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1.
Insects ; 12(3)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807543

RESUMO

The insecticidal Cry4Ba and Cry11Aa crystal proteins from Bacillus thuringiensis subsp. israelensis (Bti) are highly toxic to Ae. aegypti larvae. The glycosylphosphatidylinositol (GPI)-anchored APN was identified as an important membrane-bound receptor for multiple Cry toxins in numerous Lepidoptera, Coleoptera, and Diptera insects. However, there is no direct molecular evidence to link APN of Ae. aegypti to Bti toxicity in vivo. In this study, two Cry4Ba/Cry11Aa-binding Ae. aegypti GPI-APN isoforms (AeAPN1 and AeAPN2) were individually knocked-out using CRISPR/Cas9 mutagenesis, and the AeAPN1/AeAPN2 double-mutant homozygous strain was generated using the reverse genetics approach. ELISA assays showed that the high binding affinity of Cry4Ba and Cry11Aa protoxins to the midgut brush border membrane vesicles (BBMVs) from these APN knockouts was similar to the background from the wild-type (WT) strain. Likewise, the bioassay results showed that neither the single knockout of AeAPN1 or AeAPN2, nor the simultaneous disruption of AeAPN1 and AeAPN2 resulted in significant changes in susceptibility of Ae. aegypti larvae to Cry4Ba and Cry11Aa toxins. Accordingly, our results suggest that AeAPN1 and AeAPN2 may not mediate Bti Cry4Ba and Cry11Aa toxicity in Ae. aegypti larvae as their binding proteins.

2.
Eur Urol ; 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33824031

RESUMO

CONTEXT: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations. OBJECTIVE: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC. EVIDENCE ACQUISITION: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner. EVIDENCE SYNTHESIS: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps. CONCLUSIONS: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons. PATIENT SUMMARY: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.

3.
Mikrochim Acta ; 188(5): 153, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821319

RESUMO

A novel oxygen-doped g-C3N4 nanoplate (OCNP) structure that can serve as an efficient sulfadimethoxine (SDM) sensing platform has been developed. Taking advantage of its inherent oxygen-containing functional groups and 2D layered structure with π-conjugated system, OCNP exhibits effective radiative recombination of surface-confined electron-hole pairs and efficient π-π interaction with SDM. This causes rapid fluorescence response and thus ensures the fast and continuous monitoring of SDM. Based on the fluorescence experiments and band structure calculation, the mechanism of the SDM-induced quenching phenomenon was mainly elucidated as the photoinduced electron transfer process under a dynamic quenching mode. Under optimized conditions, the as-proposed nanosensor, which emitted strong fluorescence at 375 nm with an excitation wavelength at 255 nm, presents an excellent analytical performance toward SDM with a wide linear range from 3 to 60 µmol L-1 and a detection limit of 0.85 µmol L-1 (S/N = 3). In addition, this strategy exhibits satisfactory recovery varied from 94 to 103% with relative standard derivations (RSD) in the range 0.9 to 6.8% in real water samples. It also shows marked tolerability to a series of high concentrations of metals and inorganic salts. This strategy not only broadens the application of oxygen-doped g-C3N4 nanomaterial in antibiotic sensing field but also presents a promising potential for on-line contaminant tracing in complex environments.

