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1.
Anal Chem ; 93(40): 13734-13741, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34605236

RESUMO

Precisely detecting biomarkers in living systems holds tremendous promise for disease diagnosis and monitoring. Herein, we developed a covalent organic framework (COF)-based tricolor fluorescent nanoprobe for simultaneously imaging biomarkers with different spatial locations in living cells. Briefly, a TAMRA-labeled survivin mRNA antisense nucleotide and a Cy5-labeled transmembrane glycoprotein mucin 1 (MUC1) aptamer were adsorbed on a nanoscale fluorescent COF. To enhance the interactions between COF nanoparticles (NPs) and nucleic acid molecules, a freezing method was employed for improving the nucleic acid loading density and ensuring detection performance. The fluorescence signals of dyes on DNAs were first quenched by the COF NPs. Internalization and distribution of the nanoprobes can be real-time visualized by the autofluorescence of COF NPs. In living cells, recognition between MUC1 with MUC1 aptamers causes fluorescence signal recovery of Cy5, while hybridization between survivin mRNA and its antisense DNA induces the signal recovery of TAMRA. Therefore, this COF-based multicolor nanoprobe could be employed for visualizing MUC1 on the cell membrane and survivin mRNA in the cytoplasm. Cancer cell-specific diagnostic imaging and monitoring of the process of cancer cell exosomes infecting normal cells using the nanoprobe were achieved. This work not only offers a versatile nanoprobe for bioanalysis but also provides new insights for developing novel COF-based nanoprobes.

2.
Acta Otolaryngol ; : 1-6, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633897

RESUMO

BACKGROUND: The success rate of stapedotomy in otosclerosis patients with cochlea involvement was unknown. AIMS/OBJECTIVES: To determine the difference of surgical outcomes and symptomatology in otosclerosis patients with or without cochlea involvement on CT. MATERIAL AND METHODS: 79 otosclerosis patients were included and grouped by HRCT, including cochlear-involved otosclerosis (C-group) or non-cochlear-involved otosclerosis (NC-group, control group). Patients were defined as NC-group in the presence of normal or solely fenestral involvement, or C-group if the hypodensities involve other parts of the labyrinthine bone Patients in the control group were collected at a 2:1 ratio to the C-group with similar follow-up times. Detailed complaints and surgical outcomes were compared between these groups. RESULTS: Chief complaints were similar in the C-group and NC-group. Although postoperative AC, BC, and ABG decreased significantly in both groups, the success rate was significantly higher in C-group regarding the postoperative ABG ≤10 dB. Furthermore, diffuse lesions may indicate a more severe disease and a poorer prognosis. CONCLUSIONS AND SIGNIFICANCE: Stapedotomy was effective for clinical otosclerosis. The surgical outcome was inferior favorable for cochlea involvement patients, especially for cases with widely involvement. There was no difference in chief complaints among patients with different CT degree of otosclerosis.

3.
J Pediatr Orthop ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34608040

RESUMO

BACKGROUND: Progressive spinal deformity following laminectomy and resection surgery of spinal tumor has been well-documented. However, the postlaminectomy deformity in adolescent patients often bring challenge to clinical treatment, which may be subjected to rapid progression of kyphosis during the growth spurt. The aim of this study is to investigate the clinical outcome of long fusion correction surgery for thoracic or thoracolumbar kyphotic deformity secondary to laminectomy and tumor resection in adolescent patients. METHODS: Records of 12 cases underwent correction surgery of postlaminectomy thoracic (n=6) or thoracolumbar (n=6) kyphotic deformity were reviewed. The Cobb angle of sagittal and coronal curve before surgery, immediately after surgery, and at the final follow-up were measured to evaluate the correction of deformity and loss of correction. Neurological function was evaluated using the Frankel grading system. Back pain was assessed by using the visual analog score (VAS). Disability status was evaluated by the Oswestry Disability Index (ODI). Patients' satisfaction to surgery was assessed by the patient satisfactory index. RESULTS: The mean kyphosis angle reduced from 76±20 degrees before surgery to 34±18 degrees immediately after surgery and remained at 39±17 degrees at the final follow-up with the average correction rate of 58.6% and 51.0%, respectively. For 7 patients with concomitant scoliosis, the Cobb angle of major curve reduced from 52±21 degrees before surgery to 16±9 degrees immediately after surgery and 20±9 degrees at the final follow-up. The average corrective rate was 69.5% and 62.4%, respectively. The mean ODI score improved from 19.9±7.5 to 10.8±8.0, whereas the mean VAS score improved from 5.3±2.0 to 1.5±1.4. The sagittal and coronal balance of the spine, Frankel grading, ODI, and VAS were improved, and the patient satisfactory index was 100%. One patient had inferior paraplegia recovered to Frankel grade E after treatment. CONCLUSIONS: Satisfactory clinical outcomes can be achieved after long fusion surgery for thoracic or thoracolumbar kyphotic deformity secondary to laminectomy for spinal tumor. Due to the high risk of secondary kyphotic deformity in adolescent patients, internal fixation should be performed simultaneously with the resection of spinal tumor, especially for the cases in the thoracic or thoracolumbar region. LEVEL OF EVIDENCE: Level III.

