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1.
Biomaterials ; 279: 121237, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34749071

RESUMO

As a vital bacteria-secreted toxin, hydrogen peroxide (H2O2) can destroy infected tissues and increase vascular permeability, leading to life-threatening systemic bacteremia or sepsis. No strategy that can alleviate H2O2-induced injury and prevent systemic sepsis has been reported. Herein, as a proof of concept, we demonstrate the use of H2O2-reactive metal-organic framework nanosystems (MOFs) for treating H2O2-secreting bacteria. In mice infected with Streptococcus pneumoniae (S. pneumoniae) isolated from patients, MOFs efficiently accumulate in the lungs after systemic administration due to infection-induced alveolar-capillary barrier dysfunction. Moreover, MOFs sequester pneumococcal H2O2, reduce endothelial DNA damage, and prevent systemic dissemination of bacteria. In addition, this nanosystem exhibits excellent chemodynamic bactericidal effects against drug-resistant bacteria. Through synergistic therapy with the antibiotic ampicillin, MOFs eliminate over 98% of invading S. pneumoniae, resulting in a survival rate of greater than 90% in mice infected with a lethal dose of S. pneumoniae. This work opens up new paths for the clinical treatment of toxin-secreting bacteria.

2.
Nat Commun ; 12(1): 5465, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526500

RESUMO

Peptide-protein interactions are involved in various fundamental cellular functions and their identification is crucial for designing efficacious peptide therapeutics. Recently, a number of computational methods have been developed to predict peptide-protein interactions. However, most of the existing prediction approaches heavily depend on high-resolution structure data. Here, we present a deep learning framework for multi-level peptide-protein interaction prediction, called CAMP, including binary peptide-protein interaction prediction and corresponding peptide binding residue identification. Comprehensive evaluation demonstrated that CAMP can successfully capture the binary interactions between peptides and proteins and identify the binding residues along the peptides involved in the interactions. In addition, CAMP outperformed other state-of-the-art methods on binary peptide-protein interaction prediction. CAMP can serve as a useful tool in peptide-protein interaction prediction and identification of important binding residues in the peptides, which can thus facilitate the peptide drug discovery process.


Assuntos
Algoritmos , Biologia Computacional/métodos , Aprendizado Profundo , Peptídeos/metabolismo , Proteínas/metabolismo , Sítios de Ligação , Modelos Moleculares , Peptídeos/química , Ligação Proteica , Domínios Proteicos , Proteínas/química , Reprodutibilidade dos Testes
3.
Stroke Vasc Neurol ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429364

RESUMO

BACKGROUND: Tenecteplase (TNK) possesses several pharmacological characteristics superior to conventional alteplase (rt-PA), with well-established safety and efficacy profile in Caucasians. There exists controversy over the optimal dose of intravenous rt-PA for East Asians with acute ischaemic stroke (AIS). Current study aimed to determine the safety dose range of recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) for patients with AIS in China. METHODS: This multicentre, prospective, randomised, open-label, blinded end-point, phase II study compared three tiers of 0.1, 0.25, 0.32 mg/kg rhTNK-tPA (to a maximum of 40 mg) with standard 0.9 mg/kg rt-PA (to a maximum of 90 mg) in patients who were eligible for intravenous thrombolysis. The safety outcome were symptomatic intracranial haemorrhage (sICH) within 36 hours. RESULTS: Between May 2018 and February 2020, 240 patients were randomly assigned to four group, 4 of whom did not receive study treatment. The intention-to-treat analysis included 236 patients. There was no difference in the improvement on National Institutes of Health Stroke Scale at day 14 in the 3 tiers and control group (63.3%, 77.2%, 66.7% vs 62.7%). The number of sICH was 3 of 60 (5.0%) in the 0.1 mg/kg group, none in the 0.25 mg/kg group, 2 of 60 (3.3%) in the 0.32 mg/kg group and 1 (1.7%) of 59 in the rt-PA group. There were no significant between-group differences in severe adverse events. CONCLUSIONS: Similar to the Caucasians, rhTNK-tPA was well tolerated in Chinese patients with AIS at all doses administered within 3 hours of symptom onset. The dose-efficacy profile of rhTNK-tPA needs to be established with future investigations. TRIAL REGISTRATION NUMBER: NCT04676659.

