after lentivirus-AR-shRNA was delivered to the myocardium post MI. In addition, silencing AR ameliorated cardiac function by decreasing the extent of CF. Furthermore, the levels of EGFR pathway components in endothelial cells extracted from infarct border myocardium were all significantly decreased in lentivirus-AR-shRNA-treated MI mice. Our results demonstrate that AR induces CF post MI by enhancing EndMT in endothelial cells. Thus, targeting the regulation of AR may provide a potentially novel therapeutic option for CF after MI.
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Anfirregulina/genética , Células Endoteliales/metabolismo , Transición Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Infarto del Miocardio/genética , Miocardio/metabolismo , Actinas/genética , Actinas/metabolismo , Anfirregulina/metabolismo , Animales , Cadherinas/genética , Cadherinas/metabolismo , Supervivencia Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III , Vasos Coronarios/cirugía , Modelos Animales de Enfermedad , Fibrosis Endomiocárdica , Células Endoteliales/patología , Receptores ErbB/metabolismo , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ligadura , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocardio/patología , Protocadherinas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Vimentina/genética , Vimentina/metabolismoRESUMEN
Azo dyes constitute a significant environmental burden due to its toxicity, carcinogenicity, and hard biodegradation. The report here is focused on the decolorization and degradation treatment of azo dye methyl red (MR). Decolorization of MR using Aspergillus versicolor LH1 isolated from activated sludge was investigated. The maximum decolorization rate of 92.3% was obtained under the optimized conditions of sucrose as carbon source, 5d incubation age, pH 6.0, 140 mg/L initial concentration of MR and 2.5 g/L initial concentration of NaNO3. Biodegradation products of MR were investigated using HPLC-MS, FTIR, and GC-MS assays. It was revealed the three bonds of -C-N = in MR aromatic nucleus were disrupted, and benzoic acid was detected. Micronucleus test with Glycine max L. and Vicia faba L. demonstrated that MCN (micronucleus permillage) of MR metabolites was less than MR solution. These findings provided evidence that A. versicolor LH1 is a candidate for MR degradation in industrial wastewater treatment.
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Aspergillus/metabolismo , Compuestos Azo/metabolismo , Aguas Residuales/microbiología , Contaminantes Químicos del Agua/metabolismo , Purificación del Agua , Biodegradación AmbientalRESUMEN
Silicon carbide (SiC) chains and silicon carbide nanotubes (SiCNTs), as promising one-dimensional nanostructures, have potential applications in more controllable nanoelectronic devices. In this paper, we design a completely new hybrid structure with encapsulation of a linear SiC chain inside a SiCNT, using first-principles calculation and the non-equilibrium Green's function formalism to systematically investigate the structural stability and electronic properties, particularly the quantum transport properties. It is found that, due to the nanotube-chain interaction, the stability of this structure is mainly provided by the charge transfer from the hosting tube to the guest chain. Furthermore, the transport properties of the hybrid structure confirm that encapsulation of a SiC chain within a SiCNT can significantly enhance the electronic transport of the component system in a wide range of high voltage. The distance and the unique coupling configuration between the encapsulated system and the electrodes are demonstrated to be other important factors that affect the transport behaviours. We hope that our study of encapsulation may offer a significant starting point for the design of new materials related to low-dimensional SiC nanostructures and possibly open a novel path towards stability and conductivity enhancement.
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1. Schisandra chinensis, also called wuweizi in Chinese, is the fruit of Schisandra chinensis (Turcz.) Baill., and has been officially utilized as an astringent tonic for more than two thousand years in China. This study aims to evaluate the inhibition of carboxylesterases (CESs) by the major ingredients isolated from Schisandra chinensis, including Anwuligan, Schisandrol B, Schisanhenol, deoxyschizandrin, and Schisandrin B. 2. In vitro human liver microsomes (HLMs)-catalyzed hydrolysis of 2-(2-Benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) was employed as the probe reaction for CES1 and CES2, respectively. Initial screening, inhibition kinetics determination (inhibition type and parameters (Ki)), and in silico docking method were carried out. 3. Schisandrin B showed strong inhibition on the activity of CES1, and the activity of CES2 was strongly inhibited by Anwuligan and Schisandrin B. Schisandrin B exhibited noncompetitive inhibition towards CES1 and CES2. Anwuligan showed competitive inhibition towards CES2. The inhibition kinetic parameters (Ki) were calculated to be 29.8, 0.6, and 8.1 uM for the inhibition of Schisandrin B on CES1, Anwuligan on CES2, and Schisandrin B on CES2. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the inhibition of Schisandrin B on CES1, Anwuligan on CES2, and Schisandrin B on CES2. All these information will be helpful for understanding the adverse effects of Schisandra chinensis due to the inhibition of CESs-catalyzed metabolism.
