Hypoxia-inducible factor 1alpha and vascular endothelial growth factor in Glioblastoma Multiforme:a systematic review going beyond pathologic implications

Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression.Specifically,hypoxia is known to activate inducible factors,such as hypoxia-inducible factor 1alpha(HIF-1α),which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators,such as the vascular endothelial growth factor(VEGF).Here,we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data,as potential biomarkers of GBM prognosis and treatment efficacy.We performed a systematic review(Medline/Embase,and Pubmed database search was completed by 16th of April 2024 by two independent teams;PRISMA 2020).We evaluated methods of immunoassays,cell viability,or animal or patient survival methods of the retrieved studies to assess unbiased data.We used inclusion criteria,such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression,other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression,application of immunoassays for protein expression,and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression.We used exclusion criteria,such as data not reporting both HIF-1αand VEGF or prognosis.We included 50 studies investigating in total 1319 GBM human specimens,18 different cell lines or GBM-derived stem cells,and 6 different animal models,to identify the association of HIF-1α/VEGF immunophenotypes,and with other prognostic factors,clinical and macroscopic data in GBM prognosis and therapeutic approaches.We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors,such as miR-210-3p,Oct4,AKT,COX-2,PDGF-C,PLDO3,M2 polarization,or ALK,leading to unfavorable survival.Reduced HIF-1α/VEGF expression correlates with FIH-1,ADNP,or STAT1 upregulation,as well as with clinical manifestations,like epileptogenicity,and a favorable prognosis of GBM.Based on our data,HIF-1αor VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression.Finally,HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy,including combined first-line treatment with histone deacetylase inhibitors,thimerosal,or an active metabolite of irinotecan,as well as STAT3 inhibitors alone,and resulting in a favorable tumor prognosis and patient survival.These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes.Data limitations may include the use of less sensitive detection methods in some cases.Overall,our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.

Long non-coding RNA CDKN2B-AS1 promotes hepatocellular carcinoma progression via E2F transcription factor 1/G protein subunit alpha Z axis

BACKGROUND A series of long non-coding RNAs(lncRNAs)have been reported to play a crucial role in cancer biology.Some previous studies report that lncRNA CDKN2B-AS1 is involved in some human malignancies.However,its role in hepatocellular carcinoma(HCC)has not been fully deciphered.AIM To decipher the role of CDKN2B-AS1 in the progression of HCC.METHODS CDKN2B-AS1 expression in HCC was detected by quantitative real-time polymerase chain reaction.The malignant phenotypes of Li-7 and SNU-182 cells were detected by the CCK-8 method,EdU method,and flow cytometry,respectively.RNA immunoprecipitation was executed to confirm the interaction between CDKN2B-AS1 and E2F transcription factor 1(E2F1).Luciferase reporter assay and chromatin immunoprecipitation were performed to verify the binding of E2F1 to the promoter of G protein subunit alpha Z(GNAZ).E2F1 and GNAZ were detected by western blot in HCC cells.RESULTS In HCC tissues,CDKN2B-AS1 was upregulated.Depletion of CDKN2B-AS1 inhibited the proliferation of HCC cells,and the depletion of CDKN2B-AS1 also induced cell cycle arrest and apoptosis.CDKN2B-AS1 could interact with E2F1.Depletion of CDKN2B-AS1 inhibited the binding of E2F1 to the GNAZ promoter region.Overexpression of E2F1 reversed the biological effects of depletion of CDKN2B-AS1 on the malignant behaviors of HCC cells.CONCLUSION CDKN2B-AS1 recruits E2F1 to facilitate GNAZ transcription to promote HCC progression.

Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells

AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B(PI3K/AKT)-HIF-1α signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia. METHODS: Esophageal carcinoma cell lines Eca109 and TE13 were cultured under hypoxia environment, and the protein, m RNA and activity levels of hypoxia inducible factor-1 alpha(HIF-1α), glucose transporter 1, hexokinase-Ⅱ, phosphofructokinase 2 and lactate dehydrogenase-A were determined. Supernatant lactic acid concentrations were also detected. The PI3K/AKT signaling pathway was then inhibited with wortmannin, and the effects of hypoxia on the expression or activities of HIF-1α, associated glycolytic enzymes and lactic acid concentrations were observed. Esophageal carcinoma cells were then transfected with interference plasmid with HIF-1α-targeting si RNA to assess impact of the high expression of HIF-1α on glycolysis.RESULTS: HIF-1α is highly expressed in the esophageal carcinoma cell lines tested, and with decreasing levels of oxygen, the expression of HIF-1α and the associated glycolytic enzymes and the extracellular lactic acid concentration were enhanced in the esophageal carcinoma cell lines Eca109 and TE13. In both normoxia and hypoxic conditions, the level of glycolytic enzymesand the secretion of lactic acid were both reduced by wortmannin. The expression and activities of glycolytic enzymes and the lactic acid concentration in cells were reduced by inhibiting HIF-1α, especially the decreasing level of glycolysis was significant under hypoxic conditions.CONCLUSION: The PI3K/AKT pathway and HIF-1α are both involved in the process of glycolysis in esophageal cancer cells.