4.
Huan Jing Ke Xue ; 42(2): 917-924, 2021 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742887

RESUMO

A pot-based planting experiment of Chinese brassica was carried out to study the influence of the compound modifier FZB (iron sulfate+zeolite+modified biochar) on the physical and chemical properties of soil, As and Cd bioavailability and morphology, and the ability of Chinese brassica to accumulate As and Cd at different dosages. The results showed that, after application of FZB, the pH, OM, and CEC contents of the rhizosphere soil tended to increase in As and Cd compound contaminated farmland soils. The concentrations of available As and available Cd in the soil gradually reduced with an increase in FZB application, with maximum reductions of 65.99% and 30.68%, respectively. The application of FZB significantly changed the morphology of heavy metals in the soil, which consequently decreased the exchangeable concentrations of As and Cd, while the concentrations of aluminum-bound As, iron-bound As, organic bound Cd, and residual Cd increased. At the same time, the application of FZB effectively reduced the concentrations of As and Cd in the roots and aerial parts of Chinese brassica. When 8 g·kg-1 of FZB was applied, compared with the control group, the concentrations of As and Cd in the aerial parts of Chinese brassica were reduced by 42.09% and 31.34%, respectively. FZB application decreased the As and Cd bioaccumulation capacity of the roots and aerial parts, and decreased the capacity of the plant to translocate As from the roots to the aerial parts. The study shows that the composite modifier FZB has good application prospects for reducing the bioavailability of As and Cd in farmland soils.

5.
Cancer Lett ; 506: 23-34, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33652085

RESUMO

The AP-1 member Fra-1 is overexpressed in TNBC and plays crucial roles in tumor progression and treatment resistance. In a previous large-scale screen, we identified PARP1 to be among 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells. PARP1 inhibitor (olaparib) is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that the Fra-1-PARP1 interaction impacts the efficacy of olaparib treatment. We show that PARP1 interacts with and downregulates Fra-1, thereby reducing AP-1 transcriptional activity. Olaparib treatment, or silencing of PARP1, consequently, increases Fra-1 levels and enhances its transcriptional activity. Increased Fra-1 can have adverse effect, including treatment resistance. We also found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We show that by inhibiting Fra-1/AP-1, non-BRCA-mutated TNBC cells can become sensitized to olaparib treatment. We identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall (P = 0.01), but not for HER-2 positive patients. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a combinatory therapeutic approach to improve olaparib treatment outcome for TNBC patients.

6.
Sci Total Environ ; 780: 146483, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33773344

RESUMO

Environment pollution is getting serious and various poisonous contaminants with chemical durability, biotoxicity and bioaccumulation have been widespreadly discovered in municipal wastewaters and surface water. The detection and removal of pollutants show great significance for the protection of human health and other organisms. Due to its distinctive physical and chemical properties, perylene diimide (PDI) has received widespread attention from different research fields, especially in the area of environment. In this review, a comprehensive summary of the development of PDI-based materials in fluorescence detection and advanced oxidation technology for environment was introduced. Firstly, we chiefly presented the recent progress about the synthesis of PDI and PDI-based nanomaterials. Then, their application in fluorescence detection for environment was presented and categorized, principally including the detection of heavy metal ions, harmful anions and organic contaminants in the environment. In addition, the application of PDI and PDI-based materials in different advanced oxidation technologies for environment, such as photocatalysis, photoelectrocatalysis, Fenton and Fenton-like reaction and persulfate activation, was also summarized. At last, the challenges and future prospects of PDI-based materials in environmental applications were discussed. This review focuses on presenting the practical applications of PDI and PDI-based materials as fluorescent probes or catalysts (especially photocatalysts) in the detection of hazardous substances or catalytic elimination of organic contaminants. The contents are aimed at supplying the researchers with a deeper understanding of PDI and PDI-based materials and encouraging their further development in environmental applications.

