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1.
J Biol Chem ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041778

RESUMO

Cell senescence is one of the most important processes determining cell fate and is involved in many pathophysiological conditions, including cancer, neurodegenerative diseases, and other aging-associated diseases. It has recently been discovered that the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1 or CHIP) is up-regulated during the senescence of human fibroblasts and modulates cell senescence. However, the molecular mechanism underlying STUB1-controlled senescence is not clear. Here, using affinity purification and MS-based analysis, we discovered that STUB1 binds to brain and muscle ARNT-like 1 (BMAL1, also called aryl hydrocarbon receptor nuclear translocator-like protein 1 [ARNTL]). Through biochemical experiments, we confirmed the STUB1-BMAL1 interaction, identified their interaction domains, and revealed that STUB1 overexpression down-regulates BMAL1 protein levels through STUB1's enzymatic activity and that STUB1 knockdown increases BMAL1 levels. Further experiments disclosed that STUB1 enhances BMAL1 degradation, which was abolished upon proteasome inhibition. Moreover, we found that STUB1 promotes the formation of Lys-48-linked polyubiquitin chains on BMAL1, facilitating its proteasomal degradation. Interestingly, we also discovered that oxidative stress promotes STUB1 nuclear translocation and enhances its co-localization with BMAL1. STUB1 expression attenuates hydrogen peroxide-induced cell senescence, indicated by a reduced signal in senescence-associated ß-galactosidase staining and decreased protein levels of two cell senescence markers, p53 and p21. BMAL1 knockdown diminished this effect, and BMAL1 overexpression abolished STUB1's effect on cell senescence. In summary, the results of our work reveal that the E3 ubiquitin ligase STUB1 ubiquitinates and degrades its substrate BMAL1 and thereby alleviates hydrogen peroxide-induced cell senescence.

2.
Sensors (Basel) ; 20(3)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050678

RESUMO

Mobile manipulation has a broad range of applications in robotics. However, it is usually more challenging than fixed-base manipulation due to the complex coordination of a mobile base and a manipulator. Although recent works have demonstrated that deep reinforcement learning is a powerful technique for fixed-base manipulation tasks, most of them are not applicable to mobile manipulation. This paper investigates how to leverage deep reinforcement learning to tackle whole-body mobile manipulation tasks in unstructured environments using only on-board sensors. A novel mobile manipulation system which integrates the state-of-the-art deep reinforcement learning algorithms with visual perception is proposed. It has an efficient framework decoupling visual perception from the deep reinforcement learning control, which enables its generalization from simulation training to real-world testing. Extensive simulation and experiment results show that the proposed mobile manipulation system is able to grasp different types of objects autonomously in various simulation and real-world scenarios, verifying the effectiveness of the proposed mobile manipulation system.

3.
Cancer Genet ; 242: 1-7, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036224

RESUMO

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the world, in which colon adenocarcinoma (COAD) is the most common histological subtype of CRC. In this study, our aim is to identify gene modules and representative candidate biomarkers for clinical prognosis of patients with COAD, and help to predict prognosis and reveal the mechanisms of cancer progression. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network and identify gene modules correlated with TNM clinical staging of COAD patients. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the module gene. Protein-protein interaction (PPI) network and hub gene identification were explored with Cytoscape software. Finally, the hub gene mRNA level was validated in Oncomine database. Five gene modules, related with the pathological TNM stage, were constructed, and the gene module was enriched in cell proliferation, invasion and migration related GO terms and metabolic related KEGG pathways. A total of top 10 hub genes was identified, and in which six of the hub genes show a significant up-regulation in COAD as compared to normal tissue, including IVL, KRT16, KRT6C, KRT6A, KRT78 and SBSN. In conclusion, we identified five gene modules and six candidate biomarkers correlated with the TNM staging of COAD patients. These findings may help us to understand the tumor progression of COAD and provide prognostic biomarkers as well as therapeutic targets.

