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Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.
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Antineoplásicos , Fibroblastos Asociados al Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Interleucina-8 , Neoplasias Pulmonares , Animales , Ratones , Antígenos CD , Antígenos de Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Interleucina-8/genética , Interleucina-8/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , FN-kappa B , HumanosRESUMEN
BACKGROUND: Nonadherence to imatinib is common in patients with gastrointestinal stromal tumor (GIST), which is associated with poor prognosis and financial burden. The primary aim of this study was to investigate the adherence rate in patients with GIST and subsequently develop a model based on machine learning (ML) and deep learning (DL) techniques to identify the associated factors and predict the risk of imatinib nonadherence. METHODS: All eligible patients completed four sections of questionnaires. After the data set was preprocessed, statistically significance variables were identified and further processed to modeling. Six ML and four DL algorithms were applied for modeling, including eXtreme gradient boosting, light gradient boosting machine (LGBM), categorical boosting, random forest, support vector machine, artificial neural network, multilayer perceptron, NaiveBayes, TabNet, and Wide&Deep. The optimal ML model was used to identify potential factors for predicting adherence. RESULTS: A total of 397 GIST patients were recruited. Nonadherence was observed in 185 patients (53.4%). LGBM exhibited superior performance, achieving a mean f1_score of 0.65 and standard deviation of 0.12. The predominant indicators for nonadherent prediction of imatinib were cognitive functioning, whether to perform therapeutic drug monitoring (if_TDM), global health status score, social support, and gender. CONCLUSIONS: This study represents the first real-world investigation using ML techniques to predict risk factors associated with imatinib nonadherence in patients with GIST. By highlighting the potential factors and identifying high-risk patients, the multidisciplinary medical team can devise targeted strategies to effectively address the daily challenges of treatment adherence.
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BACKGROUND: Breast cancer (BC) is the most common malignant tumor in women worldwide, and further elucidation of the molecular mechanisms involved in BC pathogenesis is essential to improve the prognosis of BC patients. RNA Binding Motif Protein 8 A (RBM8A), with high affinity to a myriad of RNA transcripts, has been shown to play a crucial role in genesis and progression of multiple cancers. We attempted to explore its functional significance and molecular mechanisms in BC. METHODS: Bioinformatics analysis was performed on publicly available BC datasets. qRT-PCR was used to determine the expression of RBM8A in BC tissues. MTT assay, clone formation assay and flow cytometry were employed to examine BC cell proliferation and apoptosis in vitro. RNA immunoprecipitation (RIP) and RIP-seq were used to investigate the binding of RBM8A/EIF4A3 to the mRNA of IGF1R/IRS-2. RBM8A and EIF4A3 interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence. Chromatin immunoprecipitation (Ch-IP) and dual-luciferase reporter assay were carried out to investigate the transcriptional regulation of RBM8A by TEAD4. Xenograft model was used to explore the effects of RBM8A and TEAD4 on BC cell growth in vivo. RESULTS: In this study, we showed that RBM8A is abnormally highly expressed in BC and knockdown of RBM8A inhibits BC cell proliferation and induces apoptosis in vitro. EIF4A3, which phenocopy RBM8A in BC, forms a complex with RBM8A in BC. Moreover, EIF4A3 and RBM8A complex regulate the expression of IGF1R and IRS-2 to activate the PI3K/AKT signaling pathway, thereby promoting BC progression. In addition, we identified TEAD4 as a transcriptional activator of RBM8A by Ch-IP, dual luciferase reporter gene and a series of functional rescue assays. Furthermore, we demonstrated the in vivo pro-carcinogenic effects of TEAD4 and RBM8A by xenograft tumor experiments in nude mice. CONCLUSION: Collectively, these findings suggest that TEAD4 novel transcriptional target RBM8A interacts with EIF4A3 to increase IGF1R and IRS-2 expression and activate PI3K/AKT signaling pathway, thereby further promoting the malignant phenotype of BC cells.
