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1.
J Hazard Mater ; 412: 125223, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33951863

RESUMO

Molecular dynamics simulation combined with experimental methods were used to investigate the adsorption and wetting process of 25 lauryl glucoside (APG-12) molecules on coal molecules and in turn study the dust suppression mechanism by APG-12 at the molecular level. Through wetting experiments, our preliminary findings showed that APG-12 does have a certain wetting effect on coal dust. According to density functional theory in molecular dynamics simulations, the electrostatic potential and surface charge of the APG-12 and coal molecular models were analyzed to identify their nucleophilic and electrophilic regions, and illustrate the hydrogen bond adsorption mechanism. The dynamics simulation results showed that APG-12 molecules can be easily adsorbed on the surface of coal molecules and then adsorb water molecules around them under the action of hydrogen bonds. This was consistent with the results of an analysis of the system's radial distribution function and the relative concentration distribution of each component in the Z-axis direction. The results are in good agreement with the experimental results from scanning electron microscopy and energy dispersive spectrometer analysis. These data provide further evidence that APG-12 can clearly improve the wettability and suppression of coal dust, which is of great importance for controlling coal dust pollution.

3.
Mol Ecol Resour ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893720

RESUMO

Butterfly hillstream loach (Beaufortia kweichowensis), a benthic fish in the torrential mountain streams, possesses a totally flat ventrum, flattened craniofacial and body skeletons, and enlarged paired fins covered by substantially small keratinous structures. However, little is known about the genetic basis of these specialized morphological adaptations. Here we present a 448.52 Mb genome assembly with contig N50 length of 5.53 Mb by integrating Illumina short-read sequencing, Nanopore long-read sequencing and HiC-based chromatin map. Demographic history reconstruction of the butterfly hillstream loach reveals that the population dynamics is correlated with the different stages of uplifting of the Tibetan Plateau. Comparative genomic analysis finds evidence of 6 keratin genes in butterfly hillstream loach evolving under positive selection. Within these genes, 2 keratin genes exhibit species-specific and divergent amino acid changes, suggesting a role in the formation of the unculi. Additionally, a series of positively selected genes, rapid evolving genes, specific variant genes and expanded gene families are found, including genes related to Hedgehog, Notch, and BMP pathways, which may be involved in craniofacial development. These findings may have important implications for understanding the genetic basis of phenotypic adaptation to torrential mountain stream life.

5.
Biomed Res Int ; 2021: 6637693, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33860046

RESUMO

Postherpetic neuralgia (PHN) is a complication of herpes zoster viral infection. Its main manifestations are continuous or intermittent burning-like and electroshock-like pain in the affected nerves. Electroacupuncture (EA) is widely used in clinical treatment and exerts effects in alleviating neuropathic pain. In this study, we investigated the effect and underlying mechanism of EA on PHN. Sprague-Dawley rats were treated with resiniferatoxin (RTX) to establish a PHN model and subjected to EA and/or miR-223-3p overexpression (OV) or interference. Mechanical withdrawal latency was measured as an indication of pain sensitivity. Hematoxylin-eosin staining and transmission electron microscopy were performed to observe neuron cell morphology and autophagic vacuoles, respectively. ELISA was performed to detect reactive oxygen species (ROS) production and the levels of tumor necrosis factor- (TNF-) α, inducible nitric oxide synthase (iNOS), interleukin- (IL-) 6, and IL-10. Changes in autophagy and apoptosis-related miRNAs were detected by immunofluorescence and qRT-PCR, respectively. In RTX-treated rats, OV and EA reduced pain sensitivity, decreased the number of eosinophils, and increased that of nerve cells. ROS generation and the levels of TNF-α and iNOS were significantly reduced, while those of IL-6 and IL-10 were increased. OV and EA induced fewer autophagic vacuoles than those in the model group. The expression of autophagy-related protein microtubule-associated protein 1 light chain 3-II, ATG9, and Rab1 was decreased by OV and EA, whereas that of P62 was increased. qRT-PCR revealed that miR-223-3p expression in the model group decreased but was increased by EA. EA inhibits neuron cell autophagy in PHN by increasing miR-223-3p expression.

