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Oncol Rep ; 43(3): 851-863, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020213

RESUMO

Efficient enrichment and transmembrane transport of cytotoxic reagents are considered to be effective strategies to increase the efficiency and selectivity of antitumor drugs targeting solid tumors. In the present study, a recombinant protein ABD­LDP­Ec consisting of the albumin­binding domain (ABD), the apoprotein (LDP) of lidamycin (LDM) and an EGFR­targeting oligopeptide (Ec) was prepared by DNA recombination and bacterial fermentation, and was integrated with the enediyne chromophore (AE) of lidamycin to generate its enediyne­integrated analogue ABD­LDP­Ec­AE. ABD­LDP­Ec exhibited high binding capacity to both albumin and EGFR­positive pancreatic cancer cells, and was internalized into the cytoplasm through receptor­mediated endocytosis and albumin­driven macropinocytosis of K­ras mutant cells. In animal experiments, ABD­LDP­Ec demonstrated notable selective distribution in pancreatic carcinoma xenografts by passive targeting of albumin captured in the blood and was retained in the tumor for 48 h. ABD­LDP­Ec and ABD­LDP­Ec­AE exhibited inhibitory activity in cell proliferation and AsPC­1 xenograft growth, and ABD­LDP­Ec­AE increased the tumor growth inhibition rate by 20% compared with natural LDM. The results indicated that the introduction of ABD­based multi­functional drug delivery may be an effective approach to improve the efficacy of antitumor drugs, especially for K­ras mutant cancers.

3.
Biosens Bioelectron ; 152: 112001, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32056732

RESUMO

In this study, we developed a convenient way to construct a flexible enzymatic electrode with excellent stability and electrochemical performance for implanted glucose monitoring. The electrode was constructed through the co-immobilization of the glucose oxidase micro-particles (GOD MPs) and multi-wall carbon nanotubes (CNT) on the inner surface of a gradient-structured hollow fiber membrane (GHM), where CNT improved the electron transport efficiency and GHM controlled the transfer of substances and interferences. GOD MPs showed higher stability under various operation conditions than the free enzymes due to the MnCO3 template method, which enabled the biosensor to remain relative sensitivity at >86% over 9 days. The GOD MPs biosensor also showed high selectivity, reproducibility, and linear sensing range from 0 mM to 24 mM (R2 = 0.9993) with a current sensitivity of 25 nA/mM. The combination of porous-structured membrane and the flexible CNT meshes ensures the electrical connections and sensing accuracy of the biosensor under the deformation status. In-vivo experiments showed reliable current responses to variations in blood glucose concentrations that were consistent with tail blood test results. This co-immobilization of enzyme micro-particles in the 3D porous structure method developed a bio-composite platform technology towards the applications in flexible sensing and implantable medical devices.

4.
Nanotechnology ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059208

RESUMO

Hydroxyapatite whisker (w-HA) was synthesized via dissolution-precipitation by forming calcium-ethylene diamine tetra acetic acid (Ca-EDTA) complexing. Hydroxyapatite whisker was formed with precipitation of Ca2+along the c-axis due to the space inhibition of Ca-EDTA complex during refluxing. The op-w-HA (oligomeric poly(lactic acid) modified w-HA), p-w-HA (poly(L-lactide) modified w-HA) and pc-w-HA (poly(L-lactide) and cyclodextrin modified w-HA) were obtained via surface modification of w-HA. The particle size, surface charge and biocompatibility of theses modified w-HA particles were successfully adjusted. Among these materials, pc-w-HA exhibited nearly no toxicity, better adhesion to mesenchymal stem cells (MSCs) (5 times better than w-HA) and greater osteoinductivity among the obtained materials (40% of mineralized extracellular matrix higher than w-HA) due to better surface properties. Different kind of powders (w-HA, p-w-HA and pc-w-HA) were blended with PLLA (poly(L-Lactide)) to form composite material, respectively. pc-w-HA/PLLA composite showed better mechanical properties (tensile strength of the pc-w-HA/PLLA composite was 22.3% higher than that of w-HA/PLLA), which could be attributed to mainly two factors including the structure preservation of w-HA bundles and pseudorotaxane linkage between PLA-cyclodextrin and PLLA. The MSCs adhesion of the pc-w-HA/PLLA composite was much better due to balanced hydrophilicity/hydrophobicity and surface roughness. This surface modification method could provide a new and effective strategy for the preparation of bioresorbable composite material with great bioactivity and mechanical property, which has great potential in medical device industry.