4.
Stroke Vasc Neurol ; 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446531

RESUMO

BACKGROUND AND PURPOSE: Tenecteplase (TNK) is a promising agent for treatment of acute ischaemic stroke (AIS). We hypothesised that recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) is non-inferior to rt-PA in achieving excellent functional outcome at 90 days, when administered within 4.5 hours of ischaemic stroke onset. METHODS AND DESIGN: Tenecteplase Reperfusion therapy in Acute ischemic Cerebrovascular Events (TRACE) is a phase III, multicentre, prospective, randomised, open-label, blinded-end point non-inferiority study. Patients eligible for intravenous thrombolysis therapy are randomised to rhTNK-tPA 0.25 mg/kg (single bolus) to a maximum of 25 mg or rt-PA 0.9 mg/kg (10% bolus+90% infusion/1 hour) to a maximum of 90 mg. Medications considered necessary for the patient's health may be given at the discretion of the investigator during 90-day follow-up. STUDY OUTCOMES: The primary study outcome is excellent functional outcome defined as modified Rankin Scale (mRS) 0-1 at 90 days. Secondary efficacy outcomes include favourable functional outcome defined as mRS ≤2 at 90 days, ordinal distribution of mRS and major neurological improvement on the National Institutes of Health Stroke Scale. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours and death from any cause. DISCUSSION: There is no completed registration study of TNK in AIS worldwide. TRACE II strives to provide evidence for a new drug application for rhTNK-tPA in AIS within 4.5 hours through a well-designed and rigorously executed randomised trial in China. TRIAL REGISTRATION NUMBER: NCT04797013.

5.
Nat Commun ; 12(1): 3307, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083538

RESUMO

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Algoritmos , Benchmarking , Crowdsourcing , Bases de Dados de Produtos Farmacêuticos , Aprendizado Profundo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Aprendizado de Máquina , Modelos Biológicos , Modelos Químicos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Quinases/química , Proteômica , Análise de Regressão
6.
J Hazard Mater ; 416: 125820, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33887570

RESUMO

Commodity plastic is ubiquitous in daily life and commonly disposed of via unregulated burning, particularly in developing regions. We report here the much higher emission factors (13.1 ± 7.5 g/kg) and toxicities of inhalable aerosols emitted from the unregulated burning of plastic waste based on field measurements and cellular experiments, including oxidative stress and cytotoxic tests in A549 cells. Plastic foam burning emitted aerosols possesses the highest EFs (34.8 ± 4.5 g/kg) and toxicities, which are 4.2- to 13.4-fold and 1.1- to 2.7-fold higher than those emitted from the burning of other waste types. These quantified toxicities are mainly attributed to aerosols containing carbonaceous matter, especially persistent organic pollutants, including polycyclic aromatic hydrocarbons and dioxins, which originate from incomplete combustion processes. The aerosol emission amounts were estimated from the obtained experimental results. Approximately 70.2 million tons (29%) of plastic waste was burned without regulation worldwide in 2016, leading to 0.92 ± 0.53 million tons of toxic aerosols being released into the air, a majority of which occurred in developing regions. The results indicate improved combustion technology and control strategies are urgently needed in developing regions for discarded plastic -waste to mitigate toxic exposure risks and achieve sustainable development.


Assuntos
Poluentes Atmosféricos , Hidrocarbonetos Policíclicos Aromáticos , Aerossóis/análise , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Monitoramento Ambiental , Material Particulado/análise , Plásticos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/análise
7.
Signal Transduct Target Ther ; 6(1): 165, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895786

RESUMO

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Simulação por Computador , Reposicionamento de Medicamentos , Modelos Biológicos , SARS-CoV-2/metabolismo , Humanos
8.
Sci Total Environ ; 770: 145370, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33736376

