Insulin-like growth factor receptor-1 overexpression is associated with poor response of rectal cancers to radiotherapy

AIM: To explore the potential correlation between insulin-like growth factor receptor-1 (IGF-1R) expression and rectal cancer radiosensitivity.

Effects of Insulin-like Growth Factor 1 Receptor and Its Inhibitor AG1024 on the Progress of Lung Cancer

Summary： The type 1 insulin-like growth factor receptor （IGF-1R） and its downstream signaling com- ponents have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer （NSCLC）. This study aimed to investigate the effects of IGF-1R and its in- hibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues （n=198）. Western blotting was used to determine the expressions oflGF-1 and phosphorylated IGF-1R （p-IGF-1R） in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction （FQ-PCR）, respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1 ＋AG 1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-l＋AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF- 1 and IGF inhibitor AG 1024 promotes lung cancer progression.

RNA interference affects tumorigenicity and expression of insulin-like growth factor-1,insulin-like growth factor-1 receptor,and basic fibroblast growth factor-2 in rat C6 glioma cells

BACKGROUND： Human gliomas are more likely to express basic fibroblast growth factor-2 （FGF-2） insulin-like growth factor-1（IGF-1）, and IGF-1 receptor （IGF-1R） than normal brain tissue. These factors activate signal transduction systems of Ras/MAPK and PI3K/Akl, which promote glioma growth. OBJECTIVE： To utilize RNA interference （RNAi） technique to down-regulate FGF-2, IGF-1, and IGF-1R gene expression, and to investigate the effects of these genes on rat C6 glioma cells, as well as the feasibility of RNAi for treating glioma. DESIGN, TIME AND SETTING： This neurooncological, randomized, controlled, in vivo and in vitro experiment, which used RNAi methodology, was performed at the Laboratory of Molecular Biology, Institute of Biochemistry, Chinese Academy of Sciences between August 2005 and February 2008. MATERIALS： Rat C6 cell lines were purchased from Shanghai Institute of Cellular Biology Affiliated to Chinese Academy of Sciences. Small interfering RNA （siRNA） was synthesized by Shanghai GenePharma. Anti-IGF-1, anti-IGF-1R, anti-FGF-2, anti-mouse and anti-rabbit IgG G1-HRP antibodies were provided by Santa Cruz Biotechnology, USA. Four to six week-old BALB/c nude mice were purchased from the Laboratory Animal Center, Chinese Academy of Sciences. METHODS： C6 glioma cells were transfected with siRNA, which was chemically synthesized in vitro to correspond to endogenous FGF-2, IGF-1, and IGF-1R genes. The inhibition ratio of targeting mRNA expression was detected by semiquantitative RT-PCR, and protein expression was determined by Western blot analysis. C6 glioma cell proliferation was observed using a growth curve C6 glioma cell apoptosis rate and cell cycle were detected by flow cytometry. C6 glioma cell growth regression was observed by transwell migration assay. In addition, nude mouse subcutaneous tumor models were used in this study. For studying the anti-tumor effects of IGF-1 and IGF-1R siRNA, two blank control groups, with six mice each, were set up： A （2.5 μg siRNA was injected one week after C6 cells were inoculated, Le., when tumor volume reached 8 mm × 8 mm） and B （siRNA was injected at the same time with C6 cells were inoculated. To study the effects of FGF-2 siRNA, the groups consisted of a blank control group, negative control group, 2.6 μg siRNA group, 4 μg siRNA group, and 5.3 μg siRNA group, with six mice each. MAIN OUTCOME MEASURES： mRNA and protein inhibition ratio of FGF-2, IGF-1, and IGF-1 R; C6 glioma cell proliferation, apoptosis, and cycle growth arrest; C6 glioma cell growth regression and subcutaneous tumorigenicity rates. RESULTS： All siRNA constructs proved to be effective. After 48 hours, transfection of 200 nmol/L siRNA resulted in a FGF-2 or IGF-1R gene inhibition ratio 〉 80% and an IGF-1 gene inhibition ratio of approximately 70%. Protein expression levels for FGF-2, IGF-1, and IGF-1R decreased in a dose-dependent manner following siRNA transfection, with an inhibition rate 〉 85%, 60%, and 50%, respectively. C6 glioma cell proliferation and apoptosis rates increased in proportion to siRNA. The apoptosis rate of C6 glioma cells induced by FGF-2, IGF-1, and IGF-1R siRNA was 39.96%, 15.07% and 22.47%, respectively （P 〈 0.01）. Transfection of 200 nmol/L IGF or IGF-1R siRNA for 48 hours suppressed C6 glioma cell migration. At 30 days after intratumoral injection of 2.6, 4, and 5.3 tJg FGF-2 siRNA, tumor growth regression rate of FGF-2 siRNA was 56%, 67%, and 86%, respectively. The tumor growth regression rate was 71.88% and 45.71%, respectively, when IGF-1 or IGF-1R siRNA was intratumorally injected 1 week after C6 glioma cell transplantation. When IGF-1 or IGF-1 R siRNA was intratumorally injected during C6 glioma cell transplantation, the tumor growth regression rate was 78.13% and 74.29%, respectively. CONCLUSION： siRNA transfection downregulated gene expression of FGF-2, IGF-1, and IGF-1R In addition, siRNA treatment markedly suppressed glioma cell proliferation, growth, and migration, and concomitantly reduced subcutaneous tumorigenicity.