7.
Infect Dis Poverty ; 10(1): 24, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676581

RESUMO

BACKGROUND: Antituberculosis-drug resistance is an important public health issue, and its epidemiological patterns has dramatically changed in recent decades. This study aimed to estimate the trends of multidrug-resistant tuberculosis (MDR-TB), which can be used to inform health strategies. METHODS: Data were collected from the Global Burden of Disease study 2017. The estimated annual percentage changes (EAPCs) were calculated to assess the trends of MDR-TB burden at global, regional, and national level from 1990 to 2017 using the linear regression model. RESULTS: Globally, the age-standardized rate (ASR) of MDR-TB burden including incidence, prevalence, death and disability-adjusted life years (DALYs) had pronounced increasing trends from 1990 to 1999, with the EAPCs were 17.63 [95% confidence interval (CI): 10.77-24.92], 17.57 (95% CI 11.51-23.95), 21.21 (95% CI 15.96-26.69), and 21.90 (95% CI 16.55-27.50), respectively. Particularly, the largest increasing trends were seen in areas and countries with low and low-middle sociodemographic index (SDI). However, the trends in incidence, prevalence, death and DALYs of MDR-TB decreased globally from 2000 to 2017, with the respective EAPCs were - 1.37 (95% CI - 1.62 to - 1.12), - 1.32 (95% CI - 1.38 to - 1.26), - 3.30 (95% CI - 3.56 to - 3.04) and - 3.32 (95% CI - 3.59 to - 3.06). Decreasing trends of MDR-TB were observed in most regions and countries, particularly that of death and DALYs in Slovenia were - 18.96 (95% CI - 20.82 to - 17.06) and -19.35 (95% CI - 21.10 to - 17.55), respectively. Whereas the pronounced increasing trends of MDR-TB occurred in Papua New Guinea, Singapore, and Australia. CONCLUSIONS: The ASR of MDR-TB showed pronounced decreasing trends from 2000 to 2017. However, the MDR-TB burden remains a substantial challenge to the TB control globally, and requires effective control strategies and healthcare systems.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33655479

RESUMO

Models that evaluate the potential geographic distribution of species can be used with a variety of important applications in conservation biology. Osmanthus fragrans has high ornamental, culinary, and medicinal value, and is widely used in landscaping. However, its preferred habitat and the environmental factors that determine its distribution remain largely unknown; the environmental factors that shape its suitability also require analysis. Based on 89 occurrence records and 30 environmental variables, this study constructed Maxent models for current as well as future appropriate habitats for O. fragrans. The results indicate that UV-B seasonality (19.1%), precipitation seasonality (18.8%), annual temperature range (13.1%), and mean diurnal temperature range (12.5%) were the most important factors used for interpreting the environmental demands for this species. Highly appropriate habitats for O. fragrans were mainly distributed in southwestern Jiangsu, southern Anhui, Shanghai, Zhejiang, Fujian, northern Guangdong, Guangxi, southern Hunan, southern Hubei, Sichuan, and Taiwan. Under climate change scenarios, the spatial extent of the area of suitable distribution will decrease, and the distribution center of O. fragrans will shift to the southwest. The results of this study will help land managers to avoid blindly introducing this species into inappropriate habitat while improving O. fragrans yield and quality.

9.
Stem Cell Res Ther ; 12(1): 156, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648583

RESUMO

BACKGROUND: Age-associated lung tissue degeneration is a risk factor for lung injury and exacerbated lung disease. It is also the main risk factor for chronic lung diseases (such as COPD, idiopathic pulmonary fibrosis, cancer, among others). So, it is particularly important to find new anti-aging treatments. METHODS: We systematically screened and evaluated elderly senile multiple organ dysfunction macaque models to determine whether BMMSCs inhibited lung tissue degeneration. RESULTS: The average alveolar area, mean linear intercept (MLI), and fibrosis area in the elderly macaque models were significantly larger than in young rhesus monkeys (p < 0.05), while the capillary density around the alveoli was significantly low than in young macaque models (p < 0.05). Intravenous infusion of BMMSCs reduced the degree of pulmonary fibrosis, increased the density of capillaries around the alveoli (p < 0.05), and the number of type II alveolar epithelium in elderly macaques (p < 0.05). In addition, the infusion reduced lung tissue ROS levels, systemic and lung tissue inflammatory levels, and Treg cell ratio in elderly macaque models (p < 0.05). Indirect co-cultivation revealed that BMMSCs suppressed the expression of senescence-associated genes, ROS levels, apoptosis rate of aging type II alveolar epithelial cells (A549 cells), and enhanced their proliferation (p < 0.05). CONCLUSIONS: BMMSC treatment inhibited age-associated lung tissue degeneration.

