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1.
J Am Chem Soc ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32032485

RESUMO

Biological organisms capable of controlling and performing a wide variety of functions have inspired attempts to mimic biological systems with designable intelligence. Here we develop a multimachine communication network (MMCN) to mimic the operation and function of adaptive immune response (AIR) via connecting three kinds of DNA machines built from module-functionalized gold nanoparticles. These machines simulate three critical immune cells, dendritic cells and T and B lymphocytes, their differentia-tion and coordinated interaction upon exposure and response to an invading pathogen. MMCN is composed of standard modules with track, movement and fuel components that allow for: (1) integration and adaptability of a single machine, (2) convenient spatio-temporal control of sequential activation of a single machine, (3) rapid reaction rate and high efficiency owing to an enhanced local concentration of interacting species. We show that the proposed network can sense and clear the corresponding pathogen via con-secutive activation and connection of the machines, simultaneously forming a memory to respond more rapidly and effectively upon the second invasion of pathogen. This system may be extended to construct powerful networks to execute more sophisticated tasks and accomplish diverse functions.

2.
Sci Rep ; 10(1): 1355, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992826

RESUMO

Due to its poor clinical outcome, there is an urgent need to identify novel prognostic markers for stomach adenocarcinoma (STAD). Here, we aimed to explore the relationship between VGLL3 expression and clinico-pathological features, dendritic cells, macrophages, and prognosis of STAD. VGLL3 expression levels were significantly associated with histological grade, T stage, and TNM stage. VGLL3 levels and patient's age were also independent prognostic factors of the clinical outcome of STAD. In addition, VGLL3 was associated with the abundance of macrophages and dendritic cells in tumor infiltrates, of which only VGLL3 and macrophage counts were the independent prognostic factors of immune cell infiltration in the TIMER Database. Extracellular matrix receptor interaction, focal adhesion, pathways in cancer, MAPK, JAK STAT, and WNT signaling pathways were enriched in VGLL3 high-expressing datasets as determined by Gene Set Enrichment Analysis (GSEA), while DNA replication, glyoxylate, and dicarboxylate metabolism, glutathione metabolism, homologous recombination, and glycosylphosphatidylinositol gpi banchor biosynthesis were enriched in VGLL3 low-expressing datasets. Thus, VGLL3 is a novel prognostic biomarker of both the clinical outcome and immune infiltration in STAD, and may therefore be a promising therapeutic target.

3.
Cell Death Dis ; 11(1): 71, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992690

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1) regulates gene transcription in addition to functioning as a DNA repair factor. Forkhead box O1 (FoxO1) is a transcription factor involved in extensive biological processes. Here, we report that PARP1 binds to two separate motifs on the FoxO1 promoter and represses its transcription in a polymerase-independent manner. Using PARP1-knock out (KO) cells, wild-type-PARP1-complemented cells and catalytic mutant PARP1E988K-reconstituted cells, we investigated transcriptional regulation by PARP1. PARP1 loss led to reduced DNA damage response and ~362-fold resistance to five PARP inhibitors (PARPis) in Ewing sarcoma cells. RNA sequencing showed 492 differentially expressed genes in a PARP1-KO subline, in which the FoxO1 mRNA levels increased up to more than five times. The change in the FoxO1 expression was confirmed at both mRNA and protein levels in different PARP1-KO and complemented cells. Moreover, exogenous PARP1 overexpression reduced the endogenous FoxO1 protein in RD-ES cells. Competitive EMSA and ChIP assays revealed that PARP1 specifically bound to the FoxO1 promoter. DNase I footprinting, mutation analyses, and DNA pulldown FREP assays showed that PARP1 bound to two particular nucleotide sequences separately located at -813 to -826 bp and -1805 to -1828 bp regions on the FoxO1 promoter. Either the PARPi olaparib or the PARP1 catalytic mutation (E988K) did not impair the repression of PARP1 on the FoxO1 expression. Exogenous FoxO1 overexpression did not impair cellular PARPi sensitivity. These findings demonstrate a new PARP1-gene promoter binding mode and a new transcriptional FoxO1 gene repressor.