Clinicopathological and Prognostic Significance of Hypoxia-inducible Factor-1 alpha in Lung Cancer: a Systematic Review with Meta-analysis

Hypoxia-inducible factor-1 alpha（HIF-1α） plays a vital role in the initiation, evaluation and prognosis in lung cancer. The prognostic value of HIF-1α reported in diverse study remains disputable. Accordingly, a meta-analysis was implemented to further understand the prognostic role of HIF-1α in lung cancer. The relationship between HIF-1α and the clinicopathological characteristics and prognosis of lung cancer were investigated by a meta-analysis. Pub Med and Embase were searched from their inception to January 2015 for observational studies. Fixed-effects or random-effects meta-analyses were used to calculate odds ratios and 95% confidence intervals of different comparisons. A total of 20 studies met the criteria. The results showed that HIF-1α expression in lung cancer tissues was significantly higher than that in normal lung tissues. Expression of HIF-1α in patients with squamous cell carcinoma was significantly higher than that of patients with adenocarcinomas. Similarly, non-small cell lung cancer（NSCLC） patients had higher HIF-1α expression than small cell lung cancer（SCLC） patients. Moreover, lymph node metastasized tissues had higher HIF-1α expression than non-lymph node metastasized tissues. A high level HIF-1α expression was well correlated with the expression of vascular endothelial growth factor and epidermal growth factor receptor in the NSCLC. Notably, NSCLC or SCLC patients with positive HIF-1α expression in tumor tissues had lower overall survival rate than patients with negative HIF-1α expression. It was suggested that HIF-1α expression may be a prognostic biomarker and a potential therapeutic target for lung cancer.

Modified Shenlingbaizhu decoction reduces intestinal adenoma formation in adenomatous polyposis coli multiple intestinal neoplasia mice by suppression of hypoxia-inducible factor 1α-induced CD4+CD25+forkhead box P3 regulatory T cells

OBJECTIVE： To test the hypothesis that modified Shenlingbaizhu decoction （MSD） attenuates the for- mation of intestinal adenomas by regulating activa- tion of CD4＋CD25＋ forkhead box P3 （FoxP3） regu- latory T cells （Tregs） by downregulation of hypox- ia-inducible factor la （HIF-la）. METHODS： Chemical fingerprints of ginsenoside Rbl, ginsenoside Rc, paeoniflorin, and dioscin in standard extractions were used as material bases of MSD. Adenomatous polyposis coli multiple intesti- nal neoplasia （ApcM＇n/＋） mice, which harbor a muta- tion in adenomatous polyposis coil, were used to host intestinal adenomas. Peripheral blood and spleen Tregs were analyzed by flow cytometry. Pro- tein expression was analyzed by immunohisto- chemistry and Western blotting. RESULTS： The number and size of intestinal adenomas were significantly reduced by MSD treatment. Mucosal thickening and the spleen size were also substantially decreased by MSD. The carcinogenesis process in Apc^min/＋ mice resembled that of human colorectal cancer. Molecular markers of neoplasms, such as 13-catenin, cyclooxygenase-2, prolif- erating cell nuclear antigen, and p53, were substantially ameliorated by MSD treatment. Moreover, MSD downregulated peripheral and spleen CD4＋ CD25＋FoxP3＋ Tregs and reduced in situ expression of CD4, CD25, and FoxP3 in intestinal adenomas. MSD also suppressed HIF-la expression in the intestinal adenomas, and HIF-la inhibition decreased expression of FoxP3 in Jurkat T cells under hypoxic conditions. CONCLUSION： MSD is a valid prescription to control the formation of intestinal adenomas in Apc^min/＋mice. It exerts anti-cancer effects partially through suppression of HIF-la that induced activation of CD4＋CD25＋FoxP3＋ Tregs in vivo and in vitro.

Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxininteracting protein-mediated hypoxia-inducible factor-1αpathway

BACKGROUND Extracellular vesicles(EVs)derived from hypoxia-preconditioned(HP)mesenchymal stem cells(MSCs)have better cardioprotective effects against myocardial infarction(MI)in the early stage than EVs isolated from normoxic(NC)-MSCs.However,the cardioprotective mechanisms of HP-EVs are not fully understood.AIM To explore the cardioprotective mechanism of EVs derived from HP MSCs.METHODS We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs(ADSCs)following hypoxia in vitro or MI in vivo,in order to improve the survival of cardiomyocytes(CMs)and restore cardiac function.The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays.MicroRNA(miRNA)sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs.The molecular mechanism of EVs in mediating thioredoxin-interacting protein(TXNIP)was verified by the dual-luciferase reporter assay.Co-immunoprecipitation,western blotting,and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha(HIF-1α)ubiquitination and degradation via the chromosomal region maintenance-1(CRM-1)-dependent nuclear transport pathway.RESULTS HP-EVs derived from MSCs reduced both infarct size(necrosis area)and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo.Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP,an oxidative stress-associated protein.We showed miRNA224-5p,the most upregulated miRNA in HP-EVs,directly combined the 3’untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury.Our results demonstrated that MI triggered TXNIP-mediated HIF-1αubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs,which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI.CONCLUSION The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

