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1.
Sci Rep ; 9(1): 18114, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792331

RESUMO

Thelytokous Wolbachia-infected Trichogramma spp. are widely used egg parasitoids against lepidopteran pests in biological control programs. Wolbachia may manipulate host wasps for superparasitism and is sensitive to temperature. To explore effects of temperature and superparasitism, we compared fitness parameters and Wolbachia-mediated phenotype of thelytokous Wolbachia-infected Trichogramma dendrolimi between those emerging from superparasitised or single-parasitised hosts at 17, 21, 25, or 29 °C. Infected mothers of T. dendrolimi showed reduced superparasitism and parasitism increased with temperature. Wolbachia titre decreased with temperature when females emerged from singly-parasitised hosts, but there was no correlation in superparasitised hosts. Females showed higher Wolbachia titres at 21, 25, or 29 °C when developing from superparasitised hosts. The daily male ratio of offspring increased with temperature, and the day-age threshold for 5%, 50%, or 95% daily male ratio decreased with temperature in both parasitism forms. Females that emerged from superparasitised hosts had a shorter life span and reduced fecundity. These results indicate that Wolbachia may affect host behaviour by increasing superparasitism to enhance its spread, but this has negative effects on thelytokous Wolbachia-infected T. dendrolimi.

2.
J Viral Hepat ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31785059

RESUMO

Mother-to-child transmission within the perinatal period was the major route of hepatitis B virus (HBV) infection in Chinese children, which has been efficiently prevented by injection of hepatitis B vaccine and immunoglobulin. However, the properties of HBV transmission at present remain unclear. Data of 59,912 Chinese children aged 1-15 years from 12 regions were collected. The age- and regional-specific distributions of HBV seromarkers and their correlations with local per capita disposable income and mean annual temperature were analyzed. The parents of children with positive hepatitis B surface antigen (HBsAg) were surveyed for the potential infection source. The average prevalence of HBsAg was 0.31% in the children. HBsAg prevalence was less than 0.1% in children aged 1-2 years and increased during the age of 2 to 6 years, which correlated with the decline of the hepatitis B surface antibody (HBsAb)-positive rate in the duration. Local per capita disposable incomes correlated with the HBsAb-positive rates in children aged 1 year, but it did not correlate with the risk of HBV infection and the average HBsAb-positive rate. However, local mean average temperatures correlated with HBsAg prevalence in children aged 6 years. Most of the HBsAg-positive children were born in HBV-carrier families. Horizontal transmission is emerging as a noteworthy route of HBV infection in young children without seroprotective HBsAb. A booster vaccination would be needed to prevent horizontal transmission to young children living with HBV infected family members.

3.
Bioresour Technol ; : 122451, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31787516

RESUMO

This study used a metagenomic approach to investigate the effects of earthworms on ARGs and HPB during the vermicomposting of dewatered sludge. Results showed that 139 types of ARGs were found in sludge vermicompost, affiliated to 30 classes. Compared with the control, the total abundance of ARGs in sludge vermicompost decreased by 41.5%. Moreover, the types and sequences of plasmids and integrons were also decreased by vermicomposting. Proteobacteria and Actinobacteria were the most dominant hosts of ARGs in sludge vermicompost. In addition, earthworms reduced the total HPB abundance and modified their diversity, thus leading to higher abundance of Enterobacteriaceae in sludge vermicompost. However, the sludge vermicompost was still ARG and HPB enriched, indicating a remaining environmental risk for agricultural purpose. The observed change of microbial community and the reduction of mobile genetic elements caused by earthworm activity are the main reasons for the alleviation of ARG pollution during vermicomposting.

