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1.
BMC Med ; 22(1): 278, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956533

RESUMO

BACKGROUND: APRI and FIB-4 scores are used to exclude clinically significant fibrosis (defined as stage ≥ F2) in patients with chronic viral hepatitis. However, the cut-offs for these scores (generated by Youden indices) vary between different patient cohorts. This study aimed to evaluate whether serum dithiothreitol-oxidizing capacity (DOC), i.e., a surrogate test of quiescin sulfhydryl oxidase-1, which is a matrix remodeling enzyme, could be used to non-invasively identify significant fibrosis in patients with various chronic liver diseases (CLDs). METHODS: Diagnostic performance of DOC was compared with APRI and FIB-4 for identifying significant fibrosis. ROC curve analyses were undertaken in: a) two chronic hepatitis B (CHB) cohorts, independently established from hospitals in Wenzhou (n = 208) and Hefei (n = 120); b) a MASLD cohort from Wenzhou hospital (n = 122); and c) a cohort with multiple CLD etiologies (except CHB and MASLD; n = 102), which was identified from patients in both hospitals. Cut-offs were calculated using the Youden index. All CLD patients (n = 552) were then stratified by age for ROC curve analyses and cut-off calculations. RESULTS: Stratified by CLD etiology or age, ROC curve analyses consistently showed that the DOC test was superior to APRI and FIB-4 for discriminating between clinically significant fibrosis and no fibrosis, when APRI and FIB-4 showed poor/modest diagnostic performance (P < 0.05, P < 0.01 and P < 0.001 in 3, 1 and 3 cohort comparisons, respectively). Conversely, the DOC test was equivalent to APRI and FIB-4 when all tests showed moderate/adequate diagnostic performances (P > 0.05 in 11 cohort comparisons). DOC had a significant advantage over APRI or FIB-4 scores for establishing a uniform cut-off independently of age and CLD etiology (coefficients of variation of DOC, APRI and FIB-4 cut-offs were 1.7%, 22.9% and 47.6% in cohorts stratified by CLD etiology, 2.0%, 26.7% and 29.5% in cohorts stratified by age, respectively). The uniform cut-off was 2.13, yielded from all patients examined. Surprisingly, the uniform cut-off was the same as the DOC upper limit of normal with a specificity of 99%, estimated from 275 healthy control individuals. Hence, the uniform cut-off should possess a high negative predictive value for excluding significant fibrosis in primary care settings. A high DOC cut-off with 97.5% specificity could be used for detecting significant fibrosis (≥ F2) with an acceptable positive predictive value (87.1%). CONCLUSIONS: This proof-of-concept study suggests that the DOC test may efficiently rule out and rule in significant liver fibrosis, thereby reducing the numbers of unnecessary liver biopsies. Moreover, the DOC test may be helpful for clinicians to exclude significant liver fibrosis in the general population.


Assuntos
Biomarcadores , Ditiotreitol , Cirrose Hepática , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/sangue , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Feminino , Adulto , Idoso , Oxirredução , Curva ROC , Estudos de Coortes , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/sangue , Estudo de Prova de Conceito
2.
Pharmacol Res ; 185: 106490, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36216131

RESUMO

Acquired drug resistance and epithelial-mesenchymal transition (EMT) mediated metastasis are two highly interacting determinants for non-small-cell lung cancer (NSCLC) prognosis. This study investigated the common mechanisms of drug resistance and EMT from the perspective of metabolic reprogramming, which may offer new ideas to improve anticancer therapy. Acquired resistant cells were found to grow faster and have a greater migratory and invasive capacity than their parent cells. Metabolomics analysis revealed that acquired resistant cells highly relied on glutamine utilization and mainly fluxed into oxidative phosphorylation energy production. Further mechanistic studies screened out glutamate dehydrogenase 1 (GLUD1) as the determinant of glutamine addiction in acquired resistant NSCLC cells, and provided evidence that GLUD1-mediated α-KG production and the accompanying reactive oxygen species (ROS) accumulation primarily triggered migration and invasion by inducing Snail. Pharmacological and genetic interference with GLUD1 in vitro significantly reversed drug resistance and decreased cell migration and invasion capability. Lastly, the successful application of R162, a selective GLUD1 inhibitor, to overcome both acquired resistance and EMT-induced metastasis in vivo, identified GLUD1 as a promising and druggable therapeutic target for malignant progression of NSCLC. Collectively, our study offers a potential strategy for NSCLC therapy, especially for drug-resistant patients with highly expressed GLUD1.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/uso terapêutico , Glutamina/metabolismo , Glutamina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fatores de Transcrição da Família Snail/metabolismo
3.
Occup Environ Med ; 79(4): 253-258, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34969777