Phosphatase and tensin homology deleted in chromosome 10,hypoxia-inducible factor-1 alpha gene expression in colorectal adenoma and adenocarcinoma and their relation to vascular endothelial growth factor protein expression

To examine phosphatase and tensin homology deleted in chromosome 10 (PTEN),hypoxia-inducible factor-1 alpha (HIF-1 alpha) gene expressions and their relation to vascular endothelial growth factor(VEGF) protein expression in the patients with human colorectal adenomas and adenocarcinomas.Methods The expression of PTEN,HIF-1 alpha gene was detected by using in situ hybridization,and the VEGF expression levels by immunohistochemistry in colorectal adenomas and primary colorectal adenocarcinoma.Results Strong expression of HIF-1 alpha was detectable in the majority of colorectal dadenocarcinoma,particularly surrounding areas of necrosis in adenocarcinoma.PTEN,HIF-1 alpha mRNA and VEGF protein were positive in 51.6%,67.7% and 59.7% respectively in 62 cases of adenocarcinomas,and 77.8%,44.4% and 33.3% respectively in 18 cases of adenomas.The positive rate of VEGF was higher in the patients with colorectal adenocarcinomas than that in those with adenomas,whereas that of PTEN mRNA was contrary.HIF-1 mRNA expression was correlated significantly with lymph node metastasis,liver metastasis,Duke’s stage and recurrence.During colorectal tumor progression,the expression of HIF-1 alpha mRNA was positively correlated with the VEGF protein expression (χ2= 4.751 ,P<0.05),but negatively with the PTEN mRNA expression(χ2=21.84,P<0.01).Conclusion The absence or low expression of PTEN and the increased levels of HIF-1α and VEGF may paly an important role in carcinogenesis and progression of colorectal carcinoma.These results suggest that VEGF upregulated by HIF-1 alpha gene may be involved in angiogenesis of colorectal adenocarcinoma.4 refs,1 tab.

Expression of hypoxia-inducible factor la and vascular endothelial growth factor in hepatocellular carcinoma: Impact on neovascularization and survival

AIM: To study the expression of hypoxia-inducible factor 1α(HIF-1α) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) and the impact on neovascularization and survival. METHODS: Expressions of HIF-1α, VEGF and microvessel density (MVD) are studied through immunohistochemistry in 36 cases of HCC and the corresponding paraneoplastic tissue and 6 cases of normal liver tissue. The relationship of the expressions of HIF-1α and VEGF with the clinicopathological data and survival are analyzed. RESULTS: The positive rate of VEGF in HCC was 32/36, which is significantly higher than that in paraneoplastic tissue and normal liver tissue (P<0.05). The expression of HIF-1aaaaaa in HCC tissue is 24/36, also higher than that in paraneoplastic tissue and normal liver tissue (P<0.05). The expression of VEGF and HIF-1α in HCC with microscopic venous invasion is significantly higher than that in HCC without microscopic venous invasion (P<0.05). Spearman correlation analysis does not only show the expression of HIF-1α as correlated with the expression of VEGF (rs = 0.459, P<0.01), but it also shows the expression of HIF-1α and VEGF as correlated with MVD (rs=0.412 and 0.336, respectively, P<0.05). The differences of the survival rates among VEGF positive group and VEGF negative group are significant (P<0.05), whereas the differences of the survival rates among the HIF-1α negative group and positive group are not significant (P>0.05). CONCLUSION: HIF-1α plays important roles in neovascularization in HCC possibly through regulation of VEGF transcription.