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Neoplasias de la Mama , Proteínas de Unión al ADN , Regulación Neoplásica de la Expresión Génica , Proteínas Musculares , Proteínas de Unión al ARN , Receptor IGF Tipo 1 , Factores de Transcripción de Dominio TEA , Animales , Femenino , Humanos , Ratones , Apoptosis/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones Desnudos , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Unión Proteica , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Receptores de Somatomedina/metabolismo , Receptores de Somatomedina/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal , Factores de Transcripción de Dominio TEA/metabolismoRESUMEN
Spin-correlated radical pairs generated by photoinduced electron transfer are characterised by a distinctive spin polarisation and a unique behaviour in pulse electron paramagnetic resonance (EPR) spectroscopy. Under non-selective excitation, an out-of-phase echo signal modulated by the dipolar and exchange coupling interactions characterising the radical pair is observed and allows extraction of geometric information in the two-pulse out-of-phase electron spin echo envelope modulation (ESEEM) experiment. The investigation of the role of spin-correlated radical pairs in a variety of biological processes and in the fundamental mechanisms underlying device function in optoelectronics, as well as their potential use in quantum information science, relies on the ability to precisely address and manipulate the spins using microwave pulses. Here, we explore the use of shaped pulses for controlled narrowband selective and broadband non-selective excitation of spin-correlated radical pairs in two model donor-bridge-acceptor triads, characterised by different spectral widths, at X- and Q-band frequencies. We demonstrate selective excitation with close to rectangular excitation profiles using BURP (band-selective, uniform response, pure-phase) pulses and complete non-selective excitation of both spins of the radical pair using frequency-swept chirp pulses. The use of frequency-swept pulses in out-of-phase ESEEM experiments enables increased modulation depths and, combined with echo transient detection and Fourier transformation, correlation of the dipolar frequencies with the EPR spectrum and therefore the potential to extract additional information on the donor-acceptor pair geometry.
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BACKGROUND: Being one of the most widespread, pervasive, and troublesome illnesses in the world, depression causes dysfunction in various spheres of individual and social life. Regrettably, despite obtaining evidence-based antidepressant medication, up to 70% of people are going to continue to experience troublesome symptoms. Quetiapine, as one of the most commonly prescribed antipsychotic medication worldwide, has been reported as an effective augmentation strategy to antidepressants. The right quetiapine dose and personalized quetiapine treatment are frequently challenging for clinicians. This study aimed to identify important influencing variables for quetiapine dose by maximizing the use of data from real world, and develop a predictive model of quetiapine dose through machine learning techniques to support selections for treatment regimens. METHODS: The study comprised 308 depressed patients who were medicated with quetiapine and hospitalized in the First Hospital of Hebei Medical University, from November 1, 2019, to August 31, 2022. To identify the important variables influencing the dose of quetiapine, a univariate analysis was applied. The prediction abilities of nine machine learning models (XGBoost, LightGBM, RF, GBDT, SVM, LR, ANN, DT) were compared. Algorithm with the optimal model performance was chosen to develop the prediction model. RESULTS: Four predictors were selected from 38 variables by the univariate analysis (p < 0.05), including quetiapine TDM value, age, mean corpuscular hemoglobin concentration, and total bile acid. Ultimately, the XGBoost algorithm was used to create a prediction model for quetiapine dose that had the greatest predictive performance (accuracy = 0.69) out of nine models. In the testing cohort (62 cases), a total of 43 cases were correctly predicted of the quetiapine dose regimen. In dose subgroup analysis, AUROC for patients with daily dose of 100 mg, 200 mg, 300 mg and 400 mg were 0.99, 0.75, 0.93 and 0.86, respectively. CONCLUSIONS: In this work, machine learning techniques are used for the first time to estimate the dose of quetiapine for patients with depression, which is valuable for the clinical drug recommendations.