6.
Sci Total Environ ; 783: 147008, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33872908

RESUMO

The particulate matter (PM) emitted by a trackless rubber-tyred vehicle (TRTV) in coal mines can seriously threaten the health and safety of the exposed workers underground. In this paper, in order to effectively reduce the PM concentration and improve the underground working environment, a combination of numerical simulations and field measurements was adopted to study the migration distribution of the PM emitted by a TRTV at an idle speed for 60 s under different movement conditions, and the dilution effects of the ventilation rate on the PM. The results showed that under different movement conditions, the PM mainly moved along the floor of the roadway, but upward diffusion trends were shown overall, which meant that the chambers are in high-risk areas. Field measurements were then performed under the two conditions to verify the effectiveness of the simulations. Furthermore, the dilution effects of the increased ventilation rate on the PM were analyzed. It was concluded that the optimal dilution ventilation rate under condition 1 was 4600m3/min, and that under condition 2 was 2800m3/min. Accordingly, the driver of the TRTV should try to move forward when entering the chamber.

7.
Ecotoxicol Environ Saf ; 215: 112108, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33799132

RESUMO

Fluoride which is widespread in our environment and food due to its geological origin and industrial pollution has been identified as a developmental neurotoxicant. Gut-brain axis provides new insight into brain-derived injury. We previously found the psychoactive effects of a probiotic strain, Lactobacillus johnsonii BS15 against fluoride-induced memory dysfunction in mice by modulating the gut-brain axis. In this study, we aimed to detect the link between the reconstruction of gut microbiota and gut-brain axis through which probiotic alleviate fluoride-induced memory impairment. We also added an hour of water avoidance stress (WAS) before behavioral tests and sampling, aiming to demonstrate the preventive effects of the probiotic on fluoride-induced memory impairment after psychological stress. Mice were given fluoridated drinking water (sodium fluoride 100 ppm, corresponding to 37.8 ± 2.4 ppm F¯) for 70 days and administered with PBS or a probiotic strain, Lactobacillus johnsonii BS15 for 28 days prior to and throughout a 70 day exposure to sodium fluoride. Results showed that fluoride increases the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and reduces the exploration ratio in novel object recognition (NOR) test and the spontaneous exploration during the T-maze test in mice following WAS, which were significantly improved by the probiotic. 16S rRNA sequencing showed a significant separation in ileal microbiota between the fluoride-treated mice and control mice. Lactobacillus was the main targeting bacteria and significantly reduced in fluoride-treated mice. BS15 reconstructed the fluoride-post microbiota and increased the relative abundance of Lactobacillus. D-lactate content and diamine oxidase (DAO) activity, two biomarkers of gut permeability were reduced in the serum of probiotic-inoculated mice. ZO-1, an intestinal tight junction protein was reduced by fluoride in mRNA, and its protein levels were increased by the probiotic treatment. Moreover, the hippocampus which is essential to learning and memory, down-regulated mRNA level of both the myelin-associated glycoprotein (MAG), and protein levels of brain-derived neurotrophic factor (BDNF), including the improvement of cAMP response element-binding protein (CREB) by BS15 in fluoride-exposed mice after WAS. Via spearman correlation analysis, Lactobacillus displayed significantly positive associations with the behavioral tests, levels of nerve development related factors, and intestinal tight junction proteins ZO-1, and negative association with TNF-α of the hippocampus, highlighting regulatory effects of gut bacteria on memory potential and gut barrier. These results suggested the psychoactive effects of BS15 on fluoride-induced memory dysfunction after psychological stress. In addition, there may be some correlations between fluoride-induced memory dysfunction and reconstruction of gut microbiota. AVAILABILITY OF DATA AND MATERIALS: 16S rRNA sequencing reads have uploaded to NCBI. The accession code of 16S rRNA sequencing reads in the National Center for Biotechnology Information (NCBI) BioProject database: PRJNA660154.


