In the environment, nanoplastic particles, such as nanopolystyrene, potentially cause toxicity on organisms at various aspects. We here employed endpoints of lifespan and aging-related phenotypes to ...further investigate the possible long-term effects of nanopolystyrene (100 nm) in Caenorhabditis elegans. After exposure from L1-larvae to adult day-3, nanopolystyrene at high concentrations (100 and 1000 μg/L) reduced the lifespan. Although nanopolystyrene (1 or 10 μg/L) did not affect the lifespan, nanopolystyrene (1 or 10 μg/L) could induce the more severe intestinal reactive oxygen species (ROS) production and decrease in locomotion behavior during the aging process compared with control. Moreover, nanopolystyrene exposure could cause the severe decrease in expressions of some immune response genes, hsp-6 gene, and genes encoding manganese-superoxide dismutases (Mn-SODs) during aging process, suggesting the severe suppression in innate immune response, inhibition in antioxidation defense system, and suppression in mitochondrial unfolded protein response (mt UPR) by nanopolystyrene. Our results highlight the potential of long-term nanopolystyrene exposure in reducing longevity and in affecting health state during the aging process in environmental organisms.
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•We investigated the long-term effects of nanoplastics on nematodes.•Nanopolystyrene at high concentrations reduced the lifespan.•Nanopolystyrene (1–10 μg/L) induced adverse effects during aging process.•Our results suggest that nanoplastics may affect health quality during aging process.
In order to realize high contrast imaging with portable devices for potential mobile healthcare, we demonstrate a hand-held smartphone based quantitative phase microscope using the transport of ...intensity equation method. With a cost-effective illumination source and compact microscope system, multi-focal images of samples can be captured by the smartphone's camera via manual focusing. Phase retrieval is performed using a self-developed Android application, which calculates sample phases from multi-plane intensities via solving the Poisson equation. We test the portable microscope using a random phase plate with known phases, and to further demonstrate its performance, a red blood cell smear, a Pap smear and monocot root and broad bean epidermis sections are also successfully imaged. Considering its advantages as an accurate, high-contrast, cost-effective and field-portable device, the smartphone based hand-held quantitative phase microscope is a promising tool which can be adopted in the future in remote healthcare and medical diagnosis.
Study Objective
The objective of the present study was to examine the frequency distribution of five single‐nucleotide polymorphisms (SNPs; rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, ...and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL).
Design
This was a retrospective single‐center study, and all analyses were exploratory.
Setting
Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Patients
One hundred and forty pediatric patients with ALL.
Intervention
All patients were treated according to the Chinese Children's Leukemia Group (CCLG)‐ALL 2008 protocol.
Measurements and Main Results
Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations; significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations; and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p < 0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose‐normalized concentrations of MTX in serum at 24 h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p = 0.04). Compared with children with AA‐CC‐AA‐CC‐CC diplotype, a significantly higher risk of relapse was observed in children with AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes (p = 0.03 and 0.003, respectively).
Conclusions
The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes were significantly associated with higher risk of relapse of ALL.
Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining macromolecules and trafficking immune ...cells from the central nervous system (CNS) into cervical lymph nodes (CLNs), and thus represent a potential therapeutic target for treating neurodegenerative and neuroinflammatory diseases. However, the roles of MLVs in brain tumor drainage and immunity remain unexplored. Here we show that dorsal MLVs undergo extensive remodeling in mice with intracranial gliomas or metastatic melanomas. RNA-seq analysis of MLV endothelial cells revealed changes in the gene sets involved in lymphatic remodeling, fluid drainage, as well as inflammatory and immunological responses. Disruption of dorsal MLVs alone impaired intratumor fluid drainage and the dissemination of brain tumor cells to deep CLNs (dCLNs). Notably, the dendritic cell (DC) trafficking from intracranial tumor tissues to dCLNs decreased in mice with defective dorsal MLVs, and increased in mice with enhanced dorsal meningeal lymphangiogenesis. Strikingly, disruption of dorsal MLVs alone, without affecting basal MLVs or nasal LVs, significantly reduced the efficacy of combined anti-PD-1/CTLA-4 checkpoint therapy in striatal tumor models. Furthermore, mice bearing tumors overexpressing VEGF-C displayed a better response to anti-PD-1/CTLA-4 combination therapy, and this was abolished by CCL21/CCR7 blockade, suggesting that VEGF-C potentiates checkpoint therapy via the CCL21/CCR7 pathway. Together, the results of our study not only demonstrate the functional aspects of MLVs as classic lymphatic vasculature, but also highlight that they are essential in generating an efficient immune response against brain tumors.