4.
Neurosci Lett ; 714: 134595, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682872

RESUMO

The pathogenesis of cancer induced bone pain (CIBP) is extremely complex, and glutamate receptor dysfunction plays an important role in the formation of CIBP. Synapse-associated protein 102 (SAP102) anchors glutamate receptors in the postsynaptic membrane. However, its effect on hyperalgesia formation in CIBP has not been clarified. This study investigated the role of SAP102 in the formation of hyperalgesia in rats with CIBP SAP102 is present in spinal dorsal horn neurons, but not in astrocytes or microglia. NMDAR-NR2B is localized with neurons. In addition, SAP102 and NMDAR-NR2B expression levels in spinal dorsal horn tissues were detected by Western blot and co-immunoprecipitation. Intrathecal injection of lentiviral vector of RNAi to knockdown SAP102 expression in the spinal dorsal horn significantly attenuated abnormal mechanic pain when compared to non-coding lentiviral vector. These findings indicate that SAP102 can anchor NMDA receptors to affect hyperalgesia formation in bone cancer pain.

5.
Surg Today ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858238

RESUMO

PURPOSE: We implemented the individualized treatment (IT) regimen for children with inguinal hernia and the Lichtenstein hernioplasty using an acellular tissue matrix patch (LHAP) for those with high risks. This retrospective study compares the complications of conventional laparoscopic high hernia sac ligation (LHSL) with those of the IT regimen for the management of pediatric inguinal hernia and investigates whether the recurrence rate of inguinal hernias in children treated by IT is lower than that of those treated by LHSL. METHODS: The subjects of this retrospective study were 3006 children who underwent LHSL or IT for inguinal hernia between February, 2008 and February, 2016 at the Beijing Chao-Yang Hospital (Beijing, China). They comprised 1516 (50.4%) children who underwent LHSL between February, 2008 and December, 2012, and 1490 (49.6%) who underwent IT between January, 2013 and June, 2016. We analyzed the patients' data, including clinical characteristics and postoperative complications. The mean follow-up was 85.31 months for the LHSL group and 43.34 months for the IT group (P < 0.01). Given the difference in the follow-up periods, the log-rank test was used to analyze the recurrence rate. RESULTS: The mean age, weight, and height of these children at the time of surgery were 6 years old, 24.17 kg, and 114.48 cm in the LHSL group and 6 years old, 24.57 kg, and 115.18 cm in the IT group, respectively (P = 0.647, P = 0.393, P = 0.505). The mean age, body weight, and height for adolescents at the time of surgery were 14.7 years old, 57.19 kg, and 168.37 cm in the LHSL group and 14.9 years old, 57.96 kg and 169.21 cm in the IT group, respectively (P = 0.099, P = 0.061, P = 0.059). The male/female ratio was 5.1:1 (1268/248) in the LHSL group and 4.9:1 (1241/249) in the IT group (P = 0.795). The side ratio of inguinal hernia (right/left/bilateral) was about 10:7:8 (602/430/484) in the LHSL group and 3.8:2.8:3.4 (567/422/501) in the IT group (P = 0.551). The comorbidities of the male patients included hydrocele (206), cryptorchidism (15), umbilical hernia (12), congenital heart disease (16), and other congenital diseases (25). The comorbidities in the female patients included round ligament cysts (11). There was no significant difference between the groups in postoperative complications including hydrocele (P = 0.687), hematoma (P = 0.061), surgical site infection (P = 0.742), testicular atrophy (not found), and umbilical trocar hernia (P = 0.585). There were two cases of recurrence in the IT group and eight in the LHSL group (P = 0.07). The frequency of postoperative recurrence of adolescent inguinal hernia was 3.16% (7/221) in the LHSL group, 0 (0/223) in the IT group (P = 0.008), and 0 (0/128) in the LHSL subgroup in the IT group (P = 0.045). CONCLUSION: The favorable outcomes of IT, which had a lower recurrence rate than LHSL for adolescent inguinal hernia, demonstrate that this is a reasonable treatment regimen for pediatric inguinal hernia.

6.
Mol Med Rep ; 20(5): 4695-4705, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702022

RESUMO

Treatment of cancer­induced bone pain (CIBP) is challenging in clinical settings. Oxycodone (OXY) is used to treat CIBP; however, a lack of understanding of the mechanisms underlying CIBP limits the application of OXY. In the present study, all rats were randomly divided into three groups: The sham group, the CIBP group, and the OXY group. Then, a rat model of CIBP was established by inoculation of Walker 256 tumor cells from rat tibia. Phosphoproteomic profiling of the OXY­treated spinal dorsal cords of rats with CIBP was performed, and 1,679 phosphorylated proteins were identified, of which 160 proteins were significantly different between the CIBP and sham groups, and 113 proteins were significantly different between the CIBP and OXY groups. Gene Ontology analysis revealed that these proteins mainly clustered as synaptic­associated cellular components; among these, disks large homolog 3 expression was markedly increased in rats with CIBP and was reversed by OXY treatment. Subsequent domain analysis of the differential proteins revealed several significant synaptic­associated domains. In conclusion, synaptic­associated cellular components may be critical in OXY­induced analgesia in rats with CIBP.