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Perovskite solar cell (pero-SC) has attracted extensive studies as a promising photovoltaic technology, wherein the electron extraction and transfer exhibit pivotal effect to the device performance. The planar SnO2 electron transport layer (ETL) has contributed the recent record power conversion efficiency (PCE) of the pero-SCs, yet still suffers from surface defects of SnO2 nanoparticles which brings energy loss and phase instability. Herein, we report a localized oxidation embellishing (LOE) strategy by applying (NH4 )2 CrO4 on the SnO2 ETL. The LOE strategy builds up plentiful nano-heterojunctions of p-Cr2 O3 /n-SnO2 and the nano-heterojunctions compensate the surface defects and realize benign energy alignment, which reduces surface non-radiative recombination and voltage loss of the pero-SCs. Meanwhile, the decrease of lattice mismatch released the lattice distortion and eliminated tensile stress, contributing to better stability of the devices. The pero-SCs based on α-FAPbI3 with the SnO2 ETL treated by the LOE strategy realized a PCE of 25.72 % (certified as 25.41 %), along with eminent stability performance of T90 >700â h. This work provides a brand-new view for defect modification of SnO2 electron transport layer.
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Side chain engineering plays a vital role in exploring high-performance small molecule acceptors (SMAs) for organic solar cells (OSCs). In this work, we designed and synthesized a series of A-DA'D-A type SMAs by introducing different N-substituted alkyl and ester alkyl side chains on benzotriazole (BZ) central unit and aimed to investigate the effect of different ester substitution positions on photovoltaic performances. All the new SMAs with ester groups exhibit lower the lowest unoccupied molecular orbital (LUMO) energy levels and more blue-shifted absorption, but relatively higher absorption coefficients than alkyl chain counterpart. After blending with the donor PM6, the ester side chain-based devices demonstrate enhanced charge mobility, reduced amorphous intermixing domain size and long-lived charge transfer state compared to the alkyl chain counterpart, which are beneficial to achieve higher short-circuit current density (Jsc ) and fill factor (FF), simultaneously. Thereinto, the PM6 : BZ-E31 based device achieves a higher power conversion efficiency (PCE) of 18.33 %, which is the highest PCE among the OSCs based on the SMAs with BZ-core. Our work demonstrated the strategy of ester substituted side chain is a feasible and effective approach to develop more efficient SMAs for OSCs.
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BACKGROUND: Apostichopus japonicus is an economically important species in the global aquaculture industry. Russian A. japonicus, mainly harvested in the Vladivostok region, exhibits significant phenotypic differentiation, including in many economically important traits, compared with Chinese A. japonicus owing to differences in their habitat. However, both the genetic basis for the phenotypic divergence and the population genetic structure of Russian and Chinese A. japonicus are unknown. RESULT: In this study, 210 individuals from seven Russian and Chinese A. japonicus populations were sampled for whole-genome resequencing. The genetic structure analysis differentiated the Russian and Chinese A. japonicus into two groups. Population genetic analyses indicated that the Russian population showed a high degree of allelic linkage and had undergone stronger positive selection compared with the Chinese populations. Gene ontology terms enriched among candidate genes with group selection analysis were mainly involved in immunity, such as inflammatory response, antimicrobial peptides, humoral immunity, and apoptosis. Genome-wide association analysis yielded eight single-nucleotide polymorphism loci significantly associated with parapodium number, and these loci are located in regions with a high degree of genomic differentiation between the Chinese and Russia populations. These SNPs were associated with five genes. Gene expression validation revealed that three of these genes were significantly differentially expressed in individuals differing in parapodium number. AJAP08772 and AJAP08773 may directly affect parapodium production by promoting endothelial cell proliferation and metabolism, whereas AJAP07248 indirectly affects parapodium production by participating in immune responses. CONCLUSIONS: This study, we performed population genetic structure and GWAS analysis on Chinese and Russian A. japonicus, and found three candidate genes related to the number of parapodium. The results provide an in-depth understanding of the differences in the genetic structure of A. japonicus populations in China and Russia, and provide important information for subsequent genetic analysis and breeding of this species.