Assuntos
Fluoretos/metabolismo , Microbioma Gastrointestinal/fisiologia , Probióticos/farmacologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Lactobacillus/metabolismo , Masculino , Memória , Transtornos da Memória/induzido quimicamente , Camundongos , Microbiota , Sistema Hipófise-Suprarrenal/metabolismo , RNA Ribossômico 16S/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
8.
Zhongguo Zhen Jiu ; 41(3): 295-302, 2021 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-33798313

RESUMO

OBJECTIVE: To screen protein target in prevention and treatment with electroacupuncture (EA) for Alzheimer's disease (AD) and explore the potential mechanism of EA in prevention of AD. METHODS: A total of 40 APP/PS1 transgenic young male mice, 1.5-month old, were randomized into an EA group and a model group, 20 mice in each one, and 20 C57BL/6J mice were chosen as the normal control group. After adaptive housing for 1 week, the mice in the EA group were stimulated with EA at "Baihui" (GV 20), "Fengfu" (GV 16) and "Shenshu" (BL 23), with intermittent wave, 10 Hz in frequency and 2 mA in electric intensity. EA was given once daily, 20 min each time. There was 1 day at interval after EA for 6 days each week. Totally, the intervention lasted for 16 weeks. On day 3 after the end of EA intervention, Morris water maze test was adopted to detect learning and memory abilities of mice in each group. After water maze test, the label-free method was used to measure the difference expressions in cerebral cortex and hippocampus. Using Western blot method, the expressions of guanylate binding protein beta 5 (GNB 5) and histone-H 3 in cerebral cortex and hippocampus were verified. Using immunohistochemical method, the expressions of amyloid beta protein (Aß) in cerebral cortex and hippocampus were detected. RESULTS: Compared with the normal control group, the escape latency (on day 2, 3 and 4) was prolonged, the frequency of crossing platform and the duration of platform stay were decreased in the mice of the model group (P<0.05). Compared with the model group, the escape latency (on day 3 and 4) was shortened, the frequency of crossing platform and the duration of platform stay were increased in the mice of the EA group (P<0.05). By the comparison among the three groups, the high mobility group nucleosome-binding domain-containing protein 5, band 3 anion transport protein, histone-H 3, epoxide hydrolase 4 (fragment), neurolysin (mitochondria), phosphoglycerate mutase 2, GNB5 and Aß were the differential proteins with the larger fold-change difference in expression. Compared with the normal control group, the expression of histone-H 3 in cerebral cortex and hippocampus was reduced (P<0.001) and the expressions of GNB 5 and Aß were increased (P<0.001, P<0.01) in the mice of the model group. Compared with the model group, the expression of histone-H 3 in cerebral cortex and hippocampus was increased (P<0.001) and the expressions of GNB 5 and Aßwere reduced (P<0.001, P<0.05) in the mice of the EA group. CONCLUSION: The intervention with EA effectively prevents from the decline of learning and memory ability and the formation of Aß senile plaques in cerebral cortex and hippocampus in young mouse models of AD after growing up. Besides, EA plays a regulatory function for protein expression differences induced by AD model.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/genética , Animais , Modelos Animais de Doenças , Hipocampo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica
9.
Eur J Med Chem ; 217: 113335, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33751979

RESUMO

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.

10.
Nurs Open ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33725398

RESUMO

AIM: The study aimed to prove that both rationality and emotion are indispensable for older people to maintain their ability to live independently during the twilight of their lives. The resilience of older people to dementia were investigated by considering the interactions between educational levels and marriage status. DESIGN: A quantitative study was conducted using questionnaires. METHODS: Four sociodemographic variables (age, sex, educational level and marital status) were collected from 1,177 older Chinese participants, whose mini-mental state examination scores (MMSE scores) were measured. RESULTS: A lower educational level coupled with being widowed caused a greater risk for severe cognitive impairment (relative risk [RR] 1.48; 95% confidence interval [CI] 1.20-1.82; p < .001) for high-aged older participants (age range: ≥80) than for their low-aged counterparts (age range: ≥60 and <80). In contrast, a higher educational level coupled with being married levelled this age-related risk for cognitive loss (RR 0.91; 95% CI 0.65-1.27; p = .62).

