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1.
BMC Cardiovasc Disord ; 20(1): 73, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046639

RESUMO

BACKGROUND: Metabolic syndrome (MS) is a disorder, characterized by clusters of cardiovascular risk factors such as central obesity, insulin resistance, dyslipidemia and hypertension. Patients with MS may have a higher plaque burden that increases their risk of major adverse cardiovascular events (MACEs). This study aimed to analyze the prevalence of high-risk coronary plaques in patients with and without MS by coronary computed tomography angiography (CCTA) and to investigate the relationship between MS, high-risk coronary plaques, and their prognosis. METHODS: This was a retrospective cohort study of 1136 patients who underwent CCTA due to chest pain without obstructive heart disease (≥50% coronary stenosis) between January 2014 and December 2015 in our hospital. The relationships between high risk coronary plaques, MS, and other clinical factors were assessed. Multicollinearity analysis was performed to identify the collinearity between the variables. The proportional hazard assumption was checked and using Schoenfeld residual test. Cox proportional hazards model and Kaplan-Meier survival analysis assessed the relationship between MS, high-risk coronary plaques and MACEs. RESULTS: High-risk plaques were more frequent in the MS group than non-MS group (P = 0.004). MS (HR = 2.128, 95%CI: 1.524-2.970, P < 0.001), presence of high-risk plaques (HR = 11.059, 95%CI: 7.749-57.232, P < 0.001) and high sensitivity C-reactive protein (hsCRP) (HR = 1.629, 95%CI: 1.128-2.352, P = 0.009) were related with an increased risk of MACEs in patients with risk factors for coronary heart disease. In patients with high-risk plaques, MS (HR = 2.265, 95%CI: 1.629-3.150, P < 0.001) and hsCRP (HR = 1.267, 95%CI: 1.191-1.348, P = 0.004) were related with an increased risk of MACEs. Kaplan-Meier analysis showed differences in MACEs between the MS and non-MS groups in the whole population and those with high-risk plaques (both P < 0.0001). CONCLUSIONS: High-risk plaques were more common in patients with MS. MS and the presence of high-risk plaques were independent risk factors for MACEs.

2.
J Cell Physiol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020639

RESUMO

Diabetic retinopathy (DR) is a leading cause of acquired blindness among adults. High glucose (HG) induces oxidative injury and apoptosis in retinal ganglion cells (RGCs), serving as a primary pathological mechanism of DR. MIND4-17 activates nuclear-factor-E2-related factor 2 (Nrf2) signaling via modifying one cysteine (C151) residue of Kelch-like ECH-associated protein 1 (Keap1). The current study tested its effect in HG-treated primary murine RGCs. We show that MIND4-17 disrupted Keap1-Nrf2 association, leading to Nrf2 protein stabilization and nuclear translocation, causing subsequent expression of key Nrf2 target genes, including heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. Functional studies showed that MIND4-17 pretreatment significantly inhibited HG-induced cytotoxicity and apoptosis in primary murine RGCs. Reactive oxygen species production and oxidative injury in HG-treated murine RGCs were attenuated by MIND4-17. Nrf2 silencing (by targeted small interfering RNA) or knockout (by CRISPR/Cas9 method) abolished MIND4-17-induced RGC cytoprotection against HG. Additionally, Keap1 knockout or silencing mimicked and abolished MIND4-17-induced activity in RGCs. In vivo, MIND4-17 intravitreal injection activated Nrf2 signaling and attenuated retinal dysfunction by light damage in mice. We conclude that MIND4-17 activates Nrf2 signaling to protect murine RGCs from HG-induced oxidative injury.