RESUMO

BACKGROUND: Although the therapeutic effect of antineoplastic drugs is incontestable, these agents can also potentially act as carcinogens, mutagens and/or teratogens in people. The aim of this study was to assess the effect of occupational exposure to antineoplastic drugs on DNA damage, assessed by the comet assay and cytokinesis-block micronucleus (CBMN) assay, in nurses. METHODS: The cross-sectional study enrolled 305 nursing staff members from 7 public hospitals in Shenzhen who handled antineoplastic drugs, and 150 healthy nursing staff members who were not exposed to antineoplastic drugs as the control group. DNA damage was assessed by the comet and CBMN assay. Multiple linear regressions and logistic regressions models were used to analyse the effect of occupational exposure to antineoplastic drugs on DNA damage. RESULTS: After adjustment for confounding factors, compared with non-exposure to antineoplastic drugs, exposure to antineoplastic drugs was positively related to tail moment, olive moment, tail length and tail DNA per cent, and adjusted ß or OR (95% CI) was 0.17 (0.08 to 0.26), 0.18 (0.10 to 0.27), 1.03 (0.47 to 1.60) and 1.16 (1.04 to 1.29) (all p<0.05). Moreover, similar significant relationships were observed for the biomarkers of the CBMN assay. Additionally, other than age, there was no interaction between antineoplastic drug exposure and other variables for the levels of biomarkers of the CBMN assay and the comet assay. CONCLUSIONS: The present results showed that exposure to antineoplastic drugs was positively related to the risk of DNA damage in nurses. The results imply that occupational exposure to antineoplastic agents is an important global public health problem that requires urgent attention.


Assuntos
Antineoplásicos , Exposição Ocupacional , Antineoplásicos/efeitos adversos , Biomarcadores , Ensaio Cometa , Estudos Transversais , Dano ao DNA , Humanos , Linfócitos , Testes para Micronúcleos/métodos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise
4.
Int J Mol Sci ; 22(24)2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34948018

RESUMO

Objective: Prostate cancer (PCa) is the most common malignant tumor diagnosed in men in developed countries. In developing countries, the PCa morbidity and mortality rates are also increasing rapidly. Since androgen receptor (AR) is a key driver and plays a critical role in the regulation of PCa development, AR-targeted agents provide a key component of current therapy regimens. However, even new-generation AR antagonists are prone to drug resistance, and there is currently no effective strategy for overcoming advanced PCa aggressiveness, including drug-resistance progression. The aim of this study was to evaluate the potential efficacy and novel therapy strategy of proxalutamide (a newly developed AR antagonist) in PCa. Methods: Four PCa cell lines with various biological heterogeneities were utilized in this study, namely, androgen-sensitive/-insensitive with/without AR expression. Proliferation, migration and apoptosis assays in PCa cells were used to evaluate the effective therapeutic activity of proxalutamide. The changes in lipid droplet accumulation and lipidomic profiles were analyzed to determine the influence of proxalutamide on lipogenesis in PCa cells. The molecular basis of the effects of proxalutamide on lipogenesis and the AR axis was then further investigated. Results: Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). Proxalutamide induced the caspase-dependent apoptosis of PCa cells. Proxalutamide significantly diminished the level of lipid droplets in PCa cells, changed the lipid profile of PCa cells and reduced the content of most lipids (especially triglycerides) in PCa cells. Proxalutamide attenuated de novo lipogenesis by inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, proxalutamide also decreased AR expression in PCa cells, and its inhibitory effect on lipogenesis did not depend on its ability to down-regulate AR expression. However, Enz had no effect on AR expression, lipid accumulation or lipid de novo synthesis in PCa cells. Conclusions: By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.


