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1.
Toxicology ; 452: 152697, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33524428

RESUMO

Trichloroethylene (TCE), a prevalent environmental contaminant, has been shown to induce cardiac malformations. Resveratrol (RSV) is a natural polyphenolic compound exhibiting protective effects on heart development. To investigate if RSV could protect against TCE-induced heart defects, we exposed zebrafish embryos to TCE (10 ppb) in the presence or absence of RSV (1 µg/mL). Our results showed that RSV significantly attenuated TCE-induced heart defects in zebrafish embryos. The TCE-induced ROS (reactive oxygen species) generation, 8-OHdG (8-hydroxy-2`-deoxyguanosine) formation and cell proliferation were significantly counteracted by RSV. Moreover, RSV attenuated the TCE-induced changes in mRNA expression or activity of genes involved in AHR and Nrf2 signal pathways. We further showed that RSV might inhibit TCE-enhanced cell proliferation by rescuing the downregulation of the p53/p21 axis. In conclusion, our data demonstrates that RSV protects against the cardiac developmental toxicity of TCE by inhibiting AHR activity, oxidative stress and cell proliferation.

2.
Water Res ; 193: 116851, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33540343

RESUMO

This study investigated the mechanisms of mixed IO3-/I- system under UV irradiation in drinking water and compared the iodinated trihalomethanes (I-THMs) formation of a mixed IO3-/I- system to that of single I- and IO3- systems during subsequent chloramination. The effects of initial I-/IO3- molar ratio, pH, and UV intensity on a mixed IO3-/I- system were studied. The introduction of I- enhanced the conversion rate of IO3- to reactive iodine species (RIS). Besides, IO3- degradation rate increased with the increase of initial I- concentration and UV intensity and the decrease of pH value. In a mixed IO3-/I- system, IO3- could undergo direct photolysis and photoreduction by hydrated electron (eaq-). Moreover, the enhancement of I-THM formation in a mixed IO3-/I- system during subsequent chloramination was observed. The I-THM yields in a mixed IO3-/I- system were higher than the sum of I-THMs produced in a single IO3- and I- systems at all the evaluated initial I- concentrations and pH values. The difference between I-THM formation in a mixed IO3-/I- system and the sum of I-THMs in a single IO3- and I- systems increased with the increase of initial I- concentration. As the initial pH decreased from 9 to 5, the difference of I-THM yields enhanced, while the total I-THM yield of a mixed IO3-/I- system and single I- and IO3- systems decreased slightly. Besides, IO3--I--containing water with DOC concentration of 2.5-4.5 mg-C/L, which mainly contained humic-acid substances, had a higher risk in I-THMs formation than individual I--containing and IO3--containing water.

3.
Alcohol Clin Exp Res ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33587293

RESUMO

BACKGROUND: Alcohol abuse disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We aimed to identify whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). METHODS: Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment, 6- and 12-month follow-ups. Spearman correlation was carried out to study the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and alcohol abstinent effects. RESULTS: At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels positively correlated to the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, but did not fully return to baseline levels. CONCLUSIONS: Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33599074

RESUMO

Herein, we report a rhodium catalyzed directing-group free regioselective C-H allylation of simple arenes. Readily available gem -difluorinated cyclopropanes can be employed as highly reactive allyl surrogates via a sequence of C-C and C-F bond activation, providing allyl arene derivatives in good yields with high regioselectivity under mild conditions. The robust methodology enables facile late-stage functionalizations of complex bioactive molecules. The high efficiency of this reaction is also demonstrated by the high turnover number (TON, up to 1700) of the rhodium catalyst on gram-scale experiments. Preliminary success on kinetic resolution of this transformation is achieved, providing a promising access to enantio-enriched gem -difluorinated cyclopropanes.