5.
J Affect Disord ; 266: 201-206, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-32056877

RESUMO

BACKGROUND: Maternal psychopathology can be an important factor associated with psychological adjustment of children. However, there is limited research on long-term impacts of maternal posttraumatic stress disorder (PTSD) on children's mental health. This study examined how PTSD trajectories of women exposed to the 2008 Wenchuan earthquake in China predicted their children's mental health symptoms 10 years after the earthquake. METHODS: 410 dyads of mothers and their adolescent children who exposed to the Wenchuan earthquake were investigated at 12 and 18 months post-earthquake. While the mothers completed measures of earthquake exposure and PTSD symptoms, the children completed measures of earthquake exposure, PTSD, depression and anxiety symptoms. In the 10-year follow up, 257 out of the 410 children completed measures of PTSD, depression and anxiety symptoms. Data were analyzed using linear regression. RESULTS: Four trajectories of maternal PTSD symptoms were identified: (a) chronic (9.5%); (b) resilient (66.3%); (c) delayed (7.6%); and (d) recovery (16.6%); More importantly, the findings demonstrated that children whose mothers experienced chronic PTSD reported higher level of PTSD and anxiety symptoms 10 years after the earthquake. LIMITATIONS: Only two waves of maternal PTSD were collected, self-reported tools other than clinical reviews were used to collect data, and a significant proportion of participants did not respond at the 10-year follow-up. CONCLUSIONS: This study identified maternal PTSD trajectories following the Wenchuan earthquake. Chronic PTSD symptoms in mothers were associated with increased risk of children's PTSD and anxiety 10 years after the earthquake.

7.
Br J Pharmacol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32022249

RESUMO

BACKGROUND AND PURPOSE: Regulating macrophage-hepatocyte crosstalk through P2X7 receptor (P2X7R) has led to the emergence of new pharmacologic strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu) purified from Polygonum multiflorum modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis. EXPERIMENTAL APPROACH: Alcoholic hepatosteatosis was established by intragastrically administering ethanol to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS/ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7R. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 h prior to LPS/ATP stimulation. HepG2 cells were cultured with the conditioned medium from the LPS/ATP-activated THP-1 macrophages. KEY RESULTS: Knockdown or overexpression of P2X7R in THP-1 macrophages altered the release of mature IL-1ß. P2X7R gene expression in the THP-1 macrophages modulated lipid metabolism in the HepG2 cells via LKB-AMPK axis. 2354glu significantly ameliorated hepatosteatosis in mice after alcohol expose by regulating LKB1-AMPK-SREBP1 axis and its target genes. The suppression of P2X7R activation by 2354glu administration inhibited IL-1ß release, and reduced macrophage and neutrophil infiltration. The expression of P2X7R, caspase-1 and NF-κB, the release of IL-1ß, calcium influx and PI uptake were reduced by 2354glu in macrophages stimulated with LPS/ATP. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced, when HepG2 cells were cultured with conditioned medium from LPS/ATP-activated THP-1 macrophages pretreated with 2354glu. CONCLUSIONS AND IMPLICATIONS: Alteration of P2X7R in macrophages might regulate lipid accumulation in hepatocytes during alcoholic hepatosteatosis, and 2354glu might be a promising candidate that targets P2X7R in macrophages interacting with hepatocytes during alcoholic hepatosteatosis.