RESUMO

Triple-layered thin film composite (TFC) forward osmosis (FO) membranes prepared on interlayer-based supports have overcome the limitations of conventional porous substrates due to the formation of ultrathin and highly selective polyamide (PA) layers. However, mitigating the internal concentration polarization (ICP) and biofouling of TFC membranes remain a great challenge. Herein, we designed a novel triple-layered thin film nanocomposite (TFN) FO membrane with incorporation of silver (Ag) decorated graphene oxide quantum dots (GOQD) into PA layer via interfacial polymerization on a carbon nanotube (CNT) interlayer-based polyether sulfone substrate. By contrast with the TFC membranes, the newly developed GOQD/Ag incorporated triple-layered TFN membrane (TFN-GOQD/Ag) exhibited a great alleviation for ICP accompanied with a prominently enhanced water flux of 65.8 L·m-2·h-1 and decreased specific reverse salt flux of 1.4 g·m-2·h-1 by employing 1 M NaCl solution as draw solution. Moreover, the TFN-GOQD/Ag membrane possessed prominent antibacterial activity against both E. coli (99.8%) and S. aureus (97.3%). Noteworthy, the obtained TFN membrane demonstrated a controlled release of Ag+ along with long-term antibacterial potential and outstanding fouling resistance during the FO process. This work provides a new avenue to fabricate newly FO membranes with superior performance for water cleaning treatment.


Assuntos
Nanocompostos , Água , Antibacterianos , Escherichia coli , Membranas Artificiais , Staphylococcus aureus
9.
PLoS Comput Biol ; 17(3): e1008842, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33770074

RESUMO

Translation elongation is regulated by a series of complicated mechanisms in both prokaryotes and eukaryotes. Although recent advance in ribosome profiling techniques has enabled one to capture the genome-wide ribosome footprints along transcripts at codon resolution, the regulatory codes of elongation dynamics are still not fully understood. Most of the existing computational approaches for modeling translation elongation from ribosome profiling data mainly focus on local contextual patterns, while ignoring the continuity of the elongation process and relations between ribosome densities of remote codons. Modeling the translation elongation process in full-length coding sequence (CDS) level has not been studied to the best of our knowledge. In this paper, we developed a deep learning based approach with a multi-input and multi-output framework, named RiboMIMO, for modeling the ribosome density distributions of full-length mRNA CDS regions. Through considering the underlying correlations in translation efficiency among neighboring and remote codons and extracting hidden features from the input full-length coding sequence, RiboMIMO can greatly outperform the state-of-the-art baseline approaches and accurately predict the ribosome density distributions along the whole mRNA CDS regions. In addition, RiboMIMO explores the contributions of individual input codons to the predictions of output ribosome densities, which thus can help reveal important biological factors influencing the translation elongation process. The analyses, based on our interpretable metric named codon impact score, not only identified several patterns consistent with the previously-published literatures, but also for the first time (to the best of our knowledge) revealed that the codons located at a long distance from the ribosomal A site may also have an association on the translation elongation rate. This finding of long-range impact on translation elongation velocity may shed new light on the regulatory mechanisms of protein synthesis. Overall, these results indicated that RiboMIMO can provide a useful tool for studying the regulation of translation elongation in the range of full-length CDS.


Assuntos
Biologia Computacional/métodos , Aprendizado Profundo , Modelos Genéticos , Elongação Traducional da Cadeia Peptídica/genética , Ribossomos , Códon/genética , Códon/metabolismo , Escherichia coli/genética , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/genética
11.
PLoS One ; 16(2): e0245993, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33621225

RESUMO

The water ecology of salt marshes plays a crucial role in climate regulation, industrial production, and flood control. Due to a poor understanding of water ecology and the extensive mining of salt resources, concerns are mounting about declining groundwater levels, shrinking salt marshes, and other problems associated with the simple yet extremely fragile water ecosystem of salt marshes in arid salt lake areas. This study assessed the ecological status of water resources in the downstream salt marsh area of West Taijinar Lake in the Qaidam Basin, China (2010-2018). Using data from a field investigation, the water ecosystem was divided into an ecological pressure subsystem, an environmental quality subsystem, and a socio-economic subsystem according to an analytic hierarchy process. Each subsystem was quantitatively assessed using the ecological footprint model, the single-factor index, and available data for the salt marsh area. The results showed that water resources were always in a surplus state during the study period, whose development and utilization had a safe status. Surface water had low plankton diversity with no evidence of eutrophication, but its Cl- and SO42- concentrations were too high for direct industrial water uses. Groundwater quality was classified into class V because of high salt concentrations, which could be considered for industrial use given the demand of industrial production. The socio-economic efficiency of water resources was high, as distinguished by decreased water consumption per 10,000 yuan GDP and excellent flood resistance. In conclusion, the ecological status of water resources was deemed good in the study area and this could help sustain regional development. However, since the water ecology in this area is mainly controlled by annual precipitation, it would be challenging to deal with the uneven distribution of precipitation and flood events and to make full use of them for groundwater recharge. This study provides insight into the impact of salt lake resource exploration on water ecology, and the results can be useful for the rational utilization of water resources in salt marshes in other arid areas.