4.
J Appl Toxicol ; 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34601724

RESUMO

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3 ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 µM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 µM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.

5.
Cell Rep ; 36(10): 109684, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34496245

RESUMO

Sensory cues that precede reward acquire predictive (expected value) and incentive (drive reward-seeking action) properties. Mesolimbic dopamine neurons' responses to sensory cues correlate with both expected value and reward-seeking action. This has led to the proposal that phasic dopamine responses may be sufficient to inform value-based decisions, elicit actions, and/or induce motivational states; however, causal tests are incomplete. Here, we show that direct dopamine neuron stimulation, both calibrated to physiological and greater intensities, at the time of reward can be sufficient to induce and maintain reward seeking (reinforcing) although replacement of a cue with stimulation is insufficient to induce reward seeking or act as an informative cue. Stimulation of descending cortical inputs, one synapse upstream, are sufficient for reinforcement and cues to future reward. Thus, physiological activation of mesolimbic dopamine neurons can be sufficient for reinforcing properties of reward without being sufficient for the predictive and incentive properties of cues.

6.
Cancer Commun (Lond) ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520132

RESUMO

BACKGROUND: DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. METHODS: Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. RESULTS: Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. CONCLUSIONS: We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

7.
Nano Lett ; 21(18): 7862-7869, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34494442

RESUMO

Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.


Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Glicólise , Morte Celular Imunogênica , Imunossupressão , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Pró-Fármacos/uso terapêutico
8.
Support Care Cancer ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34585301

RESUMO

PURPOSE: Family may play an important role in hematopoietic stem cell transplantation (HSCT) recovery; however, little is known about the effect of family functioning on an individual's health. The purpose of this study was to examine the effect of family cohesion (family functioning) on the trajectory of HSCT recipients' symptom distress (symptom frequency and symptom bother) before, during, and after HSCT. METHODS: Secondary analysis was conducted using data collected from178 individuals who underwent HSCT. Longitudinal parallel process (LPP) modeling was used to examine how family cohesion and HSCT-associated symptoms (symptom frequency and symptom bother) change over time, and how these longitudinal changes relate to each other. RESULTS: The trajectory of family cohesion predicted the trajectories of HSCT-associated symptom frequency and bother. HSCT recipients who experienced higher family cohesion at baseline (T1) showed lower symptom frequency (p < .01) as well as symptom bother (p < .01) at T1. This trajectory analysis also showed that HSCT recipients who had improved family cohesion over time reported decrease in symptom frequency (p < .01) as well as bother (p < .01) over time. CONCLUSION: Findings indicate that higher family cohesion predicts decrease in symptom distress over the HSCT trajectory. Interventions aimed at enhancing family cohesion have the potential to lower HSCT recipients' symptom distress. Further research is needed to understand the critical role of family cohesion and family functioning and their relationship with HSCT symptom distress prevention, early detection, and risk stratification.

