Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

BACKGROUND Growth arrest-specific gene 2(GAS2)plays a role in modulating in reversible growth arrest cell cycle,apoptosis,and cell survival.GAS2 protein is universally expressed in most normal tissues,particularly in the liver,but is depleted in some tumor tissues.However,the functional mechanisms of GAS2 in hepatocellular carcinoma(HCC)are not fully defined.AIM To investigate the function and mechanism of GAS2 in HCC.METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting.Cell proliferation was analyzed by counting,MTS,and colony formation assays.Cell cycle analysis was performed by flow cytometry.Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting.RESULTS GAS2 protein expression was lower in HCC than in normal tissues.Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53,while knockdown of GAS2 promoted the proliferation of hepatocytes(P<0.05).Furthermore,GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells,particularly the elevation of sub G1(P<0.01).Apoptosis induced by GAS2 was dependent on p53,which was increased by etoposide addition.The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated,but became diminished upon downregulation of GAS2.In the clinic specimen,GAS2 was downregulated in more than 60%of HCCs.The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues(P<0.05).CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis,possibly by regulating the cell cycle and p53-dependent apoptosis pathway.

Influence of edaravone on growth arrest and DNA damage-inducible protein 34 expression following focal cerebral ischemia-reperfusion in rats

Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34(GADD34).Methods:A total of 108 healthy male Sprague-Dawlcy rats were randomly divided into sham operation group,model group and edaravone.group(36 cases for each group).Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawlev rats.Then.GAOD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats.Results:The GADD34 expression was detected in the peri-infaret regions of rats 1 h after reperfusion,which reached its peak 24 h after reperfusion.And edaravone could significantly down-regulate the GAOD34 expression.Conclusions:Edaravon could down-regulate GADD34 expression,which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.

Effect of resuscitation after selective cerebral ultraprofound hypothermia on expressions of nerve growth factor and glial cell line-derived neurotrophic factor in the brain of monkey

Objective To investigate the expression of nerve growth factor （NGF） and glial cell line-derived neurotrophic factor （GDNF） in monkeys of resuscitation after selective cerebral ultraprofound hypothermia and blood flow occlusion. Methods The monkeys were immediately removed brain after death in operation of group A （identical temperature perfusion group） and group B （ultraprofound hypothermia perfusion group）. Immunohistochemical technique was used to determine frontal cellular expression of NGF and GDNF. Statistics were analyzed by ANOVA analyses with significance level at P 〈 0.05. Results The expressions of NGF and GDNF in the group B were significantly higher than those in the group A （P 〈 0.05）. Conclusion NGF and GDNF increased significantly in the monkeys of resuscitation after selective cerebral ultraprofound hypothermia and blood flow occlusion. It may be a protective mechanism for neuron survival and neural function recovery.

Tyrosine kinase of insulin-like growth factor receptor as target for novel treatment and prevention strategies of colorectal cancer

AIM： To investigate the antineoplastic potency of the novel insulin-like growth factor 1 receptor （IGF-1R） tyrosine kinase inhibitor （TKI） NVP-AEW541 in cell lines and primary cell cultures of human colorectal cancer （CRC）. METHODS： Cells of primary colorectal carcinomas were from 8 patients. Immunostaining and crystal violet staining were used for analysis of growth factor receptor protein expression and detection of cell number changes, respectively. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase （LDH）. The proportion of apoptotic cells was determined by quantifying the percentage of sub-G1 （hypodiploid） cells. Cell cycle status reflected by the DNA content of the nuclei was detected by flow cytometry. RESULTS： NVP-AEW541 dose-dependently inhibited the proliferation of colorectal carcinoma cell lines and primary cell cultures by inducing apoptosis and cell cycle arrest. Apoptosis was characterized by caspase-3 activation and nuclear degradation. Cell cycle was arrested at the G1/S checkpoint. The NVP-AEW541-mediated cell cycle-related signaling involved the inactivation of Akt and extracellular signal-regulated kinase （ERK） 1/2, the upregulation of the cyclin-dependent kinase inhibitors p21^waf1/CIP1 and p27^kjp1, and the downregulation of the cell cycle promoter cyclin D1. Moreover, BAX was upregulated during NVP-AEW541-induced apoptosis, whereas Bcl-2 was downregulated. Measurement of LDH release showed that the antineoplastic effect of NVP-AEW541 was not due to general cytotoxicity of the compound. However, augmented antineoplastic effects were observed in combination treatments of NVP-AEW541 with either 5-FU, or the EGFR-antibody cetuximab, or the HMG-CoA-reductase inhibitor fluvastatin. CONCLUSION： IGF-1R-TK inhibition is a promising novel approach for either monoor combination treatment strategies of colorectal carcinoma and even for CRC chemoprevention.