3.
J Mater Chem B ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32022096

RESUMO

Mesenchymal stem cells (MSCs) have shown promising therapeutic effects in cell-based therapies and regenerative medicine. Efficient tracking of MSCs is an urgent clinical need that will help us to understand their behavior after transplantation and allow adjustment of therapeutic strategies. However, no clinically approved tracers are currently available, which limits the clinical translation of stem cell therapy. In this study, a nanoparticle (NP) for computed tomography (CT)/fluorescence dual-modal imaging, Au@Albumin@ICG@PLL (AA@ICG@PLL), was developed to track bone marrow-derived mesenchymal stem cells (BMSCs) that were administered intratracheally into mice with silica-induced pulmonary fibrosis, which facilitated understanding of the therapeutic effect and the possible molecular mechanism of stem cell therapy. The AuNPs were first formed in bovine serum albumin (BSA) solution and modified with indocyanine green (ICG), and subsequently coated with a poly-l-lysine (PLL) layer to enhance intracellular uptake and biocompatibility. BMSCs were labeled with AA@ICG@PLL NPs with high efficiency without an effect on biological function or therapeutic capacity. The injected AA@ICG@PLL-labeled BMSCs could be tracked via CT and near-infrared fluorescence (NIRF) imaging for up to 21 days after transplantation. Using these NPs, the molecular anti-inflammatory mechanism of transplanted BMSCs was revealed, which included the downregulation of proinflammatory cytokines, suppression of macrophage activation, and delay of the fibrosis process. This study suggests a promising role for imaging-guided MSC-based therapy for pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF) and pneumoconiosis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32008189

RESUMO

The present study investigated the impacts of humic acid (HA) and surfactants (SDBS and CTAB), which were ubiquitously found in the aquatic environments, on the removal of Cr(VI) by the hydroxylated MWCNTs-OH. The results showed that MWCNTs-OH could remove Cr(VI) from aqueous solution via adsorption coupled with reduction, and the kinetics followed the pseudo-first-order model with the rate of 3.5 × 10-3 h-1. In the presence of anionic SDBS, the removal percentage of Cr(VI) was greatly inhibited because the hydrophobic interaction and π-π interaction between SDBS and MWCNTs-OH surfaces not only decreased the adsorption sites for Cr(VI) but also made the surfaces more negatively charged. On the contrary, the existence of cationic CTAB could lead to the surfaces more positively charged, which consequently enhance the electrostatic attraction between Cr(VI) and the surfaces as well as the removal of Cr(VI). Noticeably, the presence of HA could promote the removal of Cr(VI), which was attributed to the reduction of Cr(VI) by the adsorbed HA. The ESR spectra indicated the existence of π-type radicals in HA structure and conduction electrons in MWCNTs-OH, and then the π-π interaction between MWCNTs-OH and adsorbed HA possibly increase the electron-donating ability of HA. Moreover, the promotive effect of HA could be enhanced with the addition of Ca2+. This study was helpful for us to understand the role of MWCNTs-OH in controlling the fate of Cr(VI) when HA and surfactants were present.

5.
J Sports Sci ; : 1-6, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028853

RESUMO

The aim of this study was to assess if tactical and technical performance indicators (PIs) could be used in combination to model match outcomes in Australian Football (AF). A database of 101 technical PIs and 14 tactical PIs from every match in the 2009-2016 Australian Football League (AFL) seasons was merged. Two outcome measures Win-loss and Score margin were used as dependent variables. The top 45 ranked technical and tactical PIs from a feature selection process were used to model match outcome using decision tree and Generalised Linear Models (GLMs). Of the top 45 selected features, this included seven tactical PIs. The Win-loss-based Decision tree model achieved a classification accuracy of 89.0% and GLM 93.2%. A Score margin-based GLM achieved a root mean squared error (RMSE) of 6.9 points. A combined approach to the classification of match outcomes provided no improvement in model accuracy compared with previous literature. However, this study has established the relative importance of technical and tactical measures of performance in relation to successful team performance in AF.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32033952

