Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 217
Filtrar
1.
Cancers (Basel) ; 14(22)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36428687

RESUMO

Breast cancer (BC) is a serious threat to women's health and metastasis is the major cause of BC-associated mortality. Various techniques are currently used to preoperatively describe the metastatic status of tumors, based on which a comprehensive treatment protocol was determined. However, accurately staging a tumor before surgery remains a challenge, which may lead to the miss of optimal treatment options. More severely, the failure to detect and remove occult micrometastases often causes tumor recurrences. There is an urgent need to develop a more precise and non-invasive strategy for the detection of the tumor metastasis in lymph nodes and distant organs. Based on the facts that tumor metastasis is closely related to the primary tumor microenvironment (TME) evolutions and that metabolomics profiling of the circulatory system can precisely reflect subtle changes within TME, we suppose whether metabolomic technology can be used to achieve non-invasive and real-time monitoring of BC metastatic status. In this study, the metastasis status of BC mouse models with different tumor-bearing times was firstly depicted to mimic clinical anatomic TNM staging system. Metabolomic profiling together with metastasis-related changes in TME among tumor-bearing mice with different metastatic status was conducted. A range of differential metabolites reflecting tumor metastatic states were screened and in vivo experiments proved that two main metastasis-driving factors in TME, TGF-ß and hypoxia, were closely related to the regular changes of these metabolites. The differential metabolites level changes were also preliminarily confirmed in a limited number of clinical BC samples. Metabolite lysoPC (16:0) was found to be useful for clinical N stage diagnosis and the possible cause of its changes was analyzed by bioinformatics techniques.

2.
Sensors (Basel) ; 22(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36366075

RESUMO

Automated inspection technology based on computer vision is now widely used in the manufacturing industry with high speed and accuracy. However, metal parts always appear in high gloss or shadow on the surface, resulting in the overexposure of the captured images. It is necessary to adjust the light direction and view to keep defects out of overexposure and shadow areas. However, it is too tedious to adjust the position of the light direction and view the variety of parts' geometries. To address this problem, we design a photometric-stereo-based defect detection system (PSBDDS), which combines the photometric stereo with defect detection to eliminate the interference of highlights and shadows. Based on the PSBDDS, we introduce a photometric-stereo-based defect detection framework, which takes images captured in multiple directional lights as input and obtains the normal map through the photometric stereo model. Then, the detection model uses the normal map as input to locate and classify defects. Existing learning-based photometric stereo methods and defect detection methods have achieved good performance in their respective fields. However, photometric stereo datasets and defect detection datasets are not sufficient for training and testing photometric-stereo-based defect detection methods, thus we create a photometric stereo defect detection (PSDD) dataset using our PSBDDS to eliminate gaps between learning-based photometric stereo and defect detection methods. Furthermore, experimental results prove the effectiveness of the proposed PSBBD and PSDD dataset.


Assuntos
Algoritmos , Fotogrametria , Fotogrametria/métodos , Fotometria
3.
Biomater Sci ; 10(23): 6718-6730, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36279005

RESUMO

Low intracellular delivery efficiency and multidrug resistance are among major barriers to effective cancer therapy. Herein, we report a novel, virus-mimicking, endosomolytic liposomal drug-delivery platform to address these two key challenges. The pH-responsive, comb-like pseudopeptides were prepared by grafting relatively long alkyl side chains onto a polyamide, poly(L-lysine isophthalamide), to mimic fusogenic peptides in viral spikes. The cholesterol-containing liposome, which mimics the viral envelope, was readily coated with these pseudopeptides due to their hydrophobic side chains acting as membrane anchors. These endosomolytic pseudopeptides displayed high adsorption onto the liposomal membrane and enabled the significantly higher cellular uptake. The virus-mimicking system showed a pH-triggered content-release profile which could be manipulated by varying the structure and concentration of the adsorbed polymers. The endosomolytic ability of the multifunctional liposome and its use for efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) were demonstrated. The virus-mimicking liposomal system with DOX encapsulation exhibited considerably higher potency against HeLa cervical cancer cells, A549 lung cancer cells, MES-SA uterus cancer cells, and MES-SA/DX5 multidrug-resistant cancer cells than DOX-loaded bare liposomes and free DOX. These results suggest its potential applications for enhanced cytoplasmic delivery and cancer treatment.