15-PGDH is reduced and induces apoptosis and cell cycle arrest in gastric carcinoma

AIM: To investigate the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in human gastric cancer and it's mechanism in apoptosis and cell cycle arrest. METHODS: Expression of 15-PGDH mRNA and protein was examined by immunohistochemistry, immunocytochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting in tissue from human gastric cancer, gastric precancerous state (gastric polyps and atrophic gastritis), normal stomach, and gastric cancer cell lines. The relationship between gastric cancer, gastric precancerous state and 15-PGDH expression was determined. The association between expression of 15-PGDH and various clinicopathological parameters in gastric cancer was evaluated. Human gastric cancer cell line SGC-7901 was transfected with 15-PGDH expression plasmids. The effect of 15-PGDH on the cell cycle was examined by flow cytometry. The effect of 15-PGDH on apoptosis was examined by transmission electron microscopy, flow cytometry and transferasemediated nick end labeling (TUNEL) assay. Expression of cell cycle (p21, p27, p16 and p53) and apoptosis (Survivin, BCL-2, BCL-XL, BAK and BAX) genes was analyzed by RT-PCR. RESULTS: Expression of 15-PGDH mRNA and protein in human gastric cancer tissues was significantly lower than in normal gastric tissues (P < 0.01). Expression in human gastric cancer cell lines MKN-28 and MKN-45 was reduced, and absent in SGC-7901 cells (P < 0.05). Reduction of 15-PGDH expression was also found in precancerous tissues, such as gastric polyps and atrophic gastritis (P < 0.01). There was a significant difference in expression of 15-PGDH among various gastric cancer pathological types (P < 0.05), with or without distant metastasis (P < 0.05) and different TNM stage (P < 0.01). Flow cytometry demonstrated a significant increase in apoptotic cells in SGC-7901 cells transfected with pcDNA3/15-PGDH plasmid for 24 and 48 h (P < 0.01), and an increased fraction of sub-G1 phase after transfection (P < 0.05). TUNEL assay showed an increased Apoptotic Index in cells overexpressing 15-PGDH (P < 0.01). After transfection, expression of proapoptotic genes, such as BAK (P < 0.05), BAX and p53 (P < 0.01), was increased. Expression of antiapoptotic genes was decreased, such as Survivin, BCL-2 and BCL-XL (P < 0.01). Expression of cyclin-dependent kinase inhibitors p21 and p16 (P < 0.01) was significantly upregulated in cells overexpressing 15-PGDH. CONCLUSION: Reduction of 15-PGDH is associated with carcinogenesis and development of gastric carcinoma. 15-PGDH induces apoptosis and cell cycle arrest in SGC-7901 cells.

Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

Peroxisome proliferator-activated receptors （PPAR） belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARy, such as troglitazone （TGZ）, can inhibit cell proliferation and promote cell differentiation independent of PPARy. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARγ. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinasesignaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell pro- liferation by promoting EGFR degradation and attenuating Akt phosphorylation.

Nuclear-targeted therapy of nerve growth factor conjugated with ^(125)I for human glioma U251 cells

The present study investigated the nuclear transportation phenomenon of ^125I-nerve growth factor （NGF） and the DNA-damaging changes to U251 cells using microautoradiography and single cell electrophoresis. The results showed that ^125I-NGF inhibited the survival of p53 mutant U251 human glioma cell/tumor and enhanced the therapeutic effectiveness of vincristine in in vivo and in vitro models. In vitro experiments showed ^125I-NGF was transported into the nucleus and damaged the DNA in U251 cells. Moreover, ^125I-NGF locked the U251 cells in the G2 phase. Further investigation showed that ^125I-NGF decreased cyclin B1 protein levels in a dose dependent manner, but the level of cyclin B1 mRNA expression remained unchanged. ^125I-NGF increased phosphorylated Chkl, Chk2 and Cdc25c protein levels in U251 cells, but did not influence p53 and p21 protein expression. Moreover, ^125I-NGF and vincristine exhibited synergistic effects on reducing cyclin B1 protein levels. These results indicate that ^125I-NGF can provide anti-tumor effects by activating the ATM and ATR pathways through DNA damage.