RESUMO

Blakeslea trispora is an industrial strain for large-scale production of carotenoids. However, light-regulated physiological processes, such as carotenoids biosynthesis and phototropism in B. trispora, are not fully understood. In this study, we isolated and characterized three photoreceptor genes, btwc-1a, btwc-1b and btwc-1c in B. trispora Bioinformatics analyses of these genes and their protein sequences revealed that their functional domains (PAS/LOV domain and zinc finger structure) have significant homology to other fungal blue-light regulator proteins from Mucor circinelloides and Neurospora crassa The photoreceptor proteins were synthesized by heterologous expression in Escherichia coli The chromogenic groups FAD and FMN were detected to accompany BTWC-1 proteins by using high performance liquid chromatography (HPLC) and fluorescence spectrometry, demonstrating that the proteins may be photosensitive. The absorbance change of the purified BTWC-1 proteins in dark and light indicated that they were light responsive and underwent a characteristic photocycle by light induction. Site-directed mutagenesis of the cysteine residual (Cys) in BTWC-1 did not affect the normal expression of the protein in E. coli, but led to the loss of photocycle response, indicating that Cys is flavin-binding domain for photon detection. We then analyzed the functions of BTWC-1 proteins by complementing btwc-1a, btwc-1b and btwc-1c into their counterpart knockout strains of M. circinelloides for each mcwc-1 gene. Transformation of the btwc-1a-complement into mcwc-1a knockout strains restored the positive phototropism, while the addition of btwc-1c-complement remedied the deficiency of carotene biosynthesis in the mcwc-1c knockout strains under illumination. These results indicate that btwc-1a and btwc-1c is involved in phototropism and light-inducible carotenogenesis. Thus, btwc-1 genes share a conserved flavin-binding domain and act as photoreceptor for control different light transduction pathways in B. trispora. IMPORTANCE Studies have confirmed that light-regulated carotenogenesis is prevalent in filamentous fungi, especially in mucorales. However, few investigations have been done to understand photoinduced synthesis of carotenoids and mechanism in B. trispora, a well-known industrial microbial strains. In the present study, three photoreceptor genes in B. trispora were cloned, expressed, and characterized by bioinformatics and photoreception analyses, then functional analyses of these genes in vivo were constructed in M. circinelloides The results of this study will lead to a better understanding of photoreception and light-regulated carotenoid synthesis and other physiological response in B. trispora.

7.
Life Sci ; 243: 117246, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31904367

RESUMO

AIMS: Obesity induce low-grade inflammation and elicit insulin resistance (IR), exercise training accompanied by a low-fat diet has been prescribed as part of the treatment for managing obesity and IR. The purpose of this study is to evaluate the effect of eccentric exercise accompanied by a low-fat diet on glycolipid metabolism, exercise capacity, and macrophage polarization in obesity-induced IR mice. MATERIALS AND METHODS: Mice were fed with 60% high fat diet (HFD) for 12 weeks and subsequently treated with eccentric exercise or/and dietary restriction for 8 weeks. Related biochemical index were examined both before and during intervention to evaluate the ability of glycolipid metabolism. Exercise capacity was measured to verify the results of biochemical index. At 12 weeks and 12 + 8 weeks, infiltration was observed by H&E staining in adipose tissue, and macrophage polarization was detected by Immunofluorescence staining and ELISA. KEY FINDING: 1) obesity-induced IR model was established by HFD fed for 12 weeks accompanied by impaired exercise ability and increased M1 macrophage, 2) eccentric exercise accompanied by a low-fat diet markedly rescued obesity-induced IR and improved exercise capacity, 3) eccentric exercise accompanied by a low-fat diet markedly inhibited M1 macrophage polarization and activated M2 macrophage. SIGNIFICANCE: Eccentric exercise accompanied by a low-fat diet rescued obesity-induced IR and improved exercise capacity, which were associated with the inhibition of M1 macrophage polarization and the activation of M2 macrophage. These indicate that macrophage polarization provides the potential target of intervention for inflammation and IR in obesity.

8.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 49-53, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31950789

RESUMO

Objective: To compare the effect of different first-trimester screening programmes for Down syndrome in Sichuan Province. Methods: We retrospectively collected the data of singleton pregnancies that were screened by serum biochemistry markers combined with nuchal translucency screening tests in the first trimester in Prenatal Diagnosis Center of West China Second University Hospital of Sichuan University from January 2011 to December 2017. The fetal chromosome results were obtained by amniocentesis or by telephone follow-up. The screening effect of maternal age, nuchal translucency thickness, maternal serum biochemistry markers and combined screening in the first trimester were analyzed. Results: Among the 21 723 singleton pregnancies, 33 cases were diagnosed as Down syndrome, and 19 cases were diagnosed as trisomy 18 sex chromosome abnormalities were found in 4 cases, and other chromosome abnormalities were found in 8 cases. For the combined screening, the detection rate of Down syndrome was 72.73%, and the false positive rate was 2.49%; the detection rate of trisomy 18 syndrome was 73.68% with the false positive rate of 0.39%. With a 5% false positive rate, maternal age, nuchal translucency thickness, serum biochemistry markers and combined screening would respectively detect 15.15%, 57.58%, 60.61% and 87.88% of Down syndrome fetuses. Conclusion: Compared with the other three screening programmes, the combined screening can effectively screen fetuses with Down syndrome and other chromosomal abnormalities.


