Objective To explore the effect of heme oxygenase-1 (HO-1) on differentiation of CD4+CD25+Treg derived from spleen T lymphocytes in mice in vitro and its underlying mechanism. Methods Lymphocytes were prepared from spleen of mice and pretreated with PBS, Copp (cobalt protoporphyrin, HO-1 inducer, 50μmol/L) and Znpp (zinc protoporphyrin, HO-1 inhibitor, 50μmol/L) respectively, for 12h. The expressions of HO-1 mRNA and protein in each group were determined by real-time qPCR and Western blotting. The ratio of CD4+CD25+Tregs was detected by flow cytometry. The level of Th1 and Th2 cytokines in the supernatant was determined by ELISA. Results Compared with PBS group, the expressions of HO-1 mRNA and protein, and the rates of CD4+CD25+Tregs increased in Copp group. At the same time, the cytokine of Th1, IL-2 and IFN-γ, significantly decreased, and the Th2 cytokines, TGF-β and IL-10, increased significantly (P<0.05). The results of Znpp group showed an opposite trend. Conclusion HO-1 could promote differentiation of T lymphocytes to CD4+CD25+Treg, and it may be related to an adjustment of the balance of Th1/Th2 cytokines.
Abstract Bromodomain 4 (BRD4), a member of the bromodomain and extra‐terminal domain protein family, has become a promising epigenetic target in cancer and inflammatory diseases; however, the detailed biological role of BRD4 in breast cancer (BRCA) remains undetermined. We analysed the BRD4 expression levels using the Oncomine and TIMER databases and evaluated the clinical impact of BRD4 on BRCA prognosis using Kaplan‐Meier plot and PrognoScan. The correlation between BRD4 and tumour‐infiltrating immune cells was investigated using TIMER. Furthermore, the correlation between BRD4 expression levels was also analysed using TIMER in addition to the GEPIA database for immune cell gene markers. BRD4 expression was significantly higher in BRCA tissues than in normal tissues, which was significantly correlated with poor overall survival (OS). Specifically, high BRD4 expression was correlated with worse OS and progression‐free survival in patients with BRCA. In addition, BRD4 expression was correlated with levels of infiltrating monocytes (CSF1R, cor = 0.204, P = 9.19e−12), tumour‐associated macrophages (CD68, cor = 0.129, P = 1.81e−05), M1/M2 macrophages and different effector T cells (including Th1/Th2/Treg) in BRCA. These findings suggest that BRD4 could be used as a prognostic biomarker for determining prognosis and immune cell infiltration levels in BRCA.
Abstract Prognosis of patients with lung cancer remains extremely poor; thus, we sought to unearth novel competing endogenous RNA (ceRNA) networks associated with the prognosis of lung adenocarcinoma (LUAD). Aberrant mRNAs were identified from the intersection of three Gene Expression Omnibus (GEO) datasets. A protein–protein interaction (PPI) network was constructed, and miRNAs and long noncoding RNAs (lncRNAs) upstream of mRNAs were predicted. In the present study, 402 upregulated and 638 downregulated genes in lung cancer tissues were identified. Functional analysis showed significant enrichment of cancer pathways. In these top hub genes, 10 upregulated and 7 downregulated genes had substantial prognostic values in LUAD. Thirty-seven miRNAs were predicted to target 17 key genes, and only five miRNAs exhibited prognostic correlation. Through stepwise reverse prediction and validation from miRNA to lncRNA, four key lncRNAs were identified using expression and survival analysis. Ultimately, the co-expression analysis identified LINC00665-miR-let-7b- CCNA2 as the key ceRNA network associated with the prognosis of LUAD. We successfully constructed a novel ceRNA network wherein each component was significantly associated with the prognosis of LUAD. Hence, we propose that this network may provide key biomarkers or potential therapeutic targets for LUAD prognosis.