4.
Sci Total Environ ; 716: 137111, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32059314

RESUMO

Microscale zero-valent iron in situ reaction zone (mZVI-IRZ) has proved to be effective and efficient for the removal of chlorinated aliphatic hydrocarbons (CAHs) from groundwater. However, nitrate (NO3-), which is ubiquitous in groundwater, affects the mZVI-based attenuation of CAHs in a complicated manner. Both the reaction rate constant (k) and electron efficiency (EE) of mZVI must be considered to comprehensively reflect the effects of NO3- on the short and long-term remediation performances of mZVI. Therefore, the influence of NO3- on trichloroethylene (TCE) removal under high-pollution-load (iron limited) and low-pollution-load (iron excess) conditions was investigated. Low concentrations of NO3- (10 and 50 mg N L-1) were found to enhance the TCE removal rate and efficiency, whereas high concentrations of NO3- (100 mg N L-1) inhibited the reaction. Although TCE removal was increased at low concentrations of NO3-, the EE of mZVI was dramatically decreased in the presence of NO3- at all concentration levels. Therefore, both the short-term TCE removal characteristics and the EE of mZVI should be considered when evaluating the long-term remediation effectiveness of mZVI-IRZ technology. The effects of NO3- on the TCE removal trends under high- and low-pollution-load scenarios were similar, but had different magnitudes. NO3- affected the TCE removal mainly by promoting mZVI corrosion, competing for electrons and affecting passivation product evolution. Our results provide guidance for the practical application of mZVI-IRZ technology.

5.
Dig Dis Sci ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32078087

RESUMO

BACKGROUND: The specific and accurate pathogenesis of diarrhea-type irritable bowel syndrome is still unclear. AIMS: We explored the mechanism of heat shock protein 27 (HSP27) in diarrhea-type irritable bowel syndrome to identify the key targets for the disease. METHODS: The human colonic epithelial cell lines Caco-2 and NCM460 were pretreated with KRIBB3 (a phosphorylation inhibitor of HSP27) and then stimulated with lipopolysaccharide for different times. The apoptosis ratios of Caco-2 and NCM460 cells were examined with Annexin V/PI assays. Cell growth was determined using the cell counting kit-8 assay, and the expression levels of IL-1ß and IL-6 in the cell supernatant were analyzed by ELISA. In addition, the expression levels of HSP27 and the nuclear factor-κB (NF-κB) signaling pathway were examined by Western blot assay. RESULTS: Stimulation with lipopolysaccharide promoted the expression of HSP27 in colonic epithelial cells. HSP27 was phosphorylated at serine 78 and 82 after exposure to LPS. Apoptosis, growth inhibition, and inflammatory factor expression of lipopolysaccharide-induced colonic epithelial cells were greatly exacerbated by KRIBB3 treatment. In addition, KRIBB3 inhibited the phosphorylation of IκB-α and the activation of NF-κB. Gene silencing by small interfering RNA indicated that phosphorylation of HSP27 may regulate the NF-κB pathway. CONCLUSIONS: HSP27 plays an important role in the inflammatory response of intestinal human colonic epithelial cells. HSP27 may protect intestinal epithelial cells against damage by regulating the NF-κB pathway.

6.
Carbohydr Polym ; 234: 115927, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070546

RESUMO

Natural active compounds with antioxidant properties and other potential health benefits, like quercetin (Qu), have aroused wide concern for developing bio-functional products. However, their applications are hindered by their intrinsic poor water solubility and chemical instability. In this paper, a natural antioxidant alpha lipoic acid (ALA) was grafted onto chitosan (CS) to synthesize a novel graft polymer (CS-graft-ALA). In particular, this graft-polymer could self-assemble into spherical nanomicelles in water, with a low critical micelle concentration (CMC) of 0.0076 mg/mL. As a robust and active nanocarrier, the CS-graft-ALA micelles showed high efficiency in encapsulating Qu and dispersing Qu in water. As found, the antioxidant activity of Qu was effectively enhanced when entrapped within CS-graft-ALA micelles. Moreover, CS-graft-ALA micelles could significantly improve the photo-stability and temperature-stability of Qu. The Qu/CS-graft-ALA micelles with excellent water dispersability, stability and improved antioxidant activity hold a great potential for wide applications.