子宫内膜癌患者血清sVEGFR1、YKL-40、IGF-1表达水平及临床意义研究

目的探究子宫内膜癌患者血清可溶性血管内皮生长因子受体1(sVEGFR1)、甲壳质酶蛋白40(YKL-40)、胰岛素样生长因子1(IGF-1)表达水平及临床意义。方法择取本院100例子宫内膜癌患者作为观察组;另选取同期100例健康体检者作为对照组。比较两组sVEGFR1、YKL-40、IGF-1表达水平并分析观察组不同分期表达水平。结果观察组sVEGFR1表达水平较对照组低,YKL-40、IGF-1表达水平较对照组高,差异有统计学意义(P<0.05)。观察组Ⅰ~Ⅳ期sVEGFR1表达水平明显降低,YKL-40、IGF-1表达水平升高,差异有统计学意义(P<0.05)。结论在子宫内膜癌患者中,sVEGFR1、YKL-40、IGF-1均出现异常表达,不同分期患者存在较大差异,可为疾病诊断与分期提供可靠的数据参考。

Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer

AIM:To investigate the expression of insulin-like growth factor-1(IGF-1)/insulin-like growth factor-1 receptor(IGF-1R)in colorectal cancer(CRC)tissues and to analyze their correlation with lymphangiogenesis and lymphatic metastasis.METHODS:Immunohistochemistry was used to evaluate IGF-1 and IGF-1R expression and lymphatic vessel density(LVD)in 40 CRC specimens.The correlation between IGF-1/IGF-1R and LVD was investigated.Effects of IGF-1 on migration and invasion of CRC cells were examined using transwell chamber assays.A LoVo cell xenograft model was established to further detect the role of IGF-1 in CRC lymphangiogenesis in vivo. RESULTS:Elevated IGF-1 and IGF-1R expression in CRC tissues was correlated with lymph node metastasis(r=0.715 and 0.569,respectively,P<0.05)and tumor TNM stage(r=0.731 and 0.609,P<0.05).A higher LVD was also found in CRC tissues and was correlated with lymphatic metastasis(r=0.405,P<0.05).A positive correlation was found between LVD and IGF-1R expression(r=0.437,P<0.05).Transwell assays revealed that IGF-1 increased the migration and invasion of CRC cells.In vivo mouse studies showed that IGF-1 also increased LVD in LoVo cell xenografts.CONCLUSION:IGF-1/IGF-1R signaling induces tumorassociated lymphangiogenesis and contributes to lymphatic metastasis of CRC.

Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis

Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats.