11.
Eur J Med Chem ; 218: 113328, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773286

RESUMO

Targeted therapy of treating patients with specific tyrosine kinase inhibitors (TKIs) is currently the standard care for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. However, the inevitably developed drug resistance in patients to EGFR TKIs is the biggest obstacle for cancer targeted therapy. About 60% of drug resistance to the 1st generation of EGFR TKIs was resulted from an acquired T790M mutation in the kinase domain of EGFR protein. Proteolysis targeting chimera (PROTAC) is a lately-developed technology to target point of interest proteins for degradation. Because EGFR-mutant lung cancers are highly dependent on EGFR proteins, designing specific PROTAC molecules to degrade EGFR proteins from cancer cells provides a very promising strategy to treat such patients and eradicate drug resistance. Currently, there is no cereblon (CRBN)-based PROTAC reported able to degrade T790M-containing EGFR resistant proteins. In this study, we synthesized two novel CRBN-based EGFR PROTACs, SIAIS125 and SIAIS126, based on EGFR inhibitor canertinib and cereblon ligand pomalidomide. These two degraders displayed potent and selective antitumor activities in EGFR TKI resistant lung cancer cells. Firstly, they could selectively degrade EGFRL858R+T790M resistant proteins in H1975 cells at the concentration of 30-50 nM, and EGFREx19del proteins in PC9 cells. But they did not degrade EGFREx19del+T790M mutant proteins in PC9Brca1 cells or wild type EGFR in A549 lung cancer cells. They could also selectively inhibit the growth of EGFR mutant lung cancer cells but not that of normal cells or A549 cells. Secondly, the degradation of EGFRL858R+T790M proteins was long lasting up to 72 h. Thirdly, these degraders displayed better inhibition of EGFR phosphorylation in H1975 cells and PC9Brca1 cells comparing to canertinib. Finally, these degraders could also induce significant apoptosis and cell cycles arrest in H1975 cells. Pre-incubation with canertinib, pomalidomide or ubiquitination inhibitor MLN4924 totally blocked EGFR degradation by PROTACs. Mechanistic studies showed that PROTAC could induce autophagy in lung cancer cells. PROTAC-induced EGFR degradation acted through both ubiquitin/proteosome system and ubiquitin/autophagy/lysosome system. Elevating autophagy activities enhanced EGFR degradation and cell apoptosis induced by PROTACs. Our research not only offered a novel PROTAC tool to target EGFR TKI drug resistance in lung cancer, but also firstly demonstrated that the involvement of autophagy/lysosome system in PROTAC- mediated target protein degradation.