8.
Redox Biol ; 29: 101402, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31926626

RESUMO

Oxidative stress is a major cause of adverse outcomes in preeclampsia (PE). Ferroptosis, i.e. programmed cell death from iron-dependent lipid peroxidation, likely mediates PE pathogenesis. We evaluated specific markers for ferroptosis in normal and PE placental tissues, using in vitro (trophoblasts) and in vivo (rat) models. Increase in malondialdehyde content and total Fe2+ along with reduced the glutathione content and glutathione peroxidase activity was observed in PE placenta. While the trophoblasts experienced death under hypoxia, inhibitors of ferroptosis, apoptosis, autophagy, and necrosis increased the cell viability. Microarrays, bioinformatic analysis, and luciferase reporter assay revealed that upregulation of miR-30b-5p in PE models plays a pivotal role in ferroptosis, by downregulating Cys2/glutamate antiporter and PAX3 and decreasing ferroportin 1 (an iron exporter) expression, resulting in decreased GSH and increased labile Fe2+. Inhibition of miR-30b-5p expression and supplementation with ferroptosis inhibitors attenuated the PE symptoms in rat models, making miR-30b-5p a potential therapeutic target for PE.

9.
Small ; : e1906830, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31971669

RESUMO

Metal hydroxide nanomaterials are widely applied in the energy and environment fields. The electrochemical performance of such materials is strongly dependent on their crystal phases. However, as there are always multiple factors relating to the phase-dependent electrochemistry, it is still difficult to identify the determining one. The well-defined crystal phases of α- and ß-FeOOH nanorods are characterized through the transmission electron microscopy by a series of rotation toward one rod, where the cross-section shape and the growth direction along the [001] crystalline are first verified for 1D FeOOH nanostructures. The electrosensitivity of the two materials toward Pb(II) is tested, where α-FeOOH performs an outstanding sensitivity whilst it is only modest for ß-FeOOH. Experiments via Fourier transform infrared spectroscopy, X-ray absorption fine structure (XAFS), etc., show that α-FeOOH presents a larger Pb(II) adsorption capacity due to more surficial hydroxyl groups and weaker PbO bond strength. The reaction kinetics are simulated and the adsorption capacity is found to be the determining factor for the distinct Pb(II) sensitivities. Combining experiment with simulation, this work reveals the physical insights of the phase-dependent electrochemistry for FeOOH and provides guidelines for the functional application of metal hydroxide nanomaterials.

10.
J Agric Food Chem ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31989819

RESUMO

Squalene has wide applications in the food and pharmaceutical industries. Engineering microbes to produce squalene is a promising alternative for traditional production approaches. In this study, squalene production was enhanced to 978.24 mg/L through stepwise overexpression of the enzymes that catalyze acetyl-CoA to squalene. Subsequently, to increase the activity of HMG-CoA reductase and alleviate the high dependence on NADPH, the HMG-CoA reductase (NADH-HMGR) from Silicibacter pomeroyi, highly specific for NADH, was introduced, which increased squalene production to 1086.31 mg/L. Native ethanol dehydrogenase ADH2 and acetaldehyde dehydrogenase ADA from Dickeya zeae were further overexpressed, which enhanced the capability to utilize ethanol for squalene synthesis and endowed the engineered strain with greater adaptability to high ethanol concentrations. Finally, a remarkable squalene production of 9472 mg/L was obtained from ethanol via carbon source-controlled fed-batch fermentation. This study will greatly accelerate the process of developing microbial cell factories for squalene production.