Assuntos
Lipossomos , Neoplasias , Feminino , Humanos , Lipossomos/farmacologia , Resistência a Múltiplos Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Doxorrubicina/química , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral
4.
Eur J Med Chem ; 244: 114806, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36223681

RESUMO

Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory (eeAChE IC50 = 0.07 ± 0.01 µM; hAChE IC50 = 0.38 ± 0.04 µM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H2O2 and Aß1-42 aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and Aß1-42. At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Camundongos , Animais , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase , Fator 2 Relacionado a NF-E2/metabolismo , Peróxido de Hidrogênio , Peptídeos beta-Amiloides/metabolismo , Desenho de Fármacos , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 243: 114729, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36084535

RESUMO

Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 µM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Aß1-42 induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Humanos , Butirilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Estrutura Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Aminas/farmacologia , Aminas/uso terapêutico , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular
6.
ACS Med Chem Lett ; 13(8): 1286-1294, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35978698

RESUMO

As a crucial target which is overexpressed in a variety of cancers, aldo-keto reductase 1C3 (AKR1C3) confers chemotherapeutic resistance to many clinical agents. However, a limited number of AKR1C3-selective inhibitors are applied clinically, which indicates the importance of identifying active compounds. Herein, we report the discovery, synthesis, and evaluation of novel and potent AKR1C3 inhibitors with structural diversity. Molecular dynamics simulations of these active compounds provide reasonable clarification of the interpreted biological data. Moreover, we demonstrate that AKR1C3 inhibitors have the potential to be superior therapeutic agents for re-sensitizing drug-resistant cell lines to chemotherapy, especially the pan-AKR1C inhibitor S07-2010. Our study identifies new structural classes of AKR1C3 inhibitors and enriches the structural diversity, which facilitates the future rational design of inhibitors and structural optimization. Moreover, these compounds may serve as promising therapeutic adjuvants toward new therapeutics for countering drug resistance.

7.
J Med Chem ; 65(16): 11365-11387, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35969197

RESUMO

Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar KD value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aß1-42. The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade
8.
Front Psychol ; 13: 874101, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936301

RESUMO

This study investigated the effectiveness of the teaching design scheme called the Immersive Virtual Reality Teaching Model (IVRTM) on a small learner population at the researcher's university. The study was based on one-term experimental teaching among the undergraduates. An ecological class was set up, extending classroom teaching to 3-layer teaching space, including a physical layer (classroom-based), an information layer (internet-based), and a virtual-reality layer (VR-based). The research aimed (1) to create an online-offline spatial ecological learning environment for higher learning efficiency with a series of learning activities, (2) to uncover the learning effectiveness of VR assistance in oral English, and (3) to acquire the students' attitudes toward the IVRTM. The study approaches involved literature review, empirical method, questionnaire, interviews, and data analysis. The findings would have a positive significance for the promotion of new technology applications in SLA teaching and provide novel and preliminary references for teachers pursuing an effective teaching design of ecological classes based on IVR spatial fusion.

9.
Curr Drug Targets ; 23(15): 1430-1452, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36017847

RESUMO

The leukocyte immunoglobulin (Ig)-like receptors (LILRs) are constituted by five inhibitory subpopulations (LILRB1-5) and six stimulatory subpopulations (LILRA1-6). The LILR populations substantially reside in immune cells, especially myeloid cells, functioning as a regulator in immunosuppressive and immunostimulatory responses, during which the nonclassical major histocompatibility complex (MHC) class I molecules are widely involved. In addition, LILRs are also distributed in certain tumor cells, implicated in the malignancy progression. Collectively, the suppressive Ig-like LILRB2 is relatively well-studied to date. Herein, we summarized the whole family of LILRs and their biologic function in various diseases upon ligation to the critical ligands, therefore providing more information on their potential roles in these pathological processes and giving the clinical significance of strategies targeting LILRs.