10.
Pharmacol Res ; 167: 105563, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33746053

RESUMO

Macrophages are heterogeneous cells that have different physiological functions, such as chemotaxis, phagocytosis, endocytosis, and secretion of various factors. All physiological functions of macrophages are integral to homeostasis, immune defense and tissue repair. However, in several diseases, macrophages are recruited from the blood towards inflammatory sites. This process is called macrophage migration, which promotes deleterious disease progression. Macrophage migration is a key player in many inflammatory diseases, autoimmune diseases and cancers because it contributes to the accumulation of proinflammatory factors, the destruction of tissues and the development of tumors. Therefore, macrophage migration is proposed to be a potential therapeutic target. Macrophages migrate between two-dimensional (2D) and three-dimensional (3D) environments, implying that distinct migratory features and mechanisms are involved. Compared with the 2D migration of macrophages, 3D migration involves more complex variations in cellular morphology and dynamics. The structure of the extracellular matrix, a key factor, is modified in diseases that influence macrophage 3D migration. Macrophage 3D migration relates to disease pathology. Research that focuses on macrophage 3D migration is an emerging field and was reviewed in this article to indicate the molecular and cellular mechanisms of macrophage migration in 3D environments and to provide potential targets for controlling disease progression associated with this migration.

11.
Chemosphere ; 274: 129798, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33540314

RESUMO

The extracellular polymeric substances (EPS) of activated sludge are a mixture of high molecular weight polymers secreted by microorganisms, which are mainly composed of proteins, polysaccharides and humic substances. It is widely accepted that EPS have a good adsorption ability for pollutants with different functional groups. However, recent studies showed the EPS had an inhibitory effect on pollutant sorption, which is contradictory to previous viewpoint. Therefore, in this study, three types of activated sludge with different EPS contents and compositions were used to investigate the role of EPS in an antibiotic-trimethoprim (TMP) sorption process at environmentally relevant concentration. The in situ experiments results showed the adsorption capacity of activated sludge for TMP were increased from 2.98, 5.37 and 28.33 µg/g VSS to 7.87, 12.93 and 150.24 µg/g VSS in nitrifying activated sludge, wastewater treatment plant activated sludge and anaerobic ammonia-oxidized activated sludge, respectively after EPS extracted. The adsorption process can be well described by the pseudo-second-order kinetic model. Results of zeta potential, contact angles and infrared spectrum showed TMP replacing proteins embedded into the cell membrane enhancing the TMP adsorption capacity of activated sludge after EPS extraction. Our results demonstrated that less proteins in EPS of activated sludge is more beneficial for TMP adsorption removal.

12.
Sci Total Environ ; 774: 145585, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-33607432

RESUMO

Bioaccessibility/bioavailability (bioac-bioav) is an important criterion in the risk assessment of polycyclic aromatic hydrocarbons (PAHs), especially in the restoration of contaminated sites. Although, the bioac-bioav concept is widely employed in PAH risk assessment for both humans and wildlife, their growth and integration in risk assessment models are seldom discussed. Consequently, the relevant literature listed on Web of Science (WOS)™ was retrieved and analyzed using the bibliometric software Citespace in order to gain a comprehensive understanding of this issue. Due to the limitations of the literature search software, we manually searched the articles about PAHs bioac-bioav that were published before 2000. This stage focuses on research on the distribution coefficient of PAHs between different environmental phases and laid the foundation for the adsorption-desorption of PAHs in subsequent studies of the bioac-bioav of PAHs. The research progress on PAH bioac-bioav from 2000 to the present was evaluated using the Citespace software based on country- and discipline-wise publication volumes and research hotspots. The development stages of PAH bioac-bioav after 2000 were divided into four time segments. The first three segments (2000-2005, 2006-2010, and 2011-2015) focused on the degradation of PAHs and their in vivo (bioavailability)-in vitro (bioaccessibility) evaluation method and risk assessment. Meanwhile, the current (2016-present) research focuses on the establishment of analytical methods for assessing PAH derivatives at environmental concentrations and the optimization of various in vitro digestion methods, including chemical optimization (sorptive sink) and biological optimization (Caco-2 cell). The contents are aimed at supplying researchers with a deeper understanding of the development of PAH bioac-bioav.