Prolonged propagation of rat neural stem cells relies on inhibiting autocrine/paracrine bone morphogenetic protein and platelet derived growth factor signals

Continuous expansion of rat neural stem cell lines has not been achieved due to proliferation arrest and spontaneous differentiation in vitro. In the current study, neural precursor cells derived from the subventricular zone of adult rats spontaneously underwent astroglial and oligodendroglial differentiation after limited propagation. This differentiation was largely induced by autocrine or paracrine bone morphogenetic protein and platelet derived growth factor signals. The results showed that, by inhibiting bone morphogenetic protein and platelet derived growth factor signals, adult rat neural precursor cells could be extensively cultured in vitro as tripotent stem cell lines. In addition to adult rat neural stem cells, we found that bone morphogenetic protein antagonists can promote the proliferation of human neural stem cells. Therefore, the present findings illustrated the role of autocrine or paracrine bone morphogenetic protein and platelet derived growth factor signaling in determining neural stem cell self-renewal and differentiation. By antagonizing both signals, the long-term propagation of rat neural stem cell lines can be achieved.

Long non-coding RNA GAS5 promotes PC12 cells differentiation into Tuj1-positive neuron-like cells and induces cell cycle arrest

Growth arrest-specific 5 (GAS5) is an anti-oncogene that has been extensively studied in tumors. However, research on GAS5 in the context of nervous system disease is rare at present. This study aimed to investigate the role of the long non-coding RNA GAS5 in rat pheochromocytoma cells (PC12 cells). GAS5-overexpressing lentivirus was transfected into PC12 cells, and expression levels of GAS5 and C-myc were detected by real-time PCR. Ratios of cells in S phase were detected by 5-ethynyl-2′-deoxyuridine. Immunohistochemical staining was used to detect the immunoreactivity of neuron microtubule markers Tuj1, doublecortin, and microtubule-associated protein 2. Apoptosis was detected by flow cytometry, while expression of acetylcholine in cells was detected by western blot assay. We found that GAS5 can promote PC12 cells to differentiate into Tuj1-positive neuron-like cells with longer processes. In addition, cell proliferation and cell cycle were significantly suppressed by GAS5, whereas it had no effect on apoptosis of PC12 cells. Our results indicate that GAS5 could increase the expression of choline acetyltransferase and acetylcholine release. Thus, we speculate that GAS5 is beneficial to the recovery of neurons and the cholinergic nervous system.

Oxidation Kinetics of Aluminum Powders in a Gas Fluidized Bed Reactor in the Potential Application of Surge Arresting Materials

In this technical paper, the oxidation mechanism and kinetics of aluminum powders are discussed in great details. The potential applications of spherical aluminum powders after oxidation to be part of the surging arresting materials are discussed. Theoretical calculations of oxidation of spherical aluminum powders in a typical gas fluidization bed are demonstrated. Computer software written by the author is used to carry out the basic calculations of important parameters of a gas fluidization bed at different temperatures. A mathematical model of the dynamic system in a gas fluidization bed is developed and the analytical solution is obtained. The mathematical model can be used to estimate aluminum oxide thickness at a defined temperature. The mathematical model created in this study is evaluated and confirmed consistently with the experimental results on a gas fluidization bed. Detail technical discussion of the oxidation mechanism of aluminum is carried out. The mathematical deviations of the mathematical modeling have demonstrated in great details. This mathematical model developed in this study and validated with experimental results can bring a great value for the quantitative analysis of a gas fluidization bed in general from a theoretical point of view. It can be applied for the oxidation not only for aluminum spherical powders, but also for other spherical metal powders. The mathematical model developed can further enhance the applications of gas fluidization technology. In addition to the development of mathematical modeling of a gas fluidization bed reactor, the formation of oxide film through diffusion on both planar and spherical aluminum surfaces is analyzed through a thorough mathematical deviation using diffusion theory and Laplace transformation. The dominant defects and their impact to oxidation of aluminum are also discussed in detail. The well-controlled oxidation film on spherical metal powders such as aluminum and other metal spherical powders can potentially become an important part of switch devices of surge arresting materials, in general.