5.
Nucleic Acids Res ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33577689

RESUMO

Knowledge of the interactions between proteins and nucleic acids is the basis of understanding various biological activities and designing new drugs. How to accurately identify the nucleic-acid-binding residues remains a challenging task. In this paper, we propose an accurate predictor, GraphBind, for identifying nucleic-acid-binding residues on proteins based on an end-to-end graph neural network. Considering that binding sites often behave in highly conservative patterns on local tertiary structures, we first construct graphs based on the structural contexts of target residues and their spatial neighborhood. Then, hierarchical graph neural networks (HGNNs) are used to embed the latent local patterns of structural and bio-physicochemical characteristics for binding residue recognition. We comprehensively evaluate GraphBind on DNA/RNA benchmark datasets. The results demonstrate the superior performance of GraphBind than state-of-the-art methods. Moreover, GraphBind is extended to other ligand-binding residue prediction to verify its generalization capability. Web server of GraphBind is freely available at http://www.csbio.sjtu.edu.cn/bioinf/GraphBind/.

6.
Sci Total Environ ; 770: 145277, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33515874

RESUMO

Halobenzoquinones (HBQs) are emerging unregulated drinking water disinfection byproducts (DBPs) that are more toxic than regulated DBPs. This study aimed to determine the distribution and formation of HBQs in drinking water from water treatment plants in China, compare their chronic cytotoxicity and their induction of chromosomal damage in Chinese hamster ovary cells, and analyze the correlation of HBQ toxicity with their physicochemical parameters. Two HBQs, 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ) and 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), were detected in finished water and tap water in China. The concentrations were in the ranges of <2.6-19.70 ng/L for 2,6-DCBQ and <0.38-1.8 ng/L for 2,6-DBBQ. Chemical oxygen demand and residual chlorine were positively correlated with HBQ formation. The HBQ concentration was lower in a drinking water treatment plant using chlorine dioxide. High Ca2+ in tap water decreased the HBQ level. The rank order of HBQ by cytotoxicity was 2-chloro-1,4-benzoquinone > 2,3-diiodo-1,4-benzoquinone > 2,6-diiodo-1,4-benzoquinone > 2,6-dibromo-1,4-benzoquinone > 2,5-dibromo-1,4-benzoquinone > 2,5-dichloro-1,4-benzoquinone > 2,6-dichloro-1,4-benzoquinone > tetrachloro-1,4-benzoquinone > 2,3,6-trichloro-1,4-benzoquinone, and for their genotoxicity, 2,5-dichloro-1,4-benzoquinone > 2,6-dichloro-1,4-benzoquinone > 2,3-diiodo-1,4-benzoquinone > 2,6-diiodo-1,4-benzoquinone > tetrachloro-1,4-benzoquinone > 2,5-dibromo-1,4-benzoquinone > 2,6-dibromo-1,4-benzoquinone > 2,3,6-trichloro-1,4-benzoquinone. The cytotoxicity of six dihalo-HBQs was negatively correlated with the octanol-water partition coefficient (r = -0.971, P < 0.05), molar refractivity (r = -0.956, P < 0.05), energy of the highest occupied molecular orbital (EHOMO) (r = -0.943, P < 0.05), and polar surface area (r = -0.829, P < 0.05). The genotoxicity of these three pairs of dihalo-HBQ isomers followed the same order as their EHOMO values. This study reveals the occurrence and formation of HBQs in drinking water in China and systematically evaluates the chromosomal damage caused by nine HBQs in mammalian cells.

7.
Org Lett ; 23(3): 896-901, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33433227

RESUMO

An efficient protocol for the asymmetric hydroarylation and hydroalkenylation of benzo[b]thiophene 1,1-dioxides with organoboranes has been developed. The combination of a rhodium(I) precatalyst and a chiral diene ligand constitutes the catalytic system, which enables the facile synthesis of 2,3-dihydrobenzo[b]thiophene 1,1-dioxides in good yields with high enantioselectivities. The merging of this asymmetric hydroarylation with the downstream alkylations delivers 2,3-dihydrobenzo[b]thiophene 1,1-dioxides that contain two continuous quaternary stereocenters with high enantioselectivities in a diastereodivergent manner.