Assuntos
Lipogênese/efeitos dos fármacos , Oxazóis/farmacologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Tioidantoínas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipidômica , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos
5.
Xenobiotica ; 48(4): 357-367, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28443723

RESUMO

1. Icaritin is a natural flavonoid with anti-osteoporosis activity. This study aimed to characterize icaritin glucuronidation by pooled human liver microsomes (HLM) and pooled human intestine microsomes (HIM), and to determine the contribution of individual UDP-glucuronosyltrans-ferase (UGT) enzyme to icaritin glucuronidation. 2. Glucuronidation rates were determined by incubating icaritin with uridine diphosphate glucuronic acid (UDPGA)-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Relative activity factors and activity correlation analysis were performed to identify main UGT isoforms. 3. UGT1A3, 1A7, 1A8, 1A9 and 2B7 were mainly responsible for catalyzing the formation of two glucuronides (G1 and G2). Icaritin 3-O-glucuronidation (G1) was significantly correlated with Chenodeoxycholic acid (CDCA) glucuronidation (r = 0.787, p = 0.002), propofol glucuronidation (r = 0.661, p = 0.019) and Zidovudine (AZT) glucuronidation (r = 0.805, p = 0.002). Similarly, icaritin 7-O-glucuronidation (G2) was also correlated with CDCA glucuronidation (r = 0.640, p = 0.025), propofol glucuronidation (r = 0.592, p = 0.043) and AZT glucuronidation (r = 0.661, p = 0.019). In addition, UGT1A3, 1A9 and 2B7 contributed 37.5, 33.8 and 21.3% for G1 in pooled HLM, respectively. Also, UGT1A3, 1A9 and 2B7 contributed 34.3, 20.0 and 8.6% for G2 in pooled HLM, respectively. 4. Icaritin was subjected to significant glucuronidation, wherein UGT1A3, 1A7, 1A8, 1A9 and 2B7 were main contributing enzymes.


Assuntos
Flavonoides/farmacocinética , Glucuronosiltransferase/metabolismo , Microssomos Hepáticos/enzimologia , Biocatálise , Humanos , Cinética , UDP-Glucuronosiltransferase 1A
6.
Int J Mol Sci ; 18(9)2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28925930

RESUMO

Wushanicaritin, a natural polyphenol compound, exerts many biological activities. This study aimed to characterize wushanicaritin glucuronidation by pooled human liver microsomes (HLM), human intestine microsomes and individual uridine diphosphate-glucuronosyltransferase (UGT) enzyme. Glucuronidation rates were determined by incubating wushanicaritin with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. Reaction phenotyping, the relative activity factor (RAF) and activity correlation analysis were performed to identify the main UGT isoforms. Wushanicaritin glucuronidation in HLM was efficient with a high CLint (intrinsic clearance) value of 1.25 and 0.69 mL/min/mg for G1 and G2, respectively. UGT1A1 and 1A7 showed the highest activities with the intrinsic clearance (CLint) values of 1.16 and 0.38 mL/min/mg for G1 and G2, respectively. In addition, G1 was significantly correlated with ß-estradiol glucuronidation (r = 0.847; p = 0.0005), while G2 was also correlated with chenodeoxycholic acid glucuronidation (r = 0.638, p = 0.026) in a bank of individual HLMs (n = 12). Based on the RAF approach, UGT1A1 contributed 51.2% for G1, and UGT1A3 contributed 26.0% for G2 in HLM. Moreover, glucuronidation of wushanicaritin by liver microsomes showed marked species difference. Taken together, UGT1A1, 1A3, 1A7, 1A8, 1A9 and 2B7 were identified as the main UGT contributors responsible for wushanicaritin glucuronidation.