TSLP、HIF-1α、RANKL在义齿修复后种植体周围炎患者龈沟液中的表达及意义

目的研究胸腺基质淋巴细胞生成素(TSLP)、缺氧诱导因子1α(HIF-1α)、核因子-κB受体活化因子配体(RANKL)在义齿修复后种植体周围炎(PI)患者龈沟液中的表达及意义。方法回顾性选取2019年8月至2023年8月大同市第五人民医院收治的义齿修复患者86例作为研究对象,根据术后3个月是否发生PI将患者分为预后良好组(n=61)和预后不良组(n=25)。比较两组患者的临床资料及术前龈沟液TSLP、HIF-1α及RANKL水平,采用多因素Logistic回归分析对龈沟液TSLP、HIF-1α及RANKL水平与义齿修复患者术后发生PI的关系进行分析,采用受试者操作特征(ROC)曲线分析TSLP、HIF-1α及RANKL水平对义齿修复患者的预后评估价值。结果两组患者临床资料(性别、年龄、病程、义齿种植原因及种植颗数)比较,差异均无统计学意义(P>0.05)。预后良好组患者的龈沟液中TSLP、HIF-1α、RANKL水平分别为(122.57±11.30)ng/L、(417.79±115.43)ng/mL、(116.02±13.45)pg/μL,均明显低于预后不良组[(138.93±12.70)ng/L、(576.55±177.60)ng/mL、(133.24±15.69)pg/μL],差异均有统计学意义(P<0.05)。Logistic回归分析义齿修复患者预后,结果显示龈沟液中TSLP水平升高、HIF-1α水平升高和RANKL水平升高是义齿修复患者术后发生PI的独立危险因素(OR=1.119,95%CI:1.048~1.195;OR=1.007,95%CI:1.002~1.013;OR=1.065,95%CI:1.016~1.117;P<0.05)。ROC曲线分析龈沟液中TSLP、HIF-1α、RANKL水平预测义齿修复患者预后的价值,结果显示曲线下面积(AUC)值分别为0.833、0.786和0.809。其中,RANKL具有最高的特异度(0.852),而HIF-1α具有最高的敏感度(0.800),具有较好的预测价值(P<0.05)。结论龈沟液中TSLP、HIF-1α、RANKL水平升高是义齿修复患者术后并发PI的独立危险因素,且均具有较高的预测义齿修复患者预后的价值。

益气升清方调节HIF-1α/NLRP3信号通路对缺血性脑卒中大鼠神经元焦亡的影响

目的 探究益气升清方调节缺氧诱导因子-1α(HIF-1α)/NOD样受体热蛋白结构域相关蛋白3(NLRP3)信号通路对缺血性脑卒中大鼠神经元焦亡的影响。方法 将SD大鼠随机分为假手术组(S组),模型组(M组),益气升清方低、中、高剂量组(3.465、6.930、13.860 g/kg)及益气升清方高剂量+HIF-1α激活剂DMOG组(13.860 g/kg益气升清方+40 mg/kg DMOG),每组15只。采用线栓法构建脑卒中模型。造模成功后进行神经功能缺陷评估;TTC染色评估脑梗死体积;ELISA法检测血清白细胞介素(IL)-1β、IL-18水平;HE染色检测缺血皮质区病理变化;TUNEL染色检测神经元凋亡;Western blot检测焦亡及HIF-1α/NLRP3通路相关蛋白表达。结果 与S组比较,M组神经功能缺陷评分、梗死体积、IL-1β含量、IL-18含量、神经细胞凋亡率、胞膜穿孔蛋白D-N端(GSDMD-N)、胱天蛋白酶1(Caspase-1)、HIF-1α、NLRP3蛋白水平均上升(P<0.05);与M组比较,低、中、高剂量益气升清方组神经功能缺陷评分、梗死体积、IL-1β含量、IL-18含量、神经细胞凋亡率、GSDMD-N、Caspase-1、HIF-1α、NLRP3蛋白水平均下调(P<0.05);DMOG减弱了高剂量益气升清方对缺血性脑卒中大鼠神经元焦亡的改善作用。结论 益气升清方可能通过下调HIF-1α/NLRP3信号通路减轻缺血性脑卒中大鼠神经元焦亡。

不同方法联合放疗治疗薄型瘢痕疙瘩的疗效及对MMPs、HIF-1α、TGF-β1的影响

目的探讨不同方法联合放疗治疗薄型瘢痕疙瘩的疗效及对基质金属蛋白酶(MMPs)、缺氧诱导因子-1α(HIF-1α)及转化生长因子-β1(TGF-β1)的影响。方法回顾性选取2020年10月至2022年9月内蒙古医科大学附属肿瘤医院(内蒙古自治区肿瘤医院)整形外科收治的胸腹部瘢痕疙瘩患者62例(瘢痕疙瘩数94个),依据治疗方法不同分为激光联合放疗(LCR)组(30例,瘢痕疙瘩数47个)、手术联合放疗(SCR)组(32例,瘢痕疙瘩数47个)。LCR组行CO 2点阵LCR,SCR组行SCR。观察两组治疗12个月后临床疗效、复发情况。比较两组治疗前、治疗12个月后的患者与观察者瘢痕评估量表(POSAS)评分、温哥华瘢痕量表(VSS)评分、瘢痕组织基质金属蛋白酶(MMP)-2、MMP-9、HIF-1α、TGF-β1等细胞因子水平的变化。结果LCR组总有效率(93.62%)大于SCR组(76.60%),复发率(4.26%)小于SCR组(19.15%),差异均有统计学意义(P<0.05)。治疗12个月后,LCR组POSAS、VSS评分分别为(23.96±2.64)、(5.28±0.54)分,均低于SCR组[(33.96±3.59)、(6.55±0.68)分],差异均有统计学意义(P<0.05)。LCR组瘢痕组织MMP-2、MMP-9及HIF-1α、TGF-β1表达量分别为111.65±13.55、106.76±12.68、1.24±0.14、1.10±0.12,均低于SCR组(127.96±14.71、121.08±14.33、1.55±0.17、1.22±0.13),差异均有统计学意义(P<0.05)。两组不良反应发生率比较(38.30%vs.46.81%),差异无统计学意义(P>0.05)。结论LCR和SCR均可改善薄型瘢痕疙瘩症状,抑制瘢痕疙瘩复发,但LCR的治愈率更高,复发率更低,对瘢痕组织MMPs及HIF-1α、TGF-β1表达抑制作用更强,且安全性较高,值得临床推荐。