8.
Neuromolecular Med ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33389570

RESUMO

Glioma ranks first among the aggressive brain tumors all over the world. LncRNA LINC00689 has been confirmed to play key roles in the progression of cancers, and LINC00689 was upregulated in glioma. However, the biological function of LINC00689 in glioma is unclear. qRT-PCR was applied to detect the expressions of LINC00689 and miR-526b-3p in glioma cells. Dual-luciferase report was performed to examine the relation among LINC00689, miR-526b-3p, and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). Then, the growth, migration, and invasion of glioma cells were detected by colony formation, flow cytometry, and transwell assay, respectively. The expressions of p21, cleaved caspase 3, and MAPK signaling-related proteins in glioma cells were tested by western blotting. Finally, xenograft mice model was established to detect the effect of LINC00689 on tumor growth of glioma in vivo. LINC00689 was upregulated in glioma cells, while miR-526b-3p was downregulated. In addition, LINC00689 bound to miR-526b-3p, and IGFBP1 was targeted by miR-526b-3p. Moreover, LINC00689 knockdown or upregulation of miR-526b-3p inhibited the proliferation of glioma cells and induced the apoptosis. Consistently, the migration and invasion of glioma cells were notably reduced by LINC00689 shRNA/miR-526-3p mimics. miR-526b-3p inhibitor or IGF2BP1 upregulation could reverse the effect of LINC00689 knockdown or miR-526b-3p mimics. Finally, knockdown of LINC00689 inhibited the tumor growth of glioma in vivo through regulating miR-526b-3p/IGF2BP1/MAPK axis. In conclusion, silencing of LINC00689 could inhibit the tumorigenesis of glioma via mediation of miR-526b-3p/IGF2BP1 axis. LINC00689 may serve as a new target for the treatment of glioma.

9.
Neuroimage Clin ; 29: 102527, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33341723

RESUMO

This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

10.
J Mater Chem B ; 9(1): 80-84, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33313613

RESUMO

Specific and expeditious identification and enrichment of target proteins in living cells is often a challenging task. The hexahistidine (6His) tag is frequently used to label artificially engineered proteins produced in prokaryotic or eukaryotic cells. Utilizing the interaction between 6His-tag and nitrilotriacetic acid (NTA) mediated by divalent metal ions (Ni2+, Cu2+, Zn2+ or Co2+), we designed and synthesized a series of Nap-G/Biotin/ANA-FFpYGK-NTA probes that, assisted by alkaline phosphatase (ALP), self-assemble into nanofibers. The probe consists of an NTA group that specifically binds to 6His-tag, an FFpY group that promotes self-assembly facilitated by ALP, and a hydrophobic (Nap-G/ANA/Biotin) capping group for various applications. We demonstrate that the ANA-FFpYGK-NTA(Ni2+) nanofibers are fit for real-time tracking of His-tagged protein in living cells, and the Biotin-FFpYGK-NTA(Ni2+) nanofibers are for isolating His-tagged proteins and other proteins that they interact with.

11.
J Environ Manage ; 278(Pt 1): 111493, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33126196

RESUMO

The emission of nitrogenous pollution from agricultural lands in form of ammonia volatilization, leaching, runoff, N2O emissions, etc. is still a serious challenge to which agricultural sector faces. In this context, a vast number of decision support systems have been developed and tested to find the best nitrogen application rate. These models are highly dependent on crop simulation models, mathematical and regression models, evolutionary algorithms and artificial intelligent, GIS-based models, etc., while in most cases have ignored to be interfered with regional and national regulations established by experts in the field. In this study, a new framework combining analytical hierarchy (AHP)/modified AHP methods (MAHP) plus metaheuristic optimization techniques has been suggested to find the best nitrogen application rate considering regional capacities and requirements. To reach the objectives of the present study a three yield field experiment was conducted upon which crop yield, nitrogen use efficiency, nitrogen uptake, soil nitrate, ammonia volatilization, N2O emissions, and N leaching were monitored or measured. Using the results from the field experiments and a survey from local experts, the models were developed. AHP-assisted optimization model could cause some biases in the final results due to its intrinsic nature which avoids direct pairwise comparison among indicators (so called sub-criteria) under two different main-criteria. On the contrary, MAHP-assisted model could well reflect the concerns of experts and notably decrease hotspot pollution. Such decision support system can satisfy both farmers and environmentalists' need because of the created high profit and low environmental pollution, while saving resources and ensuring a sustainable production system.