Assuntos
Síndrome de Down , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal , Amniocentese , Biomarcadores/análise , Biomarcadores/sangue , China , Aberrações Cromossômicas , Síndrome de Down/sangue , Síndrome de Down/diagnóstico por imagem , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Estudos Retrospectivos
9.
J Org Chem ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31944119

RESUMO

The metal-free-catalyzed synthesis of allyl nitriles from Csp2-Csp3 coupling between olefins and azobis was carried out. Key on this work was that the synthesis of allyl nitriles directly using olefin as a starting material was considered to be more efficient and economical than the alkyne, alkynyl carboxylic acid, or cinnamic acid used in previous works. Moreover, in this reaction, iodine served as the sole promoter, azobis served as a cyanation reagent, and N2 was the only nontoxic byproduct that could avoid the utilization of metal catalysts and virulent nitrile reagents and generation of toxic wastes. With an optimum condition in hand, more than 30 examples of desired products including aromatic and aliphatic nitriles have been synthesized in good to excellent yields. Based on control experiments and literature data, a plausible mechanism of cyanation was proposed.

10.
PLoS Pathog ; 16(1): e1008178, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31968013

RESUMO

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/- mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.

11.
Mov Disord ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951047

RESUMO

BACKGROUND: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications. OBJECTIVES: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. METHODS: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 through September 2019. Mutational analysis of MYORG was performed in 435 primary familial brain calcification probands who were negative for mutations in the other four known primary familial brain calcification-causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1). RESULTS: Biallelic MYORG mutations were identified in 14 primary familial brain calcification patients from 10 unrelated families. Interestingly, 12 heterozygous carriers from seven of these families also exhibited mild-to-moderate brain calcifications. Moreover, single heterozygous mutations were detected in an additional 9 probands and in 7 of their family members affected with brain calcifications. In our cohort, clinical and imaging penetrance of individuals with biallelic mutations were 100%, whereas among individuals with heterozygous mutations, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 carriers had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG mutations, individuals with heterozygous mutations had brain calcifications with much lower calcification scores (P < 2e-16). CONCLUSIONS: Presence of brain calcifications in individuals with heterozygous MYORG mutations suggested a semidominant inheritance pattern with incomplete penetrance. This finding further expanded the genotype-phenotype correlations of MYORG-related primary familial brain calcification. © 2020 International Parkinson and Movement Disorder Society.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31953331

RESUMO

As an ideal carotenoids producer, Blakeslea trispora has gained lots of attentions due to its large biomass and high production of ß-carotene and lycopene. However, carotenogenesis regulation in B. trispora still needs to be clarified since few investigations have been conducted at molecular level in B. trispora In this study, the homologous gene of carotenogenesis regulatory gene (crgA) was cloned from the mating type (-) of B. trispora and the deduced CrgA protein was analyzed for its primary structure and domains. In order to clarify the crgA-mediated regulation in B. trispora, we used the strategies of gene knockout and complementation to investigate the effect of crgA expression on the phenotype of B. trispora In contrast to the wild-type strain, the crgA null mutant was defective in sporulation, but accumulated much more ß-carotene (31.2% improvement at the end) accompanied by the enhanced transcription levels of three structural genes (hmgR, carB and carRA) for carotenoids over whole culture time. When the wild-type copy of crgA was complemented into the crgA null mutant, sporulation, transcription level of structural gene and carotenoids production were restored as present in wild-type strain. Gas chromatography-mass spectrometry (GC-MS)-based metabolomic approach and multivariate statistical analyses were performed to investigate the intracellular metabolite profiles. The reduced levels of tricarboxylic acid (TCA) cycle components and some amino acids and enhanced levels of glycolysis intermediates and fatty acids indicate that more metabolic flux was driven into the mevalonate (MVA) pathway, thus the increase of precursors and fat content contributes to the accumulation of carotenoids.IMPORTANCE The zygomycete Blakeslea trispora is an important strain for the production of carotenoids in large scale. However, the regulation mechanism of carotenoid biosynthesis is still not well understood in this filamentous fungus. In the current study, we sought to investigate how crgA influences the expression of structural genes for carotenoids, carotenoid biosynthesis and other anabolic phenotypes. This will lead to a better understanding of global regulation mechanism of carotenoid biosynthesis and facilitate engineering this strain in the future for enhanced production of carotenoids.