Assuntos
Flavonoides/metabolismo , Glucuronosiltransferase/metabolismo , Mucosa Intestinal/metabolismo , Microssomos Hepáticos/metabolismo , Animais , Dissacarídeos/metabolismo , Cães , Cobaias , Haplorrinos , Humanos , Inativação Metabólica , Intestinos/citologia , Isoformas de Proteínas/metabolismo , Coelhos , Ratos , Especificidade da Espécie
7.
Cell Rep Phys Sci ; 5(6): 102021, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38947181

RESUMO

In colloids, the shape influences the function. In silica, straight nanorods have already been synthesized from water-in-oil emulsions. By contrast, curly silica nanofibers have been less reported because the underlying growth mechanism remains unexplored, hindering further morphology control for applications. Herein, we describe the synthetic protocol for silica nanofibers with a tunable curliness based on the control of the water-in-oil emulsion droplets. Systematically decreasing the droplet size and increasing their contact angle, the Brownian motion of the droplets intensifies during the silica growth, thus increasing the random curliness of the nanofibers. This finding is supported by simplistic theoretical arguments and experimentally verified by varying the temperature to finely tune the curliness. Assembling these nanofibers toward porous disordered films enhances multiple scattering in the visible range, resulting in increased whiteness in contrast to films constructed by spherical and rod-like building units, which can be useful for, e.g., coatings and pigments.

8.
Adv Sci (Weinh) ; 11(5): e2305099, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38044310

RESUMO

2D transition metal carbides and nitrides (MXenes) suggest an uncommonly broad combination of important functionalities amongst 2D materials. Nevertheless, MXene suffers from facile oxidation and colloidal instability upon conventional water-based processing, thus limiting applicability. By experiments and theory, It is suggested that for stability and dispersibility, it is critical to select uncommonly high permittivity solvents such as N-methylformamide (NMF) and formamide (FA) (εr  = 171, 109), unlike the classical solvents characterized by high dipole moment and polarity index. They also allow high MXene stacking order within thin films on carbon nanotube (CNT) substrates, showing very high Terahertz (THz) shielding effectiveness (SE) of 40-60 dB at 0.3-1.6 THz in spite of the film thinness < 2 µm. The stacking order and mesoscopic porosity turn relevant for THz-shielding as characterized by small-angle X-ray scattering (SAXS). The mechanistic understanding of stability and structural order allows guidance for generic MXene applications, in particular in telecommunication, and more generally processing of 2D materials.

9.
Small Methods ; : e2301229, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528393

RESUMO

The charge-transfer (CT) interactions between organic compounds are reflected in the (opto)electronic properties. Determining and visualizing crystal structures of CT complexes are essential for the design of functional materials with desirable properties. Complexes of pyranine (PYR), methyl viologen (MV), and their derivatives are the most studied water-based CT complexes. Nevertheless, very few crystal structures of CT complexes have been reported so far. In this study, the structures of two PYRs-MVs CT crystals and a map of the noncovalent interactions using 3D electron diffraction (3DED) are reported. Physical properties, e.g., band structure, conductivity, and electronic spectra of the CT complexes and their crystals are investigated and compared with a range of methods, including solid and liquid state spectroscopies and highly accurate quantum chemical calculations based on density functional theory (DFT). The combination of 3DED, spectroscopy, and DFT calculation can provide important insight into the structure-property relationship of crystalline CT materials, especially for submicrometer-sized crystals.

10.
Environ Pollut ; 331(Pt 2): 121842, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37225075

RESUMO

The construction of noise maps is of great significance for the management and control of urban noise and the protection of residents' physical and mental health. The European Noise Directive recommends using computational methods to construct strategic noise maps when possible. The current noise maps based on model calculation rely on complex noise emission and propagation models, and their huge number of regional grids needs to consume a lot of calculation time. This seriously restricts the update efficiency of noise maps, making it difficult to realize large-scale application and real-time dynamic update of noise maps. In order to improve the computational efficiency of noise maps, based on big data-driven technology, this paper combines the traditional CNOSSOS-EU noise emission modeling method with the multivariate nonlinear regression modeling method, and proposes an efficient calculation method of large-region dynamic traffic noise maps based on hybrid modeling method. First, this paper constructs the (daily and nightly) noise contribution prediction models of road sources with different classes, considering the daily and nightly periods and different urban road classes. Parameters of the proposed model are evaluated by using the multivariate nonlinear regression method to replace the complex nonlinear acoustic mechanism modeling. On this basis, in order to further improve the computational efficiency, noise contribution attenuations of the constructed models are parameterized and evaluated quantitatively. And then, the database containing the index table of the road noise sources-receivers and the corresponding noise contribution attenuations is constructed. The experimental results show that compared with the traditional calculation methods based on acoustic mechanism model, the noise map calculation method based on hybrid model proposed in this paper greatly reduces the model computations of noise map, improves the efficiency of noise mapping. It will provide technical support for constructing dynamic noise maps of large urban regions.