Assuntos
Lagos , Sais , Recursos Hídricos/provisão & distribuição , Áreas Alagadas , China , Monitoramento Ambiental
12.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33526657

RESUMO

RNA polymerase II (Pol II) generally pauses at certain positions along gene bodies, thereby interrupting the transcription elongation process, which is often coupled with various important biological functions, such as precursor mRNA splicing and gene expression regulation. Characterizing the transcriptional elongation dynamics can thus help us understand many essential biological processes in eukaryotic cells. However, experimentally measuring Pol II elongation rates is generally time and resource consuming. We developed PEPMAN (polymerase II elongation pausing modeling through attention-based deep neural network), a deep learning-based model that accurately predicts Pol II pausing sites based on the native elongating transcript sequencing (NET-seq) data. Through fully taking advantage of the attention mechanism, PEPMAN is able to decipher important sequence features underlying Pol II pausing. More importantly, we demonstrated that the analyses of the PEPMAN-predicted results around various types of alternative splicing sites can provide useful clues into understanding the cotranscriptional splicing events. In addition, associating the PEPMAN prediction results with different epigenetic features can help reveal important factors related to the transcription elongation process. All these results demonstrated that PEPMAN can provide a useful and effective tool for modeling transcription elongation and understanding the related biological factors from available high-throughput sequencing data.


Assuntos
Genoma Humano , Aprendizado de Máquina , Modelos Biológicos , Elongação da Transcrição Genética , Sequência de Bases , Sítios de Ligação , Metilação de DNA/genética , Epigênese Genética , Células HEK293 , Células HeLa , Histonas/metabolismo , Humanos , Motivos de Nucleotídeos/genética , Processamento de Proteína Pós-Traducional , RNA Polimerase II/metabolismo , Sítios de Splice de RNA/genética , Splicing de RNA/genética
13.
Stroke ; 52(3): 772-780, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33588596

RESUMO

BACKGROUND AND PURPOSE: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS). METHODS: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization. RESULTS: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12-1.81]; P=0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49-3.43 versus 1.14, 0.85-1.52). CONCLUSIONS: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02430350.

14.
Adv Mater ; 33(3): e2006160, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33296121

RESUMO

Nanomedicines that target specific blood cells represent an emerging strategy to improve drug biodistribution. However, the protein corona usually disrupts nanomedicine targeting to cells and tissues. Herein, instead of exploring synthetic methods to mitigate the impact of the protein corona, its natural interactions with blood cells are leveraged and turn the protein corona into an active ingredient in treating lung inflammation. It is discovered that molecularly engineered liposomes with inverse phosphocholine lipids rapidly enrich complement fragment iC3b by "voluntary opsonization," which triggers neutrophil hijacking through complement receptor 3 phagocytosis. This neutrophil targeting is cell-state dependent as only those activated by acute inflammation display efficient neutrophil reconstruction. The liposome-loaded neutrophils migrate across the alveolar-capillary barrier, accumulate in the inflamed lung parenchyma within hours, and release their payloads to kill the bacteria. This work shows that, in addition to biological cells, the protein corona can be a new platform for active and precision nanomedicine.


Assuntos
Nanomedicina/métodos , Proteínas Opsonizantes/metabolismo , Medicina de Precisão/métodos , Engenharia , Inflamação/imunologia , Inflamação/terapia , Neutrófilos/imunologia , Receptores de Complemento/metabolismo
15.
Int J Nurs Stud ; 114: 103825, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33352438