9.
J Biol Chem ; 297(4): 101160, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34480896

RESUMO

Pheromone receptors (PRs) recognize specific pheromone compounds to guide the behavioral outputs of insects, which are the most diverse group of animals on earth. The activation of PRs is known to couple to the calcium permeability of their coreceptor (Orco) or putatively with G proteins; however, the underlying mechanisms of this process are not yet fully understood. Moreover, whether this transverse seven transmembrane domain (7TM)-containing receptor is able to couple to arrestin, a common effector for many conventional 7TM receptors, is unknown. Herein, using the PR BmOR3 from the silk moth Bombyx mori and its coreceptor BmOrco as a template, we revealed that an agonist-induced conformational change of BmOR3 was transmitted to BmOrco through transmembrane segment 7 from both receptors, resulting in the activation of BmOrco. Key interactions, including an ionic lock and a hydrophobic zipper, are essential in mediating the functional coupling between BmOR3 and BmOrco. BmOR3 also selectively coupled with Gi proteins, which was dispensable for BmOrco coupling. Moreover, we demonstrated that trans-7TM BmOR3 recruited arrestin in an agonist-dependent manner, which indicates an important role for BmOR3-BmOrco complex formation in ionotropic functions. Collectively, our study identified the coupling of G protein and arrestin to a prototype trans-7TM PR, BmOR3, and provided important mechanistic insights into the coupling of active PRs to their downstream effectors, including coreceptors, G proteins, and arrestin.

10.
Cancer Nurs ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34387237

RESUMO

BACKGROUND: Children undergoing treatment for acute lymphocytic leukemia (ALL) report co-occurring symptoms of fatigue, sleep disturbances, and depression as a symptom cluster. Physical activity (PA) may influence symptom severity and quality of life (QOL). OBJECTIVES: This study examined changes in symptoms and QOL during ALL maintenance in children categorized by symptom cluster and explored the influence of PA and symptoms on QOL. METHODS: Self-report of fatigue, sleep disturbance, and depression; QOL; and PA were measured at the beginning and end of maintenance in 42 children aged 3 to 18 years with ALL. Children were categorized into symptom cluster groups based on measurements at the beginning of maintenance. RESULTS: Two latent classes of symptom clusters (low and high) were identified with significant differences between groups in symptoms at both the beginning and end maintenance (P < .01). Each group's symptom levels did not change during maintenance. Quality-of-life was different between groups at both time points (P < .01) and did not improve. Children with low symptoms and high PA at the beginning of maintenance had better QOL as treatment ended compared with the physically active high-symptom group and the inactive high-symptom group (P < .01). CONCLUSIONS: Children with higher symptoms did not experience an improvement with time. Symptom and PA levels may influence QOL at the end of treatment. IMPLICATIONS FOR PRACTICE: Maintenance therapy is a long time (1.5 years) in a child's life. Symptom assessment is needed early in maintenance; interventions are needed for children with high levels.

11.
PLoS Comput Biol ; 17(8): e1009266, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34339418

RESUMO

It is of great interest and potential to discover causal relationships between pairs of exposures and outcomes using genetic variants as instrumental variables (IVs) to deal with hidden confounding in observational studies. Two most popular approaches are Mendelian randomization (MR), which usually use independent genetic variants/SNPs across the genome, and transcriptome-wide association studies (TWAS) (or their generalizations) using cis-SNPs local to a gene (or some genome-wide and likely dependent SNPs), as IVs. In spite of their many promising applications, both approaches face a major challenge: the validity of their causal conclusions depends on three critical assumptions on valid IVs, and more generally on other modeling assumptions, which however may not hold in practice. The most likely as well as challenging situation is due to the wide-spread horizontal pleiotropy, leading to two of the three IV assumptions being violated and thus to biased statistical inference. More generally, we'd like to conduct a goodness-of-fit (GOF) test to check the model being used. Although some methods have been proposed as being robust to various degrees to the violation of some modeling assumptions, they often give different and even conflicting results due to their own modeling assumptions and possibly lower statistical efficiency, imposing difficulties to the practitioner in choosing and interpreting varying results across different methods. Hence, it would help to directly test whether any assumption is violated or not. In particular, there is a lack of such tests for TWAS. We propose a new and general GOF test, called TEDE (TEsting Direct Effects), applicable to both correlated and independent SNPs/IVs (as commonly used in TWAS and MR respectively). Through simulation studies and real data examples, we demonstrate high statistical power and advantages of our new method, while confirming the frequent violation of modeling (including valid IV) assumptions in practice and thus the importance of model checking by applying such a test in MR/TWAS analysis.