高血压合并焦虑病人血清微RNA-451a、胰岛素样生长因子-1受体表达水平与焦虑程度的关系

目的探讨高血压合并焦虑病人血清微RNA-451a(miR-451a)、胰岛素样生长因子-1受体(IGF1R)表达水平与焦虑程度的关系。方法选取2020年2月至2022年1月在汉中市中心医院进行治疗的高血压病人160例,根据临床诊断和汉密尔顿焦虑量表(HAMA)评估将病人分为高血压组60例、高血压合并轻度焦虑情绪组48例、高血压合并中度焦虑情绪组32例和高血压合并重度焦虑情绪组20例,收集整理所有病例的临床基础资料。采用实时荧光定量PCR法检测血清miR-451a表达水平、ELISA法检测血清IGF1R表达水平;比较分析高血压病人和高血压合并焦虑情绪病人的临床病理特征;采用Pearson法分析HAMA评分与血清miR-451a、IGF1R表达水平的相关性;采用logistic回归分析高血压合并焦虑的影响因素。结果高血压组、轻度焦虑、中度焦虑和重度焦虑组病人血清miR-451a水平依次降低(0.88±0.30,0.59±0.14,0.48±0.11,0.38±0.09),IGF1R水平依次升高[(2.14±0.60)μg/L,(2.66±0.62)μg/L,(3.08±0.66)μg/L,(3.51±0.74)μg/L];血清miR-451a水平与HAMA评分呈负相关(r=−0.50,P<0.05),血清IGF1R水平与HAMA评分呈正相关(r=0.43,P<0.05);高血压合并焦虑组收缩压[(142.26±18.51)mmHg,(135.29±17.84)mmHg]、舒张压[(84.25±11.30)mmHg,(78.23±10.25)mmHg]、C-反应蛋白[(4.47±0.96)mg/L,(4.16±0.91)mg/L]、IL-6水平[(36.95±6.31)μg/L,(27.48±5.49)μg/L]显著高于高血压组,IL-10水平[(12.34±3.26)ng/L,(16.24±3.91)ng/L]显著低于高血压组(P<0.05);多因素logistic回归分析结果显示,收缩压[OR 95%CI=1.33(1.06,1.67)]、舒张压[OR 95%CI=1.20(1.00,1.45)]、IL-6[OR 95%CI=1.89(1.22,2.93)]、IL-10[OR 95%CI=0.38(0.17,2.93)]、miR-451a[OR 95%CI=0.01(0.00,0.47)]、IGF1R[OR 95%CI=7.62(1.21,48.03)]水平为高血压合并焦虑的影响因素(P<0.05)。结论高血压合并焦虑病人血清中miR-451a低表达,IGF1R高表达,且与病人焦虑程度密切相关。

雷公藤多苷联合他克莫司及激素治疗难治性肾病综合征的效果及对血清sTNF-R1、IGFBP-2、CFH水平的影响

目的 探讨雷公藤多苷联合他克莫司及激素治疗难治性肾病综合征(RNS)的疗效对血清可溶性肿瘤坏死因子受体1(s TNF-R1)、胰岛素样生长因子结合蛋白-2(IGFBP-2)、补体因子H(CFH)水平的影响。方法 研究对象为2018年8月至2021年8月于江南大学附属医院治疗的RNS患者102例,以随机数字表法分为对照组(n=51,采取甲泼尼龙片加他克莫司胶囊治疗)和观察组(n=51,在对照组基础上给予雷公藤多苷片治疗)。评估两组的治疗效果、血清相关指标,统计两组的不良反应。结果 观察组治疗总有效率(96.08%)高于对照组(80.39%)(χ^(2)=6.044,P=0.014);治疗后,观察组患者血清白蛋白、CFH水平[分别为(36.54±8.11) g·L^(-1)、(586.20±100.72)μg·m L^(-1)],高于对照组[分别为(32.58±6.12) g·L^(-1)、(540.11±100.47)μg·m L^(-1)],差异均有统计学意义(t=2.783,P=0.006;t=2.314,P=0.023);观察组患者24 h尿蛋白、肌酐、s TNF-R1、IGFBP-2水平[分别为(2.67±0.69) g、(82.25±16.13)μmol·L^(-1)、(1.56±0.45) ng·m L^(-1)、(51.34±10.44) ng·m L^(-1)],低于对照组[分别为(3.24±1.02) g、(92.68±17.35)μmol·L^(-1)、(1.91±0.58) ng·m L^(-1)、(57.79±12.58) ng·m L^(-1)],差异均有统计学意义(t=3.306,P=0.001;t=3.135,P=0.002;t=3.405,P=0.001;t=2.820,P=0.005);观察组复发率(1.96%)低于对照组(13.73%)(χ^(2)=4.883,P=0.027)。结论 公藤多苷联合他克莫司及激素治疗RNS效果佳,降低复发率,改善肾功能,减轻炎症,有望作为辅助治疗RNS的药物。