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Carboxilesterasa/antagonistas & inhibidores , Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Schisandra/química , Carboxilesterasa/química , Carboxilesterasa/metabolismo , Hidrolasas de Éster Carboxílico/química , Hidrolasas de Éster Carboxílico/metabolismo , Ciclooctanos/farmacología , Dioxoles/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Interacciones Farmacológicas , Inhibidores Enzimáticos/química , Humanos , Lignanos/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Simulación del Acoplamiento Molecular , Compuestos Policíclicos/farmacologíaRESUMEN
Cardiac fibrosis (CF), a main process of ventricular remodeling after myocardial infarction (MI), plays a crucial role in the pathogenesis of heart failure (HF) post-MI. It is known that amphiregulin (AR) is involved in fibrosis of several organs. However, the expression of AR and its role post-MI are yet to be determined. This study aimed to investigate the impact of AR on CF post-MI and related mechanisms. Significantly upregulated AR expression was evidenced in the infarct border zone of MI mice in vivo and the AR secretion was enhanced in macrophages, but not in cardiac fibroblasts. In vitro, treatment with AR increased cardiac fibroblast migration, proliferation and collagen synthesis, and upregulated the expression of epidermal growth factor receptor (EGFR) and the downstream genes such as Akt, ERK1/2 and Samd2/3 on cardiac fibroblasts. All these effects could be abrogated by pretreatment with a specific EGFR inhibitor. To verify the functions of AR in MI hearts, lentivirus-AR-shRNA and negative control vectors were delivered into the infarct border zone. After 28 days, knock-down of AR increased the survival rate and improved cardiac function, while decreasing the extent of myocardial fibrosis of MI mice. Moreover, EGFR and the downstream genes were significantly downregulated in lentivirus-AR-shRNA treated MI mice. Our results thus indicate that AR plays an important role in promoting CF after MI partly though activating the EGFR pathway. Targeting AR might be a novel therapeutic option for attenuating CF and improve cardiac function after MI.
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Anfirregulina/metabolismo , Receptores ErbB/metabolismo , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Función Ventricular Izquierda , Remodelación Ventricular , Anfirregulina/genética , Animales , Movimiento Celular , Proliferación Celular , Células Cultivadas , Colágeno/metabolismo , Modelos Animales de Enfermedad , Receptores ErbB/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Función Ventricular Izquierda/genética , Remodelación Ventricular/genéticaRESUMEN
We perform detailed investigations on the electronic and magnetic properties in double perovskites Ba2MOsO6 (M = K, Ca, and Sc), with formal valences of Os7+ (5d1), Os6+ (5d2), and Os5+ (5d3), respectively, using first-principles calculations. To understand the effects of Coulomb interaction ( U), spin-orbit coupling (SOC), and magnetic order, we carry out different calculations within density functional theory. It is shown that SOC and U energy not only provide the magneto crystalline anisotropies but also significantly affect the size of the local moments and the magnetic structures in these compounds. The electronic configuration of 5d1 and 5d2 of Os in Ba2MOsO6 (M = K and Ca) have the metal-insulator transition (MIT) as the direction of the local moment changes, while the electronic structure of half-filled 5d3 orbitals of Os in Ba2ScOsO6 is insulator, independent of the local moment direction. Our results indicate that both SOC and U interactions are necessary in enlarging the band gaps and putting these compounds into the MIT correlated insulators.
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The quantum anomalous Hall (QAH) effect is superior to the quantum spin Hall (QSH) effect, which can avoid the inelastic scattering of two edge electrons located on one side of a topological nontrivial material, and thus it has attracted both theoretical and experimental interest. Here, we systematically investigate the lattice structures, and electronic and magnetic properties of hydrogenated arsenene decorated with certain transition metals (Cr, Mo and Cu) based on density-functional theory. A unique QAH effect in Mo@AsH is predicted, whose Chern number (C = 1) indicates only one chiral edge channel located on its one side. Then, we prove that this QAH effect realization is closely related with band inversion, which is the competitive result between its spin-orbit coupling (SOC) strength and exchange field. The quantum state of Mo@AsH can also be tuned by an external strain, similar to SOC, and it is noted that its increased topological gap of about 35 meV under 5.0% tensile strain, is large enough to realize the QAH effect at room-temperature. Additionally, the quantum valley Hall effect in Cu@AsH contributed by the inequality of AB sublattices is also found. Our results reveal the physical mechanism to realize the QAH effect in TM@AsH and provide a platform for electrically controllable topological states, which are highly desirable for nanoelectronics and spintronics.