Assuntos
Leucócitos , Receptores Imunológicos , Humanos , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Ligantes , Imunoglobulinas
10.
Acta Pharm Sin B ; 12(4): 1781-1804, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35847506

RESUMO

Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.

11.
Bioorg Chem ; 127: 106004, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35843015

RESUMO

Cardiac glycosides (CGs) show potential broad-spectrum antiviral activity by targeting cellular host proteins. Herein are reported the isolation of five new (1-5) and eight known (7-13) CGs from the roots of Streblus asper Lour. Of these compounds 1 and 7 exhibited inhibitory action against EBV early antigen (EA) expression, with half-maximal effective concentration values (EC50) being less than 60 nM, and they also showed selectivity, with selectivity index (SI) values being 56.80 and 103.17, respectively. Preliminary structure activity relationships indicated that the C-10 substituent, C-5 hydroxy groups, and C-3 sugar unit play essential roles in the mediation of the inhibitory activity of CGs against EBV. Further enzyme experiments demonstrated that these compounds might inhibit ion pump function and thereby change the intracellular signal transduction pathway by binding to Na+/K+-ATPase, as validated by simulated molecular docking. This study is the first report that CGs can effectively limit EBV lytic replication, and the observations made in this study may be of value for lead compound development.


Assuntos
Glicosídeos Cardíacos , Infecções por Vírus Epstein-Barr , Moraceae , Glicosídeos Cardíacos/química , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4/metabolismo , Simulação de Acoplamento Molecular , Moraceae/química
12.
Mikrochim Acta ; 189(8): 293, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35881205

RESUMO

CuO nanorods bearing Au nanoparticles (Au/CuO nanocomposites) were prepared by a solution-phase synthesis and exhibited efficient hydroquinone (HQ)-oxidase activity with good specificity. The Au/CuO nanocomposites effectively catalyzed the oxidation of colorless HQ to brown benzoquinone with an absorbance maximum at 376 nm but did not catalyze the conversions of catechol or resorcinol. Kinetic studies indicated that the Au/CuO nanocomposites exhibited a strong affinity for HQ, with a Michaelis-Menten constant of Km = 0.33 mM. Owing to the high catalytic activity and specificity, a strong color was observed at low concentrations of HQ. Quantitative measurement of HQ was performed via colorimetric analysis, which yielded a detection limit of 3 µM with a linear range of 5-200 µM. This colorimetric sensor was successfully applied to an HQ assay of real water samples with satisfactory results.


Assuntos
Nanopartículas Metálicas , Nanocompostos , Colorimetria/métodos , Cobre , Ouro , Hidroquinonas , Cinética
13.
Angew Chem Int Ed Engl ; 61(42): e202209542, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-35909082

RESUMO

The universal limit on the pH conditions is disturbing peroxymonosulfate (PMS)-triggered high-valent iron-oxo systems in environmental applications. Here, we propose for the first time the construction of a neutral microenvironment on the surface of Zn-Fe layered double hydroxide (ZnFe-LDH) by using the amphoteric properties of zinc hydroxide, which continuously generates ≡FeIV =O over a wide pH range of 3.0-11.0 in activating PMS. The ≡Zn(OH)2 moiety offers a neutral microenvironment at the phase interface, which mitigates the self-decomposition of ≡FeIV =O by protons and the hydrolysis reaction of iron by hydroxyl groups, which is supported by the Mossbauer spectra, density functional theory calculations and designed experiments. Consequently, ZnFe-LDH/PMS can satisfy the stability in long-term experiments, selectivity under conditions with high salinity or natural organic matter and efficient treatment of actual wastewater.