Assuntos
Ruído dos Transportes , Acústica , Bases de Dados Factuais
11.
BMC Genom Data ; 24(1): 67, 2023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37968621

RESUMO

BACKGROUND: In 2022, a global outbreak of monkeypox occurred with a significant shift in its epidemiological characteristics. The monkeypox virus (MPXV) belongs to the B.1 lineage, and its genomic variations that were linked to the outbreak were investigated in this study. Previous studies have suggested that viral genomic variation plays a crucial role in the pathogenicity and transmissibility of viruses. Therefore, understanding the genomic variation of MPXV is crucial for controlling future outbreaks. METHODS: This study employed bioinformatics and phylogenetic approaches to evaluate the key genomic variation in the B.1 lineage of MPXV. A total of 979 MPXV strains were screened, and 212 representative strains were analyzed to identify specific substitutions in the viral genome. Reference sequences were constructed for each of the 10 lineages based on the most common nucleotide at each site. A total of 49 substitutions were identified, with 23 non-synonymous substitutions. Class I variants, which had significant effects on protein conformation likely to affect viral characteristics, were classified among the non-synonymous substitutions. RESULTS: The phylogenetic analysis revealed 10 relatively monophyletic branches. The study identified 49 substitutions specific to the B.1 lineage, with 23 non-synonymous substitutions that were classified into Class I, II, and III variants. The Class I variants were likely responsible for the observed changes in the characteristics of circulating MPXV in 2022. These key mutations, particularly Class I variants, played a crucial role in the pathogenicity and transmissibility of MPXV. CONCLUSION: This study provides an understanding of the genomic variation of MPXV in the B.1 lineage linked to the recent outbreak of monkeypox. The identification of key mutations, particularly Class I variants, sheds light on the molecular mechanisms underlying the observed changes in the characteristics of circulating MPXV. Further studies can focus on functional domains affected by these mutations, enabling the development of effective control strategies against future monkeypox outbreaks.


Assuntos
Monkeypox virus , Mpox , Humanos , Monkeypox virus/genética , Mpox/epidemiologia , Filogenia , Surtos de Doenças , Genômica
12.
ACS Appl Mater Interfaces ; 15(5): 7063-7073, 2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36694305

RESUMO

Cost-effective and high-performance H2S sensors are required for human health and environmental monitoring. 2D transition-metal carbides and nitrides (MXenes) are appealing candidates for gas sensing due to good conductivity and abundant surface functional groups but have been studied primarily for detecting NH3 and VOCs, with generally positive responses that are not highly selective to the target gases. Here, we report on a negative response of pristine Ti3C2Tx thin films for H2S gas sensing (in contrast to the other tested gases) and further optimization of the sensor performance using a composite of Ti3C2Tx flakes and conjugated polymers (poly[3,6-diamino-10-methylacridinium chloride-co-3,6-diaminoacridine-squaraine], PDS-Cl) with polar charged nitrogen. The composite, preserving the high selectivity of pristine Ti3C2Tx, exhibits an H2S sensing response of 2% at 5 ppm (a thirtyfold sensing enhancement) and a low limit of detection of 500 ppb. In addition, our density functional theory calculations indicate that the mixture of MXene surface functional groups needs to be taken into account to describe the sensing mechanism and the selectivity of the sensor in agreement with the experimental results. Thus, this report extends the application range of MXene-based composites to H2S sensors and deepens the understanding of their gas sensing mechanisms.

13.
Yao Xue Xue Bao ; 47(9): 1134-40, 2012 Sep.
Artigo em Zh | MEDLINE | ID: mdl-23227541

RESUMO

This study is to establish an artificial neural network (ANN) for predicting blood tacrolimus concentration in liver transplantation recipients. Tacrolimus concentration samples (176 samples) from 37 Chinese liver transplantation recipients were collected. ANN established after network parameters were optimized by using momentum method combined with genetic algorithm. Furthermore, the performance of ANN was compared with that of multiple linear regression (MLR). When using accumulated dose of 4 days before therapeutic drug monitoring (TDM) of tacrolimus concentration as input factor, mean prediction error and mean absolute prediction error of ANN were 0.02 +/- 2.40 ng x mL(-1) and 1.93 +/- 1.37 ng x mL(-1), respectively. The absolute prediction error of 84.6% of testing data sets was less than 3.0 ng x mL(-1). Accuracy and precision of ANN are superior to those of MLR. The correlation, accuracy and precision of ANN are good enough to predict blood tacrolimus concentration.