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Stichopus , Animales , Estudio de Asociación del Genoma Completo , Fitomejoramiento , Polimorfismo de Nucleótido Simple , Stichopus/genética , Genoma de PlantaRESUMEN
OBJECTIVES: Diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) is a newly proposed MRI method to noninvasively measure the function of the blood-brain barrier (BBB). We aim to investigate whether the water exchange rate across the BBB, estimated with DP-pCASL, is changed in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and to analyze the association between the BBB water exchange rate and MRI/clinical features of these patients. METHODS: Forty-one patients with CADASIL and thirty-six age- and sex-matched controls were scanned with DP-pCASL MRI to estimate the BBB water exchange rate (kw). The MRI lesion burden, the modified Rankin scale (mRS), and the neuropsychological scales were also examined. The association between kw and MRI/clinical features was analyzed. RESULTS: Compared with that in the controls, kw in patients with CADASIL was decreased at normal-appearing white matter (NAWM) (t = - 4.742, p < 0.001), cortical gray matter (t = - 5.137, p < 0.001), and deep gray matter (t = - 3.552, p = 0.001). After adjustment for age, gender, and arterial transit time, kw at NAWM was negatively associated with the volume of white matter hyperintensities (ß = - 0.754, p = 0.001), whereas decreased kw at NAWM was independently associated with an increased risk of abnormal mRS scale (OR = 1.058, 95% CI: 1.013-1.106, p = 0.011) in these patients. CONCLUSIONS: This study found that the BBB water exchange rate was decreased in patients with CADASIL. The decreased BBB water exchange rate was associated with an increased MRI lesion burden and functional dependence of the patients, suggesting the involvement of BBB dysfunction in the pathogenesis of CADASIL. CLINICAL RELEVANCE STATEMENT: DP-pCASL reveals BBB dysfunction in patients with CADASIL. The decreased BBB water exchange rate is associated with MRI lesion burden and functional dependence, indicating the potential of DP-pCASL as an evaluation method for disease severity. KEY POINTS: ⢠DP-pCASL reveals blood-brain barrier dysfunction in patients with CADASIL. ⢠Decreased BBB water exchange rate, an indicator of BBB dysfunction detected by DP-pCASL, was associated with MRI/clinical features of patients with CADASIL. ⢠DP-pCASL can be used as an evaluation method to assess the severity of disease in patients with CADASIL.
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Barrera Hematoencefálica , CADASIL , Humanos , Barrera Hematoencefálica/diagnóstico por imagen , CADASIL/diagnóstico por imagen , CADASIL/patología , CADASIL/psicología , Marcadores de Spin , Imagen por Resonancia Magnética , Agua , Encéfalo/patologíaRESUMEN
AIMS: This study aimed to establish a prediction model of quetiapine concentration in patients with schizophrenia and depression, based on real-world data via machine learning techniques to assist clinical regimen decisions. METHODS: A total of 650 cases of quetiapine therapeutic drug monitoring (TDM) data from 483 patients at the First Hospital of Hebei Medical University from 1 November 2019 to 31 August 2022 were included in the study. Univariate analysis and sequential forward selection (SFS) were implemented to screen the important variables influencing quetiapine TDM. After 10-fold cross validation, the algorithm with the optimal model performance was selected for predicting quetiapine TDM among nine models. SHapley Additive exPlanation was applied for model interpretation. RESULTS: Four variables (daily dose of quetiapine, type of mental illness, sex and CYP2D6 competitive substrates) were selected through univariate analysis (P < .05) and SFS to establish the models. The CatBoost algorithm with the best predictive ability (mean [SD] R2 = 0.63 ± 0.02, RMSE = 137.39 ± 10.56, MAE = 103.24 ± 7.23) was chosen for predicting quetiapine TDM among nine models. The mean (SD) accuracy of the predicted TDM within ±30% of the actual TDM was 49.46 ± 3.00%, and that of the recommended therapeutic range (200-750 ng mL-1 ) was 73.54 ± 8.3%. Compared with the PBPK model in a previous study, the CatBoost model shows slightly higher accuracy within ±100% of the actual value. CONCLUSIONS: This work is the first real-world study to predict the blood concentration of quetiapine in patients with schizophrenia and depression using artificial intelligent techniques, which is of significance and value for clinical medication guidance.