13.
J Environ Sci (China) ; 102: 159-169, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33637241

RESUMO

Nitrated polycyclic aromatic hydrocarbons (NPAHs) have toxic potentials that are higher than those of their corresponding parent polycyclic aromatic hydrocarbons (PAHs) and thus have received increasing attention in recent years. In this study, the occurrence, distribution, source, and human health risk assessment of 15 NPAHs and 16 PAHs were investigated in the surface water from 20 sampling sites of Lake Taihu during the dry, normal, and flood seasons of 2018. The ΣPAH concentrations ranged from 255 to 7298 ng/L and the ΣNPAH concentrations ranged from not-detected (ND) to 212 ng/L. Among the target analytes, 2-nitrofluorene (2-nFlu) was the predominant NPAH, with a detection frequency ranging from 85% to 90% and a maximum concentration of 56.2 ng/L. The three-ringed and four-ringed NPAHs and PAHs comprised the majority of the detected compounds. In terms of seasonal variation, the highest levels of the ΣNPAHs and ΣPAHs were in the dry season and flood season, respectively. Diagnostic ratio analysis indicated that the prime source of NPAHs was direct combustion, whereas in the case of PAHs the contribution was predominantly from a mixed pattern including pollution from unburned petroleum and petroleum combustion. The human health risk of NPAHs and PAHs was evaluated using a lifetime carcinogenic risk assessment model. The carcinogenic risk level of the targets ranged from 2.09 × 10-7 to 5.75 × 10-5 and some surface water samples posed a potential health risk.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , China , Monitoramento Ambiental , Humanos , Lagos , Nitratos , Hidrocarbonetos Policíclicos Aromáticos/análise , Medição de Risco , Água , Poluentes Químicos da Água/análise
14.
Environ Pollut ; 277: 116767, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33640823

RESUMO

Microplastics, as emerging pollutant, are predicted to act as carriers for organic pollutants, but the carrier role and bio-toxic effects with other pollutants in environments are poorly acknowledged. In this study, both the single and combined effects of polyethylene (PE, 10 and 40 mg/L) with the particle size of 100-150 µm and 9-Nitroanthracene (9-NAnt, 5 and 500 µg/L) on zebrafish (Danio rerio) had been investigated. The results illustrated that PE could be as 9-NAnt carrier to enter into zebrafish body, but significantly reduced the bioaccumulation of 9-NAnt, due to the occurrence of adsorption interactions between the simultaneous presence of both PE and 9-NAnt. After 4 days, the enzymes activity of cytochrome P4501A, acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH), and the abundance of malondialdehyde (MDA), lipid peroxide (LPO) responded strongly to low-dose PE exposure (10 mg/L). After 7 days exposure to PE-9-NAnt (40 mg/L), the P4501A activity increased significantly, but the activities of AChE and LDH were inhibited clearly, causing certain neurotoxicity and disorders of energy metabolism to zebrafish. The analysis of integrated biomarker response index (IBR) suggested that PE had greater bio-toxicity to zebrafish in all exposure groups after short-term exposure, but the PE-9-NAnt complex showed greater bio-toxicity after 7 days, which indicated that complex exposure of PE-9-NAnt had a delayed effect on the bio-toxicity of zebrafish. Furthermore, analysis of the intestinal microbiota exhibited that under the conditions of the exposure group with 9-NAnt, the relative abundance of the five dominant bacterial phyla (Proteobacteria, Firmicutes, Fusobacteriota, Bacteroidota and Verrucomicrobiota) changed greatly. Overall, this study confirmed that PE could carry 9-NAnt into fish causing bioaccumulation, but in the case of coexisting exposures, PE reduced 9-NAnt bioaccumulation, suggesting that microplastics with other emerging pollutants in chronic toxicity are probably next objects in future works.