13.
Nat Prod Res ; : 1-6, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928368

RESUMO

One new flavanonol 4 H-​1-​benzopyran-​4-​one,2-​(4-​hydroxyphenyl)​-​3,​7-​dihydroxy-​5-​methoxy-​8-​[5-​methyl-​2-​(1-​methylethenyl)​-​4-​hexenyl]​(21), and twenty-six known compounds 1-20, 22-27 were isolated from the dried root of Sophora flavescens (S. flavescens) in this chemical study. Their structures were elucidated according to the spectroscopic and spectrometric methods. All the isolated compounds were evaluated for their cytotoxicity against lung cancer A549 cells and colon cancer HCT116 cells. Among them, compound 21 showed relatively predominant cell proliferation inhibition effect on the two tumor cell lines. Moreover, it induced cells apoptosis as evidenced by the Annexin V/PI double staining assay as well as the increased cleaved-PARP expression. The aforementioned data indicated that the flavonoids of S. flavescens have potential anti-cancer effect.

14.
Adv Mater ; : e1904320, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31943439

RESUMO

Carbon-based materials have been considered as the most promising anode materials for both sodium-ion batteries (SIBs) and potassium-ion batteries (PIBs), owing to their good chemical stability, high electrical conductivity, and environmental benignity. However, due to the large sizes of sodium and potassium ions, it is a great challenge to realize a carbon anode with high reversible capacity, long cycle life, and high rate capability. Herein, by rational design, N-doped 3D mesoporous carbon nanosheets (N-CNS) are successfully synthesized, which can realize unprecedented electrochemical performance for both SIBs and PIBs. The N-CNS possess an ultrathin nanosheet structure with hierarchical pores, ultrahigh level of pyridinic N/pyrrolic N, and an expanded interlayer distance. The beneficial features that can enhance the Na-/K-ion intercalation/deintercalation kinetic process, shorten the diffusion length for both ions and electrons, and accommodate the volume change are demonstrated. Hence, the N-CNS-based electrode delivers a high capacity of 239 mAh g-1 at 5 A g-1 after 10 000 cycles for SIBs and 321 mAh g-1 at 5 A g-1 after 5000 cycles for PIBs. First-principles calculation shows that the ultrahigh doping level of pyridinic N/pyrrolic N contributes to the enhanced sodium and potassium storage performance by modulating the charge density distribution on the carbon surface.

15.
Sex Transm Dis ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31977972

RESUMO

BACKGROUND: There is benefit to early HIV-1 diagnosis and treatment, but there is no FDA-approved quantitative assay with a diagnostic claim. We compared the performance of the Hologic Aptima HIV-1 Quant (APT-Quant) and Aptima HIV-1 Qual (APT-Qual) assays for diagnostic use and the performance of a diagnostic algorithm consisting of Bio-Rad BioPlex 2200 HIV Ag-Ab assay (BPC) followed by APT-Quant (two-test) compare to BPC followed by Geenius HIV-1/2 supplemental assay (Geenius) with reflex to APT-Qual (three-test). METHODS: 524 plasma, which included 419 longitudinal specimens from HIV-1 seroconverters (78 were after initiating antiretroviral therapy (ART)) and 105 from ART-naïve persons with established HIV-1 infections, were used to evaluate APT-Quant performance for diagnostic use. Specimens from 200 HIV-negative persons were used to measure specificity. For the algorithm comparison, BPC-reactive specimens were evaluated with the two-test or three-test algorithm. McNemar's test was used to compare performance. RESULTS: APT-Quant detected more samples early in infection compared with APT-Qual. APT-Quant specificity was 99.8%. Before ART initiation, the algorithms performed similarly among samples from different stages of infection. After ART initiation, the three-test algorithm performed significantly better (p=0.0233). CONCLUSIONS: APT-Quant has excellent performance for diagnostic use. The two-test algorithm works well in ART-naïve samples, but its performance decreases after the IgG response is elicited and with ART-induced suppressed viremia. Providing confirmation and VL with one test result could be advantageous for patient care. However, additional factors and challenges associated with the implementation of this two-test algorithm such as cost, specimen type and collection need further evaluation.