非小细胞肺癌组织中lncRNA GAS5、LHPP表达与上皮间质化相关性及临床意义

目的探讨非小细胞肺癌(NSCLC)患者癌组织中长链非编码核糖核酸生长抑制特异性基因5(lncRNA GAS5)、磷酸赖氨酸磷酸组氨酸无机焦磷酸盐磷酸酶(LHPP)表达与上皮间质化(EMT)相关性及临床意义。方法收集2018年6月至2020年1月在河北北方学院附属第一医院行手术切除的NSCLC 90例患者的癌组织及癌旁组织,采用实时荧光定量聚合酶链反应检测lncRNA GAS5、LHPP和EMT相关蛋白[E-钙黏蛋白(E-Cad)、N-钙黏蛋白(N-Cad)和波形蛋白(VIM)]表达。分析NSCLC患者癌组织中lncRNA GAS5、LHPP mRNA与临床病理特征的关系,并通过Pearson相关性分析NSCLC患者癌组织中lncRNA GAS5、LHPP mRNA与EMT相关蛋白表达的相关性。采用Kaplan-Meier法绘制不同lncRNA GAS5、LHPP mRNA表达的NSCLC患者生存曲线,多因素Cox回归分析NSCLC患者预后的影响因素。结果NSCLC患者癌组织中lncRNA GAS5、LHPP mRNA、E-Cad mRNA表达低于癌旁组织,N-Cad mRNA、VIM mRNA表达高于癌旁组织,差异有统计学意义(P<0.05)。Pearson相关性分析显示,NSCLC患者癌组织中lncRNA GAS5与E-Cad mRNA表达呈正相关(r=0.724,P<0.001),与N-Cad mRNA、VIM mRNA表达呈负相关(r=-0.699、-0.689,P<0.001);lncRNA GAS5与LHPP mRNA表达呈正相关(r=0.651,P<0.001)。不同分化程度、肿瘤TNM分期、淋巴结转移的NSCLC患者癌组织中lncRNA GAS5、LHPP mRNA表达比较差异有统计学意义(P<0.05)。Kaplan-Meier生存曲线分析显示,lncRNA GAS5高表达组的3年总生存率[68.18%(30/44)]高于lncRNA GAS5低表达组的3年总生存率[36.96%(17/46)];LHPP mRNA高表达组的3年总生存率[67.39%(31/46)]高于LHPP mRNA低表达组的3年总生存率[36.36%(16/44)],差异有统计学意义(χ^(2)=10.274、10.322,P<0.05)。低分化、肿瘤TNM分期Ⅲ期、有淋巴结转移为NSCLC患者死亡的独立危险因素,lncRNA GAS5≥1.32、LHPP mRNA≥1.12为独立保护因素(P<0.05)。结论NSCLC患者癌组织中lncRNA GAS5、LHPP mRNA低表达,与EMT相关蛋白表达、分化程度、肿瘤TNM分期、淋巴结转移和预后有关,可能成为NSCLC诊治的新靶点。

糖尿病视网膜病变中Gas6/MerTK/GPX4信号通路参与铁诱导的细胞死亡的作用研究

目的探讨糖尿病视网膜病变(DR)中配体生长停滞特异性蛋白6(Gas6)/Mer酪氨酸激酶(MerTK)信号通路参与铁诱导的细胞死亡的作用。方法人视网膜色素上皮细胞(ARPE-19)分为对照组、HG组、HG+sh-Gas6组和HG+Gas6组。将细胞暴露于25 mmol/L D-葡萄糖用于模拟体外高血糖(HG)环境。对照组暴露于20 mmol/L甘露醇+5.5 mmol/L葡萄糖环境。将大鼠随机分为正常对照组、DR组、DR+Gas6组,每组20只。通过腹膜内注射STZ溶液建立DR模型。通过细胞计数检测试剂盒-8(CCK-8)评估细胞增殖。通过流式细胞术测量脂质活性氧(ROS)水平,并通过生化测定丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)水平来评估铁死亡。通过Western blot法分析Gas6、MerTK蛋白表达情况。结果与HG组相比,HG+Gas6组细胞活力、SOD、GSH-Px水平显著增加(P<0.05),脂质-ROS、MDA水平显著降低(P<0.05);HG+sh-Gas6组细胞活力、SOD、GSH-Px水平显著降低(P<0.05),脂质-ROS、MDA水平显著增加(P<0.05)。此外,HG+Gas6组细胞中谷胱甘肽过氧化物酶4(GPX4)蛋白表达较HG组显著增加(P<0.05),HG+sh-Gas6组细胞中GPX4蛋白表达较HG组显著减少(P<0.05)。与对照组相比,DR组大鼠的平均视网膜神经纤维层厚度显著降低(P<0.05),DR+Gas6组则较DR组显著增加(P<0.05)。此外,DR+Gas6组视网膜色素上皮(RPE)组织中MDA、铁水平显著降低(P<0.05),GSH水平和Gas6、MerTK、GPX4蛋白表达显著增加(P<0.05)。结论HG处理通过抑制Gas6/MerTK信号通路,加速GPX4的清除,诱导ARPE-19细胞的铁死亡和细胞生长抑制。此外,通过上调DR大鼠视网膜组织中Gas6/MerTK信号表达,减轻RPE组织中铁死亡和氧化应激,并有助于恢复视网膜平均视网膜神经纤维层厚度。