Assuntos
Fertilizantes , Solo , Agricultura , China , Poluição Ambiental , Articulações/química , Nitrogênio/análise , Óxido Nitroso/análise
12.
Chem Commun (Camb) ; 57(6): 797-800, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33355564

RESUMO

Caspase-3/8 are key members of the cysteine-aspartyl protease family with pivotal roles in apoptosis. We have designed and synthesized self-assembling probes, Nap-GFFpYDEVD-AFC and Nap-GFFpYIETD-AFC, with fluorescence 'turn-on' properties for real-time monitoring of Caspase-3/8 activity in living cells.

13.
J BUON ; 25(5): 2482-2489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33277872

RESUMO

PURPOSE: The purpose of the present study was to identify differential gene expressions (DEGs) and key pathways in neuroblastoma with MEIS2 depletion through bioinformatics. METHODS: The microarray gene expression dataset GSE56003 was downloaded from the Gene Expression Omnibus (GEO) database. DEGs were identified using Gene Level RMA sketch and Transcriptome Analysis Console. Gene ontology (GO) function and KEGG pathway enrichment analysis of DEGs were performed using the DAVID online tool. Protein-protein interaction (PPI) networks were constructed by mapping the DEGs onto Cytoscape software. MCODE algorithm was used to select the module and Centiscape was used to screen the hub genes. The Kaplan-Meier survival curves was utilized to show the correlation of specific gene expressions and the survival situation of NB patients. Results:A total of 1352 DEGs were identified in neuroblastoma with MEIS2 depletion, which were mainly enriched during the cell cycle, DNA replication, and DNA repair. CDK2, RAD51, BRCA1, and MCM3 were selected as hub genes that have the potential as novel therapeutic targets for neuroblastoma. CONCLUSION: This study revealed the hub genes and pathway involved in neuroblastoma with MEIS2 knockdown, which offered new insights into the molecular networks underlying MEIS2 depletion in neuroblastoma. Additionally, this study provided a valuable resource of potential biomarkers and therapeutic targets.

15.
Diabetes Res Clin Pract ; : 108582, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33307130

RESUMO

AIMS: To determine if HLA-DP loci independently contribute to classic type 1 diabetes (T1D) of all ages, childhood-onset T1D and latent autoimmune diabetes in adults (LADA) among Chinese Han population. METHODS: A total of 518 patients with classic T1D (Among them 180 participants manifested T1D between 1-14 years), 519 patients with LADA and 527 normal controls were genotyped for both HLA-DPA1 and -DPB1 loci. The frequencies of DP alleles and haplotypes in patients were directly compared to those in controls, followed by adjustment for linkage disequilibrium (LD) with DR-DQ haplotypes. RESULTS: In the direct comparison, DPA1*01:03, DPB1*04:01 and DPA1*01:03-DPB1*04:01 showed disease-predisposing effects in both the overall T1D group and the childhood-onset T1D group mainly due to their conjunction with the known susceptible DR3 haplotype. Conditioning on DR-DQ haplotypes, only DPA1*02:02-DPB1*02:02 significantly increased T1D risk among those diagnosed during childhood (OR = 2.02, 95% CI = 1.35-3.01). Whether or not adjusted for LD, no statistically significant HLA-DP association could be observed for LADA. CONCLUSION: HLA-DP is implicated in the pathogenesis of childhood-onset T1D in Chinese, independent of the predominant DR-DQ loci and might serve as additional markers in genetic models for the recognition of those genetically at-risk individuals.