16.
World J Gastroenterol ; 26(2): 134-153, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31969776

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer with a poor prognosis. Previous studies revealed that the tumor microenvironment (TME) plays an important role in HCC progression, recurrence, and metastasis, leading to poor prognosis. However, the effects of genes involved in TME on the prognosis of HCC patients remain unclear. Here, we investigated the HCC microenvironment to identify prognostic genes for HCC. AIM: To identify a robust gene signature associated with the HCC microenvironment to improve prognosis prediction of HCC. METHODS: We computed the immune/stromal scores of HCC patients obtained from The Cancer Genome Atlas based on the ESTIMATE algorithm. Additionally, a risk score model was established based on Differentially Expressed Genes (DEGs) between high- and low-immune/stromal score patients. RESULTS: The risk score model consisting of eight genes was constructed and validated in the HCC patients. The patients were divided into high- or low-risk groups. The genes (Disabled homolog 2, Musculin, C-X-C motif chemokine ligand 8, Galectin 3, B-cell-activating transcription factor, Killer cell lectin like receptor B1, Endoglin and adenomatosis polyposis coli tumor suppressor) involved in our risk score model were considered to be potential immunotherapy targets, and they may provide better performance in combination. Functional enrichment analysis showed that the immune response and T cell receptor signaling pathway represented the major function and pathway, respectively, related to the immune-related genes in the DEGs between high- and low-risk groups. The receiver operating characteristic (ROC) curve analysis confirmed the good potency of the risk score prognostic model. Moreover, we validated the risk score model using the International Cancer Genome Consortium and the Gene Expression Omnibus database. A nomogram was established to predict the overall survival of HCC patients. CONCLUSION: The risk score model and the nomogram will benefit HCC patients through personalized immunotherapy.

17.
Am J Physiol Heart Circ Physiol ; 318(1): H59-H71, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774703

RESUMO

Monocyte chemotactic protein-1 (MCP-1) plays a crucial role in ischemia-reperfusion (I/R) injury; however, the detailed mechanism of MCP-1 in I/R injury-induced cardiomyocyte apoptosis remains unclear. In this study, we explored the cascade downstream of I/R-induced MCP-1 that modulates cell apoptosis and determined whether Ca2+-sensing receptors (CaSRs) are involved in the process. Protein levels were detected in a cardiac muscle cell line (HL-1) and primary cultured neonatal mouse ventricular cardiomyocytes using Western blotting and immunocytochemistry. Released MCP-1 was detected using ELISA. Both Hoechst staining and flow cytometry methods were used to measure cell apoptosis. Specific pharmacological inhibitors of CC chemokine receptor 2 (RS-102895) and CaSR (NPS-2143) as well as a CaSR activator (evocalcet) were applied to confirm the roles of these factors in I/R-induced cell apoptosis. I/R inhibited cell viability and upregulated cell apoptosis. Moreover, I/R induced the release of MCP-1 from both HL-1 cells and primary cardiomyocytes. Further research confirmed that CaSR acted as an upstream effector of monocyte chemotactic protein-1-induced protein-1 (MCPIP1) and coordinately regulated cell apoptosis, which was verified by addition of an inhibitor or activator of CaSR. Moreover, MCPIP1 induced cell apoptosis through endoplasmic reticulum (ER) stress but not autophagy induced by I/R. Based on these findings, I/R-induced MCP-1 release regulates cardiomyocyte apoptosis via the MCPIP1 and CaSR pathways, suggesting a new therapeutic strategy for I/R injury.NEW & NOTEWORTHY Ischemia-reperfusion (I/R)-induced monocyte chemotactic protein-1 release regulates cardiomyocyte apoptosis via the monocyte chemotactic protein-1-induced protein-1 (MCPIP1) and Ca2+-sensing receptor pathway. The functional changes mediated by MCPIP1 involve the activation of endoplasmic reticulum stress, but not the autophagy pathway, after I/R injury.