12.
Opt Lett ; 46(16): 3933-3936, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34388778

RESUMO

A novel temperature-insensitive optical curvature sensor has been proposed and demonstrated. The sensor is fabricated by inscribing fiber Bragg gratings with short lengths into a piece of strongly coupled multicore fiber (SCMCF) and spliced to the conventional single-mode fiber. Due to the two supermodes being supported by the SCMCF, two resonance peaks, along with a deep notch between them, were observed in the reflection spectrum. The experimental results show that the depth of the notch changes with the curvature with a sensitivity up to 15.9dB/m-1 in a lower curvature range. Besides, thanks to the unique property of the proposed sensor, the notch depth barely changes with temperature. Based on the intensity demodulation of the notch depth, the temperature-insensitive curvature sensor is achieved with the cross sensitivity between the temperature, and the curvature is as low as 0.001m-1/∘C.

13.
J Behav Med ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34406549

RESUMO

The desire to engage in waterpipe tobacco smoking (WTS) may occur when smokers and nonsmokers conjure positive mental simulations of WTS. However, effects of these simulations on desire to smoke waterpipe tobacco and potential mediators are unexplored. This research addressed these effects among young adult waterpipe tobacco smokers and nonsmokers. Two online studies were conducted with adults ages 18-30. In Study 1, 200 smokers, 190 susceptible nonsmokers, and 182 nonsusceptible nonsmokers were randomized to mentally simulate or not WTS in the future. In Study 2, 234 smokers and 241 susceptible nonsmokers were randomized to four arms: no simulation or simulations that varied valence of experience (positive, negative or no valence provided). Main outcomes were immediate desire to smoke waterpipe tobacco, cognitive and affective attitudes, and perceived harms. In Study 1, mental simulations increased the desire to smoke waterpipe tobacco among smokers. In Study 2, asking participants to simulate WTS positively or with no valence instruction increased desire to smoke relative to negative valence instruction or no simulation. Negative simulations reduced perceived probability of smoking within a month compared to positive simulations. Effects on desire to engage in WTS were mediated by cognitive and affective attitudes among susceptible nonsmokers and by cognitive attitudes among smokers. These findings suggest that exploring when and how often mental simulations about WTS are evoked and their potency for promoting prevention and cessation of WTS merit further attention.

14.
Int Immunopharmacol ; 99: 108046, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34435581

RESUMO

Activation of the NLRP3 inflammasome promotes pathological cardiac remodeling induced by pressure overload. However, the therapeutic effects of NLRP3 inhibition after cardiac remodeling remain unknown. The present study aimed to investigate whether the selective NLRP3 inhibitor, MCC950, could reverse transverse aortic constriction (TAC)-induced cardiac remodeling. Mice were divided into four groups based on the treatment given: sham, sham + MCC950, TAC, and TAC + MCC950. MCC950 (10 mg/kg, intraperitoneal injection, once per day) was administered from two weeks after TAC or sham surgery for four weeks. Echocardiography, histological analysis, RT-PCR, and Western blotting were performed to explore the function of MCC950 after TAC. We found that MCC950 reversed cardiac dysfunction after TAC. MCC950 attenuated cardiac hypertrophy by down-regulating calcineurin expression and inhibiting MAPK activation. Further, it also alleviated cardiac fibrosis post-TAC by inhibiting the TGF-ß/Smad4 pathway, and reduced cardiac inflammation and macrophage infiltration post-TAC, including both M1 and M2 macrophages. Taken together, MCC950 can attenuate cardiac remodeling due to pressure overload by inhibiting hypertrophy, fibrosis, and inflammation. Our study provides a basis for the clinical application of NLRP3 inhibitors in the treatment of non-ischemic heart failure.

15.
Anal Chem ; 93(35): 11899-11909, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34427091

RESUMO

Timely diagnosis is of great benefit to improve the survival rate of cancer patients. Body fluid cancer biomarker detection is a critical kind of noninvasive method for cancer diagnosis. Nevertheless, traditional methods for cancer biomarker detection always rely on a large-scale instrument and involve sophisticated operation. Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas)-based in vitro diagnosis can simplify the detection procedures and improve sensitivity and specificity, holding great promise as the next-generation molecular diagnostic technology. In this Feature, we introduce the working mechanisms of different kinds of CRISPR/Cas systems for biosensing and CRISPR/Cas-mediated detection strategies for different kinds of cancer biomarkers including nucleic acids, proteins, and extracellular vesicles. In addition, the perspective and challenges of CRISPR/Cas-based strategies for cancer biomarkers are discussed.