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Antipsicóticos , Esquizofrenia , Humanos , Fumarato de Quetiapina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Depresión/tratamiento farmacológico , Aprendizaje AutomáticoRESUMEN
An up-conversion molecularly imprinted ratiometric fluorescent probe with a monodisperse nuclear-satellite structure and its test strip are designed which can avoid fluorescent background interference to detect Sudan I in chili powder highly selective and sensitive. The detection mechanism is based on the selective recognition of Sudan I by imprinted cavities on the surface of ratiometric fluorescent probe and the inner filter effect between Sudan I molecules and the emission of up-conversion materials (NaYF4:Yb,Tm). Under optimized experimental conditions, the response of fluorescent ratio signals (F475/F645) of this test strip show a good linear relationship in the range 0.02-50 µM Sudan I. The limits of detection and quantitation are as low as 6 nM and 20 nM, respectively. Sudan I is selectively detected in the presence of fivefold higher concentrations of interfering substances (imprinting factor up to 4.4). Detection of Sudan I in chili powder samples show ultra-low LOD (44.7 ng/g), satisfactory recoveries (94.99-105.5%) and low relative standard deviation (≤ 2.0%). This research offers a reliable strategy and promising scheme for highly selective and sensitive detection of illegal additives in complex food matrix via an up-conversion molecularly imprinted ratiometric fluorescent test strip.
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Impresión Molecular , Colorantes Fluorescentes , Polvos , Límite de DetecciónRESUMEN
High efficiency organic solar cells (OSCs) based on A-DA'D-A type small molecule acceptors (SMAs) were mostly fabricated by toxic halogenated solvent processing, and power conversion efficiency (PCE) of the non-halogenated solvent processed OSCs is mainly restricted by the excessive aggregation of the SMAs. To address this issue, we developed two vinyl π-spacer linking-site isomerized giant molecule acceptors (GMAs) with the π-spacer linking on the inner carbon (EV-i) or out carbon (EV-o) of benzene end group of the SMA with longer alkyl side chains (ECOD) for the capability of non-halogenated solvent-processing. Interestingly, EV-i possesses a twisted molecular structure but enhanced conjugation, while EV-o shows a better planar molecular structure but weakened conjugation. The OSC with EV-i as acceptor processed by the non-halogenated solvent o-xylene (o-XY) demonstrated a higher PCE of 18.27 % than that of the devices based on the acceptor of ECOD (16.40 %) or EV-o (2.50 %). 18.27 % is one of the highest PCEs among the OSCs fabricated from non-halogenated solvents so far, benefitted from the suitable twisted structure, stronger absorbance and high charge carrier mobility of EV-i. The results indicate that the GMAs with suitable linking site would be the excellent candidates for fabricating high performance OSCs processed by non-halogenated solvents.
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Benceno , Carbono , Eritromicina , Cloruro de Polivinilo , SolventesRESUMEN
Gastrointestinal (GI) cancers constitute the largest portion of all human cancers, and the most prevalent GI cancers in China are colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC). Exosomes are nanosized vesicles containing proteins, lipids, glycans, and nucleic acid, which play important roles in the tumor microenvironment and progression. Aberrant glycosylation is closely associated with GI cancers; however, little is known about the glycopattern of the exosomes from GI cancer cells. In this study, glycopatterns of HCC, CRC, and GC cell lines and their exosomes were detected using lectin microarrays. For all exosomes, (GlcNAcß1-4)n and Galß1-4GlcNAc (DSA) were the most abundant glycans, but αGalNAc and αGal (GSL-II and SBA) were the least. Different cancers had various characteristic glycans in either cells or exosomes. Glycans altered in cell-derived exosomes were not always consistent with the host cells in the same cancer. However, Fucα1-6GlcNAc (core fucose) and Fucα1-3(Galß1-4)GlcNAc (AAL) were altered consistently in cells and exosomes although they were decreased in HCC and CRC but increased in GC. The study drew the full-scale glycan fingerprint of cells and exosomes related to GI cancer, which may provide useful information for finding specific biomarkers and exploring the underlying mechanism of glycosylation in exosomes.
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Carcinoma Hepatocelular , Exosomas , Neoplasias Gastrointestinales , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Línea Celular , Exosomas/metabolismo , Neoplasias Gastrointestinales/metabolismo , Glicoproteínas/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Polisacáridos/metabolismo , Microambiente TumoralRESUMEN
Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-α (TNF-α) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-α or endogenous TNF-α (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.