7.
ACS Appl Mater Interfaces ; 11(49): 46197-46204, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31722171

RESUMO

Dichromate is a widespread contaminant in wastewater, threatening the health of humans and other organisms. Therefore, effective detection and removal of dichromate from water is of great significance. Herein, a tetraphenylethylene functionalized cationic organic network (CON-LDU2) was constructed via a facile quaternization reaction. CON-LDU2 was successfully integrated with both detection and removal functionalities toward dichromate. On the one hand, benefiting from the strong fluorescence, CON-LDU2 was employed as a chemosensor, it could efficiently and selectively probe Cr2O72- in water with "turn-off" fluorescent response. On the other hand, the cationic skeleton and free anions inside framework make CON-LDU2 an excellent adsorbent for Cr2O72-, it could capture Cr2O72- from water with rapid kinetics and high capacity. The kinetic constant for adsorption of Cr2O72- can reach up to 1.784 g mg-1 min-1, while the capacity is determined as 325 mg g-1. Furthermore, CON-LDU2 displayed good recyclability and can be reused for at least 5 cycles. Therefore, CON-LDU2 can serve as an ideal candidate not only in detection but also in removal of Cr2O72- in water medium.

8.
World J Gastroenterol ; 25(38): 5814-5825, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636474

RESUMO

BACKGROUND: Wnt1-inducible signaling pathway protein 1 (WISP1) is upregulated in several types of human cancer, and has been implicated in cancer progression. However, its clinical implications in gastric cancer (GC) remain unclear. AIM: To explore the expression pattern and clinical significance of WISP1 in GC. METHODS: Public data portals, including Oncomine, The Cancer Genome Atlas database, Coexpedia, and Kaplan-Meier plotter, were analyzed for the expression and clinical significance of WISP1 mRNA levels in GC. One hundred and fifty patients who underwent surgery for GC between February 2010 and October 2012 at the Affiliated Hospital of Jiangnan University were selected for validation study. WISP1 levels were measured at both the mRNA and protein levels by RT-qPCR, Western blot analysis, and immunohistochemistry (IHC). In addition, the in situ expression of WISP1 in the GC tissues was determined by IHC, and the patients were accordingly classified into high- and low-expression groups. The correlation of WISP1 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses. WISP1 was knocked down by RNA interference. The 50% inhibitory concentration of oxaliplatin was detected by CellTiter-Blue assay. RESULTS: WISP1 levels at both the mRNA and protein levels were remarkably upregulated in GC tissues compared to normal tissues. Moreover, IHC revealed that WISP1 expression was associated with T stage and chemotherapy outcome, but not with lymph node metastasis, age, gender, histological grade, or histological type. GC patients with high WISP1 expression showed a poor overall survival. Multivariate survival analysis indicated that WISP1 was an important prognostic factor for GC patients. Mechanistically, knock-down of WISP1 expression enhanced sensitivity to oxaliplatin by reducing DNA repair and enhancing DNA damage. CONCLUSION: Significantly upregulated WISP1 expression is associated with cancer progression, chemotherapy outcome, and prognosis in GC. Mechanistically, knock-down of WISP1 expression enhances oxaliplatin sensitivity by reducing DNA repair and enhancing DNA damage. WISP1 may be a potential therapeutic target for GC treatment or a potential biomarker for diagnosis and prognosis.