11.
JAMA Dermatol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31968061

RESUMO

Importance: It is necessary to determine whether established clinical markers of vitiligo are associated with disease progression, severity, and patient prognosis. Objective: To evaluate the utility of trichrome sign, confetti-like depigmentation, and Koebner phenomenon in assessing disease progression, severity, and prognosis in patients with vitiligo. Design, Setting and Participants: In this prospective cohort study, 425 patients with vitiligo were recruited from the outpatient department of Huashan Hospital, Fudan University in Shanghai, China, from September 1, 2016, to May 13, 2019. Main Outcomes and Measures: Disease progression, severity, and prognosis during a 12-month period. The active stage of vitiligo was defined as Vitiligo European Task Force spreading score of at least 1 or more lesions appearing as hypomelanotic with poorly defined borders using a Wood light. Progression was assessed using the Vitiligo Area Scoring Index (VASI) and serum CXCL10 level measurement. Results: Of the 458 enrolled patients, 425 (235 female [55.3%]; mean [SD] age, 30.9 [10.2] years) completed the 12-month follow-up. Of the 425 patients (224 with no clinical marker and 201 with at least 1 clinical marker) included in this analysis, the proportion in the active stage of the disease was significantly higher in the cohort with at least 1 clinical marker compared with the cohort without any clinical marker at the first visit (196 of 201 [97.5%] vs 159 of 224 [71.0%]; P < .001) and at 3-month follow up (91 of 201 [45.3%] vs 52 of 224 [23.2%]; P < .001). The proportion of patients with rapid disease progression was also higher in the group with at least 1 clinical marker at 1-month follow-up (142 of 201 [70.6%] vs 60 of 224 [26.8%]; P < .001) and 3-month follow-up (63 of 201 [31.3%] vs 9 of 224 [4.0%]; P < .001). The improvement in VASI score (SD) was significantly smaller among patients with at least 1 clinical marker compared with those without any clinical marker at 6 months (mean [SD], 0.14 [0.12] vs 0.23 [0.21]; P = .02), at 9 months (mean [SD], 0.29 [0.19] vs 0.44 [0.25]; P = .03), and at 12 months (mean [SD], 0.47 [0.21] vs 0.63 [0.23]; P = .03). Conclusions and Relevance: The presence of a clinical marker in patients with vitiligo may be associated with worse prognosis and rapid disease progression. Patients with multiple clinical markers may require more intensive treatment.

12.
Life Sci ; 245: 117356, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991181

RESUMO

AIMS: NPY-Y1R plays an important role in dietary regulation. Although germline knockdown of NPY-Y1R in mice alleviates high-fat-diet-induced obesity and increases CPT1α levels in the liver, the role of the Y1 receptor in specific tissues has not been studied. MAIN METHODS: MCD diet is the most widely used method to establish a model of lean NASH in a short time. We therefore evaluated the role of liver NPY-Y1R in NASH progression. KEY FINDINGS: In mice with liver-specific knockout of NPY-Y1R (LivKO) and wild-type control littermates fed MCD diet for 4 weeks, NPY-Y1R deficiency significantly decreased body and liver weight. Moreover, NPY-Y1R deletion protected mice against hepatic steatosis and injury. LivKO decreased TG, TC, and FFA levels in the liver and alanine aminotransferase activity in plasma. To clarify the mechanism, we evaluated the key enzymes involved in triglyceride hydrolase and fatty-acid oxidase. Expression of ATGL, CPT1α, and ACO was significantly increased in LivKO mice, whereas expression of fatty-acid synthase was significantly decreased. mRNA expression analysis revealed a marked reduction of genes involved in de-novo lipogenesis and monosaturated fatty-acid synthesis, including sterol-regulatory element-binding protein 1c and fatty-acid synthase. Moreover, liver injury-related factors were significantly decreased in LivKO mice, such as TNF-α, inducible nitric oxide synthase, and MCP-1. Thus, NPY-Y1R deficiency in the liver alleviates lipid deposition and injury. However, NPY-Y1R did not affect inflammation and fibrosis. SIGNIFICANCE: NPY-Y1R deficiency in the liver directly suppresses not only hepatic steatosis, but also liver injury, and thus provides a treatment option for NASH.