子宫内膜癌组织中ZEB2和IGF1R表达情况及其与患者淋巴结转移及预后的关系

目的探讨E盒结合锌指蛋白2(ZEB2)和胰岛素样生长因子1受体(IGF1R)在子宫内膜癌组织中的表达情况及其与淋巴结转移及预后的关系。方法选取2018年6月至2020年6月邯郸市中心医院收治的137例行手术治疗的子宫内膜癌患者作为研究对象,收集患者在手术过程中切除的癌组织及癌旁组织。采用免疫组化方法检测组织中ZEB2和IGF1R的表达情况,进一步分析患者的病理特征与ZEB2和IGF1R表达情况的关系及不同临床特征与淋巴结转移的关系。进行定期随访,根据随访结果采用Kaplan-Meier法分析患者预后生存情况,采用Cox回归模型进行患者预后不良的多因素分析。结果子宫内膜癌组织中ZEB2和IGF1R阳性表达率均高于癌旁组织(P<0.05)。子宫内膜癌组织中ZEB2和IGF1R表达水平与与国际妇产科联盟(FIGO)分期、淋巴结是否转移有关(P<0.05)。淋巴结转移情况与肿瘤直径、FIGO分期有关(P<0.05)。子宫内膜癌组织ZEB2阳性表达患者3年生存率低于ZEB2阴性表达患者(P<0.05),子宫内膜癌组织IGF1R阳性表达患者3年生存率低于IGF1R阴性表达患者(P<0.05)。FIGO分期、淋巴结转移、ZEB2和IGF1R阳性表达均为子宫内膜癌患者预后不良的影响因素(P<0.05)。结论与癌旁组织比较,子宫内膜癌组织中ZEB2和IGF1R阳性表达率较高,且与患者的FIGO分期、淋巴结转移情况有关。

Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells

OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.

CXCR1、ESM-1及IGFBP-2与COPD合并肺部感染患者疾病严重程度、预后的关系

目的 分析血清趋化因子受体1(CXCR1)、内皮细胞特异性分子-1(ESM-1)、胰岛素样生长因子结合蛋白2(IGFBP-2)水平与慢性阻塞性肺疾病(COPD)合并肺部感染患者疾病严重程度、预后的关系。方法 选取2021年1月至2023年1月于阜阳市人民医院就诊的COPD患者325例,根据肺部感染情况分为感染组及未感染组。比较两组入院时的血清CXCR1、ESM-1、IGFBP-2水平及常规感染指标[C-反应蛋白(CRP)、降钙素原(PCT)]水平,采用Pearson相关分析感染组上述指标的关系。比较不同病情严重程度COPD合并肺部感染患者入院时的CXCR1、ESM-1、IGFBP-2水平。对感染组患者跟踪随访6个月或死亡止,根据预后情况分为存活亚组及死亡亚组,比较两亚组患者入院时的血清CXCR1、ESM-1、IGFBP-2水平;采用受试者工作曲线(ROC)分析上述指标对COPD合并肺部感染患者死亡的预测价值。结果 325例COPD患者包括感染组109例及未感染组216例。感染组患者入院时的血清CXCR1、ESM-1、IGFBP-2、CRP、PCT水平高于未感染组,差异有统计学意义(P<0.05)。不同病情严重程度COPD合并肺部感染患者入院时的血清CXCR1、ESM-1、IGFBP-2水平比较差异有统计学意义(P<0.05)。Pearson相关分析显示,感染组入院时的血清CRP水平与CXCR1、ESM-1水平呈正相关(P<0.05)。随访期间感染组死亡19例(17.43%),存活90例(82.57%),死亡亚组入院时的血清CXCR1、ESM-1、IGFBP-2水平高于存活亚组,差异有统计学意义(P<0.05)。ROC结果显示,血清CXCR1、IGFBP-2水平预测COPD合并肺部感染患者死亡具有一定局限性(AUC=0.636、0.769),ESM-1的预测效能较好(AUC=0.827),CXCR1+ESM-1+IGFBP-2三项联合诊断的预测效能最佳(AUC=0.904)。结论 血清CXCR1、ESM-1、IGFBP-2水平在COPD合并肺部感染患者的疾病严重程度及预后评估方面具有一定指导意义。