4.
J Exp Clin Cancer Res ; 38(1): 481, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801598

RESUMO

BACKGROUND: Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. Here, we clarify the function and molecular mechanism of shisa3 as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties. METHODS: The suppresser genes involved in EGFR-TKI resistance were identified and validated by transcriptome sequencing, quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Biological function analyses, cell half maximal inhibitory concentration (IC50), self-renewal, and migration and invasion capacities, were detected by CCK8, sphere formation and Transwell assays. Tumorigenesis and therapeutic effects were investigated in nonobese diabetic/severe combined immunodeficiency (nod-scid) mice. The underlying mechanisms were explored by Western blot and immunoprecipitation analyses. RESULTS: We found that low expression of shisa3 was related to EGFR-TKI resistance in lung adenocarcinoma patients. Ectopic overexpression of shisa3 inhibited CSC properties and the cell cycle in the lung adenocarcinoma cells resistant to gefitinib/osimertinib. In contrast, suppression of shisa3 promoted CSC phenotypes and the cell cycle in the cells sensitive to EGFR-TKIs. For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. Furthermore, combinational administration of inhibitors of FGFR/AKT/mTOR and cell cycle signaling could overcome EGFR-TKI resistance associated with shisa3-mediated CSC capacities in vivo. CONCLUSION: Taken together, shisa3 was identified as a brake to EGFR-TKI resistance and CSC characteristics, probably through the FGFR/AKT/mTOR and cell cycle pathways, indicating that shisa3 and concomitant inhibition of its regulated signaling may be a promising therapeutic strategy for reversing EGFR-TKI resistance.

5.
Sci Total Environ ; : 134876, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31740062

RESUMO

The bacterial communities on microplastics in marine and freshwater environments have been described by many studies. However, the migration and transportation processes of bacterial communities on microplastics in estuarine areas remain unclear. In this study, the bacterial communities on three substrates (microplastics, surface water and sediment) in estuarine areas (the Haihe Estuary (HHE) in Bohai Bay, China) were investigated based on 16S rRNA sequencing. The mean OTUs of the three substrates - water, microplastics and sediments - were 1091, 2213 and 3419, respectively. The partitioning of the OTUs among the three substrates indicated that the microplastics could be messengers facilitating the bacterial transportation between water and sediment. According to nMDS and relative abundance analyses, it was found that the microplastics enriched the particular bacteria (e.g., Halobacteriaceae and Pseudoalteromonadaceae) and weakened the influence of environmental variation. In addition, taxonomic and metabolic-pathway analyses indicated that the abundance of potentially pathogenic bacteria (e.g., Pseudomonas and Bacillus) on microplastics was significantly higher than that in the ambient environment. Meanwhile, the microplastic polymer types had little effect on the abundance and structure of the bacterial communities. Compared with surface water and sediments, microplastics could be a good habitat for bacterial communities and could lead to potential ecological risks because of the high stability, pathogenicity and stress tolerance of the bacterial communities on microplastics.

6.
Clin Cancer Res ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694833

RESUMO

PURPOSE: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value. EXPERIMENTAL DESIGN: Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced-stage incurable disease who received first line chemotherapy. RESULTS: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 LCNEC patients were classified into small cell lung cancer (SCLC)-like and non-small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival (OS) than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared to pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared to etoposide-platinum or pemetrexed-platinum in NSCLC-like LCNEC patients. CONCLUSIONS: Genomic subtyping has potentials in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.

7.
Comp Biochem Physiol C Toxicol Pharmacol ; 228: 108669, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31712185

RESUMO

Toxaphene is a restricted-use pesticide produced by reacting chlorine gas with camphene. It was heavily used as a pesticide for agricultural purposes in the 1960-1970s, but despite being banned >30 years ago, it can remain elevated in the soil due to its resistance to metabolic degradation; this has led to longstanding concerns about elevated levels of toxaphene and other organochlorine pesticides (OCPs) in the environment. The objective of this study were to determine the effects of waterborne exposure to toxaphene on early life stages of zebrafish. Based on the LC50, zebrafish embryos were exposed to control (embryo rearing media or DMSO) or to one dose of toxaphene ranging between 0.011 and 111.1 µg/mL from 6 h post fertilization (hpf) up to 120 hpf. Significant mortality and hatch time delays were observed in embryos exposed to toxaphene (at or above 0.11 and 1.11 µg/mL, depending on the assay). Higher prevalence of deformities was noted at higher doses (≥0.011 µg/mL), and these included pericardial edema and skeletal deformities. As energy production is important for normal development, mitochondrial bioenergetics were assessed in embryos following toxaphene exposure. Embryos exposed to 11.1 or 111 µg/mL toxaphene for 24 h showed lower non-mitochondrial respiration (~30%) compared to both solvent and no treatment controls. Expression of transcripts related to oxidative damage responses and apoptosis were measured and heat shock protein 70 was significantly increased with 111 µg/mL toxaphene (14.5 fold), while the expression levels of caspase 3, caspase 9, and superoxide dismutase 1 were not changed. These data demonstrate that developmental deformities induced by toxaphene include pericardial edema and skeletal deformity, and that toxaphene can affect oxidative phosphorylation in early staged zebrafish.