13.
Microbiologyopen ; 9(1): e00955, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31782623

RESUMO

Lake anchovy (Coilia ectenes taihuensis) is a sedentary, dominant fish species that forms an unmanaged fishery in Taihu Lake, eastern China. The environment and developmental stage of lake anchovy are likely important drivers of their gut microbiome, which is linked to host health and development. To investigate the relationship between the gut microbiome and three defined factors (fish sex, fish body size, and the local habitat), high-throughput sequencing of the 16S ribosomal RNA gene was used to study the microorganisms of 184 fish samples and four water samples collected in Taihu Lake. Four dominant bacterial phyla (Proteobacteria, Firmicutes, Planctomycetes, and Cyanobacteria) were present in all fish samples. We compared the microbial communities of males and females and found that the relative abundance of Corynebacteriaceae was significantly higher in males than in females, while the opposite trend was detected for Sphingomonadaceae. We also discovered that the relative abundance of Firmicutes was positively correlated with fish body size and that the proportions of Proteobacteria and Tenericutes were lower in larger fish than in fish of other sizes. Finally, we found that the difference in microbial richness between eastern and northern Taihu Lake was the most marked. Lake anchovy was rich in Lactobacillus and Clostridium in the eastern site, while those in the northern site had the highest abundance of Sphingomonas and Methylobacterium, suggesting that the local habitat may also influence the intestinal microbiome. These findings will not only help researchers understand the community composition of the intestinal microflora of lake anchovy but also contribute to the protection of fish resources in Lake Taihu and the sustainable use of lake anchovy.

14.
ACS Appl Mater Interfaces ; 12(1): 1378-1386, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31818093

RESUMO

Graphene aerogel (GA) as a rising multifunctional material has demonstrated great potential for energy storage and conversion, environmental remediation, and high-performance sensors or actuators. However, the commercial use of GA is obstructed by its fragility and high cost. Herein, by a simple stirring-induced foaming of the mixed aqueous solutions of natural rubber latex (NRL) and graphene oxide liquid crystal (GOLC), we obtained tough, ultralight (4.6 mg cm-3), high compressibility (>90%), and water-adhesive graphene/NRL hybrid aerogel (GA/NRL). Of particular note, the NRL particles are conformally wrapped by graphene layers to form a sandwichlike cell wall with a biomimetic rose-petal-like surface. These distinct hierarchical structures endow GA/NRL not only with high toughness to bear impact, torsion (>90°), and even ultrasonication but also with strong adhesion to water. As proof of concept, the utilization of the as-prepared GA/NRL for collecting water droplets suspended in moist air and its improved solar-thermal harvest capacity have been demonstrated. This facile, green, and cost-effective strategy opens a new route for tailoring the microstructure and functionality of GA, which will facilitate its large-scale production and commercial application.

15.
Metab Eng ; 57: 151-161, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31711816

RESUMO

Engineering microbes to produce terpenes from renewable feedstock is a promising alternative to traditional production approaches. Generally, terpenes are not readily secreted by microbial cells, and their distribution within cells is usually obscure and often a restricting factor for the overproduction of terpenes due to the storage limitation. Here, we determined that squalene overproduced in the cytoplasm of Saccharomyces cerevisiae was distributed in a form similar to oil droplets. Interestingly, these suspected oil droplets were confirmed to be inflated peroxisomes that were swollen along with the production of squalene, indicating that peroxisomes in S. cerevisiae are dynamic depots for the storage of squalene. In view of this, harnessing peroxisomes as subcellular compartments for squalene synthesis was performed, achieving a 138-fold improvement in squalene titer (1312.82 mg/L) relative to the parent strain, suggesting that the peroxisome of S. cerevisiae is an efficient subcellular factory for the synthesis of terpenes. By dual modulation of cytoplasmic and peroxisomal engineering, the squalene titer was further improved to 1698.02 mg/L. After optimizing a two-stage fed-batch fermentation method, the squalene titer reached 11.00 g/L, the highest ever reported. This provides new insight into the synthesis and storage of squalene in peroxisomes and reveals the potential of harnessing peroxisomes to overproduce terpenes in S. cerevisiae through dual cytoplasmic-peroxisomal engineering.