14.
Eur J Med Chem ; 239: 114510, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-35728508

RESUMO

Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM, and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Aß amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Cognição , Grelina , Humanos , Estrutura Molecular , Neuroproteção
15.
Drug Deliv ; 29(1): 1358-1369, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35506467

RESUMO

The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-ß plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-ß receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-ß blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.


Assuntos
Pró-Fármacos , Imunoterapia , Micelas , Pró-Fármacos/farmacologia , Fator de Crescimento Transformador beta , Microambiente Tumoral
16.
Diabetes Metab Syndr Obes ; 15: 943-962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35378831

RESUMO

Purpose: Using network pharmacology and molecular docking to explore the mechanism of Yishen Capsule in the treatment of diabetic nephropathy. Materials and Methods: Active components of Yishen Capsule were obtained using database such as TCMSP and TCMID. UniProt protein database was used to screen and standardize the human-derived targets of the active chemical components. Diabetic nephropathy (DN) targets were obtained from databases such as GeneCards, OMIM, TTD, DisGeNET and DrugBank. A network of "Yishen Capsule Components-diabetic nephropathy Targets-Pathways" was constructed by analyzing data above to screening out core targets for molecular docking verification. DN is induced by streptozocin in rats after left nephrectomy. Renal tubular epithelial cells (RTECs) was isolated  and cultured under high glucose conditions. Based on these experimental models, key pathway target genes screened by network pharmacology were verified both in vitro and in vivo. Results: The main active components of Yishen Capsule in the treatment of DN include quercetin, kaempferol, gallic acid, astragaloside IV, etc. Some key targets (such as AR, AKT1, TP53, ESR1, JUN) and important signal pathways (such as AGE-RAGE, HIF-1 and JAK-STAT signal pathway) were included in the treatment of DN with Yishen Capsule. Molecular docking assay showed that most of the targets have good binding activity with the components of Yishen Capsule. Based on the results of network pharmacology, key target proteins in HIF-1α and JAK2/STAT3 signaling pathways were selected for experimental verification. Results presented that HIF-1α, JAK2, STAT3, TGF-ß and MCP-1 were increased under high glucose environment. With the treatment of Yishen Capsule, the expression of HIF-1α further increased, while the expression of JAK2, STAT3, MCP-1 and TGF-ß was decreased. Conclusion: This study revealed the mechanism of Yishen Capsule in the treatment of DN, which possesses the characteristics of multi-component, multi-target, and multi-pathway. Further experiments confirmed that Yishen Capsule interfered with HIF-1α and JAK/STAT signaling pathways to reduce inflammation and fibrosis damage in the kidney tissue of rats with diabetic nephropathy.

17.
Infect Drug Resist ; 15: 605-617, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237053

RESUMO

BACKGROUND: Ceftaroline fosamil has demonstrated superior clinical efficacy versus ceftriaxone for hospitalized adults with moderate-to-severe community-acquired pneumonia (CAP) in a Phase 3 trial in Asia and in a meta-analysis of three trials in Asia, North America, and Europe. Efficacy and safety outcomes for the subset of patients in China in the ASIA CAP trial were analyzed to determine if the same conclusions hold in the China subpopulation. METHODS: Hospitalized adults with Pneumonia Outcomes Research Team risk class III-IV CAP were randomized (1:1) to receive either intravenous ceftaroline fosamil 600 mg every 12 h or ceftriaxone 2 g every 24 h for 5-7 days. The primary efficacy variable was clinical response at test-of-cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included microbiological responses and safety. RESULTS: Of 302 patients randomized in China, 205 were included in the CE population. Clinical cure rates at TOC were 80/105 (76.2%) for ceftaroline fosamil and 61/100 (61.0%) for ceftriaxone (difference 15.2%, 95% CI 2.5, 27.6), thereby meeting predefined non-inferiority and superiority criteria for the overall study. Subgroup analyses of the primary endpoint demonstrated consistency of favourable efficacy of ceftaroline fosamil across age groups, Pneumonia Outcomes Research Team risk classes and CURB-65 scores. Microbiological responses were presumed from clinical outcomes. Adverse events were consistent with the study treatments' known safety profiles. CONCLUSION: The China subset results are consistent with the overall study population, despite the smaller sample size. Ceftaroline fosamil was both non-inferior and superior to ceftriaxone for empiric treatment of Chinese patients with moderate-to-severe CAP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01371838.