18.
Theor Appl Genet ; 133(1): 297-315, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31628527

RESUMO

KEY MESSAGE: Major and environmentally stable QTL for flag leaf-related traits in wheat were identified and validated across ten environments using six populations with different genetic backgrounds. Flag leaf size and posture are two important factors of "ideotype" in wheat. Despite numerous studies on genetic analysis of flag leaf size including flag leaf length (FLL), width (FLW), area (FLA) and the ratio of length/width (FLR), few have focused on flag leaf posture including flag leaf angle (FLANG), opening angle (FLOA) and bend angle (FLBA). Further, the numbers of major, environmentally stable and verified genetic loci for flag leaf-related traits are limited. In this study, QTL for FLL, FLW, FLA, FLR, FLANG, FLOA and FLBA were identified based on a recombinant inbred line population together with values from up to ten different environments. Totally, eight major and stably expressed QTL were identified. Three co-located chromosomal intervals for seven major QTL were identified. The five major QTL QFll.sicau-5B.3 and QFll.sicau-2D.3 for FLL, QFlr.sicau-5B for FLR, QFlw.sicau-2D for FLW and QFla.sicau-2D for FLA were successfully validated by the tightly linked Kompetitive Allele Specific PCR (KASP) markers in the other five populations with different genetic backgrounds. A few genes related to leaf growth and development in intervals for these major QTL were predicated. Significant relationships between flag leaf- and yield-related traits were evidenced by analyses of Pearson correlations, conditional QTL and genetic mapping. Taken together, these results provide valuable information for understanding flag leaf size and posture of "ideotype" as well as fine mapping and breeding utilization of promising loci in bread wheat.

19.
RNA Biol ; 17(2): 240-253, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31607223

RESUMO

Background: Vascular endothelial cell dysfunction, characterized by cell apoptosis and migration, plays a crucial role in ischaemia/reperfusion (I/R) injury, a common aspect of cardiovascular diseases. Recent studies have suggested that non-coding RNAs, such as circular RNAs (circRNA), play a role in cell dysfunction in I/R injury, although the detailed mechanism is unclear.Methods: Human umbilical vein endothelial cells (HUVECs) were used for in vitro I/R model. Protein expression was detected by western blotting (WB) and immunocytochemistry. The CRISPR/Cas9 system, WB, cell viability assays, Hoechst staining and a 3D migration model were used to explore functional changes. RNA expression was evaluated using quantitative real-time PCR and a FISH assay combined with lentivirus transfection regulating circRNAs and miRNAs. A mouse myocardial I/R model using C57 mice was established to confirm the in vitro findings.Results: In HUVECs, I/R induced a significant time-dependent decrease in HECTD1 associated with an approximately 45% decrease in cell viability and increases in cell apoptosis and migration, which were attenuated by HECTD1 overexpression. I/R-induced upregulation of endoplasmic reticulum stress was also attenuated HECTD1 overexpression. Moreover, miR-143 mimics inhibited HECTD1 expression, which was restored by circDLGAP4 overexpression, providing insight as to the molecular mechanism of I/R-induced HECTD1 in endothelial cell dysfunction.Conclusion: Our results suggest a critical role for circDLGAP4 and HECTD1 in endothelial cell dysfunction induced by I/R, providing novel insight into potential therapeutic targets for the treatment of myocardial ischaemia.

20.
Int J Radiat Biol ; 96(2): 187-196, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31682784

RESUMO

Purpose: This study evaluated the DNA double strand breaks (DSBs) induced by indirect actions and its misrepairs to estimate the relative biological effectiveness (RBE) of proton beams.Materials and methods: From experimental data, DSB induction was evaluated in cells irradiated by 62 MeV proton beams in the presence of dimethylsulphoxide (DMSO) and under hypoxic conditions. The DNA damage yields for calculating the RBE were estimated using Monte Carlo Damage Simulation (MCDS) software. The repair outcomes (correct repairs, mutations and DSB conversions) were estimated using Monte Carlo Excision Repair (MCER) simulations.Results: The values for RBE of 62 MeV protons (LET = 1.051 keV/µm) for DSB induction and enzymatic DSB under aerobic condition (21% O2) was 1.02 and 0.94, respectively, as comparing to 60Co γ-rays (LET = 2.4 keV/µm). DMSO mitigated the inference of indirect action and reduced DSB induction to a greater extent when damaged by protons rather than γ-rays, resulting in a decreased RBE of 0.86. DMSO also efficiently prevented enzymatic DSB yields triggered by proton irradiation and reduced the RBE to 0.83. However, hypoxia (2% O2) produced a similar level of DSB induction with respect to the protons and γ-rays, with a comparable RBE of 1.02.Conclusions: The RBE values of proton beams estimated from DSB induction and enzymatic DSB decreased by 16% and 12%, respectively, in the presence of DMSO. Our findings indicate that the overall effects of DSB induction and enzymatic DSB could intensify the tumor killing, while alleviate normal tissue damage when indirect actions are effectively interrupted.

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