雄激素受体、胰岛素生长受体1表达与三阴性乳腺癌的靶向治疗疗效及预后的相关性研究

目的 分析AR和IGF1R与三阴性乳腺癌的靶向治疗疗效及预后的相关性。方法 选择72例三阴性乳腺癌患者;患者均接受比卡鲁胺联合戈舍瑞林治疗;根据实体瘤的疗效评价标准对患者治疗疗效进行评估;采用S-P免疫组化法检测组织中AR和IGF1R表达水平;绘制卡米尔生存曲线分析AR阳性表达和IGF1R阳性表达患者生存期。结果 AR-IGF1R-、AR+IGF1R-、AR-IGF1R+、AR+IGF1R+亚组患者治疗疗效存明显差异,其中AR+IGF1R+组患者治疗疗效明显优于其他亚组(P<0.05);AR和IGF1R阳性表达与患者治疗疗效呈显著正相关关系(P<0.05);AR-IGF1R-、AR+IGF1R-、AR-IGF1R+、AR+IGF1R+亚组患者生存期间有明显差异,AR+IGF1R+组患者生存期最长(P<0.05)。结论 AR、IGF1R阳性表达与三阴性乳腺癌的靶向治疗疗效呈显著正相关关系,且AR、IGF1R阳性表达可有效改善患者生存期。

ACTR调控IGF-1R对肝癌细胞生长的影响

目的探究ACTR调控IGF-1R的表达对肝癌细胞生长的影响及意义。方法外源性免疫共沉淀、内源性免疫共沉淀检测ACTR与IGF-1R之间的相互作用。应用细胞免疫荧光共定位,检测ACTR与IGF-1R在肝癌细胞内共定位情况。qRT-PCR及Western blot实验,检测肝癌细胞中ACTR对IGF-1R表达的影响。将肝癌细胞系分为阴性对照组、转染ACTR组、敲低IGF-1R组、敲低IGF-1R+转染ACTR组,应用CCK8法测定各组细胞生长情况。结果外源性免疫共沉淀、内源性免疫共沉淀均证实ACTR与IGF-1R之间存在相互作用。细胞免疫荧光共定位证实ACTR与IGF-1R在肝癌细胞内存在共定位表达。qRT-PCR证实敲低ACTR后,IGF-1R mRNA表达水平降低(P<0.05),回转ACTR后IGF-1R mRNA表达水平亦可恢复。Western blot证实敲低ACTR后IGF-1R表达降低,而回转ACTR后IGF-1R表达可恢复。细胞生长曲线说明ACTR能够促进肝癌细胞的生长(P<0.05),当应用siRNA敲低IGF-1R后,ACTR的促细胞生长作用减弱。结论ACTR与IGF-1R之间存在相互的作用,IGF-1R介导了ACTR促进肝癌细胞生长的过程,ACTR/IGF-1R轴在肝癌细胞的生长中发挥了必要的作用,有可能成为治疗肝癌的靶点之一,为肝癌的防治提供新的思路。