8.
Mol Genet Genomic Med ; : e1023, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31774634

RESUMO

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

9.
ACS Chem Biol ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31714745

RESUMO

The limited therapeutic options and increasing drug-resistance call for next-generation influenza antivirals. Due to the essential function in viral replication and high sequence conservation among influenza viruses, influenza polymerase PA-PB1 protein-protein interaction becomes an attractive drug target. Here, we developed an in vitro split luciferase complementation-based assay to speed up screening of PA-PB1 interaction inhibitors. By screening 10,000 compounds, we identified two PA-PB1 interaction inhibitors, R160792 and R151785, with potent and broad-spectrum antiviral activity against a panel of influenza A and B viruses, including amantadine-, oseltamivir-, or dual resistant strains. Further mechanistic study reveals that R151785 inhibits PA nuclear localization, reduces the levels of viral RNAs and proteins, and inhibits viral replication at the intermediate stage, all of which are in line with its antiviral mechanism of action. Overall, we developed a robust high throughput-screening assay for screening broad-spectrum influenza antivirals targeting PA-PB1 interaction and identified R151785 as a promising antiviral drug candidate.

10.
BMC Health Serv Res ; 19(1): 836, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727062

RESUMO

BACKGROUND: The objectives of this study are to test the psychometric properties of the safety attitudes and safety climate questionnaire Chinese simplified version (SAQ-CS), to test the safety attitudes of health professionals in tertiary hospitals in the Liaoning province and to explore the effects of demographic factors on safety attitudes. METHODS: The SAQ-CS was used to conduct a cross-sectional survey in nine tertiary hospitals in Liaoning province. RESULTS: Cronbach's alpha of each subscale of SAQ-CS were > 0.7, the values of GFI, TLI, and CFI were > 0.8, and RMSEA values ranged from 0.048-0.199. The mean of the safety attitudes of 2157 health professionals was 4.00, indicating a good safety attitude, with a positive response rate (% of items that scored ≥4) of 51.1%. The stress recognition subscale had the lowest score, with a mean of 2.73 and a positive response rate of 17.8%. A multiple linear regression equation revealed that demographic factors like gender, age, and training participation significantly affected the scores (ßgender > 0.06, ßage < - 0.08, ßtraining < - 0.07, p < 0.05). CONCLUSIONS: The psychometric properties of SAQ-CS are good and stable. Health professionals rate teamwork climate, safety climate, perception of management, and work conditions in Liaoning province are perceived as good; however, the stress of the health professionals is poor. To improve safety attitudes, it is necessary to not only reduce the stress of health professionals, but also to pay more attention to men, older health professionals, and health professionals who have not participated in safety training.

11.
Proc Natl Acad Sci U S A ; 116(47): 23473-23479, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685612

RESUMO

The layered oxide Na0.67CoO2 with Na+ occupying trigonal prismatic sites between CoO2 layers exhibits a remarkably high room temperature oxygen evolution reaction (OER) activity in alkaline solution. The high activity is attributed to an unusually short O-O separation that favors formation of peroxide ions by O--O- interactions followed by O2 evolution in preference to the conventional route through surface O-OH- species. The dependence of the onset potential on the pH of the alkaline solution was found to be consistent with the loss of H+ ions from the surface oxygen to provide surface O- that may either be attacked by solution OH- or react with another O-; a short O-O separation favors the latter route. The role of a strong hybridization of the O-2p and low-spin CoIII/CoIV π-bonding d states is also important; the OER on other CoIII/CoIV oxides is compared with that on Na0.67CoO2 as well as that on IrO2.