Assuntos
Microbioma Gastrointestinal , Poluentes Químicos da Água , Animais , Antracenos , Biomarcadores/metabolismo , Estresse Oxidativo , Plásticos , Polietileno , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
15.
J Immunol ; 206(6): 1161-1170, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33568397

RESUMO

Helicobacter pylori is the major etiological agent for most gastric cancer. CagA has been reported to be an important virulence factor of H. pylori, but its effect on the immune response is not yet clear. In this study, wild-type C57BL/6 mice and Ptpn6me-v/me-v mice were randomly assigned for infection with H. pylori We demonstrated that CagA suppressed H. pylori-stimulated expression of proinflammatory cytokines in vivo. Besides, we infected mouse peritoneal macrophages RAW264.7 and AGS with H. pylori Our results showed that CagA suppressed expression of proinflammatory cytokines through inhibiting the MAPKs and NF-κB pathways activation in vitro. Mechanistically, we found that CagA interacted with the host cellular tyrosine phosphatase SHP-1, which facilitated the recruitment of SHP-1 to TRAF6 and inhibited the K63-linked ubiquitination of TRAF6, which obstructed the transmission of signal downstream. Taken together, these findings reveal a previously unknown mechanism by which CagA negatively regulates the posttranslational modification of TRAF6 in innate antibacterial immune response and provide molecular basis for new therapeutics to treat microbial infection.

16.
Int J Nanomedicine ; 16: 1127-1141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33603372

RESUMO

Background: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP. Methods: We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice. Results: The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity. Conclusion: Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.


Assuntos
Mercaptopurina/química , Mercaptopurina/farmacocinética , Nanomedicina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Administração Oral , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Mercaptopurina/administração & dosagem , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Environ Sci Technol ; 55(4): 2541-2552, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33499587

RESUMO

Degradation kinetics of antibiotic resistance genes (ARGs) by free available chlorine (FAC), ozone (O3), and UV254 light (UV) were investigated in phosphate buffered solutions at pH 7 using a chromosomal ARG (mecA) of methicillin-resistant Staphylococcus aureus (MRSA). For FAC, the degradation rates of extracellular mecA (extra-mecA) were accelerated with increasing FAC exposure, which could be explained by a two-step FAC reaction model. The degradation of extra-mecA by O3 followed second-order reaction kinetics. The degradation of extra-mecA by UV exhibited tailing kinetics, which could be described by a newly proposed kinetic model considering cyclobutane pyrimidine dimer (CPD) formation, its photoreversal, and irreversible (6-4) photoproduct formation. Measured rate constants for extra-mecA increased linearly with amplicon length for FAC and O3, or with number of intrastrand pyrimidine doublets for UV, which enabled prediction of degradation rate constants of extra-mecA amplicons based on sequence length and/or composition. In comparison to those of extra-mecA, the observed degradation rates of intracellular mecA (intra-mecA) were faster for FAC and O3 at low oxidant exposures but significantly slower at high exposures for FAC and UV. Differences in observed extra- and intracellular kinetics could be due to decreased DNA recovery efficiency and/or the presence of MRSA aggregates protected from disinfectants.