16.
Biol Blood Marrow Transplant ; 26(2): 242-253, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31682978

RESUMO

Although thymus-independent donor-derived T cell expansion may determine the occurrence of graft-versus-host disease (GVHD) and relapse after transplantation, the characteristics and dynamics of the expansion process remain unclear. To address this issue, we monitored T cell receptor ß repertoire at day 0, day 28, and day 61 after transplantation in 30 patients with hematologic malignancies by next-generation sequencing. The clonality index showed an increasing clonality over time (P = .001). The top 200 clonotypes accounted for more than half of the total clonotypes (median frequency, 63.55%) at day 61, and there was a remarkable overlapping between the top 200 clonotypes of each repertoire and its former repertoire (>50%). A normalized index, called the T Cell Response Index (TCRI), was designed on the basis of rank-shift analysis to quantify antigen-driven expansion. The TCRI during the first month was not related to relapse or GVHD (P> .05), whereas the TCRI during the second month was related to relapse (P = .006). Recipients with a TCRI below 1.0 during the second month had a higher cumulative relapse rate (31.25% versus 0%, P = .0323) and had a lower 1-year survival rate (56.25% versus 78.57%, P = .281). The clonotypes with strong competitiveness in the second month in the nonrelapse group preferentially used TRBV2, TRBV12-3, TRBJ1-1 and TRBJ1-5 segments (P< .01). In conclusion, homeostatic expansion predominates in the first month due to nonspecific T cell proliferation, whereas antigen-driven expansion predominates in the second month and results in a graft-versus-tumor (GvT) effect. Moreover, TCRI could serve as a quantitative indicator of GvT against relapse within the first year. The difference in V and J segment usage reveals that T cells responsible for potent GvT effect are similar among patients.

20.
Phytomedicine ; 66: 153113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790901

RESUMO

BACKGROUND: Natural killer (NK) cells play important roles in immune responses and have been wildly used in immunotherapy. Nevertheless, some limitations remain. It is urgent to explore novel and safe strategies to enhance NK cell activity. PURPOSE: The aim of this study was to investigate the immuno-stimulatory effects and to reveal the molecular mechanism of LJ101019C, a derivative of a natural small-molecule compounds cajanine, on NK cells. METHODS: Cell proliferation was examined by CCK8 assay, then we used the cytotoxicity detection kit to detect the cytotoxicity of NK cells. The change of cell cycle, intracellular reactive oxygen species (ROS) level and mitochondrial mass were evaluated by FACS and Operetta high-content image analysis, respectively. Furthermore, the IFN-γ secretion of NK cells were measured by ELISA. The Kv1.3 protein expression and function were detected by western blot and patch-clamp technique, respectively. The role of Kv1.3 in AKT/mTOR pathway activation was determined by western blot. RESULTS: The results showed that LJ101019C at relatively low concentrations (0.05-0.1 µM) significantly increased the proliferation of NK cells. And 1 µM LJ101019C could elevate the proportion of NK cells in the S-phase of the cell cycle (*p < 0.1). Furthermore, the cytotoxic effects of NK cells targeting MIA PaCa-2 cells were significantly enhanced by 0.1 and 1 µM LJ101019C, and were associated with the enhanced secretion of IFN-γ by NK cells (*p < 0.1; **p < 0.05). 0.1 and 1 µM LJ101019C increased intracellular levels of ROS (**p < 0.05), and 0.1 µM LJ101019C elevated mitochondrial mass (*p < 0.1). Electrophysiological recordings indicated that LJ101019C led to a remarkably increase the Kv1.3 current density. Moreover, western blot results indicated that LJ101019C elevated Kv1.3 protein expression and activated AKT/mTOR signaling via increasing the expression of Kv1.3 in NK cells. CONCLUSION: LJ101019C increases the proliferation and the cytotoxicity of NK cells at relatively low concentrations. The mechanism is the activation of AKT/mTOR signaling pathway driven by up-regulation of Kv1.3 in NK cells. These suggest LJ101019C is a promising candidate for improving the efficacy of NK cell-based immunotherapies.

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