MiR-181c-5p对卵巢癌干细胞样细胞肿瘤血管生成拟态的作用及其机制

目的探讨miR-181c-5p对卵巢癌干细胞样细胞(OCS-LCs)肿瘤血管生成拟态(VM)的作用及其机制。方法采用无血清悬浮培养法将人卵巢癌细胞系OVCAR3细胞诱导形成OCS-LCs。将OVCAR3细胞分为A~C组,各组分别转染NC-miR-181c-5p、siRNA-miR-181c-5p和pRNA-miR-181c-5p。通过成球实验评估A~C组细胞成球能力。采用实时荧光定量PCR(RT-qPCR)方法检测A~C组细胞miR-181c-5p的相对表达量,采用Western blot实验检测A~C组细胞Oct-4、Nanog、HIF-1α和VEGF蛋白相对表达量。采用CCK-8实验检测A~C组细胞的活性,采用三维立体培养实验检测A~C组的血管形成率。结果OVCAR3细胞成功被诱导形成OCS-LCs。RT-qPCR实验结果显示,B组细胞的miR-181c-5p相对表达量显著低于A组,C组高于A组(t=2.25、8.68,P<0.05)。成球实验结果显示,B组与A组、A组与C组相比,细胞的成球周期显著缩短,最大的细胞球直径显著增大,成球率显著增加(t=5.56~33.66,P<0.05)。Western blot实验结果表明,B组与A组、A组与C组相比,Oct-4、Nanog、HIF-1α和VEGF蛋白相对表达量显著升高(t=4.51~56.15,P<0.05)。CCK-8实验结果显示,B组的细胞活性高于A组,C组低于A组(F=97.70~281.80,P<0.05)。三维立体培养实验结果显示,B组与A组、A组与C组相比较,血管形成率显著性提高(t=3.70、18.67,P<0.05)。结论miR-181c-5p可能通过降低细胞中HIF-1α和VEGF蛋白的表达,从而抑制OCS-LCs的VM形成。

丁苯酞软胶囊联合瑞舒伐他汀治疗急性脑梗死患者的临床观察及对血清HIF-1α、Lp-PLA、Sestrin2水平的影响

目的探究丁苯酞软胶囊联合瑞舒伐他汀治疗急性脑梗死患者的疗效及对血清缺氧诱导因子-1α(HIF-1α)、脂蛋白相关磷脂酶A2(Lp-PLA)、应激诱导蛋白2(Sestrin2)水平的影响。方法前瞻性选取2021年1月至2022年12月在秦皇岛市第一医院治疗的急性脑梗死患者101例作为研究对象,按照信封法将患者分为对照组(n=50)和研究组(n=51)。对照组行常规治疗并瑞舒伐他汀治疗,研究组在对照组基础上联合丁苯酞软胶囊治疗。统计分析两组患者治疗前及治疗14 d后的美国国立卫生研究院脑卒中量表(NIHSS)评分、FuglMeyer评测法(FMA)评分、改良Rankin量表(mRS)评分、血流动力学指标(血浆黏度、全血高切黏度、低切黏度、红细胞压积、红细胞变形指数)、血清HIF-1α、Lp-PLA、Sestrin2水平并比较临床疗效的组间差异。结果治疗14 d后,两组患者的NIHSS评分和mRS评分均较治疗前降低,FMA较治疗前升高,且研究组患者的NIHSS评分和mRS评分分别为(4.03±0.38)、(3.01±0.45)分,均低于对照组,FMA为(80.64±9.16)分,高于对照组,差异均有统计学意义(P<0.05)。治疗14 d后,两组患者的血浆黏度、全血高切黏度、低切黏度、红细胞压积均较治疗前降低,红细胞变形指数均较治疗前升高,且研究组的血浆黏度、全血高切黏度、低切黏度、红细胞压积分别为(1.56±0.33)mPa·s、(4.78±0.31)mPa·s、(9.81±0.64)mPa·s、(0.37±0.05)%,均低于对照组,红细胞变形指数为0.78±0.11,高于对照组,差异均有统计学意义(P<0.05)。治疗14 d后,两组患者的血清HIF-1α、Lp-PLA、Sestrin2水平均降低,且研究组患者血清HIF-1α、Lp-PLA、Sestrin2水平分别为(690.56±65.12)ng/mL、(13.65±2.13)μg/L、(11.33±1.45)ng/mL,均显著低于对照组,差异均有统计学意义(P<0.05)。两组近期疗效比较,差异有统计学意义(P<0.05);研究组总有效率为90.20%,高于对照组(64.00%),差异有统计学意义(P<0.05)。结论采用丁苯酞软胶囊联合瑞舒伐他汀治疗急性脑梗死患者可显著提高患者临床治疗效果,提高肢体活动能力,缓解神经功能损伤,降低血清HIF-1α、Lp-PLA、Sestrin2水平,具有较高的临床应用潜力。