miR-100调节IGF1R/mTOR信号通路对牙周炎牙周膜干细胞增殖和成骨分化的影响

目的:探究MicroRNA-100(miR-100)对牙周炎牙周膜干细胞(PDLSCs)增殖和成骨分化的影响及潜在机制。方法:丝线结扎法构建牙周炎大鼠模型,建模后分为模型组、NC-agomir组、miR-100 agomir组、NC-antagomir组和miR-100 antagomir组(n=10),另取10只大鼠为对照组。体外培养PDLSCs,分为对照组、TNF-α组、miR-100-NC+TNF-α组、miR-100 mimics+TNF-α组、miR-100 inhibitor+TNF-α组、miR-100 mimics+TNF-α+Oe-NC组、miR-100 mimics+TNF-α+Oe-IGF1R组。细胞经相应处理后检测有关因子表达。结果:上调miR-100可显著降低牙周炎大鼠血清TNF-α、IL-6和IL-1β水平和牙周组织IGF1R和mTOR的mRNA水平(P<0.05),减轻牙周组织病变,而下调miR-100表现出相反作用。在PDLSCs中,miR-100过表达可显著抑制IGF1R和mTOR表达,上调Cyclin E1、Cyclin D1及分化相关蛋白八聚体结合转录因子4(Oct4)、性别决定区Y-box2(Sox2)、Runt相关转录因子2(Runx2)表达,促进炎性微环境下PDLSCs增殖和成骨分化(P<0.05);而下调miR-100表现出相反作用;且过表达IGF1R可减弱miR-100过表达对TNF-α诱导的PDLSC增殖和成骨分化的促进作用(P<0.05)。结论:过表达miR-100可能通过抑制IGF1R/mTOR信号通路促进牙周炎PDLSCs的增殖和成骨分化。

基于IGF-1R/PI3K/AKT的益气固表丸对慢性阻塞性肺疾病模型大鼠的影响及作用机制研究

目的:益气固表丸对慢性阻塞性肺疾病(COPD)有明显的治疗作用,但具体作用机制尚不清楚。本研究旨在探讨益气固表丸对脂多糖(LPS)联合烟雾暴露构建慢性阻塞性肺病模型大鼠的治疗作用机制。方法:通过大鼠气管内灌注LPS和吸入香烟烟雾构建慢性阻塞性肺病模型,同时给予模型大鼠低、中、高剂量益气固表丸治疗14 d。观察呼吸参数及肺组织病理变化。采用酶联免疫吸附试验测定支气管肺泡灌洗液(BALF)及血清胰岛素样生长因子1型受体(IGF-1R)、白细胞介素-1β(IL-1β)、IL-10水平。采用蛋白质印迹法检测大鼠肺组织样品中胰岛素样生长因子1受体(IGF-1R)/PI3K/AKT信号通路组分的磷酸化状态。结果:与对照组和低剂量益气组比较,大剂量益气固表丸治疗可显著改善COPD大鼠呼吸参数,减轻肺损伤和炎症,降低BALF和血清炎症介质水平。此外,高剂量益气固表丸干预的COPD大鼠肺组织标本中磷酸化IGF-1R、p-PI3K、p-AKT、p-GSK3、p-mTOR蛋白水平显著降低。结论:益气固表丸对COPD有明显的治疗作用,可能与靶向IGF-1R/PI3K/AKT信号通路有关。

Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease

Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid p accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS 1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS 1 /1 RS2-mediated signaling in the central nervous system and cognitive decline.

Effect of Kaiyu Qingwei Granule (开郁清胃颗粒) on Insulin Receptor in Liver and Skeletal Muscular Cell Membrane in Diabetes Mellitus Rats

Objective: To investigate the effect of Kaiyu Qingwei granule (KYQWG, on the insulin binding capacity of liver and skeletal muscular cell membrane and serum insulin-like growth factor-1 (IGF-1) in streptozotocin-induced diabetic rats. Methods: Rats in four experimental groups were investigated: the control group, the model group, the KYQWG group and the Metformin group. The insulin binding rate (IBR) of liver and skeletal muscular cell membrane was detected by receptor-ligand ra-diometric method and changes of serum levels of glucose, insulin and IGF-1 were observed before and after 4 weeks of medication. Results: The KYQWG group had a lower blood glucose level and ffiR of liver and muscular cell membrane, as compared with those in the model group (P<0. 01 or P<0.05), and a higher level of IGF-1 than that in the model group(P<0.01), but had no obvious changes in the serum level of insulin. Conclusion: KYQWG may increase the serum level of IGF-1 in diabetic rats, thus to decrease the insulin resistance at ante-receptor sites and improve the sugar metabolic disturbance in rats with diabetes mellitus.