9.
Front Oncol ; 9: 921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31649870

RESUMO

Identification of effective biomarkers is crucial for monitoring the treatment and remission of colorectal cancer (CRC) and improving survival. It is particularly important to diagnose CRC before the tumor metastasizes (stage I-II disease) where possible, to provide the greatest opportunity for patient recovery. Here, we evaluated the clinical value of serum chemokine (C-X-C) ligand 7 (CXCL7) concentration as a biomarker for CRC diagnosis. An enzyme-linked immunosorbent assay was used to measure CXCL7 concentration in 560 serum samples from patients with CRC and controls. Logistic regression and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic efficacy and build mathematical diagnostic models. The concentration of CXCL7 in the CRC group was significantly higher than that in the control group (P < 0.001), with an area under the ROC curve (AUC) value of 0.862 [95% confidence interval (CI): 0.831-0.890]. Further, the AUC of a regression model including the markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125), along with CXCL7, was 0.933 (95% CI: 0.909-0.952). For stage I-II tumors, CXCL7 had the highest AUC (0.823, 95% CI: 0.783-0.858) among the four individual biomarkers. The AUC value for combination model analysis of samples from patients with stage I-II tumors was 0.904 (95% CI: 0.872-0.930), with a sensitivity of 82.76% and a specificity of 87.14%, and an optimal cut-off value of 2.66. AUC values for application of the regression model in subgroup analysis were 0.947 (0.917-0.968) and 0.919 (0.874-0.951) for males and females, respectively. These results suggest that CXCL7 has potential as a serum diagnostic biomarker for detection of CRC. Importantly, the combination of CXCL7, CEA, CA125, and CA19-9 may facilitate diagnosis of CRC with relatively high sensitivity and specificity. Clinical Trial Registration Number: LS2017001.

10.
Clin Transl Gastroenterol ; 10(10): e00074, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31609743

RESUMO

OBJECTIVE: Increasing evidence has indicated an association between gut microbiota in gastrointestinal cancer and clinical outcome. Herein, we aim to develop a prognosis-prediction tool based on an immune-lipid metabolism signature, tumor cell-associated immune microenvironment, and lipid metabolism proteins inferred from the function of gut microbiota. METHODS: 16S gene ribosomal RNA sequencing was performed on 10 fecal samples obtained after tumor resection but before chemotherapy (EBVaGC = 4 and EBVnGC = 6). Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to screening for highly accurate marker proteins. A compound score based on the fraction of screened markers was then constructed using a LASSO logistic regression model. RESULTS: The Tax4Fun analysis based on Kyoto Encyclopedia of Genes and Genomes data indicated differentially expressed tumor pathway between EBVnGC and EBVaGC. Using the LASSO logistic model, a compound score was established consisting of 14 types of immune microenvironment and lipid metabolism proteins. In the training set (378 patients), significant differences were found between high- and low-compound score groups in overall survival across and within subpopulations with an identical EBV. Multivariable analysis revealed that the compound score was an independent prognostic factor (hazard ratio, 2.26; 95% confidence interval = 2.28-3.36). The prognostic value ;of the compound score was also confirmed in the validation (162 patients) and entire (540 patients) sets. DISCUSSION: The proposed compound score is a promising signature for estimating overall survival in patients with gastric cancer having EBVaGCs or EBVnGCs.

11.
Pathol Res Pract ; 215(11): 152510, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31591054

RESUMO

Accumulating evidence indicates a strong correlation between type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC), but the underlying pathophysiology is still elusive. We aimed to identify unrecognized but important genes and pathways related to T2DM and HCC by bioinformatic analysis. The GSE64998 and GSE15653 datasets (for T2DM), the GSE121248 dataset and the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset (for HCC) were downloaded. Differential expression analysis, functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction, survival analysis, transcription factor (TF) prediction, and correlation of gene expression with methylation and tumour-infiltrating immune cells were conducted. Nine genes, namely, CDNF, CRELD2, DNAJB11, DTL, GINS2, MANF, PDIA4, PDIA6, and VCP, were recognized as hub genes. Enrichment analysis revealed several enriched terms and pathways. Transcription factors such as Kruppel-like factor 6, abnormal methylation and immune dysregulation might help explain the dysregulation of hub genes. Our study identified nine hub genes that might play a critical role in both T2DM and HCC. However, more studies are warranted to clarify the mechanisms of these genes.