Cardiac endothelium communicates closely with adjacent cardiac cells by multiple cytokines and plays critical roles in regulating fibroblasts proliferation, activation, and collagen synthesis during ...cardiac fibrosis. E26 transformation-specific (ETS)-related gene (ERG) belongs to the ETS transcriptional factor family and is required for endothelial cells (ECs) homeostasis and cardiac development. This study aims at investigating the potential role and molecular basis of ERG in fibrotic remodeling within the adult heart. We observed that ERG was abundant in murine hearts, especially in cardiac ECs, but decreased during cardiac fibrosis. ERG knockdown within murine hearts caused spontaneously cardiac fibrosis and dysfunction, accompanied by the activation of multiple Smad-dependent and independent pathways. However, the direct silence of ERG in cardiac fibroblasts did not affect the expression of fibrotic markers. Intriguingly, ERG knockdown in human umbilical vein endothelial cells (HUVECs) promoted the secretion of endothelin-1 (ET-1), which subsequently accelerated the proliferation, phenotypic transition, and collagen synthesis of cardiac fibroblasts in a paracrine manner. Suppressing ET-1 with either a neutralizing antibody or a receptor blocker abolished ERG knockdown-mediated deleterious effect in vivo and in vitro. This pro-fibrotic effect was also negated by RGD (Arg-Gly-Asp)-peptide magnetic nanoparticles target delivery of ET-1 small interfering RNA to ECs in mice. More importantly, we proved that endothelial ERG overexpression notably prevented pressure overload-induced cardiac fibrosis. Collectively, endothelial ERG alleviates cardiac fibrosis via blocking ET-1-dependent paracrine mechanism and it functions as a candidate for treating cardiac fibrosis.
Graphical abstract
• ERG is abundant in murine hearts, especially in cardiac ECs, but decreased during fibrotic remodeling.
• ERG knockdown causes spontaneously cardiac fibrosis and dysfunction.
• ERG silence in HUVECs promotes the secretion of endothelin-1, which in turn activates cardiac fibroblasts in a paracrine manner.
• Endothelial ERG overexpression prevents pressure overload-induced cardiac fibrosis.
Sarcopenia remains poorly managed in clinical practice due to the lack of simple and accurate screening tools. This study aimed to identify the cutoff values of the SARC-F questionnaire and Ishii's ...score using the variables age, grip strength, and calf circumference in older inpatients in China to compare the accuracy of the two methods and to explore their predictive ability for adverse outcomes (rehospitalization, falls, fracture, and death). Hospitalized patients (n=138) aged ≥60 years were included. The accuracy of the two tools was evaluated using the reference diagnosis recommended by the Asian Working Group on Sarcopenia (assessing patients with measurements of muscle mass, handgrip strength, and usual gait speed). Follow-up data were obtained by telephone and clinical visits combined with the inpatient medical record system after discharge for at least one year. The results showed that the SARC-F score reached the highest Youden's index when a score of 3 was set as the cutoff value. Ishii's score presented a higher accuracy than SARC-F (area under the receiver operating curve: 0.78 vs 0.64, P=0.01). The Kaplan-Meier survival analysis demonstrated a higher cumulative incidence of rehospitalization in sarcopenic individuals compared to non-sarcopenic individuals according to SARC-F (log-rank test, P<0.001). Cox analysis revealed that SARC-F was an independent risk factor for rehospitalization (adjusted hazard ratio: 4.23, 95%CI: 2.12-9.79, P<0.001). The SARC-F and Ishii's scores might facilitate the early detection of sarcopenia and help identify older adults at risk for adverse outcomes in clinical practice.