12.
Huan Jing Ke Xue ; 42(4): 1626-1635, 2021 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742797

RESUMO

In order to reveal the chemical composition characteristics and pollution sources of fine particulate matter (PM2.5) in autumn and winter in Yuncheng, PM2.5 samples were continuously collected using a four-channel small-flow particulate sampler from October 15, 2018 to March 15, 2019. The study prediminantly analyzed the chemical components of water-soluble ions, elemental carbon, organic carbon, and metal elements. Additionally, the chemical mass reconstruction method of particulate matter and the positive matrix factorization model (PMF) were combined for an in-depth discussion. During the sample period, the PM2.5 mass concentrations range was 29.37-370.11 µg·m-3, and 101 days during the sampling period exhibited concentrations that were higher than the secondary standard in China's Ambient Air Quality Standards (GB 3095-2012), with an exceeding rate of 70.63%. These results indicate that the air pollution in Yuncheng in autumn and winter is serious. According to the air quality index (AQI), the collected samples are classified as clean, light-moderate pollution, and heavy-severe pollution. Water-soluble ions, OC, EC and metal elements account for 40%, 19%, 5%, and 7% on clean days, 46%, 18%, 4%, and 5% on days with light-moderate pollution, and 46%, 21%, 4%, and 4% on days with heavy-severe pollution, respectively. Secondary ions NO3-, SO42-, and NH4+ are the primary components of water-soluble ions, accounting for 81% (clean days), 87% (light-moderate pollution), and 87% (heavy-severe pollution) of the total ion concentration, respectively. The OC/EC ratios during the sampling period were 3.78 (clean days), 4.02 (light-moderate pollution), and 5.37 (heavy-severe pollution). With the intensification of pollution, the pollution of secondary organic aerosols in the atmosphere becomes increasingly serious. In addition, as the air pollution increased, the concentration of Fe and Cr elements gradually decreased, while the concentration of other metal elements showed an overall upward trend. The results of the chemical mass reconstruction demonstrate that among the different pollution levels of atmospheric PM2.5 in Yuncheng, the mass percentages of secondary inorganic salt, sea salt, heavy metals, mineral dust, construction dust, organic matter, and elemental carbon were 36%, 2%, 2%, 8%, 1%, 33%, and 5% (clean days), 41%, 1%, 1%, 5%, 0.01%, 31%, and 5% (light-moderate pollution), and 41%, 1%, 1%, 4%, 0.004%, 34%, and 4% (heavy-severe pollution). The proportion of secondary inorganic ions increased and mineral dust decreased with the deterioration of air quality. The PMF analysis results suggest that secondary related sources, coal combustion sources, vehicle exhaust sources, biomass burning, and secondary organic matter are the predominant sources of PM2.5 during serious air pollution in Yuncheng.

13.
Acta Pharmacol Sin ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785860

RESUMO

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.

14.
J Colloid Interface Sci ; 594: 604-620, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33780765

RESUMO

A three-dimensional hollow NiCo2O4 structure was successfully prepared with a precipitation-hydrothermal method. A balance between magnetic and dielectric losses was achieved by using a hollow NiCo2O4 structure loaded with benzotriazole (BTA), and thus the performance of electromagnetic waves was attenuated. The minimum reflection loss value of BTA@NiCo2O4 at 16.01 GHz was -35.39 dB when the absorber thickness was 2 mm, at which the absorption bandwidth for an RL of less than -10 dB is as high as 4.64 GHz. The absorption mechanism was characterized by the synergy among interfacial polarization, multiple reflection, and dipole polarization enhancement between NiCo2O4 and BTA. Interestingly, the epoxy/BTA@NiCo2O4 coating not only exhibited an outstanding microwave absorption (MA) performance but also has excellent anticorrosion and self-healing properties, as shown by the results of electrochemical impedance spectroscopy and confocal laser scanning microscopy. This work would be very helpful to the development of novel coatings with excellent MA performance and anticorrosion and self-healing properties.

15.
J Med Chem ; 64(6): 3234-3248, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33705128

RESUMO

A series of conformationally constrained novel benzo[1,3]oxazinyloxazolidinones were designed, synthesized, and evaluated on their activities against Mycobacterium tuberculosis, Gram-positive bacteria, and Gram-negative bacteria. The studies identified a new compound 20aa that displayed good to excellent antibacterial and antitubercular profiles against drug-resistant TB strains (MIC = 0.48-0.82 µg/mL), MRSA (MIC = 0.25-0.5 µg/mL), MRSE (MIC = 1 µg/mL), VISA (MIC = 0.25 µg/mL), and VRE (MIC = 0.25 µg/mL) and some linezolid-resistant strains (MIC 1-2 µg/mL). Compound 20aa was demonstrated as a promising candidate through ADME/T evaluation including microsomal stability, cytotoxicity, and inhibition of hERG and monoamine oxidase. Notably, 20aa showed excellent mouse PK profile with high plasma exposure (AUC0-∞ = 78 669 h·ng/mL), high peak plasma concentration (Cmax = 10 253 ng/mL), appropriate half-life of 3.76 h, and superior oral bioavailability (128%). The present study not only successfully provides a novel benzo[1,3]oxazinyloxazolidinone scaffold with superior druggability but also lays a good foundation for new antibacterial drug development.