13.
World J Emerg Med ; 10(4): 222-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534596

RESUMO

BACKGROUND: Many controversies still exist regarding ventilator parameters during cardiopulmonary resuscitation (CPR). This study aimed to investigate the CPR ventilation strategies currently being used among physicians in Chinese tertiary hospitals. METHODS: A survey was conducted among the cardiac arrest team physicians of 500 tertiary hospitals in China in August, 2018. Surveyed data included physician and hospital information, and preferred ventilation strategy during CPR. RESULTS: A total of 438 (88%) hospitals completed the survey, including hospitals from all 31 mainland Chinese provinces. About 41.1% of respondents chose delayed or no ventilation during CPR, with delayed ventilations all starting within 12 minutes. Of all the respondents who provided ventilation, 83.0% chose to strictly follow the 30:2 strategy, while 17.0% chose ventilations concurrently with uninterrupted compressions. Only 38.3% respondents chose to intubate after initiating CPR, while 61.7% chose to intubate immediately when resuscitation began. During bag-valve-mask ventilation, only 51.4% of respondents delivered a frequency of 10 breaths per minute. In terms of ventilator settings, the majority of respondents chose volume control (VC) mode (75.2%), tidal volume of 6-7 mL/kg (72.1%), PEEP of 0-5 cmH2O (69.9%), and an FiO2 of 100% (66.9%). However, 62.0% of respondents had mistriggers after setting the ventilator, and 51.8% had high pressure alarms. CONCLUSION: There is a great amount of variability in CPR ventilation strategies among cardiac arrest team physicians in Chinese tertiary hospitals. Guidelines are needed with specific recommendations on ventilation during CPR.

14.
Cent Eur J Immunol ; 44(2): 159-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31530986

RESUMO

The results on associations of tumor necrosis factor (TNF)-receptor associated factor 1/complement component 5 (TRAF1/C5) rs10818488 and rs3761847 polymorphisms with rheumatoid arthritis (RA) are controversial, thus this study was performed to examine whether the aforementioned polymorphisms were associated with RA in a Chinese population. Furthermore, an updated meta-analysis was conducted. The polymorphisms were genotyped in 328 Chinese RA patients and 449 healthy controls. Studies examining the association of TRAF1/C5 rs10818488 and/or rs3761847 polymorphism with RA were exhaustively searched. No significant difference in either genotype or allele distribution between RA patients and controls was found. The updated meta-analysis was conducted based on 19 articles including the present study. A significant association of RA with TRAF1/C5 rs10818488 polymorphism G allele in Europeans (OR = 0.843, 95% CI = 0.730-0.975, p = 0.021) and in Asians (OR = 1.070, 95% CI = 1.009-1.136, p = 0.024) was found. Additionally, a significant association of RA with TRAF1/C5 rs10818488 polymorphism G allele under the recessive model in Asians (OR = 1.129, 95% CI = 1.023-1.246, p = 0.016) and in Africans (OR = 0.657, 95% CI = 0.507-0.851, p = 0.001) was found. Only a borderline significant association of RA with TRAF1/C5 rs3761847 polymorphism A allele was found in Europeans. Non-significant associations of RA with TRAF1/C5 rs10818488 and rs3761847 polymorphisms were found in our study. The updated meta-analysis results demonstrate that TRAF1/C5 rs10818488 polymorphism is associated with RA in Europeans, Asians and Africans, and TRAF1/C5 rs3761847 polymorphism is associated with RA in Europeans with borderline significant evidence.

15.
Front Oncol ; 9: 776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497531

RESUMO

Colorectal cancer (CRC) is one of the most prevalent digestive tumors in China. Recent studies indicate that long intergenic non-coding RNAs (lincRNAs) play a crucial role in predicting survival for CRC patients. However, the novel lincRNA, LINC00957, is largely unclear in CRC. The purpose of the current study was to determine LINC00957 expression, assess its the clinical significance and explore the potential mechanism in CRC. The qRT-PCR was used to quantify the expression levels of LINC00957 in tissues and cell lines. Our research revealed that LINC00957 was significantly higher expression in CRC. In addition, the LINC00957 expression was associated with TNM stage and chemotherapy outcome, but age, gender, tumor size, histological grade, primary tumor location. CRC patients with high LINC00957 expression level showed poor overall survival (P = 0.002). Multivariate survival analysis indicated that LINC00957 was a prognostic factor for CRC patients (P = 0.010). Mechanically, inhibition of LINC00957 expression reversed 5-FU resistance by down-regulating P-gP. In summary, our study indicated that this novel lncRNA expression signature might be a useful biomarker of the prognosis and therapeutic target for CRC patients.