7.
Phys Chem Chem Phys ; 22(4): 2115-2121, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31904063

RESUMO

MXenes represent a family of surface-functionalized two-dimensional (2D) carbides and nitrides with potential applications in the field of flexible electronics, which rely on their elasticity and flexibility. However, the knowledge on such aspects is rather limited. Here, taking the four most typical MXenes, namely, Ti2CTx, Ti3C2Tx, Nb2CTx and Nb4C3Tx (T = O, OH and F) as examples, we evaluate their intrinsic in-plane stiffness and out-of-plane rigidity at the nanoscale with respect to their functional groups, chemical components and thickness by first-principles calculations. We find that both the in-plane stiffness (C) and out-of-plane bending rigidity (D) of MXenes are highly dependent on the thickness of MX and the surface functional groups. Specifically, the thickness and surface functionalization increase C and D significantly. The Foppl-von Karman numbers per area (C/D), as the flexibility descriptor, of MXenes are comparable with that of the MoS2 monolayer, indicating MXenes as a class of strong yet bendable materials. The effective thickness, the critical parameter bridging C and D, of MXenes is determined to be only two-thirds of the average layer spacing. This study provides a fundamental basis for quantifying the rigidity of MXenes at the nanoscale.

8.
J Chem Inf Model ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31935095

RESUMO

Methamphetamine (METH) is one of the highly addictive nonopioid psychostimulants, acting as a xenobiotic-associated molecular pattern (XAMP) to target TLR4 and activate microglia. However, the molecule recognition of METH by innate immune receptor TLR4/MD-2 is not well-understood. METH exists in two enantiomeric forms, and it is unclear whether the TLR4 innate immune recognition with METH is stereoselective. Herein, molecular dynamics (MDs) simulations were performed to dissect the recognition of (+)-METH and (-)-METH by TLR4/MD-2 at the atomic level. Amphetamine (AMPH), which is an analogue of METH, was also investigated for comparison. Computational simulations indicate that METH binds into the interaction interface between MD-2 as well as TLR4* that is from the adjacent copy of TLR4-MD-2, therefore stabilizing the active heterotetramer (TLR4/MD-2)2 complex. The calculated binding free energies and potential of mean force (PMF) values show that (-)-METH and (+)-METH have similar TLR4/MD-2 binding affinity. Further dynamics analyses of bindings with TLR4/MD-2 indicate that (-)-METH and (+)-METH behave similarly. Unlike the stereoselective neuron-stimulating activities of METH, no enantioselectivity was observed for METH interacting with TLR4/MD-2 complex as well as activating TLR4 signaling. Compared to METH, AMPH showed much weaker interactions with TLR4/MD-2, indicating that the substituted methyl group is critical in the molecular recognition of METH by TLR4/MD-2. In all, this study provides molecular insight into the innate immune recognition of METH, which demonstrates that METH could be nonenantioselectively sensed by TLR4/MD-2.