Assuntos
Neoplasias , Ácidos Nucleicos , Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas/genética , Humanos , Neoplasias/diagnóstico , Neoplasias/genética
16.
Dalton Trans ; 50(32): 11249-11258, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34341816

RESUMO

Promoting the separation of photogenerated electron-hole pairs and enhancing the charge carrier transfer are critical in photocatalysis. In our work, a ball-flower-like NiS/Zn3In2S6/g-C3N4 photocatalyst fabricated by a hydrothermal method exhibited superior performance for photocatalytic water splitting. The optimized 2.0% NiS/Zn3In2S6/g-C3N4 rivaled noble metal based Pt/g-C3N4 and showed an apparent quantum efficiency (AQE) of 24.3% at 420 nm, with a H2 yield of 4.135 mmol g-1 h-1, which was 30.4 and 9.51 times that of pure g-C3N4 and binary Zn3In2S6/g-C3N4 composites, respectively. The experimental and characterization results suggested that the heterojunction formed between Zn3In2S6/g-C3N4 and the decorating NiS co-catalyst cooperatively suppressed the electron-hole recombination and facilitated the charge carrier transfer, thus resulting in significant improvement of the H2 evolution performance. Moreover, the increased specific surface area and the enhanced visible-light absorption also contributed to superior water splitting performance. The prepared ternary catalytic system with the heterojunction and non-noble metal co-catalyst has great potential as an alternative to noble metals for achieving cost-efficient water splitting systems.

17.
Anal Chem ; 93(34): 11751-11757, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34398599

RESUMO

Developing nanoplatforms that simultaneously integrate diagnostic imaging and therapy functions has been a promising but challenging task for cancer theranostics. Herein, we report the rational design of a smart nucleic acid-gated covalent organic framework (COF) nanosystem for cancer-specific imaging and microenvironment-responsive drug release. Cy5 dye-labeled single-stranded DNA (ssDNA) for mRNA recognition was adsorbed on the surface of doxorubicin (Dox)-loaded COF nanoparticles (NPs). Dox loaded in the pores of COF NPs could strengthen the interactions between ssDNA and COF and enhance the fluorescence quenching effect toward Cy5, while the densely coated ssDNA could prevent the leakage of Dox from COF NPs. The obtained nanosystem exhibited low fluorescence signal and Dox release in normal cells; however, the ssDNA could be released by the overexpressed TK1 mRNA in cancer cells to recover the intense fluorescence signal of Cy5, and the loaded Dox could be further released for chemotherapy. Therefore, cancer cell-specific diagnostic imaging and drug release were realized with the rationally developed nanosystem. This work offers a universal nanoplatform for cancer theranostics and a promising strategy for regulating the interaction between COFs and biomolecules.


Assuntos
Estruturas Metalorgânicas , Nanopartículas , Neoplasias , Ácidos Nucleicos , Diagnóstico por Imagem , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
18.
Theranostics ; 11(16): 7869-7878, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335969

RESUMO

Goals: Chemotherapy, the most conventional modality for cancer therapy, usually brings serious side effects because of the low cancer-therapeutic specificity and bioavailability. It is of great significance for cancer treatment to develop new effective strategies to regulate biochemical reactions in organelles, enhance the specificity of chemotherapeutic drugs and reduce their side effects. Methods: We report herein a zeolitic imidazole framework-90 (ZIF-90) based nanoplatform, which was used to initiate a series of mitochondrial cascade reactions using ATP as a molecular switch for cancer therapy. The thioketal linked camptothecin (camptothecin prodrug, TK-CPT) and 2-Methoxyestradiol (2-ME) were encapsulated into the pores of ZIF-90 nanoparticles using a simple one-pot method, and the nanoplatform was finally coated with a layer of homologous cell membrane. Results: Mitochondrial ATP can efficiently degrade ZIF-90 and then release the loaded 2-ME and CPT prodrugs. 2-ME can inhibit the activity of superoxide dismutase (SOD), which induces the up-regulation of reactive oxygen species (ROS) in situ. The thioketal linkers in CPT prodrug can respond to ROS, thereby achieving subsequent release of parent CPT drug. This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis, due to the increased ROS level and the liberation of CPT. Conclusion: We constructed an ATP-triggered strategy using nanoscale ZIF-90 to initiate mitochondrial cascade reactions for cancer therapy. The ZIF-90 based nanoplatform exhibited low cytotoxicity, good mitochondria-targeting ability, and excellent therapeutic effect. In vivo experiments demonstrated that the growth of tumor can be efficiently inhibited in a mouse model. This ATP-triggered strategy to induce mitochondrial biochemical reactions offers more possibilities for developing organelle-targeted therapeutic platforms.