Two two‐dimensional supramolecular Nickel(II) and Cobalt(III) complexes, Ni(L2)2·2CH3OH (1) and 2Co(L2)2 (2) (HL2 = 1‐(2‐{(E)‐3‐bromo‐5‐chloro‐2‐hydroxybenzylideneamino}phenyl)ethanone oxime), were ...synthesized via complexation of salts acetate with HL1 (2‐(3‐bromo‐5‐chloro‐2‐hydroxyphenyl)‐4‐methyl‐1,2‐dihydroquinazoline 3‐oxide, H is the deprotonatable hydrogen). During the reaction, the C–N bond in HL1 is converted into the C=N–OH group in HL2. The spectroscopic data of both complexes were compared with the ligand HL1. HL1 and both complexes were determined by single‐crystal X‐ray crystallography. The differently geometric features of the obtained complexes 1 and 2 are observed. In the crystal structure, 1 and 2 form an infinite 1‐D chain‐like and 2‐D supramolecular frameworks. EPR spectroscopy of 2 was investigated. Moreover, electrochemical properties and antimicrobial activities of both complexes were also studied. In addition, the calculated HOMO and LUMO energies show the character of HL1, complexes 1 and 2. The electronic transitions and spectral features of HL1 and both complexes were discussed by TD‐DFT calculations.
Two two‐dimensional supramolecular nickel(II) and cobalt(III) complexes were synthesized from a quinazoline‐type ligand. The spectroscopic data of both complexes were compared with the ligand. HL1 and both complexes were determined by single‐crystal X‐ray crystallography. Electrochemical properties and antimicrobial activities of both complexes were studied. EPR spectroscopy of 2 was also investigated. The calculated HOMO and LUMO energies show the character of HL1, complexes 1 and 2. The electronic transitions and spectral features of these compounds were discussed by TD‐DFT calculations.
The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell ...survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.
Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer (TNBC). More and more experts ...have noticed that AR signaling pathway plays an important role in the occurrence and development of TNBC. The purpose of this study is to detect the inhibitory efficacy and mechanism of Bicalutamide on the proliferation and invasion of TNBC cells.MDA-MB-231 cells of human breast cancer cells were treated with 0, 25, 100 μmol/L of Bicalutamide, cell proliferation assay was performed to assess cell proliferation viability by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide assay and cell invasion was evaluated by Transwell assay. Meanwhile, flow cytometric analysis and western blotting were performed to investigate the mechanism of Bicalutamide on the proliferation and invasion of MDA-MB-231 cells.Bicalutamide could efficiently inhibit the proliferation and invasion of MDA-MB-231 cells in a dose-dependent manner. In addition, Bicalutamide could significantly induce the cell cycle arrest at G0/G1 phase and decrease the protein expression of AR, cyclin D1, matrix metalloprotease-2 (MMP-2), and matrix metalloprotease-9 (MMP-9).The present study indicated the Bicalutamide inhibited the proliferation and invasion process of triple negative breast cancer cells by targeting AR signaling pathway and down-regulating MMP-2/-9 protein expression levels.
Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with ...clinicopathologic characteristics and disease prognosis in the Asian population.
A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival.
The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors (
= 0.007, other
< 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all
< 0.001), whereas in mucosal melanoma, only C-KIT was (
= 0.006). Although correlated with BRAF mutations (
= 0.001 and
< 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival (
= 0.406 and 0.256, respectively).
The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact.
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