9.
J Appl Toxicol ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31922269

RESUMO

Iron oxide nanoparticles are nanomaterials that are used extensively in the biomedical field, but they are associated with adverse effects, including mitochondrial toxicity. Mitochondrial homeostasis is achieved through dynamic stability based on two sets of antagonistic balanced processes: mitochondrial biogenesis and degradation as well as mitochondrial fission and fusion. In this study, we showed that PEG-COOH-coated Fe3 O4 (PEG-Fe3 O4 ) nanoparticles induced mitochondrial instability in dendritic cells (DCs) by impairing mitochondrial dynamics due to promotion of mitochondrial biogenesis through activation of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) pathway, inhibiting mitochondrial degradation via decreased autophagy, and facilitating mitochondrial fragmentation involving increased levels of DRP1 and MFN2. The resulting reduced levels of dextran uptake, CD80, CD86 and chemokine receptor 7 (CCR7) suggested that PEG-Fe3 O4 nanoparticles impaired the functionally immature state of DCs. Autophagy inhibitor 3-methyladenine (3-MA) alleviated PEG-Fe3 O4 nanoparticle-induced mitochondrial instability and impairment of the functionally immature state of DCs due to unexpected enhancement of PGC1α/MFN2-mediated coordination of mitochondrial biogenesis and fusion.

10.
Cancer Med ; 9(4): 1495-1502, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31891230

RESUMO

We aimed to explore the molecular substrate underlying EGFR-TKI resistance and investigate the effects of N-acetylcysteine (NAC) on reversing EGFR-TKI resistance. In the current research, the effects of NAC in combination with gefitinib on reversing gefitinib resistance were examined using CCK-8 assay, combination index (CI) method, matrigel invasion assay, wound-healing assay, flow cytometry, western blot, and quantitative real-time PCR (qRT-PCR). CCK8 assay showed that NAC plus gefitinib combination overcame EGFR-TKI resistance in non-small cell lung cancer (NSCLC) cells by lowering the value of half maximal inhibitory concentration (IC50). CI calculations demonstrated a synergistic effect between the two drugs (CI < 1). Matrigel invasion assay and wound healing assay demonstrated a decrease in migration and invasion ability of PC-9/GR cells after NAC and gefitinib treatment. Flow cytometry displayed enhanced apoptosis in the combination group. Western blot and qRT-PCR revealed that increased E-cadherin and decreased vimentin in the combination group. When PP2 was administered with gefitinib, the same effects were seen. Our findings suggest that NAC could restore the sensitivity of gefitinib-resistant NSCLC cells to gefitinib via suppressing Src activation and reversing epithelial-mesenchymal transition.

11.
Cancer Lett ; 474: 36-52, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31931030

RESUMO

Tumor-associated macrophages (TAMs) are important immunocytes associated with cancer metastasis. However, whether TAMs play a dominant role in mediating CXCL12/CXCR4-induced liver metastasis of colorectal cancer (CRC) remains unexplored. Herein, we found that CD206+ TAMs, which infiltrated at the invasive front, were correlated with CXCR4 expression and liver metastasis of CRC in clinical specimens. Several miRNAs (miR-25-3p, miR-130b-3p, miR-425-5p), upregulated in CRC cells by activation of the CXCL12/CXCR4 axis, could be transferred to macrophages via exosomes. These exosomal miRNAs induced M2 polarization of macrophages by regulating PTEN through activation of PI3K/Akt signaling pathway. In turn, M2 polarized macrophages promoted cancer metastasis by enhancing epithelial-mesenchymal transition (EMT) and secreting vascular endothelial growth factor (VEGF). Co-culture of CRC cells with macrophages transfected with these miRNAs or treated with exosomes enhanced their metastatic capacity both in vitro and in vivo. Clinically, the serum levels of exosomal miR-25-3p, miR-130b-3p and miR-425-5p were correlated with progression and metastasis of CRC. In conclusion, these results reveal a crucial role of exosomal miRNAs in mediating the crosstalk between CXCR4 overexpressing cancer cells and TAMs, providing potential therapeutic targets for circumventing liver metastasis of CRC.