Assuntos
Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Zeolitas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , China , Liberação Controlada de Fármacos/fisiologia , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Camundongos , Mitocôndrias/metabolismo , Nanopartículas/administração & dosagem , Neoplasias/metabolismo , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Zeolitas/metabolismo , Zeolitas/farmacologia
19.
BMC Infect Dis ; 21(1): 752, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348685

RESUMO

BACKGROUND: Moistening of surgical instruments affects the quality of instrument cleaning, thereby affecting the degree of cross-contamination and in-hospital infection among patients. Surgical instruments should be kept moist immediately after use in order to avoid concentrations of contamination remaining on surgical instrument surfaces. Implementation and pass rates of surgical instrument moistening have been rarely studied. We aimed to investigate the factors affecting implementation and pass rates of surgical instrument moistening. METHODS: A cross-sectional study was conducted to investigate surgical instrument moistening procedures within 22 clinical departments of the West China Second University Hospital, Sichuan University over 122 days between September and December 2019. We collected data from departmental staff using an interviewer-administrated questionnaire. Data about implementation and pass rates of surgical instrument moistening was analyzed in SPSS20.0. RESULTS: Implementation and pass rates of surgical instrument moistening were 57.25% and 31.98%, respectively. Factor analysis showed that implementation rates of moistening were affected by instrument structure (X2 = 143.670; P = 0.001), the number of instruments inside the pack (X2 = 140.135; P = 0.001), and the person responsible for keeping surgical instruments moist (X2 = 8.052; P = 0.005). Correlation analysis showed that instrument structure and the number of instruments inside the pack were negatively correlated with implementation rates of moistening. The more complex the structure and the greater the number of the instruments inside the pack, the lower implementation rates of moistening. CONCLUSION: Implementation and pass rates of surgical instrument moistening were low, and failed to meet the central sterile supply department applicable industrial standard, hence the potential risk of hospital-acquired infection was considerable. Staff that manipulate reusable surgical instruments should be trained to properly moisten the instruments and institutional protocols should be established to ensure standardization and respect of guidelines.


Assuntos
Infecção Hospitalar , Esterilização , China , Estudos Transversais , Humanos , Instrumentos Cirúrgicos
20.
J Pharm Pharmacol ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343333

RESUMO

OBJECTIVES: Investigate if azilsartan protects against myocardial hypertrophy by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated pathways. METHODS: Abdominal aortic constriction (AAC)-induced cardiac hypertrophy in rats was applied. Azilsartan or vehicle was administered daily for 6 weeks in sham or AAC rats. Cardiac morphology and ventricular function were determined. Azilsartan effects upon neonatal rat cardiomyocyte (NRCM) hypertrophy and molecular mechanisms were studied in angiotensin (Ang) II-stimulated NRCMs in vitro. Nrf2-small interfering RNA (siRNA) was used to knockdown Nrf2 expression. Messenger RNA (mRNA)/protein expression of Kelch-like erythroid cell-derived protein (Keap)1 and Nrf2 and its downstream antioxidant enzymes was determined by real-time reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. KEY FINDINGS: Azilsartan treatment ameliorated cardiac hypertrophy/fibrosis significantly in AAC rats. Azilsartan increased expression of Nrf2 protein but decreased expression of Keap1 protein. Upregulation of protein expression of Nrf2's downstream antioxidant enzymes by azilsartan treatment was observed. Azilsartan inhibited Ang II-induced NRCM hypertrophy significantly and similar effects on the Keap1-Nrf2 pathway were observed in vivo. Nrf2 knockdown markedly counteracted the beneficial effects of azilsartan on NRCM hypertrophy and the Keap1-Nrf2 pathway. CONCLUSIONS: Azilsartan restrained pressure overload-induced cardiac remodelling by activating the Keap1-Nrf2 pathway and increasing expression of downstream antioxidant enzymes to alleviate oxidative stress.

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