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BACKGROUND: Acute pancreatitis (AP) is a common acute gastrointestinal disorders. Increasing evidence indicated that autophagy is involved in the development of AP. Resolvin D1 is an endogenous pro-resolving lipid mediator, which can protect mice from cerulein-induced acute pancreatitis and facilitate autophagy in macrophage, but its mechanism remians unclear. AIMS: To investigate the effect of resolvin D1 on autophagy in mouse models of cerulein-induced AP. METHODS: C57BL/6 mice were randomly divided into control group, AP group and resolvin D1 group. The models of cerulein-induced AP were constructed by intraperitoneally cerulein. Resolvin D1 group was established by intraperitoneally resolvin D1 based on AP models, simultaneously, control group received normal saline. The severity of AP, the level of inflammatory cytokines, the number of autophagic vacuoles, and the expression of autophagy-related markers were evaluated among three groups. RESULTS: The AP models were established successfully. Compared to control group, the number of autophagic vacuoles and expressions of autophagy-related markers including Beclin-1, p62 and LC3-II were increased in AP models, In contrast, the degree of inflammation and levels of inflammatory cytokines in AP models were reduced after resolvin D1 treatment. Moreover, resolvin D1 attenuated the number of autophagic vacuoles and expressions of autophagy-related markers. CONCLUSIONS: Autophagic flux is impaired in cerulein-induced AP. Resolvin D1 ameliorate the severity of mice with cerulein-induced acute pancreatitis, possible attributing to its reducing impaired autophagy and restoring autophagic flux.
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Autofagia , Ácidos Docosahexaenoicos/farmacología , Pancreatitis Aguda Necrotizante , Animales , Antiinflamatorios/farmacología , Autofagia/efectos de los fármacos , Autofagia/fisiología , Beclina-1/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Infusiones Parenterales/métodos , Activación de Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Pancreatitis Aguda Necrotizante/tratamiento farmacológico , Pancreatitis Aguda Necrotizante/metabolismo , Resultado del TratamientoRESUMEN
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 µM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver-Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 2.3, 0.07 and 4.4 µM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively. 3. In vitro-in vivo extrapolation (IVIVE) showed that [I]/Ki value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.
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Inhibidores Enzimáticos/farmacología , Everolimus/farmacología , Glucuronosiltransferasa/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Glucuronosiltransferasa/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Simulación del Acoplamiento Molecular , Isoformas de Proteínas/metabolismoRESUMEN
BACKGROUND/AIMS: Ultraviolet B (UVB) damage is the most essential etiological factor in skin carcinogenesis, and apoptosis leads to the efficient elimination of UVB-damaged cells. However, the mechanisms underlying resistance to UVB-induced apoptosis remain unclear. METHODS: HaCaT and A431 cells were used in the present study. Quantitative real-time PCR, single cell PCR, and western blotting were used to examine cancer-related gene expression at the mRNA and protein levels. RESULTS: We report that miR-26a, which is upregulated upon UVB irradiation, promotes UVB-induced apoptosis in HaCaT cells by targeting the histone methyltransferase EZH2. Moreover, the UVB/miR-26a/EZH2 regulatory axis largely depends on the MYC expression level. Interestingly, treatment with EZH2 inhibitors significantly enhanced UVB-induced apoptosis. CONCLUSION: miR-26a/EZH2 might be potential targets for skin cancer prevention and therapy.
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Apoptosis/efectos de la radiación , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Rayos Ultravioleta , Regiones no Traducidas 3' , Antagomirs/metabolismo , Secuencia de Bases , Línea Celular , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/genética , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Mutagénesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Alineación de Secuencia , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND/AIMS: Reperfusion after an ischaemic insult might cause infarct extension. Mesenchymal stem cell (MSC)-derived exosomes could attenuate myocardial remodelling in animal models of myocardial ischaemia reperfusion injury (MIRI), and the present study aimed to explore the related mechanisms. METHODS: In vitro, rat H9C2 cardiomyocytes (H9C2s) were exposed to H2O2. Cell viability was detected by the CCK-8 assay, apoptosis was detected by Annexin V-PE/7-AAD staining, ROS production was detected by fluorescence microscopy and flow cytometry, and apoptosis-related proteins and signalling pathway-related proteins were detected by western blot analysis. Autophagic flux was measured using the tandem fluorescent mRFG-GFP-LC3 assay. MSC-derived exosomes were extracted using the total exosome isolation reagent. Apoptosis, myocardial infarction size, heart function and myocardial LC3B expression were examined in an in vivo I/R model by the TUNEL assay, TTC/Evan blue staining, echocardiography and immunohistochemicalstaining, respectively. RESULTS: In vitro, H2O2 dose-dependently increased ROS production and cell apoptosis in H9C2s and blocked autophagic flux after 3 h of exposure; autophagy gradually decreased thereafter, and the lowest level was detected at 12 h after exposure. MSC-derived exosomes reduced H2O2-induced ROS production and cell apoptosis and enhanced autophagy at 12 h after exposure. In H9C2 cells exposed to H2O2 for 12 h, treatment with exosomes enhanced autophagy via the AMPK/mTOR and Akt/mTOR pathways. Likewise, in vivo exosome injections in rats that underwent I/R injury significantly reduced apoptosis and the myocardial infarct size and upregulated myocardial LC3B expression as well as improved heart function. CONCLUSIONS: Our results indicate that MSC-derived exosomes could reduce MIRI by inducing cardiomyocyte autophagy via AMPK/mTOR and Akt/mTOR pathways.