急性呼吸窘迫综合征患儿外周血单个核细胞中CD73、HIF-1α的表达及其临床意义

目的探究急性呼吸窘迫综合征(ARDS)患儿外周血单个核细胞(PBMCs)中5′胞外核苷酸酶(CD73)、缺氧诱导因子1α(HIF-1α)的表达及其临床意义。方法选取2022年2月至2023年4月广安市人民医院收治的117例ARDS患儿为研究对象,根据病情严重程度分为轻症组(n=27)、中症组(n=38)和重症组(n=52)。比较3组患儿PBMCs中CD73、HIF-1α表达水平及肺部感染指数(CPIS)评分。采用Pearson相关系数分析CD73、HIF-1α表达水平与CPIS评分的相关性。治疗后随访3个月,根据患儿生存状况分为生存组(n=34)和死亡组(n=83),比较两组患儿PBMCs中CD73、HIF-1α表达水平,采用受试者工作特征(ROC)曲线评估PBMCs中CD73、HIF-1α表达水平对ARDS患儿预后的诊断价值。结果轻症组PBMCs中CD73、HIF-1α表达水平分别为0.44±0.06、0.60±0.11、(4.82±0.81)分,均显著低于中症组[0.53±0.10、0.76±0.14、(6.33±1.02)分]、重症组[0.62±0.07、0.89±0.08、(7.03±1.14)分],中症组PBMCs中CD73、HIF-1α表达水平均显著低于重症组,差异均有统计学意义(P<0.05)。Pearson相关系数分析结果显示,CD73、HIF-1α相对表达水平与CPIS评分均呈显著正相关(r=0.623、0.687,P<0.05)。生存组PBMCs中CD73、HIF-1α表达水平分别为0.53±0.08、0.74±0.15,显著低于死亡组(0.60±0.08、0.88±0.09),差异均有统计学意义(P<0.05)。ROC曲线分析结果显示,CD73、HIF-1α单独及联合预测ARDS患儿预后的敏感度分别为79.41%、85.29%、94.12%,曲线下面积(AUC)为0.746、0.801、0.843,联合检测预测价值更高。结论ARDS患儿PBMCs中CD73、HIF-1α表达水平随疾病严重程度增加而升高,且与患儿肺部感染呈显著相关性,检测患儿PBMCs中CD73、HIF-1α表达水平对预后具有较高的诊断价值。

miR-519d-3p靶向HIF-1α抑制高糖诱导的人视网膜微血管内皮细胞功能障碍及血管生成

目的:明确miR-519d-3p对高糖诱导的人视网膜微血管内皮细胞(HRMEC)功能障碍与血管生成的影响,并阐明其对低氧诱导因子-1α(HIF-1α)的调控机制。方法:通过5、30mmol/L葡萄糖分别诱导HRMEC建立正常(NG)和高糖(HG)细胞模型。将HRMEC分为对照组(HG细胞模型转染阴性对照模拟物)、甘露醇组(对照组加入25mmol/L甘露醇)、miR-519d-3p过表达组(HG细胞模型转染miR-519d-3p模拟物)、miR-519d-3p联合HIF-1α过表达组(HG细胞模型共转染miR-519d-3p模拟物和HIF-1α过表达载体)。实时荧光定量PCR法检测各组miR-519d-3p的表达情况。Western blotting法检测各组HIF-1α蛋白的表达情况。荧光素酶报告基因实验检测miR-519d-3p和HIF-1α的结合位点情况。CCK-8法检测各组细胞增殖情况。Hoechst 33342染色法检测各组细胞凋亡情况。ELISA法检测各组细胞外液炎症因子肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β、IL-6蛋白的表达情况。小管形成实验检测各组新生毛细血管管腔样结构形成情况。结果:与NG相比,HG细胞模型中miR-519d-3p表达显著减少,而HIF-1α蛋白表达显著增加(均P<0.01)。与对照组比较,miR-519d-3p过表达组中HIF-1α蛋白表达显著降低(P<0.01)。miR-519d-3p中“CGUGAAA”序列可以与HIF-1α3'-非编码区(3'-UTR)中“GCACUUU”序列特异性结合。与对照组比较,miR-519d-3p过表达组细胞24、48、72h吸光度值均显著增加,细胞凋亡率显著减少,细胞外液TNF-α、IL-1β、IL-6浓度均显著减少,新生毛细血管管腔样结构数量显著减少(均P<0.01)。与miR-519d-3p过表达组比较,miR-519d-3p联合HIF-1α过表达组细胞24、48、72h吸光度值均显著减少,细胞凋亡率显著增加,细胞外液TNF-α、IL-1β、IL-6浓度均显著增加,新生毛细血管管腔样结构数量显著增加(均P<0.01)。对照组和甘露醇组中上述各指标比较无差异(均P>0.05)。结论:高糖诱导HRMEC模型中miR-519d-3p表达下调,而HIF-1α蛋白表达上调。HIF-1α是miR-519d-3p的靶基因,miR-519d-3p靶向HIF-1α增加细胞增殖并降低细胞凋亡和炎症反应,从而减轻高糖诱导的HRMEC功能障碍并抑制血管生成。