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Lipopolisacáridos , Fibrosis Pulmonar , Aceleración , Fibroblastos/metabolismo , Glucólisis , Humanos , Ácido Láctico/metabolismo , Lipopolisacáridos/toxicidad , Pulmón/metabolismo , Macrófagos/metabolismo , Fibrosis Pulmonar/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIMS OF THIS STUDY: A randomized clinical trial was undertaken to investigate the efficacy of acupoint catgut embedding (ACE) as adjunctive therapy to tauroursodeoxycholic acid (TUDCA) therapy on gallbladder emptying and clinical symptoms in patients with gallstone disease. MATERIALS AND METHODS: Between August 2018 and January 2019, 70 patients with gallstones in our hospital were enrolled in this prospective clinical trial. All the patients were randomly divided into the ACE group (ACE+TUDCA treatment for 8 wk) and the Sham group (Sham ACE+TUDCA treatment for 8 wk). In the ACE group, all the patients were nightly given ACE every 2 weeks, and in 2 groups, every patient took TUDCA 500 mg at bedtime. The parameters about gallbladder emptying were detected by ultrasound before and after the treatment, and the clinical symptom scores were recorded at the same time points. RESULTS: A total of 63 patients with gallstone disease were included in our study, with 33 patients in the ACE group and 30 patients in the Sham group. In the ACE group, the empty volume (EV) and gallbladder ejection fraction (GBEF) were improved after treatment (P<0.05). Almost every symptom score (except symptom 7, P=0.15) and total score were decreased (P<0.05). In the Sham group, the symptom 1, 2, 4, 5 scores, and total score were significantly decreased (P<0.05). Moreover, the residual volume in the ACE group was significantly lower than in the Sham group (P=0.008). The EV and GBEF in the ACE group were higher than that in the Sham group (P<0.05). The score of symptom 6 in the ACE group was lower than that in the Sham group (P=0.008). CONCLUSION: ACE therapy could more effectively improve the gallbladder emptying with a shorter treatment course. Therefore, ACE+TUDCA therapy might be a time-saving treatment for gallstones.
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Terapia por Acupuntura , Cálculos Biliares , Puntos de Acupuntura , Catgut , Cálculos Biliares/terapia , Humanos , Estudios ProspectivosRESUMEN
Aiming to discover novel antifungal agents, a series of 2substituted4amino-quinolines and -quinazoline were prepared and characterized using IR, 1H NMR, 13C NMR, and HRMS spectroscopic techniques. Their antifungal activities against four invasive fungi were evaluated, and the results revealed that some of the target compounds exhibited moderate to excellent inhibitory potencies. The most promising compounds III11, III14, III15, and III23 exhibited potent and broad-spectrum antifungal activities with MIC values of 4-32 µg/mL. The mechanism studies showed that compound III11 (N,2-di-p-tolylquinolin-4-amine hydrochloride) did not play antifungal potency by disrupting fungal membrane, which was quite different from many traditional membrane-active antifungal drugs. Meanwhile, III11 also demonstrated a low likelihood of inducing resistance, and excellent stability in mouse plasma. In addition, some interesting structure-activity relationships (SARs) were also discussed. These results suggest that some 4aminoquinolines may serve as new and promising candidates for further antifungal drug discovery.
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Antifúngicos , Quinolinas , Animales , Hongos , Ratones , Pruebas de Sensibilidad Microbiana , Quinazolinas/farmacología , Quinolinas/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: Reactive oxygen species (ROS) plays a vital role in the apoptosis of islet ß-cells in type 2 diabetes mellitus (T2DM). Sirt3 (Sirtuin 3, a deacetylase) and FoxO1 (a transcription factor) might be involved in ROS production. This study was to investigate mechanism of ROS production and ß-cell apoptosis in T2DM. METHODS: Oxidative stress and apoptosis in islets of db/db mice and high glucose cultured ß-cells were observed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and western blotting. Then, H2O2 was used to ascertain the effect of ROS on the expression of Sirt3. Meanwhile, FoxO1, antioxidant enzymes - catalase (CAT) and manganese superoxide dismutase (MnSOD) and ß-cell apoptosis were also determined by western blotting. Finally, Sirt3 was knocked down to evaluate the effect on oxidative stress and apoptosis of ß-cells. RESULTS: Under high glucose environment, enhanced ROS made a decrease of Sirt3 expression, which increased acetylation of FoxO1, thus reduced the expression of its target proteins -MnSOD and CAT, and further significantly increased ROS levels. Increased ROS finally led to the apoptosis of ß-cells. CONCLUSION: Down-regulation of Sirt3 plays an important role in the cyclic production of ROS and ß-cell apoptosis. Targeting Sirt3 may be favorable for the treatment of T2DM.