12.
J Mater Chem B ; 8(5): 1033-1039, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31939981

RESUMO

Photothermal therapy following microscopic temperature detection can avoid overheating effects or insufficient heating, and thus improve therapeutic efficacy. In this study, biocompatible dual-functional nanoparticles (NPs) are constructed from polypyrrole (PPy) and rhodamine B (RB) by a one-step modified polymerization method. The polypyrrole serves as a photothemal agent, and rhodamine B acts as a temperature-sensing probe. The polypyrrole-rhodamine B (PPy-RB) NPs possess a high photothermal effect on irradiation by 808 nm laser, and a competent temperature sensitivity for the real-time temperature monitoring based on the emission intensity response of rhodamine B. After acting on HepG2 cells, the PPy-RB NPs can effectively induce cancer cell death, and the microscopic temperature is monitored by fluorescence feedback from rhodamine B during PTT by laser confocal microscopy. Hence, the proposed approach can supply a facile and promising way for the fabrication of effective theranostic nanoplatforms assisted by self-monitoring of cancer therapeutic processes.

13.
Sci Total Environ ; 708: 135156, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31780166

RESUMO

Fluoroquinolones (FQs) has caused increasing concerns regarding its potential environmental risks. However, their effects on bacterial community and microbial interactions in wetland system remains unclear. To verify these issues, a lab-scale constructed wetland exposed to low concentration FQs mixture was carried out for two months. The results showed that the removal efficiencies of COD and TP were negatively affected. FQs significantly increased the bacterial diversity and altered the overall bacterial community structure. Proteobacteria significantly decreased while Firmicutes exhibited opposite tendency (P < 0.05). Dechloromonas and Delftia, involved in phosphorus removal, decreased significantly (P < 0.05). Molecular ecological network analysis suggested that FQs promoted the network complexity and microbial interactions. A super module emerged at FQs and among-module connections were weakened obviously. Additionally, Nodes of Betaproteobacteria lost most interactions while Clostridia acquired more interactions at the presence of FQs. This study provided insights into how the bacterial community and their molecular ecological network respond to FQs in constructed wetland system.

14.
Cell Cycle ; 19(1): 39-52, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31774373

RESUMO

Preeclampsia (PE) is a pregnancy-specific syndrome that substantially leads to maternal and fetal mortality. Multiple factors contribute to the disease, but the exact pathogenesis still remains elusive. Here we explored the roles of lncRNA MALAT1 and miR-206 in PE. qRT-PCR was applied to measure mRNA levels of MALAT1 and miR-206 in the placenta of PE patients. Scratch wound healing assay and transwell invasion assay were conducted to test the effects of MALAT1 and miR-206 on migration and invasion of trophoblast cells. In addition, we validated MALAT1/miR-206 and miR-206/IGF-1 interactions with dual luciferase reporter assay. Western bot was used to detect protein expressions of IGF-1, p-PI3K, PI3K, p-Akt and Akt. We found that MALAT1 was decreased but miR-206 was increased in the placenta of patients with PE. Inhibition of MALAT1, knockdown IGF-1, or miR-206 mimics suppressed the trophoblast cells migration and invasion, while overexpression of MALAT1, IGF-1 or miR-206 inhibitors exhibited opposite effects. Further, miR-206 was confirmed as a direct target of MALAT1. Besides, miR-206 inhibited IGF-1 expression by directly binding to the 3'UTR. Mechanistically, our study demonstrated that MALAT1 regulates IGF-1/PI3K/Akt signaling via miR-206. Together, these results suggest that MALAT1 and miR-206 play important roles in PE. MALAT1 regulates miR-206/IGF-1 axis, thereby modulating trophoblast cells migration and invasion through PI3K/Akt signal pathway. These results show light on the underlying mechanisms of PE and provide potential targets for PE therapy.Abbreviations: PE: Preeclampsia; lncRNA: Long-non-coding RNA; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; IGF-1: Insulin-like growth factor 1; PI3k: Phosphatidylinositol-4, 5-bisphosphate 3-kinase; Akt: Protein kinase B; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; qRT-PCR: Quantitative Reverse Transcription polymerase chain reaction; shRNA: Short hairpin RNA; siRNA: Small interfering RNA; EMT: Epithelial-mesenchymal transition.