16.
IEEE Trans Cybern ; PP2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531326

RESUMO

In the field of modern industrial engineering, many mechanical systems are underactuated, exhibiting strong nonlinear characteristics and high flexibility. However, the lack of control inputs brings about many difficulties for controller design and stability/convergence analysis. Additionally, some unavoidable practical issues, e.g., plant uncertainties and actuator deadzones, make the control of underactuated systems even more challenging. Hence, with the aid of elaborately constructed finite-time convergent surfaces, this article provides the first solution to address the control problem for a class of multi-input-multi-output (MIMO) underactuated systems subject to plant uncertainties and actuator deadzones. Specifically, this article overcomes the main obstacle in sliding-mode surface analysis for MIMO underactuated systems, that is, by the presented analysis method, the asymptotic stability of the system equilibrium point is strictly proven based on the composite surfaces. In addition, the unknown parts of the actuated/unactuated dynamic equations and actuator deadzones can be simultaneously handled, which is important for real applications. Furthermore, we apply the proposed method to two kinds of typical underactuated systems, that is: 1) tower cranes and 2) double-pendulum cranes, and implement a series of hardware experiments to verify its effectiveness and robustness.

17.
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
18.
Cancer Sci ; 112(5): 1865-1877, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33544437

RESUMO

The histone acetyltransferase MOF (KAT8) is mainly involved in the acetylation of histone H4 at lysine 16 (H4K16) and some non-histone proteins. The MOF expression level is significantly reduced in many cancers, however the biological function of MOF and its underlying mechanism are still elusive in hepatocellular carcinoma (HCC). Estrogen receptor α (ERα) has been considered as a tumor suppressor in HCC. Here, we demonstrated that MOF expression is significantly reduced in HCC samples, and is positively correlated with that of ERα. MOF interacts with ERα, and participates in acetylation of ERα at K266, K268, K299, thereby inhibiting ERα ubiquitination to maintain the stability of ERα. In addition, MOF participates in the upregulation of ERα-mediated transactivation. Depletion of MOF significantly promotes cell growth, migration, and invasion in HCC cell lines. Taken together, our results provide new insights to understand the mechanism underlying the modulation function of MOF on ERα action in HCC, suggesting that MOF might be a potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Histona Acetiltransferases/metabolismo , Neoplasias Hepáticas/metabolismo , Acetilação , Acetilesterase/metabolismo , Animais , Anticorpos/uso terapêutico , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Bases de Dados Genéticas , Regulação para Baixo , Receptor alfa de Estrogênio/genética , Feminino , Xenoenxertos , Histona Acetiltransferases/deficiência , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Lisina/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Transdução de Sinais , Ativação Transcricional , Ubiquitinação , Regulação para Cima
19.
J Clin Invest ; 131(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586674

RESUMO

Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between ß-catenin and VE-cadherin by increasing ß-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33404073

RESUMO

BACKGROUND: Antibiotic resistance is increasing day by day, thereby increase the chances of more infections by resistant bacteria. In this situation, antimicrobial photodynamic therapy (aPDT) is gaining more attraction. OBJECTIVE: To evaluate the antimicrobial effect of ALA derivatives using photodynamic therapy. MATERIALS AND METHODS: In this study, we evaluated the aPDT effect of different derivatives of 5-ALA. In vivo and in vitro studies were performed to measure the antimicrobial activity. Different light doses and different concentrations of drugs were used to test anti-bacterial effect of drugs as well as to detect any physiological changes in animal model after the treatment. RESULTS: In vivo studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are potent photosensitizers. In vitro studies involved wound healing rate, body weight, and dietary intake were evaluated, and results showed that ALA, ALA-methyl ester, ALA-hexyl ester, and ALA-13A had good anti-bacterial effects, fast healing rate, and no effect on other physical parameters. CONCLUSION: Photodynamic therapy is increasingly used to treat different types of skin infections caused by bacterial strains. Our studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are promising photosensitizers for photodynamic therapy to inhibit the growth of resistant bacterial strains.

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