12.
Neuropharmacology ; 162: 107843, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31704273

RESUMO

Alzheimer's disease (AD), the most common form of dementia, still lacks effective treatment at present. Alpha-asarone (ASA) is the major compound isolated from the Chinese medicinal herb Acorus gramineus. It has been reported to enhance cognitive function in rodent models, yet its mechanism was not fully understood. In this work, we demonstrated that ASA improved the spatial memory, reduced the neuronal injury, and decreased the level of Aß1-42 in the hippocampus of aged rats. The results also showed that ASA had the neuroprotective effects against glutamate toxicity and decreased cytoplasmic calcium level in primary hippocampal neurons. By comparing the multiple properties of ASA and propofol (PPF) via computer modelling, we speculated that ASA may bind to the PPF binding site of type A gamma (γ)-aminobutyric acid receptors (GABAARs). This was further supported by the whole-cell patch-clamp recording. Our results suggested that ASA, as a GABAAR positive allosteric modulator (PAM), can improve cognitive function of aged rats by alleviating the neuronal overexcitation. Furthermore, the binding mode of ASA on GABAAR may lay a foundation for structure-based drug design in AD therapy.

13.
Mol Ther Nucleic Acids ; 18: 954-965, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31770672

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is due to the excessive lipid accumulation within hepatocytes. Metabolic nuclear receptors (MNRs) play great roles in lipid homeostasis. We have identified a novel long noncoding RNA (lncRNA), lnc-HC, which regulates hepatocytic cholesterol metabolism through reducing Cyp7a1 and Abca1 expression. Here, we further elucidate its roles in hepatic fatty acid and triglyceride (TG) metabolism through a novel lncRNA regulatory mechanism. The most prominent target of lnc-HC identified by in vitro study is PPARγ. Further studies revealed that lnc-HC negatively regulates PPARγ at both the mRNA and protein levels and suppresses hepatocytic lipid droplet formation. Importantly, the function of lnc-HC in regulating PPARγ expression depends on modulating miR-130b-3p expression from the transcriptional to the post-transcriptional level, not through lncRNA's critical modulating patterns. In vivo, the reduction of lnc-HC expression significantly decreases miR-130b-3p expression, induces PPARγ expression, and increases TG concentration in rat livers with hyperlipidemia. These findings further help in understanding the regulatory pattern of lnc-HC in hepatic lipid metabolism and might present a possible therapeutic target for improving lipid homeostasis.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31603772

RESUMO

We present a deep convolutional neural network for breast cancer screening exam classification, trained and evaluated on over 200,000 exams (over 1,000,000 images). Our network achieves an AUC of 0.895 in predicting the presence of cancer in the breast, when tested on the screening population. We attribute the high accuracy to a few technical advances. (i) Our network's novel two-stage architecture and training procedure, which allows us to use a high-capacity patch-level network to learn from pixel-level labels alongside a network learning from macroscopic breast-level labels. (ii) A custom ResNet-based network used as a building block of our model, whose balance of depth and width is optimized for high-resolution medical images. (iii) Pretraining the network on screening BI-RADS classification, a related task with more noisy labels. (iv) Combining multiple input views in an optimal way among a number of possible choices. To validate our model, we conducted a reader study with 14 readers, each reading 720 screening mammogram exams, and show that our model is as accurate as experienced radiologists when presented with the same data. We also show that a hybrid model, averaging the probability of malignancy predicted by a radiologist with a prediction of our neural network, is more accurate than either of the two separately. To further understand our results, we conduct a thorough analysis of our network's performance on different subpopulations of the screening population, the model's design, training procedure, errors, and properties of its internal representations. Our best models are publicly available at https://github.com/nyukat/breastcancerclassifier.