BlueScreen HC在食品接触材料多组分迁移物遗传毒性检测中的适用性

目的探讨基于人生长阻滞和DNA损伤诱导45α(GADD45α)基因的遗传毒性高通量筛选体系BlueScreen HC(BSHC)在食品接触材料多组分迁移物遗传毒性检测中的适用性。方法将人GADD45α基因开放阅读框上游2000 bp序列作为启动子,采用分子克隆构建入嘌呤霉素和高斯荧光素酶(Gluc)双标记的慢病毒质粒pEZX-LvPG04中,并用慢病毒感染人淋巴母细胞TK6,获得稳转细胞系TK6-Gluc。以甲基磺酸甲酯(MMS,终浓度0,1.56,3.13,6.25,12.5,25.0和50.0 mg·L^(-1))为非代谢活化条件下的阳性物质,环磷酰胺(CTX,终浓度0,0.78,1.56,3.13,6.25,12.5和25.0 mg·L^(-1))为代谢活化条件下的阳性物质,二甲基亚砜(DMSO,终浓度0,0.35,0.69,1.38,2.75,5.5和11.0 g·L^(-1))为阴性物质,分别在非活化和活化条件下验证构建的BSHC。将改性淀粉/聚对苯二甲酸-己二酸丁二醇酯(MS/PBAT)作为研究对象,采用体积分数4%乙酸及10%,20%,50%和95%乙醇作为食品模拟物,40℃、浸泡24 h获得5份MS/PBAT多组分迁移物,并用DMSO作为溶剂复溶得到5份多组分迁移溶液作为受试物。以终浓度为0,0.38,0.76,1.53,3.05,6.10和12.20 g·L^(-1)的不同受试物在活化和非活化2种条件下处理TK6-Gluc细胞。非活化条件下作用48 h;活化条件下,在添加体积分数1%大鼠肝S9代谢活化系统的同时,作用3 h后更换新鲜培养基,继续培养至48 h。处理结束后,采用CCK-8法检测细胞活性,同时采用Secrete-Pair^(TM)Gaussia Luciferase Assay试剂盒检测培养基中Gluc化学发光强度。另外,采用终浓度为3.05和12.20 g·L^(-1)的不同受试物对鼠伤寒沙门氏菌TA98和TA100进行微量波动Ames试验以及对体外培养的中国仓鼠肺细胞CHL进行体外哺乳细胞染色体畸变试验,检测受试物的致突变和染色体畸变作用,与BSHC遗传毒性结果进行对比分析。结果采用BSHC法,将相对细胞活性80%定义为生长抑制的最低有效浓度阈值,实验组相对细胞活性低于溶剂对照组的80%提示化合物引起细胞生长抑制。将实验组相对细胞活性低于溶剂对照组的30%定义为出现细胞毒性,此时将不考虑遗传毒性。在无细胞毒性前提下,活化条件下实验组Gluc化学发光强度大于溶剂对照组的1.8倍时,非活化条件下实验组Gluc化学发光强度大于溶剂对照组的1.5倍时,判定为遗传毒性阳性;反之认为无遗传毒性。与溶剂对照组相比,阴性物质DMSO所有浓度均未产生遗传毒性。非活化条件下,MMS 12.5,25.0和50.0 mg·L^(-1)产生遗传毒性;活化条件下,CTX 6.25,12.5和25.0 mg·L^(-1)产生遗传毒性。非活化条件下,MS/PBAT的95%乙醇迁移物6.10和12.20 g·L^(-1)和MS/PBAT的50%乙醇迁移物12.20 g·L^(-1)组细胞生长抑制,所有处理组均未观察到相对细胞活性低于30%的细胞毒性,且未观察到Gluc高表达,表明5种MS/PBAT多组分迁移物在非活化条件下均未产生遗传毒性。活化条件下,MS/PBAT的95%乙醇迁移物12.20 g·L^(-1)和MS/PBAT的4%乙酸迁移物6.10,12.20 g·L^(-1)组细胞表现出显著的生长抑制,所有处理组均未观察到相对细胞活性低于30%的细胞毒性,且未观察到Gluc高表达,表明5种MS/PBAT多组分迁移物在活化条件下均未产生遗传毒性。微量波动Ames试验结果表明,在活化和非活化条件下,MS/PBAT的5种多组分迁移物3.05和12.20 g·L^(-1)作用于TA98和TA1002种菌株,致突变阳性孔的数量均不超过溶剂对照组的2倍,即均未产生致突变作用;作用于CHL细胞后的细胞染色体畸变率亦均无显著变化。结论初步建立了基于GADD45α基因的遗传毒性高通量筛选方法BSHC,提示可用于食品接触材料多组分迁移物的体外遗传毒性评价,但仍需进一步探索其最低有效浓度,并应用更多种类混合物进行进一步验证。