15.
Sci Total Environ ; 708: 135095, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31812429

RESUMO

To investigate the distribution characteristics of typical toxic elements in different mineralogical phases of fly ash is of significance when fly ash is comprehensively utilized. In this study, lignite fly ash can be preliminarily separated into three mineralogical phases: unburned lignite, iron microbeads and aluminate-silicate microbeads by two methods namely screening and dry magnetic separation. Then, the aluminate-silicate microbeads were subjected to two-step leaching. The first step was to investigate whether toxic elements migrated easily in the environment by column leaching test. In the second step, the aluminate-silicate microbeads were stripped from the surface of the particles to the internal by the acid-base combined leaching method, then the structural characteristics of the product and the trend of toxic elements content were explored. The results showed that there were few toxic elements in unburned lignite and the toxic elements Cr, Ni, Mo and Cd had a relatively high proportion in the iron microbeads. Column leaching results showed that the toxic elements V, Cr, Mn, Co, Cu, Hg and Pb had higher leaching rates, which proved that these elements were significantly enriched on the surface of the particles and easily migrated in the environment. Cr, Mo, Cd and W were highly enriched in the quartz-mullite mixture. Mn, Co, Ni, Cu, Zn and As were highly enriched in the amorphous component. The toxic elements exhibited different leaching rules during the acid-base combined leaching process revealing the complex embedded relationship with constant elements.

16.
Biosens Bioelectron ; 150: 111841, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735621

RESUMO

Site-specific recognition of DNA modification or the formation of noncanonical structures has important applications in molecular biology, disease diagnosis, and gene expression analysis. In this study, we introduce a guanine-guided sensing tool using a terbium(III)-platinum(II) complex (TPC) as a time-resolved luminescence probe to site-specifically recognize DNA modification and i-motif formation in aqueous solution. The probe is composed of a TbIII center as the luminescent reporter and two PtII units as the receptor for guanine (G) nucleobase. TPC exhibits remarkable reaction selectivity for guanine nucleotides over other nucleotides, giving rise to a significant increase in luminescence. The luminescence enhancement of TPC is mainly attributed to an energy transfer from G base to the TbIII center after the specific coordination of PtII with N7 of guanine (N7-G), which would be facilitated by the phosphates through promoting the departure of coordinated water and bringing G closer to TbIIIvia noncovalent interactions. Based on such sensing feature, the enhanced luminescence of TPC sensitized by G nucleotides can correspondingly decrease upon N7-G modifications of DNA or i-motif formation through constructing simple guanine-guided sensing tools. This probe would provide a useful strategy for site-specific recognition of DNA for extensive purposes.

17.
Vaccine ; 38(3): 549-561, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31740094

RESUMO

Mycoplasma bovis is an important pathogenic bacterium affecting cows and cattle. Clinically, an inactivated vaccine of M. bovis is mainly used to prevent infection by this bacterium. The changes that occur in the antigen when M. bovis is continuously passaged in vitro remain unknown. Therefore, we performed an in vitro serial passage of the M. bovis NM-28 strain, which was isolated and identified in our laboratory. An isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics method was used to analyse the differences between generations 3 and 60. Many major membrane proteins or protective antigens reported in the literature did not exhibit changes between these generations. We found an imbalance between growth rate and nutrition in the 60th generation. The proteomics results were verified by western blotting and real-time PCR. Growth curves were also prepared based on colony-forming units (CFUs) between the 3rd and 60th generations. The number of colonies in the 60th generation in the stationary phase was 5 × 109 CFU mL-1, which was 10-fold higher than that in the 3rd generation. The 60th generation of the NM-28 strain can be used as an inactivated vaccine strain of M. bovis to lower production costs compared to use of the 3rd generation.