Assuntos
Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Transplante de Fígado , Redes Neurais de Computação , Tacrolimo/sangue , Adulto , Idoso , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade
14.
Artigo em Inglês | MEDLINE | ID: mdl-35954584

RESUMO

With the continuous expansion of urban scale with dense population and traffic and the gradual improvement of residents' requirements for environmental quality, the traditional evaluation method relying on acoustic energy is not enough to reflect the feelings of urban crowds about acoustic environment quality. The acoustic environment quality evaluation method based on human subjective perception has gradually become one of the research focuses in the field of environmental noise control. In recent years, various subjective and objective acoustic characteristic parameters have been introduced into the study of acoustic environment assessment in the global literature. However, the extraction of "effective characteristics" from a large number of physical and psychoacoustic characteristics contained in acoustic signals and the creation of a scientific and efficient subjective evaluation model have always been key technical problems in the field of acoustic environment evaluation. Based on subjective human perceptions, the overall acoustic environment quality evaluation of urban open spaces is studied in this paper. Based on the "effective characteristic" parameters and the subjective characteristic proposed in the previous research, including equivalent continuous A-weighted sound pressure level (LA), the difference between median noise and ambient background noise (L50 - L90), Sharpness (Sh), as well as satisfaction (Sat), the multivariable linear regression algorithm is used to further study the intrinsic correlation between the proposed "effective characteristics" and subjective perception. Then, a satisfaction evaluation model of the acoustic environment based on "effective characteristics" is built in this paper. Furthermore, the soundwalk evaluation experiment and the MATLAB numerical simulation experiment are carried out, which verify that the prediction accuracy of the proposed model is more than 92%, the consistency of satisfaction level is more than 88%, as well as the changes in the values of Sh and L50 - L90 have a significant impact on the satisfaction prediction of the proposed model. It shows that the proposed "effective characteristics" more comprehensively describe the quality level of the regional acoustic environment in urban open space compared with a single LA index, and the proposed acoustic environment satisfaction evaluation model based on "effective characteristics" has significant accuracy superiority and regional applicability.


Assuntos
Acústica , Som , Humanos , Ruído , Satisfação Pessoal , Psicoacústica
15.
Front Pharmacol ; 13: 932934, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105197

RESUMO

Tenofovir (TFV) ester prodrugs, a class of nucleotide analogs (NAs), are the first-line clinical anti-hepatitis B virus (HBV) drugs with potent antiviral efficacy, low resistance rate and high safety. In this work, three marketed TFV ester drugs, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide fumarate (TMF), were used as probes to investigate the relationships among prodrug structures, pharmacokinetic characteristics, metabolic activations, pharmacological responses and to reveal the key factors of TFV ester prodrug design. The results indicated that TMF and TAF exhibited significantly stronger inhibition of HBV DNA replication than did TDF in HBV-positive HepG2.2.15 cells. The anti-HBV activity of TMF was slightly stronger than TAF after 9 days of treatment (EC50 7.29 ± 0.71 nM vs. 12.17 ± 0.56 nM). Similar results were observed in the HBV decline period post drug administration to the HBV transgenic mouse model, although these three TFV prodrugs finally achieved the same anti-HBV effect after 42 days treatments. Furthermore, TFV ester prodrugs showed a correcting effect on disordered host hepatic biochemical metabolism, including TCA cycle, glycolysis, pentose phosphate pathway, purine/pyrimidine metabolism, amino acid metabolism, ketone body metabolism and phospholipid metabolism. The callback effects of the three TFV ester prodrugs were ranked as TMF > TAF > TDF. These advantages of TMF were believed to be attributed to its greater bioavailability in preclinical animals (SD rats, C57BL/6 mice and beagle dogs) and better target loading, especially in terms of the higher hepatic level of the pharmacologically active metabolite TFV-DP, which was tightly related to anti-HBV efficacy. Further analysis indicated that stability in intestinal fluid determined the actual amount of TFV prodrug at the absorption site, and hepatic/intestinal stability determined the maintenance amount of prodrug in circulation, both of which influenced the oral bioavailability of TFV prodrugs. In conclusion, our research revealed that improved pharmacokinetics of TFV ester prodrugs (especially intestinal stability) strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism, which provides new insights and a basis for the design, modification and evaluation of new TFV prodrugs in the future.