炎症反应在光气致急性肺损伤/急性呼吸窘迫综合征中的研究进展

光气目前广泛应用于工业生产,其毒性较大,在生产、储存、使用过程中因泄漏而引起的中毒问题不容忽视。急性光气暴露可引起呼吸抑制、难治性肺水肿等相关肺损伤,严重者可致急性呼吸窘迫综合征(ARDS)甚至死亡。急性光气中毒病死率高、预后差,缺乏特异性治疗,炎症反应在其中起重要作用。本文对炎症反应在光气致急性肺损伤(P-ALI)/ARDS损伤机制及治疗中的作用进行综述,并总结了可能的信号通路,讨论了更多潜在的治疗靶点,以及当前针对P-ALI/ARDS抗炎治疗的研究现状,以期帮助临床医师及研究人员迅速了解目前全球P-ALI/ARDS领域在炎症方面的最新研究动态,为治疗P-ALI/ARDS及新药物的研发提供思路和帮助。

血清标志物对老年慢性阻塞性肺疾病合并肺部感染临床诊断及预后评估的价值分析

目的探讨血清生长停滞特异性蛋白6(Gas6)、纤溶酶原激活物抑制剂1(PAI-1)和血清胆碱酯酶(S-ChE)对老年慢性阻塞性肺疾病(COPD)合并肺部感染临床诊断及预后评估的价值。方法选择首都医科大学附属北京天坛医院2021年1月至2023年1月收治的106例COPD合并肺部感染患者作为感染组,另纳入同期111例COPD未合并肺部感染患者作为非感染组。根据预后情况将感染组患者分为生存组(83例)与死亡组(23例)。比较非感染组和感染组患者血清Gas6、PAI-1、S-ChE水平。比较生存组和死亡组患者一般资料。采用受试者工作特征曲线分析血清Gas6、PAI-1和S-ChE对老年COPD患者发生肺部感染以及肺部感染患者发生死亡的预测价值;采用多因素Logistic回归方法分析影响老年COPD合并肺部感染患者预后的因素。结果感染组血清Gas6、PAI-1水平高于非感染组,S-ChE水平低于非感染组,差异均有统计学意义(均P<0.001)。受试者工作特征曲线分析结果显示,血清Gas6、PAI-1、S-ChE及三者联合诊断COPD患者发生肺部感染的曲线下面积分别为0.787、0.797、0.782、0.889,三者联合诊断的曲线下面积高于各自单独诊断(Z=4.527、5.435、4.167,均P<0.001)。死亡组COPD全球倡议Ⅲ级、合并糖尿病比例以及血清Gas6、PAI-1水平高于生存组,第1秒用力呼气容积占预计值百分比、第1秒用力呼气容积与用力肺活量比值以及S-ChE水平低于生存组(均P<0.05)。多因素Logistic回归分析结果显示,Gas6、PAI-1是老年COPD并发肺部感染患者发生死亡的危险因素,S-ChE是保护因素(均P<0.05)。受试者工作特征曲线分析结果显示血清Gas6、PAI-1、S-ChE三者联合诊断COPD合并肺部感染患者死亡的曲线下面积高于各自单独检测(均P<0.05)。结论老年COPD合并肺部感染患者血清Gas6、PAI-1水平升高,S-ChE水平降低,三者对疾病的临床诊断和预后评估具有一定的价值。