16.
ACS Omega ; 4(1): 509-517, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459345

RESUMO

Regenerated cellulose (RC) films exhibit poor water barrier performance, which seriously restricts its applications. To address this issue, an impermeable and hydrophobic graphene oxide modified by chemically grafting octadecylamine (GO-ODA) was utilized to enhance the water vapor barrier performance of RC nanocomposite films. Compared to the neat RC film, more than 20% decrease in the coefficient of water vapor permeability (P H2O) was achieved by loading only 2.0 wt % GO-ODA. The promising hydrophobicity of GO-ODA effectively retarded the formation of hydrogen bonding at the relatively weakened interface between GO and RC, compensating for the diffusion of water vapor molecules at the interface; on the other hand, the fully exfoliated GO-ODA nanosheets were inclined to align with the surface of the as-prepared RC nanocomposite films during hot-pressure drying, creating a much more tortuous pathway for diffusion of water molecules. The new insights could be valuable for widening application of cellulose such as packaging.

17.
World J Clin Cases ; 7(15): 1954-1963, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31423427

RESUMO

BACKGROUND: Vestigial like family member 3 (VGLL3) is associated with the prognosis of epithelial ovarian cancer and soft tissue sarcoma, but its role in gastric cancer (GC) is unclear. AIM: To explore the expression pattern and clinical significance of VGLL3 in GC. METHODS: Integrative analysis was performed on the GC transcriptome profiles and survival information deposited in the ONCOMINE, GEPIA, and ONCOLNC databases. The expression levels of VGLL3 mRNA and protein were analyzed in the freshly resected tumor and normal gastric tissues from GC patients by quantitative RT-PCR and Western blot, respectively. In addition, the in situ expression of VGLL3 in the GC tissues was determined by immunohistochemistry (IHC), and the patients were accordingly classified into the high and low expression groups. The correlation of VGLL3 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses. RESULTS: Analysis of the ONCOMINE and GEPIA databases showed that VGLL3 was significantly up-regulated in GC tissues (P = 0.003), and associated with the tumor TNM stage (P = 0.0163). The high VGLL3 expression group had a significantly worse prognosis compared to the low expression group, as per both GEPIA (P = 0.0057) and ONCOLNC (P = 0.01). The bioinformatics results were validated by the significantly higher VGLL3 mRNA and protein levels in the GC tissues compared to the adjacent normal tissues (P < 0.001) in a cohort of 30 GC patients. Furthermore, high in situ expression of VGLL3 protein was associated with more advanced N and TNM stages and HER2 mutation (P < 0.05) in a cohort of 172 patients. Kaplan-Meier analysis showed that the high VGLL3 expression group had a worse prognosis compared to the low expression group (P = 0.019). Multivariate analysis showed that VGLL3 expression status was an independent risk factor for prognosis. In addition, the prognostic risk model nomogram showed that VGLL3 was the most important indicator, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.613 for 3-year survival and 0.706 for 5-year survival. Finally, the protein interaction network analysis revealed that VGLL3 is likely involved in the Hippo signaling pathway. CONCLUSION: VGLL3 is overexpressed in GC tissues and associated with a poor prognosis, indicating its potential as a novel prognosis biomarker and therapeutic target for GC.

19.
Arch Pharm Res ; 42(10): 902-908, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31388826

RESUMO

Lycium barbarum polysaccharide (LBP), an active component from Goji berry which is a traditional Chinese medicine, has anti-inflammatory and antioxidant features. The aim of our study was to investigate whether LBP has any role in hyperoxia-induced acute lung injury (ALI). Using a murine model of hyperoxia-induced ALI, we investigate the effect of LBP on pulmonary pathological changes as well as Sirtuin 1 (SIRT1) and the nucleotide binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome. Exposure to 100% oxygen for 72 h in male C57BL/6 mice resulted in increased protein levels of tumor necrosis factor-α and interleukin-1ß in lung tissues, and aggravated lung histological alterations. These hyperoxia-induced changes and mortality were improved by LBP. LBP markedly suppressed the activation of NLRP3 inflammasome both in vivo and in vitro. Moreover, LBP upregulated SIRT1 expression compared with vehicle-treated group. Importantly, knockdown of SIRT1 reversed the inhibitory effect of LBP on NLRP3 inflammasome activation in vitro. LBP meliorated hyperoxia-induced ALI in mice by SIRT1-dependent inhibition of NLRP3 inflammasome activation.

20.
Cell Death Dis ; 10(8): 557, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324754

RESUMO

The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to L-kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1. Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of L-kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced L-kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.

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