血清PLGF、IGF-1及sFLT-1水平对子痫前期孕妇妊娠结局的预测价值

目的:探究血清胎盘生长因子(PLGF)、胰岛素生长因子-1(IGF-1)及可溶性血管内皮生长因子受体-1(sFlt-1)水平对子痫前期(PE)孕妇妊娠结局的预测价值。方法:选取110例PE孕妇为研究对象(PE组),根据病情严重程度、妊娠结局将孕妇分为4个亚组:轻度PE组(n=47)、重度PE组(n=63);妊娠结局不良组(n=72)、妊娠结局良好组(n=38)。另选取100例同期健康孕妇作为对照组。检测各组孕妇的一般资料及血清PLGF、IGF-1、sFLT-1水平,采用Logistic分析影响子痫前期孕妇妊娠结局的因素,采用受试者工作特征曲线(ROC)分析血清指标对妊娠结局的预测价值。结果:各组孕妇血清PLGF、IGF-1水平比较:对照组>轻度PE组>重度PE组;对照组>妊娠结局良好组>妊娠结局不良组,差异均有统计学意义(P<0.05)。血清sFlt-1浓度比较:对照组<轻度PE<重度PE组;对照组<妊娠结局良好组<妊娠结局不良组,差异均有统计学意义(P<0.05)。妊娠结局不良和妊娠结局良好组孕妇年龄、孕周、孕次及产次比较,差异均无统计学意义(P>0.05);Logistic回归分析显示,血清PLGF、IGF-1及sFLT-1均为PE患者妊娠结局的影响因素(P<0.05);ROC结果显示,PLGF、IGF-1及sFLT-1血清浓度均具有预测妊娠结局的应用价值,且三者联合预测的AUC(0.870)最高(P<0.05),敏感度、特异度分别为84.21%、77.78%。结论:PE孕妇血清中的PLGF、IGF-1和sFLT-1水平与疾病的严重程度和预后密切相关,血清PLGF和IGF-1水平越低,sFLT-1浓度越高,孕妇的疾病可能越严重,不良的妊娠结局可能性也越高。

IGF-1R在甲状腺相关眼病中的作用机制及靶向治疗进展

甲状腺相关眼病(TAO)是一种潜在的威胁视力的眼病,目前临床上采用的糖皮质激素、免疫抑制药物、眼眶局部放射及手术治疗等方法均未针对TAO的发病机制进行治疗。近年来研究发现眼眶成纤维细胞中的胰岛素样生长因子-1受体(IGF-1R)活性增强引起透明质酸合成增多,导致TAO的发生,而抑制IGF-1R的活性可以减弱或阻断信号通路。替妥木单抗(Teprotumumab)作为治疗性的靶向IGF-1R拮抗剂,药物临床试验表明此药物能够显著降低TAO的活动性、严重程度、改善疾病的临床结局,并且具有良好的安全性和持久性。因此,替妥木单抗是从病因学角度治疗TAO的新方法,值得临床医生给予更多关注。

Research on construction and identification of lentiviral vector of expressing miRNA targeting IGF1R gene regulated by survivin promoter and its inhibition to liver cancer cell growth

Objective： The aim of the study was to investigate the interference and anti-tumor effects of lentiviral vector of miRNA targeting IGF1R gene regulated by survivin promoter. Methods： The fragment of the survivin promoter was acquired by PCR amplification and inserted into pPRIME to recombinant plasmid sur-pPRIME. The complementary DNA containing both sense and antisense Oligo DNA of the targeting sequence was designed, synthesized and cloned into the sur-pPRIME vector, named sur-pPRIME-IGF1R-miR30-shRNA. Viruses were propagated on 293T cells. Viruses were purified by CsCI gradient according to standard techniques, and functional PFU titers were determined by plaque assay on 293 cells. The effect of sur-pPRIME-IGF1R-miR30-shRNA on IGF1R expression of Hep3B cells was detected by RT-PCR and Western blot. The antitumor potential of sur-pPRIME-IGF1R-miR30-shRNA to Hep3B cells was evaluated by CCK-8 assay. Results： sur-pPRIME-IGF1R-miR30-shRNA was constructed successfully. Functional PFU titers of sur-pPRIME-IGF1R-miR30-shRNA were 4.58×10^9 PFU/rnL. Sur-pPRIME-IGF1R-miR30-shRNA was more effective to inhibit IGF1R expression in mRNA or protein levels and the proliferation of Hep3B cells. Conclusion： sur-pPRIME-IGF1R-miR30-shRNA expressing IGF1R-siRNA can inhibit IGF1R expression and may be used for further investigation of gene therapy of liver cancer.