狼疮性肾炎患者血清FGF-23、Gas6水平与疾病活动性的关系

目的探讨狼疮性肾炎(LN)患者血清成纤维细胞生长因子23(FGF-23)、生长停滞特异性蛋白6(Gas6)水平与疾病活动性的关系。方法选择2021年3月—2024年3月延安市人民医院风湿免疫科收治的LN患者119例为LN组,并根据系统性红斑狼疮疾病活动指数2000(SLEDAI-2000)评分分为活动亚组70例和非活动亚组49例,另选取同期医院健康体检者105例为健康对照组。采用酶联免疫吸附试验检测血清FGF-23、Gas6水平;Pearson相关分析血清FGF-23、Gas6水平与肾功能指标、SLEDAI-2000评分的相关性;多因素Logistic回归分析LN患者疾病活动性的影响因素;受试者工作特征(ROC)曲线评价血清FGF-23、Gas6水平对LN患者疾病活动性的诊断价值。结果LN组血清FGF-23、Gas6水平均高于健康对照组(t/P=21.040/<0.001、7.389/<0.001);活动亚组收缩压、舒张压、尿素氮(BUN)、血肌酐(SCr)、尿蛋白、SLEDAI-2000评分、FGF-23、Gas6均高于非活动亚组(t/P=2.356/0.020、3.717/<0.001、11.867/<0.001、17.152/<0.001、30.579/<0.001、19.439/<0.001、11.284/<0.001、10.818/<0.001),补体C3、C4水平低于非活动亚组(t/P=6.233/<0.001、12.329/<0.001);血清FGF-23、Gas6水平分别与BUN、SCr、尿蛋白、SLEDAI-2000评分呈正相关(FGF-23:r/P=0.410/<0.001、0.395/<0.001、0.326/0.002、0.563/<0.001;Gas6:r/P=0.352/<0.001、0.384/<0.001、0.311/0.008、0.509/<0.001),与补体C3、C4水平呈负相关(FGF-23:r/P=-0.408/<0.001、-0.377/<0.001;Gas6:r/P=-0.376/<0.001、-0.321/<0.001);多因素Logistic回归分析显示,高FGF-23、Gas6、尿蛋白水平是LN患者疾病活动的独立危险因素[OR(95%CI)=2.136(1.224~3.727)、1.865(1.171~2.967)、2.539(1.416~4.554)];血清FGF-23、Gas6水平及二者联合诊断LN患者疾病活动性的曲线下面积(AUC)分别为0.804、0.834、0.938,二者联合的AUC大于各自单独诊断(Z/P=3.843/<0.001、3.270/<0.001)。结论LN患者血清FGF-23、Gas6水平均增高,且与LN肾功能损伤、补体水平降低及疾病活动性增加有关。联合检测FGF-23、Gas6可有效鉴别LN疾病活动性。

血清视黄醇结合蛋白-4、生长停滞特异性蛋白6水平与急性心肌梗死合并心力衰竭患者预后的关系

目的探讨血清视黄醇结合蛋白-4(RBP-4)、生长停滞特异性蛋白6(GAS6)水平与急性心肌梗死(AMI)合并心力衰竭(HF)患者预后的关系。方法选取2020年1月至2022年1月内蒙古自治区通辽市医院收治的186例AMI合并HF患者,根据随访1年的预后将其分为预后不良组(61例)和预后良好组(125例)。采用酶联免疫吸附试验检测两组RBP-4、GAS6水平。采用多因素logistic回归模型分析AMI合并HF患者预后不良的影响因素,采用受试者操作特征曲线分析血清RBP-4、GAS6水平对AMI合并HF患者预后不良的预测价值。结果预后不良组年龄、急性HF占比、N末端前体B型钠尿肽、RBP-4水平高于预后良好组,左室射血分数、GAS6低于预后良好组,差异有统计学意义(P<0.05)。多因素分析显示,年龄(OR=1.091,95%CI:1.016~1.173)、急性HF(OR=2.468,95%CI:1.030~5.913)、N末端前体B型钠尿肽(OR=1.002,95%CI:1.001~1.003)、RBP-4(OR=1.156,95%CI:1.076~1.242)、左室射血分数(OR=0.829,95%CI:0.725~0.948)、GAS6(OR=0.342,95%CI:0.195~0.599)均为AMI合并HF患者预后不良的影响因素(P<0.05)。受试者操作特征曲线分析显示,血清RBP-4、GAS6水平单独及联合预测AMI合并HF患者预后不良的曲线下面积分别为0.786、0.790、0.895(P<0.05)。结论血清RBP-4水平升高和GAS6水平降低与AMI合并HF患者预后不良有关,二者联合对AMI合并HF患者预后不良具有良好预测价值。

长链的非编码RNA生长停滞特异性转录本5在骨关节炎中的研究进展

骨关节炎(OA)是一种以软骨退变、骨重建为主要病理特点的慢性关节疾病。目前没有可治愈该疾病的药物及手段,治疗策略有限的根本原因是对其潜在发病机制的认识不足。长链的非编码RNA(LncRNAs)被认为是许多疾病中的一类新的调控因子,是目前研究OA发病机制的一个重要切入点。LncRNA生长停滞特异性转录本5(Cas5)参与调控细胞的增殖、分化及凋亡,是一种在软骨细胞中特异性高表达的LncRNA。然而,由于LncRNA Cas5作用机制复杂,其与OA相关具体分子机制目前仍不明确。该文针对LncRNA Cas5在OA中的软骨细胞凋亡、软骨基质代谢成骨分化及治疗方面的作用进行综述。