15.
Pharmacology ; : 1-7, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31618743

RESUMO

BACKGROUND: Transient receptor potential (TRP) channels are widely expressed in the mammals. However, the functions of canonical TRP (TRPC) in inflammatory responses are largely unknown. The present study was focused on the effect of canonical TRP5 (TRPC5) channel on the polarization of macrophage to an M1 phenotype. METHODS: Polarization of macrophages was studied in TRPC5 knockout (TRPC5-/-) mice and in Raw264.7, a mouse macrophage cell line. Indicators of M1 type polarized macrophage were measured in the aorta of mice. Inhibition of TRPC5 in macrophages was achieved by the administration of ML204 (a non-selective TRPC5 antagonist) or the silencing of the TRPC5 gene with short hairpin RNA. Lipopolysaccharide (LPS) was used to stimulate Raw264.7 cells to an M1 type polarization. Proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were measured in mice or cells, and protein expressions of Akt, phosphorylated (p)-Akt, IκBα, p-IκBα, and NF-κB were analyzed in Raw264.7 cells. RESULTS: In TRPC5-/- mice the number of M1 type polarization of macrophages infiltrating into the aortic walls were significantly increased. The serum levels of inflammatory cytokines, TNF-α and IL-6 were also increased. Furthermore, after treated with ML204 or silenced the gene of TRPC5, the releases of TNF-α, IL-1ß and IL-6 from lipopolysaccharide-stimulated RAW264.7 cells were significantly increased. Meanwhile, phosphorylations of Akt and IκBα were upregulated, and the shift of NF-κB from the cytoplasm to nucleus was markedly enhanced. CONCLUSION: The activation of TRPC5 may inhibit the polarization of macrophage to an M1 phenotype by regulating Akt/IκB/NF-κB signaling pathways.

16.
J Coll Physicians Surg Pak ; 29(10): 915-918, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31564260

RESUMO

OBJECTIVE: To determine the frequency of reflux and aspiration in children subjected to reinforced laryngeal mask during laparoscopic surgery in the Trendelenburg position, and evaluate its feasibility. STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, from January 2017 to May 2018. METHODOLOGY: A total of 300 children, who underwent laparoscopic high ligation of the hernial sac in the Trendelenburg position under general anesthesia, were enrolled into the present study. Reflux and aspiration were assessed by precise saliva pH to determine the pH value at laryngeal mask airway, and at sites on laryngeal mask corresponding to the larynx, face and peripheral area. Then, the presence of food residue was observed at various sites to determine whether there was reflux or aspiration during the operation. RESULTS: Suspected reflux (9.67%) was observed in 29 children and suspected aspiration was observed in nine children (3%). There was no definite reflux or aspiration observed in any of the children. Furthermore, the prevalence of suspected reflux was higher in children who were >3 years and overweight, compared to children with a normal body mass index and an age of <3 years. CONCLUSION: With strict fasting and water deprivation, and strict selection of laryngeal mask indications before selective operation, it is feasible to apply reinforced laryngeal mask in laparoscopic surgery in the Trendelenburg position in children.

17.
J Cell Mol Med ; 23(12): 8420-8431, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31625671

RESUMO

Growth arrest-specific transcript 5 (GAS5), along non-coding RNA (LncRNA), is highly expressed in hypoxia/reoxygenation (H/R)-cardiomyocytes and promotes H/R-induced apoptosis. In this study, we determined whether down-regulation of GAS5 ameliorates myocardial ischaemia/reperfusion (I/R) injury and further explored its mechanism. GAS5 expression in cardiomyocytes and rats was knockdown by transfected or injected with GAS5-specific small interfering RNA or adeno-associated virus delivering small hairpin RNAs, respectively. The effects of GAS5 knockdown on myocardial I/R injury were detected by CCK-8, myocardial enzyme test, flow cytometry, TTC and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. qRT-PCR and luciferase reporter assay were carried out to analyse the relationship between GAS5 and miR-335. The regulation of GAS5 on Rho-associated protein kinase 1 (ROCK1) expression, the activation of PI3K/AKT/GSK-3ß pathway and mitochondrial permeability transition pore (mPTP) opening was further evaluated. The results indicated that GAS5 knockdown enhanced the viability, decreased apoptosis and reduced the levels of lactate dehydrogenase and creatine kinase-MB in H/R-treatment cardiomyocytes. Meanwhile, down-regulation of GAS5 limited myocardial infarct size and reduced apoptosis in I/R-heart. GAS5 was found to bind to miR-335 and displayed a reciprocal inhibition between them. Furthermore, GAS5 knockdown repressed ROCK1 expression, activated PI3K/AKT, thereby leading to inhibition of GSK-3ß and mPTP opening. These suppressions were abrogated by miR-335 inhibitor treatment. Taken together, our results demonstrated that down-regulation of GAS5 ameliorates myocardial I/R injury via the miR-335/ROCK1/AKT/GSK-3ß axis. Our findings suggested that GAS5 may be a new therapeutic target for the prevention of myocardial I/R injury.