18.
Chem Biol Interact ; 357: 109886, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35288161

RESUMO

O-linked N-acetylglucosamine transferase (OGT), a key protein in O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification, catalyzes O-GlcNAcylation by linking GlcNAc from glycosyl donors to protein Ser/Thr residues to regulate multiple biological processes. OGT has become a popular research topic in the field of glycobiology as a potential target. This report consists of three parts, namely: the basic information of OGT, the relationship between OGT and diseases, and the research progress of OGT inhibitors. This report aims to improve the understanding of OGT-related fields from the perspective of its structure. OGT inhibitors could aid the effective and efficient investigation of the O-GlcNAcylation mechanism, and provide new ideas and methods for the treatment of related diseases.


Assuntos
Acetilglucosamina , Processamento de Proteína Pós-Traducional , Acetilglucosamina/metabolismo
19.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35217599

RESUMO

Percolation theory has been widely used to study phase transitions in network systems. It has also successfully explained various macroscopic spreading phenomena across different fields. Yet, the theoretical frameworks have been focusing on direct interactions among nodes, while recent empirical observations have shown that indirect interactions are common in many network systems like social and ecological networks, among others. By investigating the detailed mechanism of both direct and indirect influence on scientific collaboration networks, here we show that indirect influence can play the dominant role in behavioral influence. To address the lack of theoretical understanding of such indirect influence on the macroscopic behavior of the system, we propose a percolation mechanism of indirect interactions called induced percolation. Surprisingly, our model exhibits a unique anisotropy property. Specifically, directed networks show first-order abrupt transitions as opposed to the second-order continuous transition in the same network structure but with undirected links. A mix of directed and undirected links leads to rich hybrid phase transitions. Furthermore, a unique feature of the nonmonotonic pattern is observed in network connectivities near the critical point. We also present an analytical framework to characterize the proposed induced percolation, paving the way to further understanding network dynamics with indirect interactions.

20.
J Phys Chem Lett ; 13(1): 312-323, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-34978821

RESUMO

Among the members of the rapidly growing nanozyme family, plasmonic nanozymes stand out because of their unique localized surface plasmon resonance (LSPR) characteristics and tunable catalytic activity. We prepared a plasmonic nanozyme of Au gold nanoparticles (AuNPs) and Cu metal-organic framework nanosheets (Cu-MOFNs). The Cu-MOFNs have peroxidase-like activity, while AuNPs present unique LSPR characteristics. We found that the as-prepared AuNPs/Cu-MOFNs composite presents 1.6-fold faster reaction kinetics under LSPR excitation compared to that in the dark. Investigations of energy levels, radical capture, and dark-field scattering spectroscopy revealed that LSPR of AuNPs as well as matched energy levels can facilitate efficient hot electron transfer, which could readily cleave the chemical bond of the substrate and accelerate the reaction kinetics. On the basis of these results, we achieved enhanced antibacterial therapy and wound healing using plasmonic AuNPs/Cu-MOFNs. This study spotlights the superiority of plasmonic nanozymes in improving the enzyme-like performance of nanozymes.


Assuntos
Antibacterianos/farmacologia , Ouro/farmacologia , Estruturas Metalorgânicas/farmacologia , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/química , Células Cultivadas , Cobre/química , Cobre/farmacologia , Ouro/química , Humanos , Cinética , Nanopartículas Metálicas/química , Estruturas Metalorgânicas/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Infecções Cutâneas Estafilocócicas/patologia , Ressonância de Plasmônio de Superfície , Propriedades de Superfície , Cicatrização/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...