血清PGC-1α、VCAM-1、BSAP与创伤性股骨粗隆骨折术后骨折愈合、骨代谢的关系分析

目的分析血清过氧化物酶体增殖物激活受体γ共激活因子-lα(PGC-1α)、血管细胞黏附因子-1(VCAM-1)及骨特异性碱性磷酸酶(BSAP)与创伤性股骨粗隆骨折术后骨折愈合、骨代谢的关系。方法回顾性选取2020年10月至2022年10月北京市昌平区中医医院收治的101例创伤性股骨粗隆骨折手术患者作为骨折组,依据术后骨折延迟愈合发生情况将患者分为骨折愈合组(n=98)和骨折愈合延迟组(n=3)。另选取同期收治的98例单纯性骨质疏松患者作为骨质疏松组,选取同期体检的100名健康者作为对照组。比较不同愈合组患者性别构成比、年龄、骨折到入院时间、骨折原因、骨代谢标志物{Ⅰ型前胶原氨基端原肽(PINP)、Ⅰ型胶原羟基端肽β降解产物(β-CTX)、25羟维生素D[25(OH)D]}、PGC-1α、VCAM-1、BSAP水平等资料;采用Logistic回归分析分析影响创伤性股骨粗隆骨折术后骨折愈合的因素;比较3组研究对象的骨代谢标志物水平;采用Pearson分析VCAM-1、PGC-1α、BSAP水平与骨代谢标志物的相关性。结果两组患者性别构成比、年龄、骨折到入院的时间、骨折原因比较,差异均无统计学意义(P>0.05);骨折愈合组PINP、β-CTX、25(OH)D、PGC-1α、BSAP水平均高于骨折愈合延迟组,VCAM-1水平低于骨折愈合延迟组,差异均有统计学意义(P<0.05)。Logistic回归分析结果表明PINP、β-CTX、25(OH)D、PGC-1α、BSAP是创伤性股骨粗隆骨折患者术后骨折延迟愈合的保护因素(P<0.05),VCAM-1是创伤性股骨粗隆骨折患者术后骨折延迟愈合的独立危险因素(P<0.05)。骨折组的PINP、β-CTX水平均高于骨质疏松组和对照组,骨质疏松组的PINP、β-CTX水平均高于对照组,差异均有统计学意义(P<0.05);骨折组的25(OH)D水平显著低于骨质疏松组和对照组,骨质疏松组25(OH)D水平低于对照组,差异均有统计学意义(P<0.05)。PGC-1α、BSAP与PINP均呈负相关(P<0.05),VCAM-1与β-CTX呈正相关(P<0.05),PGC-1α、VCAM-1、BSAP水平与25(OH)D均无显著相关(P>0.05)。结论创伤性股骨粗隆骨折患者血清PGC-1α、BSAP水平升高,血清VCAM-1水平下降,骨代谢指标PINP、β-CTX水平也升高,血清PGC-1α、VCAM-1、BSAP水平与上述骨代谢指标有关,而且是骨折延迟愈合的影响因素。