18.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581639

RESUMO

Wheat stem rust caused by Puccinia graminis f. sp. tritici (Pgt) had been a devastating foliar disease worldwide during the 20th century. With the emergence of Ug99 races, which are virulent to most stem rust resistance genes deployed in wheat varieties and advanced lines, stem rust has once again become a disease threatening global wheat production. Sr52, derived from Dasypyrum villosum and mapped to the long arm of 6V#3, is one of the few effective genes against Ug99 races. In this study, the wheat-D. villosum Robertsonian translocation T6AS·6V#3L, the only stock carrying Sr52 released to experimental and breeding programs so far, was crossed with a CS ph1b mutant to induce recombinants with shortened 6V#3L chromosome segments locating Sr52. Six independent homozygous recombinants with different segment sizes and breakpoints were developed and characterized using in situ hybridization and molecular markers analyses. Stem rust resistance evaluation showed that only three terminal recombinants (1381, 1380, and 1392) containing 8%, 22%, and 30% of the distal segment of 6V#3L, respectively, were resistant to stem rust. Thus, the gene Sr52 was mapped into 6V#3L bin FL 0.92-1.00. In addition, three molecular markers in the Sr52-located interval of 6V#3L were confirmed to be diagnostic markers for selection of Sr52 introgressed into common wheat. The newly developed small segment translocation lines with Sr52 and the identified molecular markers closely linked to Sr52 will be valuable for wheat disease breeding.

19.
Hepatology ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31529720

RESUMO

The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis. We found that in steatohepatitis, γδT cells are recruited to the liver by CCR2, CCR5, and NOD2 signaling and are skewed towards an IL-17A+ phenotype in an ICOS-ICOSL dependent manner. γδT cells exhibit a distinct Vγ4+ , PD1+ , Ly6C+ CD44+ phenotype in steatohepatitis. Moreover, γδT cells upregulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced steatohepatitis and accelerates disease resolution. We demonstrate that hepatic γδT cells exacerbate steatohepatitis, independent of IL-17 expression, by mitigating conventional CD4+ T cell expansion and modulating their inflammatory program via CD1d-dependent VEGF expression.

20.
Bosn J Basic Med Sci ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31538912

RESUMO

The AGTR1 gene encodes angiotensin II receptor type 1, which is involved in cardiovascular diseases such as coronary heart disease (CHD). In the current study, we analyzed AGTR1 methylation level in a Han Chinese population by SYBR green-based quantitative methylation-specific PCR (qMSP). We collected blood samples from 761 CHD patients and 398 non-CHD controls at the Ningbo First Hospital. A data mining analysis was also performed to explore the association between AGTR1 methylation and AGTR1 gene expression, using datasets from the cBioPortal for Cancer Genomics and the Gene Expression Omnibus (GEO) database. Our results showed a significantly higher percentage of methylated reference (PMR) of AGTR1 in male CHD patients compared with male non-CHD controls (median PMR: 2.12% vs. 0.59%, p = 0.037). The data mining analysis showed that AGTR1 expression was significantly increased in human hepatoma HepG2 cells treated with the demethylation agent 5-aza-2'-deoxycytidine (fold = 3.12, p = 0.009). Further data mining analysis using the cholangiocarcinoma (TCGA, PanCancer Atlas) data indicated an inverse association between AGTR1 methylation and AGTR1 expression (r = -0.595, p = 1.29E-04). Overall, our results suggest that AGTR1 methylation is involved in the regulation of AGTR1 gene expression and that AGTR1 hypermethylation is associated with CHD in males. These findings may provide new clues about the pathogenesis of CHD.

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