18.
Eye (Lond) ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414527

RESUMO

OBJECTIVES: To evaluate the safety and efficacy of repeated corneal collagen crosslinking assisted by transepithelial double-cycle iontophoresis (DI-CXL) in the management of keratoconus progression after primary CXL. METHODS: A retrospective analysis was conducted in the patients who underwent repeated CXL between 2016 and 2018. These patients were treated with DI-CXL if keratoconus progression was confirmed after primary CXL. Scoring of ocular pain and corneal epithelial damage, visual acuity, corneal tomography, in vivo corneal confocal microscopy (IVCM) was performed before and at 3, 6, 12, and 24 months after DI-CXL. RESULTS: Overall, 21 eyes of 12 patients (mean age 17.3 ± 1.9 years) were included in this study. Before DI-CXL, an average increase of 4.26 D in Kmax was detected in these patients with a mean follow-up interval of (23.0 ± 13.7) months. After DI-CXL, corneal epithelial damage rapidly recovered within days. Visual acuity remained unchanged with follow-up of 24 months. When compared to baseline, significant decreases were observed in Kmax (at 3 months) and K2 (at 3 and 6 months) after DI-CXL. Corneal thickness of thinnest point significantly decreased at 3 months postoperatively. When compared to baseline, no significant differences were found in any of the refractive or tomographic parameters at 12 and 24 months. IVCM revealed trabecular patterned hyperdense tissues after DI-CXL in the anterior stroma at the depth of 200 µm or more. No corneal infiltration or persistent epithelial defect was recorded after DI-CXL. CONCLUSION: DI-CXL is safe and effective as a good alternative in stabilizing keratoconus progression after primary CXL.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33438124

RESUMO

Irrational application of chemical fertilizers causes soil nutrient imbalance, reduced microbial diversity, soil diseases, and other soil quality problems and is one of the main sources of non-point pollution. The application of microbial inoculant (MI) can improve the soil environment and crop growth to reduce problems caused by irrational application of chemical fertilizers. Field experiments were carried out in high-phosphorus soils to study the effects of the addition of various MIs combined with chemical fertilizers on soil properties, wheat growth, and soil microbial composition and structure. The MIs consisted of one fungal agent: Trichoderma compound agent (TC) and five bacterial agents, namely soil remediation agent (SR), anti-repeat microbial agent (AM), microbial agent (MA), plant growth-promoting rhizobacteria (PG), and biological fertilizer agent (BF). The wheat yield increased by 15.2-33.4% with the addition of MIs, and PG with Bacillus subtilis as the core microorganism had the most obvious effect on increasing the production (p < 0.05). For the entire growth period of wheat, all MIs applied significantly increased the available nitrogen (AN) (p < 0.05) but did not significantly affect the available phosphorus (AP). BF has the best effect on increasing AN in the soil. The 16S rRNA sequencing results indicated that the dominant phyla of soil bacteria were Proteobacteria, Acidobacteria, Bacteroidetes, Actinobacteria, and Verrucomicrobia. The addition of MIs increased the relative abundance of Acidobacteria, Actinobacteria, Chloroflexi and decreased Proteobacteria and Bacteroidetes. The diversity of soil bacterial community (Chao1) was significantly higher in the soil added with TC than that added with BF (p < 0.05). All bacterial agents significantly enriched various genera (p < 0.05), while the fungal agent (TC) did not enrich the genera significantly. pH and AN, but not TP, were closely related to the dominant bacteria phylum in high-P soil. The application of MIs improved AN in soil, increased the wheat yield, and changed the relative abundance of the soil dominant phylum, and these changes were closely related to the type of MIs. The results provide a scientific basis for rational use of different types of MIs in high-P soil.

20.
J Chem Inf Model ; 61(1): 516-524, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33347303

RESUMO

Clathrin is a highly evolutionarily conserved protein, which can affect membrane cleavage and membrane release of vesicles. The absence of clathrin in the cellular system affects a variety of human diseases. Effective recognition of clathrin plays an important role in the development of drugs to treat related diseases. In recent years, deep learning has been widely applied in the field of bioinformatics because of its high efficiency and accuracy. In this study, we propose a deep learning framework, DeepCLA, which combines two different network structures, including a convolutional neural network and a bidirectional long short-term memory network to identify clathrin. The investigation of different deep network architectures demonstrates that the prediction performance of a hybrid depth network model is better than that of a single depth network. On the independent test dataset, DeepCLA outperforms the state-of-the-art methods. It suggests that DeepCLA is an effective approach for clathrin prediction and can provide more instructive guidance for further experimental investigation of clathrin. Moreover, the source code and training data of DeepCLA are provided at https://github.com/ZhangZhang89/DeepCLA.

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