16.
Front Immunol ; 11: 593348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324409

RESUMO

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.

18.
Am J Transl Res ; 12(10): 6264-6276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194028

RESUMO

Full-thickness skin injury affects millions of people worldwide each year. Although bone marrow-derived mesenchymal stem cells (BM-MSCs) have been shown to promote cutaneous wound healing, they cannot functionally promote wound healing with the recovery of appendages such as hair follicles. We previously found that growth factor plus BM-MSCs could effectively promote wound healing and hair follicle regeneration. In the present study, we grafted insulin-like growth factor 1 (IGF1), a multifunctional cell growth factor, and BM-MSCs into a collagen-chitosan scaffold to investigate their effects on functional wound healing. Using scanning electron microscopy, histological staining, and quantitative analysis, we found that IGF1- and BM-MSC-incorporating collagen-chitosan scaffolds promote cutaneous wound healing with effective regeneration of hair follicles in a rat full-thickness skin injury model. In addition, IGF1/BM-MSCs inhibit inflammatory cytokines during wound healing. In vitro, we found that IGF1 promotes the proliferation and migration of BM-MSCs via the IGFR-mediated ERK1/2 signaling pathway. Collectively, in this study, we first demonstrated that IGF1 enhances BM-MSC-mediated wound healing as well as hair follicle regeneration. Our data suggest that the topical application of IGF1 and BM-MSCs incorporated in collagen-chitosan scaffolds can be used as a feasible and effective therapeutic approach to improve functional cutaneous wound healing.

19.
Aging (Albany NY) ; 122020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33197884

RESUMO

Our previous studies have shown that the δ-opioid receptor (DOR) is an important neuroprotector via the regulation of PTEN-induced kinase 1 (PINK1), a mitochondria-related molecule, under hypoxic and MPP+ insults. Since mitochondrial dysfunctions are observed in both hypoxia and MPP+ insults, this study further investigated whether DOR is cytoprotective against these insults by targeting mitochondria. Through comparing DOR-induced responses to hypoxia versus MPP+-induced parkinsonian insult in PC12 cells, we found that both hypoxia and MPP+ caused a collapse of mitochondrial membrane potential and severe mitochondrial dysfunction. In sharp contrast to its inappreciable effect on mitochondria in hypoxic conditions, DOR activation with UFP-512, a specific agonist, significantly attenuated the MPP+-induced mitochondrial injury. Mechanistically, DOR activation effectively upregulated PINK1 expression and promoted Parkin's mitochondrial translocation and modification, thus enhancing the PINK1-Parkin mediated mitophagy. Either PINK1 knockdown or DOR knockdown largely interfered with the DOR-mediated mitoprotection in MPP+ conditions. Moreover, there was a major difference between hypoxia versus MPP+ in terms of the regulation of mitophagy with hypoxia-induced mitophagy being independent from DOR-PINK1 signaling. Taken together, our novel data suggest that DOR activation is neuroprotective against parkinsonian injury by specifically promoting mitophagy in a PINK1-dependent pathway and thus attenuating mitochondrial damage.

20.
Microb Drug Resist ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33216688

RESUMO

The occurrence and characterization of carbapenemase-producing Enterobacteriaceae from companion animals in Guangzhou, China, are investigated. Six isolates (2.3%, 6/257) were positive for blaNDM-5, that is, one Enterobacter cloacae, one Citrobacter freundii, and four Escherichia coli. Three E. coli isolates obtained from the same animal hospital were ST410 and showed identical pulse field gel electrophoresis pattern, resistance profiles, and resistance genes. blaNDM-5 was located on IncX3 (n = 5) and IncK2 (n = 1) plasmid, respectively. The presence of carbapenemase-producing Enterobacteriaceae among companion animals needs continued surveillance.

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