16.
Biomater Sci ; 10(15): 4356-4366, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35786722

RESUMO

Hepatitis B represents a major global public health burden, which is caused by the hepatitis B virus (HBV) with a high infection rate. Although several anti-HBV drugs have been developed for clinical treatment of hepatitis B, the current therapeutic strategies still suffer from undeniable adverse effects, insufficient efficacy after systemic administration and chronic inflammation. Here, we develop a carrier-free metal-organic hybrid nanoassembly that is co-loaded with tenofovir (TFV), an anti-viral agent and phosphorylated glycyrrhetinic acid (GAP), an anti-inflammatory compound (TFV/GAP/NA) to enhance the anti-HBV effect and alleviate the inflammatory response for hepatitis B treatment. The nanoassembly is easily prepared through the ionic interactions between the anionic phosphonate/phosphate groups from TFV/GAP and the zirconium cation, which has a stable nanostructure and a high drug-loading capacity. The nanoassembly prolongs the circulation time with reduced drug leakage in the blood and elevates drug accumulation in the liver after intravascular administration. After internalization mediated by the GAP ligand-GA receptor interaction, TFV/GAP/NA disassembles by the phosphatase-triggered degradation of the phosphate ester bonds in GAP and releases TFV, GAP and GA within the HBV-positive hepatocytes. The released TFV interferes with the HBV polymerase to inhibit the viral DNA replication, while the released GAP and GA suppress the pro-inflammatory protein expression. In mouse models, treatment with TFV/GAP/NA inhibits HBV production and alleviates inflammation-mediated liver injury.


Assuntos
Antivirais , Hepatite B , Adenina/farmacologia , Animais , Antivirais/farmacologia , Replicação do DNA , DNA Viral/farmacologia , DNA Viral/uso terapêutico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/metabolismo , Inflamação/tratamento farmacológico , Camundongos , Organofosfatos , Fosfatos , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Replicação Viral
17.
Dalton Trans ; 47(42): 15189-15196, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30320854

RESUMO

Nanomaterials with hierarchical structures have attracted much attention recently due to their impressive behavior in many fields. Herein, hierarchical Cu2S nanorods with monoclinic and hexagonal phases are first in situ grown on copper sheets by simple hydrothermal methods. The solvent largely influences the feature of Cu2S nanorods during the growth process and the proposed mechanism is elaborately elucidated for these different Cu2S nanorods. Owing to their wheat-like architecture and higher electrical conductivity, the hexagonal Cu2S nanorods exhibit superior electrochemical performance with a specific capacitance of 346 mF cm-2 at 5 mA cm-2 and more than 90% capacitance after 2000 cycles. The solid-state asymmetrical supercapacitors based on the hexagonal Cu2S electrodes have a specific capacitance of 172 mF cm-2 at 5 mA cm-2 and excellent electrochemical stability with ∼90% capacitance after 2000 cycling tests. Moreover, the hierarchical Cu2S nanorods show great photocatalytic ability in the degradation of methylene blue (MB) and rhodamine B (RhB) dyes with the assistance of H2O2 under visible light. This work provides a way to fabricate copper sulfides with hierarchical structures and multi-functions.

18.
Data Brief ; 17: 1331-1335, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29876488

RESUMO

In this article, we provide the data analysis between controllable variables and the performance of CuS crackle based electrode, there are four important factors which could influence the formation of cracks, the colloid concentration, drying temperature, colloid dosage and ambient humidity. We carried out and summed nineteen controlled data experiments below and other variates which could affect the performance were discussed in this article.