缺氧诱导因子1α与卵泡抑素样蛋白1对老年急性脑梗死患者功能结局预测价值

目的探讨老年急性脑梗死(ACI)患者卵泡抑素样蛋白1(FSTL1)、缺氧诱导因子1α(HIF-1α)与凋亡分子的表达,对功能结局的预测价值。方法选取2021年6月至2022年6月温州市人民医院收治的220例老年ACI患者作为ACI组,同期200例老年健康体检者作为健康组。ACI患者溶栓治疗后3个月日常生活活动能力量表评分≤60分记为功能结局不良组,>60分记为功能结局良好组。检测所有入组患者血清FSTL1、HIF-1α及相关凋亡分子B淋巴细胞瘤2基因(Bcl-2)和半胱氨酸天冬氨酸蛋白酶3(Caspase-3)表达。结果ACI组血清HIF-1α、FSTL1、Caspase-3表达水平显著高于健康组,Bcl-2表达水平显著低于健康组(P<0.01)。Pearson相关性分析显示,ACI组血清HIF-1α、FSTL1表达水平与Caspase-3呈正相关(P<0.01),与Bcl-2表达水平呈负相关(P<0.01)。多因素logistic回归分析显示,入院美国国立卫生研究院卒中量表评分(OR=1.933,95%CI:1.008~3.705,P=0.047)、发病至治疗时间(OR=2.038,95%CI:1.335~3.112,P=0.001)、HIF-1α(OR=1.865,95%CI:1.202~2.892,P=0.005)和FSTL1(OR=2.160,95%CI:1.142~4.084,P=0.018)是影响老年ACI患者溶栓治疗后功能结局的独立危险因素。HIF-1α和FSTL1联合检测的敏感性(87.9%)和曲线下面积(0.804)显著高于单项检测(P<0.05)。结论HIF-1α、FSTL1可能通过调节凋亡相关蛋白Caspase-3、Bcl-2表达,HIF-1α和FSTL1与神经损伤相关,对于老年ACI患者早期溶栓后功能结局具有预测价值。

缺氧诱导因子1α(HIF-1α)/Yes相关蛋白(YAP)在非酒精性脂肪性肝病中的调控作用

非酒精性脂肪性肝病(NAFLD)是目前最为常见的慢性肝病,并与多种代谢性疾病密切相关,如2型糖尿病、胰岛素抵抗,以及与高血压和血脂异常相关的心脑血管并发症。NAFLD病因和病理机制复杂,微环境因素和基因表达调节异常存在于疾病进展的各个阶段,并通过累加效应促进疾病发展。缺氧诱导因子(HIF)是核转录因子、Yes相关蛋白(YAP)是转录辅助调节因子,二者通过调节肝脂质沉积与氧化应激,促进炎性因子释放,与NAFLD进展密切相关。本文对HIF-1α/YAP在NAFLD及其相关代谢性疾病进展中的作用进行综述,为探索NAFLD疾病进展过程中的相关治疗靶点提供理论依据。

MicroRNA-210在缺血性脑卒中中的作用研究进展

缺血性脑卒中是我国成年人致残和死亡的主要原因之一,可导致脑细胞和组织缺血缺氧性损害,引发机体神经功能障碍。其病因复杂,发病率高,预后差,一直是临床医学研究的重点。然而,目前脑卒中治疗方法仍然有限,机制尚且不明。MicroRNA-210是一种短核苷酸链,以转录后的方式调节蛋白质表达,具有治疗缺血性脑卒中的潜力。在神经细胞中,MicroRNA-210参与缺血性脑卒中的抗炎症反应、抗凋亡作用、抑制氧化应激、促进神经元可塑性和血管生成,发挥神经保护作用,这将为缺血性脑卒中的治疗提供有效靶点和干预策略。

超声下肺腺癌血流分级与肿瘤组织MVD、VEGF、HIF-1α表达及临床分期的关系及其意义

目的探讨超声下肺腺癌血流分级与肿瘤组织微血管密度(MVD)、血管内皮生长因子(VEGF)、缺氧诱导因子-1α(HIF-1α)表达及临床分期的关系及其意义。方法回顾性分析108例肺腺癌患者的临床资料,根据肿瘤超声下血流分级分为血流0级组(A组)、Ⅰ级组(B组)、Ⅱ级组(C组)、Ⅲ级组(D组)。对比4组患者肿瘤组织MVD值及VEGF、HIF-1α阳性表达情况,分析超声下肺腺癌血流分级与肿瘤组织MVD值及VEGF、HIF-1α表达及临床分期的相关性。结果各组肿瘤组织MVD值和VEGF、HIF-1α阳性表达比例比较差异均具有显著性(F=116.487,χ^(2)=7.143、6.982,P<0.05),B、C、D组肿瘤组织MVD值明显高于A组,C、D组明显高于B组,D组明显高于C组(P<0.05);C、D组VEGF、HIF-1α阳性表达比例均高于A组,D组高于B、C组(χ^(2)=4.589~112.502,P<0.05)。血流分级与肿瘤组织MVD值、VEGF阳性表达比例、HIF-1α阳性表达比例及临床分期均呈正相关(r=0.705~0.836,P<0.05)。结论超声下肺腺癌血流分级与肿瘤组织MVD值及VEGF、HIF-1α表达均具有相关性,且与临床分期相关,此有助于超声下对肿瘤早期及术前情况进行评估。