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Diabetes Mellitus Tipo 2 , Sirtuina 3 , Ratones , Animales , Sirtuina 3/genética , Sirtuina 3/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/farmacología , Apoptosis , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Estrés Oxidativo , Glucosa/farmacologíaRESUMEN
Quantum coherence effects on charge transfer and spin dynamics in a system having two degenerate electron acceptors are studied using a zinc 5,10,15-tri(n-pentyl)-20-phenylporphyrin (ZnP) electron donor covalently linked to either one or two naphthalene-1,8:4,5-bis(dicarboximide) (NDI) electron acceptors using an anthracene (An) spacer, ZnP-An-NDI (1) and ZnP-An-NDI2 (2), respectively. Following photoexcitation of 1 and 2 in toluene at 295 K, femtosecond transient absorption spectroscopy shows that the electron transfer (ET) rate constant for 2 is about three times larger than that of 1, which can be accounted for by the statistical nature of incoherent ET as well as the electron couplings for the charge separation reactions. In contrast, the rate constant for charge recombination (CR) of 1 is about 25% faster than that of 2. Using femtosecond transient infrared spectroscopy and theoretical analysis, we find that the electron on NDI2â¢- in 2 localizes onto one of the two NDIs prior to CR, thus precluding electronically coherent CR from NDI2â¢-. Conversely, CR in both 1 and 2 is spin coherent as indicated by the observation of a resonance in the 3*ZnP yield following CR as a function of applied magnetic field, giving spin-spin exchange interaction energies of 2J = 210 and 236 mT, respectively, where the line width of the resonance for 2 is greater than 1. These data show that while CR is a spin-coherent process, incoherent hopping of the electron between the two NDIs in 2, consistent with the lack of delocalization noted above, results in greater spin decoherence in 2 relative to 1.
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Photoinduced electron transfer can produce radical pairs having two quantum entangled electron spins that can act as spin qubits in quantum information applications. Manipulation of these spin qubits requires selective addressing of each spin using microwave pulses. In this work, photogenerated spin qubit pairs are prepared within chromophore-modified DNA hairpins with varying spin qubit distances, and are probed using transient EPR spectroscopy. By performing pulse-EPR measurements on the shortest hairpin, selective addressing of each spin qubit comprising the pair is demonstrated. Furthermore, these spin qubit pairs have coherence times of more than 4 µs, which provides a comfortable time window for performing complex spin manipulations for quantum information applications. The applicability of these DNA-based photogenerated two-qubit systems is discussed in the context of quantum gate operations, specifically the controlled-NOT gate.
Asunto(s)
ADN/química , Radicales Libres/química , Secuencias Invertidas Repetidas/efectos de la radiación , ADN/genética , ADN/efectos de la radiación , Radicales Libres/efectos de la radiación , Luz , Modelos Químicos , Teoría CuánticaRESUMEN
The torsional dependence of the ground state magnetic exchange coupling (J) and the corresponding electronic coupling matrix element (HDA) for eight transition metal complexes possessing donor-acceptor (D-A) biradical ligands is presented. These biradical ligands are composed of an S = 1/2 metal semiquinone (SQ) donor and an S = 1/2 nitronylnitroxide (NN) acceptor, which are coupled to each other via para-phenylene, methyl-substituted para-phenylenes, or a bicyclo[2.2.2]octane ring. The observed trends in electronic absorption and resonance Raman spectral features are in accord with a reduction in electronic and magnetic coupling between D and A units within the framework of our valence bond configuration interaction model. Moreover, our spectroscopic results highlight different orbital mechanisms that modulate coupling in these complexes, which is not manifest in the ferromagnetic JSQ-B-NN values. The work provides new detailed insight into the effects of torsional rotations which contribute to inhomogeneities in experimentally determined exchange couplings, electron transfer rates, and electron transport conductance measurements.