19.
J Pharm Biomed Anal ; 155: 157-168, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29631076

RESUMO

Corylin, an phenolic compound from Psoralea corylifolia, has been reported with various pharmacological properties but has poor bioavailability due to massive metabolism. In this study, twelve metabolites of corylin mainly involving in oxidation, hydration, glucuronidation and sulfation were detected in mice. Furthermore, the oxidation and hydration of corylin (M4) in human liver microsomes (HLM) and human intestine microsomes (HIM) were both efficient with high CLint (intrinsic clearance) values of 24.29 and 42.85 µL/min/mg, respectively. CYP1A1, 1B1 and 2C19 contributed most for M4 with the CLint values of 26.63, 33.09 and 132.41 µL/min/mg, respectively. Besides, M4 was strongly correlated with phenacetin-N-deacetylation (r = 0.885, p = 0.0001) and tolbutamide-4-oxidation (r = 0.727, p = 0.001) in twelve individual HLMs, respectively. In addition, corylin was efficiently glucuronidated (M7) in HLM (125.33 µL/min/mg) and in HIM (108.74 µL/min/mg). UGT1A1 contributed the most for M7 with the CLint value of 122.32 µL/min/mg. Meanwhile, M7 was significantly correlated with ß-estradiol-3-O-glucuronidation (r = 0.742, p = 0.006) in twelve individual HLMs. Moreover, the metabolism of corylin showed marked species differences. Taken together, corylin was subjected to massive first-pass metabolism in liver and intestine, while CYP1A1, 1B1, 2C19 and UGT1A1 were the main contributors. Finally, the proposed metabolic pathway of corylin involed CYP and UGT isoforms were summarized, which could help to understand the metabolic fate of corylin in vivo.


Assuntos
Flavonoides/metabolismo , Animais , Citocromo P-450 CYP1A1/metabolismo , Glucuronídeos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Cinética , Fígado/metabolismo , Masculino , Metabolômica/métodos , Camundongos , Microssomos Hepáticos/metabolismo , Fenóis/metabolismo , Especificidade da Espécie
20.
Food Funct ; 9(3): 1410-1423, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29318243

RESUMO

Active efflux transport of glucuronides out of cells is a critical process in elimination of drugs and food-derived compounds. Wushanicaritin, a natural polyphenol from Epimedium species, has shown many biological activities. However, the transporters responsible for excretion of wushanicaritin glucuronides still remain undefined. Herein, chemical inhibitors (Ko143, MK571, dipyridamole and leukotriene C4) and single stable knocked-down efflux transporters (BCRP, MRP1, MRP3 and MRP4) were used to determine the contributions of efflux transporters to glucuronide efflux and cellular glucuronidation in UGT1A1-overexpressing HeLa cells (HeLa1A1). Knock-down of transporters was performed by stable transfection of short hairpin RNA (shRNA) using lentiviral vectors. The HeLa1A1 cell lysate catalyzed wushanicaritin glucuronidation, generating wushanicaritin-3-O-glucuronide and wushanicaritin-7-O-glucuronide. Ko143 (a dual inhibitor of BCRP, 5-20 µM) caused a marked decrease in excretion rate (maximal 53.4%) and increase of intracellular glucuronides (maximal 86.0%), while MK-571 (an inhibitor of MRPs, 5-20 µM) resulted in a significant reduction in excretion rate (maximal 64.6%) and rise of intracellular glucuronides (maximal 98.0%). By contrast, dipyridamole and leukotriene C4 showed no inhibitory effects on glucuronide excretion. Furthermore, shRNA-mediated silencing of a target transporter led to a marked reduction in the excretion rate of wushanicaritin glucuronides (maximal 33.8% for BCRP; 25.9% for MRP1; 26.7% for MRP3; 39.3% for MRP4). Transporter silencing also led to substantial decreases in efflux clearance (maximal 61.5% for BCRP; 48.7% for MRP1; 35.1% for MRP3; 63.1% for MRP4). In conclusion, chemical inhibition and gene silencing results suggested that BCRP, MRP1, MRP3 and MRP4 were significant contributors to excretion of wushanicaritin glucuronides.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico/efeitos dos fármacos , Dicetopiperazinas/farmacologia , Dipiridamol/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Epimedium/química , Flavonoides/farmacologia , Técnicas de Silenciamento de Genes , Inativação Gênica , Glucuronosiltransferase/genética , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Propionatos/farmacologia , Quinolinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
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