肾综合征出血热患者血浆中可溶型Axl及Mer与疾病严重程度的相关性

目的观察可溶型Tyro3/Axl/Mer(TAM)受体(sTyro3、sAxl、sMer)在不同病情、病期肾综合征出血热(HFRS)患者血浆中水平的变化规律,探讨其在HFRS发病中可能发挥的作用。方法分别采集38例HFRS患者急性期与恢复期血浆,同时采集20例正常人血浆作为对照,采用ELISA检测血浆中sTyro3、sAxl及sMer含量,分别比较HFRS患者血浆中sTyro3、sAxl及sMer水平与正常人的差别,同时分析其与生长停滞特异性蛋白6(Gas6)和临床指标的相关性。结果不同病情、病期HFRS患者血浆中sTyro3水平与正常对照组相比均无显著差异(P>0.05)。危重/重型HFRS患者血浆中sAxl和sMer水平较中/轻型患者显著升高(P<0.05),危重/重型组及中/轻组均高于正常组(P<0.01,P<0.05)。与恢复期sAxl和sMer水平相比,急性期血浆中sAxl差异显著(P<0.05),sMer未见显著差异(P>0.05),两者较正常人水平均显著升高(P<0.01)。血浆sAxl、sMer和Gas6水平呈正相关。血浆sAxl水平与C反应蛋白、肌酐(Crea)、尿酸(UA)呈正相关,与血小板(PLT)计数呈负相关,与尿素氮(BUN)、白细胞(WBC)计数无相关性。sMer水平与WBC计数、PLT计数、UA呈正相关,与Crea、BUN无相关性。结论HFRS患者血浆sAxl和sMer水平与疾病的严重程度、Gas6水平及炎症指标相关,提示sAxl和sMer水平升高可能通过Gas6/TAM轴参与机体的炎症反应,此研究为进一步探讨HFRS发病中机体维持免疫自稳和炎症提供有益的见解。

贝母素乙通过调节Gas6/Axl信号通路对糖尿病大鼠心肌纤维化的影响

[目的]探讨贝母素乙(PMI)对糖尿病(DM)大鼠心肌纤维化及生长停滞特异性蛋白6(Gas6)/Axl信号通路的影响。[方法]构建DM大鼠模型,将48只造模成功大鼠随机分为DM组、贝母素乙低、高剂量组(PMI-L、PMI-H组)、贝母素乙高剂量+通路抑制剂R428组(PMI-H+R428组),各12只,另取12只正常大鼠作对照组(Control组);超声检查各组大鼠心功能指标;全自动血液分析仪检测各组大鼠空腹血糖(FBG)及血清肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)水平;苏木精-伊红(HE)染色及Masson染色分别观察各组大鼠心肌组织病理变化及纤维化程度;TUNEL染色检测心肌组织细胞凋亡情况;免疫组化检测胶原蛋白Ⅰ(COLⅠ)、胶原蛋白Ⅲ(COLⅢ)表达;蛋白免疫印迹法检测Gas6、p-Axl/Axl表达。[结果]DM组较Control组心肌纤维断裂,心肌细胞排列紊乱,细胞肥大,细胞核固缩深染,炎性细胞浸润明显,细胞减少,蓝色胶原纤维沉积增多,且排列紊乱,分布弥散,左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)和FBG、CK-MB、LDH水平及COLⅠ、COLⅢ表达升高,LVFS及Gas6、p-Axl/Axl表达降低(P<0.05);PMI-L、PMI-H组较DM组心肌纤维排列相对整齐,细胞形态相对正常,炎性细胞浸润减少,细胞增多,纤维化现象减少,蓝色胶原纤维沉积减少,且细胞排列相对整齐,LVEDD、LVESD和FBG、CK-MB、LDH水平及COLⅠ、COLⅢ表达降低,LVFS及Gas6、p-Axl/Axl表达升高(P<0.05);PMI-H+R248组较PMI-H组心肌组织病理损伤加重,炎性细胞浸润及心肌组织纤维化明显,蓝色胶原纤维沉积明显增多,LVEDD、LVESD和FBG、CK-MB、LDH水平及COLⅠ、COLⅢ表达升高,LVFS及Gas6、p-Axl/Axl表达降低(P<0.05)。[结论]贝母素乙可抑制DM大鼠心肌纤维化,其作用机制与激活GAS6/Axl信号通路有关。