RESUMO

BACKGROUND: Deep vein thrombosis represents a threat to public health and a heavy economic burden to society, and often occurs as a complication or cause of death in bedridden patients. How to prevent deep vein thrombosis is a general concern in clinical practice. However, it remains uncertain whether the risk factors for deep vein thrombosis would be affected by different bed-rest durations. Solving this issue will be invaluable for the provision of more rational medical care to prevent deep vein thrombosis. OBJECTIVE: To explore whether risk factors for deep vein thrombosis are affected by bed-rest durations and to identify different risk factors in groups with different bed-rest durations. DESIGN: A retrospective multicenter case-control study. SETTINGS AND PARTICIPANTS: This multicenter study was conducted in wards with high rates of bed rest in 25 general hospitals in China. Participants were bedridden patients from these wards. METHODS: Bedridden patients were identified from the research database of bedridden patients' major immobility complications. These data were collected from prospective descriptive studies by a standardized web-based online case report form. Cases were defined as bedridden patients who suffered deep vein thrombosis during hospitalization (n=186). Each case was matched with three controls, bedridden patients who did not suffer deep vein thrombosis in the same center with the same bed-rest duration (n=558). Descriptive statistics, univariate analysis, and multivariate conditional logistic regression models were employed. RESULTS: Among 23,985 patients, the overall incidence of deep vein thrombosis during hospitalization was 1.0%. Multivariate analysis showed that for patients with bed-rest duration of 4 weeks or less, older age (odds ratio [OR] =1.027, 95% confidence interval [CI] 1.013-1.041) and being in a surgical department (OR=2.527, 95% CI 1.541-4.144) were significantly associated with increased risk of deep vein thrombosis. Female sex (OR=4.270, 95% CI 1.227-14.862), smoking (OR=10.860, 95% CI 2.130-55.370), and special treatment (OR=3.455, 95% CI 1.006-11.869) were independent factors predicting deep vein thrombosis for patients with bed-rest durations from 5 to 8 weeks. For those with bed-rest durations from 9 to 13 weeks, Charlson Comorbidity Index (OR=1.612, 95% CI 1.090-2.385) was the only independent risk factor for deep vein thrombosis. CONCLUSIONS: Risk factors for deep vein thrombosis varied among patients with different bed-rest durations. This finding is helpful for nurses to increase their awareness of prevention of deep vein thrombosis in patients with different bed-rest durations, and lays a more solid foundation for clinical decision making.


Assuntos
Repouso em Cama , Trombose Venosa , Idoso , Repouso em Cama/efeitos adversos , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia
16.
Stroke Vasc Neurol ; 5(3): 270-278, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32792457

RESUMO

AIM: Cerebrovascular disease is the leading cause of death and disability in China, causing a huge burden among patients and their families. Hence, stroke prevention is critical, especially in the high-risk population. Here, we present the evidence-based guideline suitable for the Chinese population. METHODS: Literature search of PubMed and Cochrane library (from January 1964 to June 2019) was done. After thorough discussion among the writing group members, recommendations were listed and summarised. This guideline was reviewed and discussed by the fellow writing committees of the Chinese Stroke Association's Stroke. RESULTS: This evidence-based guideline was written in three parts: controlling the risk factors of stroke, utilisation of antiplatelet agents and assessing the risks of first-ever stroke. All recommendations were listed along with the recommending classes and levels of evidence. CONCLUSIONS: This guideline provides recommendations for primary prevention of cerebrovascular disease among high-risk population in China. Controlling related risk factors, appropriately using antiplatelet agents, assessing the risk of developing first-ever stroke should help reduce the rate of cerebrovascular disease in China.


Assuntos
Transtornos Cerebrovasculares/prevenção & controle , Medicina Baseada em Evidências/normas , Neurologia/normas , Inibidores da Agregação Plaquetária/uso terapêutico , Prevenção Primária/normas , Comportamento de Redução do Risco , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/epidemiologia , China/epidemiologia , Consenso , Avaliação da Deficiência , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Recuperação de Função Fisiológica , Medição de Risco , Fatores de Risco , Resultado do Tratamento
17.
ACS Appl Mater Interfaces ; 12(29): 32312-32320, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32578972