18.
Chem Biol Drug Des ; 95(1): 58-65, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31452330

RESUMO

In this study, a peptide-drug conjugate was designed and synthesized by connecting a transferrin receptor (TfR)-targeted binding peptide analog BP9a (CAHLHNRS) with doxorubicin (DOX) through N-succinimidyl-3-maleimidopropionate (SMP) as the cross-linker. Confocal laser scanning microscopy results indicated that free DOX mainly accumulated in the nuclei of both TfR overexpressed HepG2 hepatoma cells and L-O2 normal liver cells expressing low level of TfR; most of the BP9a-DOX conjugate displayed cytoplasmic location, and its cellular uptake by HepG2 cells was obviously reduced by TfR blockage test. Nevertheless, the cellular uptake of this conjugate by L-O2 cells was much less than that of free DOX. Meanwhile, the BP9a-DOX conjugate exhibited lower in vitro antiproliferative activity against HepG2 cells than free DOX, but its cytotoxic effect on L-O2 cells was decreased compared with that of free DOX. These results suggest that BP9a could be applied as a potential TfR-targeted peptide vector for selective drug delivery.

19.
Toxicol Lett ; 319: 138-147, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730887

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that can be induced by heavy metals such as lead. However, there is limited information on the role of blood-brain barrier (BBB) in lead induced AD-like pathology. This study investigates the potential mechanism of lead exposure aggravating the progression of Alzheimer's disease in mice through the BBB. 200 mg/L and 500 mg/L lead acetate were given to C57BL/6J and APP/PS1 mice through drinking water from a week before mating, until the offspring were 7-months-old. 8 female juvenile mice in each group were selected for this investigation. Lead exposure increased blood lead concentration which revealed the internal exposure level, accelerated Aß1-42 deposition in APP/PS1 mouse cortexes and abnormal change in Zonula Occludin-1 (ZO-1) and Claudin-5 protein. It also increased the expression of p-tau in both the C57BL/6J and APP/PS1 mice, and decreased mRNA and protein expression in low-density lipoprotein receptor (LRP-1). Additionally, it increased the mRNA and protein expression of amyloid beta precursor protein (APP) and beta secretase 1 (BACE-1). The activated astrocytes increased in the brains of APP/PS1 mice, and coalesced around the Aß1-42 deposition after lead exposure. The main vessels in deutocerebrum were attached with Aß1-42 deposition. These results offer insight into the mechanism of preventing lead induced AD through cerebrovascular pathways.


Assuntos
Doença de Alzheimer/patologia , Barreira Hematoencefálica/patologia , Exposição Ambiental/efeitos adversos , Chumbo/toxicidade , Doença de Alzheimer/induzido quimicamente , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Claudina-5/efeitos dos fármacos , Claudina-5/genética , Progressão da Doença , Feminino , Chumbo/sangue , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/toxicidade , Proteína da Zônula de Oclusão-1/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/genética
20.
Nanoscale ; 12(2): 763-771, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31830197

RESUMO

Electrochemical pseudocapacitors store energy via intercalation or electrosorption and faradaic charge transfer with redox reactions. MXenes represent the promising intercalation pseudocapacitive electrode materials for supercapacitors due to their ultrahigh theoretical capacitances. Achieving a high capacitance will greatly advance the large-scale applications as in power grids. However, a rational design concept has not been exploited to achieve the theoretical limit. Here, we show how interlayer engineering helps to achieve the limit. Interlayer engineering in this manner simultaneously creates a broadened yet uniform interlayer spacing - providing a "highway" for fast ion diffusion, and incorporates heteroatoms with lower electronegativity - offering "trucks" (redox active sites) on such a "highway" for speeding charge transfer, enabling high capacitance. Following the concept, through annealing the as-prepared Ti3C2Tx MXene under an ammonia atmosphere, the engineered MXene delivers much improved capacitance with excellent rate performance and cyclability. The overall performance of the engineered MXene outperforms that of all other pseudocapacitive electrode materials.

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