To evaluate the effect of airway pressure release ventilation (APRV) in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS), to evaluate the extent of ventilator-induced lung injury (VILI), and to explore its possible mechanism.A prospective study was conducted in the Department of Critical Care Medicine of the First Hospital of Hebei Medical University from December 2010 to February 2012. The patients with ALI/ARDS were enrolled. They were randomly divided into two groups. The patients in APRV group were given APRV pattern, while those in control group were given lung protection ventilation, synchronized intermittent mandatory ventilation with positive end-expiratory pressure (SIMV+PEEP). All patients were treated with AVEA ventilator. The parameters such as airway peak pressure (Ppeak), mean airway pressure (Pmean), pulse oxygen saturation (SpO2), mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), arterial blood gas, urine output (UO), the usage of sedation and muscle relaxation drugs were recorded. AVEA ventilator "turning point (Pflex) operation" was used to describe the quasi-static pressure volume curve (P-V curve). High and low inflection point (UIP, LIP) and triangular Pflex volume (Vdelta) were automatically measured and calculated. The ventilation parameters were set, and the 24-hour P-V curve was recorded again in order to be compared with subsequent results. Venous blood was collected before treatment, 24 hours and 48 hours after ventilation to measure lung surfactant protein D (SP-D) and large molecular mucus in saliva (KL-6) by enzyme linked immunosorbent assay (ELISA), and the correlation between the above two parameters and prognosis on 28 days was analyzed by multinomial logistic regression.Twenty-six patients with ALI/ARDS were enrolled, and 22 of them completed the test with 10 in APRV group and 12 in control group. The basic parameters and P-V curves between two groups were similar before the test. After 24 hours and 48 hours, mechanical ventilation was given in both groups. The patients' oxygenation was improved significantly, though there were no significant changes in hemodynamic parameters. The Pmean (cmH2O, 1 cmH2O = 0.098 kPa) in APRV group was significantly higher than that in control group (24 hours: 24.20±4.59 vs. 17.50±3.48, P < 0.01; 48 hours: 18.10±4.30 vs. 15.00±2.59, P < 0.05). After ventilation for 24 hours, the ratio of patients with increased Vdelta in APRV group was higher than that in control group (90% vs. 75%), but without statistical difference (P > 0.05). The SP-D level (μg/L) in serum in APRV group showed a tendency of increase (increased from 19.70±7.34 to 27.61±10.21, P < 0.05), in contrast there was a tendency of decrease in control group (decreased from 21.83±7.31 to 16.58±2.90, P > 0.05), the difference between the two groups was statistically significant (P < 0.05). After 48-hour ventilation, SP-D in APRV group was decreased, but no change was found in control group, and no significant difference was found as compared with that of the control group (16.45±8.17 vs. 17.20±4.59, P > 0.05). There was no significant difference in serum KL-6 between the two groups before and after ventilation. The SP-D and KL-6 levels in serum were unrelated with 28-day survival rate of the patients. The odds ratio (OR) of SP-D were 0.900 [95% confidence interval (95%CI) = 0.719-1.125], 1.054 (95%CI = 0.878-1.266), 1.143 (95%CI = 0.957-1.365), and the OR of KL-6 were 1.356 (95%CI = 0.668-2.754), 0.658 (95%CI = 0.161-2.685), 0.915 (95%CI = 0.350-2.394) before the test, 24 hours and 48 hours after ventilation (all P > 0.05).APRV was similar to lung protective ventilation strategy in oxygenation and improvements in the lung mechanics parameters. APRV with a higher Pmean can recruit alveolar more effectively, and it had no impact on hemo-dynamics, but might exacerbate VILI.
Abstract Background The abnormal expression of activating transcription factor 3 (ATF3), a member of the basic leucine zipper (bZIP) family of transcription factors, is associated with carcinogenesis. However, the expression pattern and exact role of ATF3 in the development and progression of hepatocellular carcinoma (HCC) remain unclear. Methods We used UALCAN, ONCOMINE, Kaplan-Meier plotter, and cBioPortal databases to investigate the prognostic value of ATF3 expression in HCC. Results ATF3 was found to be expressed at low levels in multiple HCC tumor tissues. Moreover, low ATF3 expression was significantly associated with clinical cancer stage and pathological tumor grade in patients with HCC. Therefore, low expression of ATF3 was significantly associated with poor overall survival in patients with HCC. Functional network analysis showed that ATF3 regulates cytokine receptors and signaling pathways via various cancer-related kinases, miRNAs, and transcription factors. ATF3 expression was found to be correlated with macrophage infiltration levels and with macrophage immune marker sets in HCC patients. Conclusions Using data mining methods, we clarified the role of ATF3 expression and related regulatory networks in HCC, laying a foundation for further functional research. Future research will validate our findings and establish clinical applications of ATF3 in the diagnosis and treatment of HCC.
Four neutral cyclometalated iridium(III) dithioformic acid complexes ([(ppy) 2 Ir(S^S)], Ir1-Ir4 ) were designed and synthesized. Toxicity assay revealed that these complexes showed favorable anticancer activity, especially for A549 cells. Ir1 exhibiting the best anticancer activity (11.0±0.4 μ M) was about twice that of cisplatin, meanwhile, which could availably restrain A549 cells migration. Complexes could target mitochondria, induce a decrease in mitochondrial membrane potential, result in an increase of intracellular reactive oxygen species and disruption of the cell cycle, and ultimately generate apoptosis. Western blotting experiment indicated that complexes could inhibit the expression of Bcl-2 protein, induce the expression of Bax protein and lead to a massive release of Cytochrome C, which amplified apoptosis signals by activating downstream pathway to promote apoptosis . All these confirmed the existence of mitochondrial anticancer channels for these complexes. Above all, cyclometalated iridium(III) dithioformic acid complexes possess the prospect of becoming a multifunctional cancer therapeutic platform, including mitochondria-targeted imaging, anti-migration, and anticancer agents.
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