RESUMO

The surface hydrophilicity of nanoparticles has a major impact on their biological fates. Ascertaining the correlation between nanoparticle surface hydrophilicity and their biological behaviors is particularly instructive for future nanomedicine design and their antitumor efficacy optimization. Herein, we designed a series of polymeric nanoparticles based on polyphosphoesters with well-controlled surface hydrophilicity in the molecular level and systemically evaluated their biological behaviors. The results demonstrated that high surface hydrophilicity preferred lower protein absorption, better stability, longer blood circulation, and higher tumor accumulation but lower cellular uptake. Upon encapsulation of drugs, nanoparticles with high hydrophilicity showed an excellent antitumor therapeutic efficacy in both primary and metastatic tumors as compared to the relatively hydrophobic ones. Further analyses revealed that the superior antitumor outcome was attributed to the balance of tumor accumulation and cellular uptake, demonstrating the particular importance of nanoparticle surface hydrophilicity regulation on the antitumor efficacy. Our work provides a potent guideline for a rational designation on the surface hydrophilicity of nanoparticles for cancer treatment optimization.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Sistemas de Liberação de Medicamentos , Melanoma Experimental/tratamento farmacológico , Nanomedicina , Nanopartículas/química , Polifosfatos/química , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Docetaxel/química , Ensaios de Seleção de Medicamentos Antitumorais , Interações Hidrofóbicas e Hidrofílicas , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Tamanho da Partícula , Polifosfatos/síntese química , Propriedades de Superfície
18.
ACS Nano ; 14(7): 8459-8472, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32598139

RESUMO

The efficacy of nanoradiosensitizers in cancer therapy has been primarily impeded by their limited accessibility to radioresistant cancer cells residing deep inside tumor tissues. The failure to report tumor response to radiotherapy generally delays adjustment of the treatment schedule and sets up another substantial obstacle to clinical success. Here, we develop a nanopomegranate (RNP) platform that not only visualizes the cancer radiosensitivities but also potentiates deep tissue cancer radiotherapy via elevated passive diffusion and active transcytosis. The RNPs are engineered through the programmed self-assembly of a tumor environment-targeting polymeric matrix and modular building blocks of ultrasmall gold nanoparticles (Au5). Once RNPs reach the tumors, the environmental acidity triggers the splitting and surface cationization of Au5. The small dimension of Au5 allows its passive diffusion, while positive surface charge enables its active transcytosis to cross the tumor interstitium. Meanwhile, the reporter element monitors the feedback of favorable radiotherapy responsiveness by detecting the activated apoptosis after radiation. The pivotal role of RNPs in improving and identifying radiotherapeutic outcomes is demonstrated in various tumor bearing mouse models with different radiosensitivities. In summary, our strategy offers a promising paradigm for deep tissue drug delivery as well as individualized precision radiotherapy.


Assuntos
Nanopartículas Metálicas , Nanopartículas , Neoplasias , Animais , Sistemas de Liberação de Medicamentos , Ouro/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Transcitose
19.
Chemistry ; 26(57): 13031-13038, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-32428362

RESUMO

Theranostic agents, taking the advantages of both imaging and therapeutic functions, are anticipated to be key components in the development of personalized medicine in which the therapeutic response can be real-time monitored. Herein, three metallacycles with pendent adamantane groups are prepared by coordination-driven self-assembly of PtII ligands with anticancer activities and tetraphenylethylene derivatives with emission. ß-Cyclodextrin, which shows good host-guest interactions with adamantane moieties, was added to form amphiphilic supramolecular nanoparticles with the aim to enhance the aqueous solubilities and bioactivities of these metallacycles. Moreover, when rhodamine-modified ß-cyclodextrin was used as the carrier, the release of the metallacycles from the nanoparticles could be monitored in situ through the fluorescence changes owing to the efficient fluorescence resonance energy transfer from the metallacycles to rhodamine-modified ß-cyclodextrin. In vitro and in vivo studies showed that these nanoparticles not only served as cell imaging contrast agents but also displayed improved anticancer activities, allowing them to serve as potential candidates for cancer theranostics. This study provides a simple and efficient method to prepare theranostic agents by hierarchical supramolecular self-assembly, which will pave the way for image-guided cancer therapy, targeted cancer therapy, and related biomedical fields.


Assuntos
Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Medicina de Precisão , Rodaminas , beta-Ciclodextrinas
20.
Nat Commun ; 11(1): 1126, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111847

RESUMO

The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery.


Assuntos
Quimiotaxia de Leucócito , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Neoplasias/terapia , Neutrófilos/fisiologia , Fototerapia , Animais , Membrana Externa Bacteriana/química , Membrana Externa Bacteriana/imunologia , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/química , Cisplatino/farmacocinética , Liberação Controlada de Fármacos , Vesículas Extracelulares/química , Vesículas Extracelulares/imunologia , Imunoterapia Adotiva , Inflamação/etiologia , Camundongos , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ativação de Neutrófilo , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Padrões Moleculares Associados a Patógenos/imunologia , Fototerapia/efeitos adversos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
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