Increased Midkine and Estrogen Receptor-β Expression in Human Non-Small Cell Lung Cancer

Objective： Midkine （MK）, a new member of the heparin-binding growth factor family, has been found recently to have a high expression level in many tumor specimens including lung carcinoma. Estrogens may be involved in lung carcinogenesis, and estrogen receptors, mainly estrogen receptor-β （ER-β）, are present and functional in normal lung and tumor cell lines and tissues. In addition, estrogens and growth factors may promote the progression of human non-small cell lung cancer （NSCLC）. Previously, we have immunohistochemically demonstrated that MK and ER-β proteins were overexpressed in NSCLC and their expression levels were both significantly negatively correlated with the pathological classification. The purpose of this study was to further verify their expression and its correlation with NSCLC. Methods： Taking NSCLC tissues and their corresponding paraneoplastic and normal lung as research objects, we further examined the expression of MK and ER-β by meas of RT-PCR, in situ hybridization and Western blot analyses at the levels of messenger RNA （mRNA） and protein, respectively. Results： The increased MK and ER-β mRNA expression was found in NSCLC by RT-PCR and in situ hybridization analyses. Furthermore, Western blot analysis also displayed increased expression of MK and ER-β proteins in NSCLC. Finally, their correlation analysis at the levels of mRNA and protein expression in NSCLC demonstrated that MK protein level was significantly correlated to estrogen receptor-β （P〈0.01, rs=0.535）; in spite of their correlation at the mRNA level, there was no remarkable difference between MK and ER-β （P〉0.05, rs=0.178）. Conclusion： All these results in the present study confirmed that MK and ER-β were overexpressed in human NSCLC.

Expression of voltage.gated sodium channel Nav1.5 in non.metastatic colon cancer and its associations with estrogen receptor(ER)-βexpression and clinical outcomes

Background: Voltage-gated sodium channel 1.5(Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β(ER-β)expression in non-metastatic colon cancer patients receiving radical resection.Methods: A total of 269 consecutive patients with pathologically confirmed stages Ⅰ-Ⅲ colon cancer who underwent radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry(IHC)on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models.Results: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues(5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001).The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio(OR) = 2.980;95% confidential interval(CI)1.163-7.632; P = 0.023] and high ER-β expression(OR = 2.808; 95% CI 1.243-6.343;p = 0.00 3). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival(DFS) rate in colon cancer patients(77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor(76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression[hazard ratio(HR) = 2.738; 95% CI 1.100-6.819;P = 0.030] and lymph node metastasis(HR = 2.633; 95% CI 1.632-4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients.Conclusions: High expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.

phytoestrogens/insoluble fibers and colonic estrogen receptor β: randomized, double-blind, placebo-controlled study

AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.

Involvement of Estrogen Receptors in the Anxiolytic-Like Effect of Phytoestrogen Genistein in Rats with 12-Weeks Postovariectomy

Phytoestrogens are natural compounds found in some vegetables, and they replicate many of the physiochemical and physiological properties of estrogens, including the regulation of mood. The phytoestrogen genistein exerts anxiolytic-like effects in rats with a chronic absence of ovarian hormones, but the mechanism involved in this effect remains to be explored. The present study explored the participation of estrogen receptor-β in the anxiolytic-like effect of genistein (1.0 mg/kg, i.p., for 4 days) in Wistar rats with 12-weeks postovariectomy, considered as experimental model of post-surgical menopause. In the light/dark test, a useful tool for anxiety study and for the screening of anxiolytic drugs, genistein reduced the latency to enter and increased the time spent in the light compartment and significantly increased the frequency and time spent exploring the light compartment compared with the control group, which is considered as an anxiolytic-like effect at experimental level. All behavioral effects produced by genistein in the light/dark test were blocked by previous tamoxifen administration (5.0 mg/kg, s.c., for 6 days), a non selective antagonist for estrogen receptor-β. The effects produced by genistein or tamoxifen in this test were not related to significant changes in general motor activity evaluated in the open field test. In conclusion, the specific contribution of present investigation was identify that estrogen receptor-β is involved in the anxiolytic-like effect produced by phytoestrogen genistein in rats with a long-term absence of ovarian hormones;supporting the hypothesis that estrogen receptor-β participates in the regulation of anxiety associated with low concentration of ovarian hormones and in the anxiolytic-like effects produced by natural estrogenic compounds such as phytoestrogens.

骨碎补总黄酮对亚硝酸钠模型小鼠学习记忆能力的改善作用

目的:研究骨碎补总黄酮对亚硝酸钠模型小鼠学习记忆障碍的改善作用。方法:昆明雄性小鼠随机分为空白组、亚硝酸钠模型组100 mg/(kg·d)、抗脑衰胶囊组585 mg/(kg·d)、骨碎补总黄酮97.5 mg/(kg·d)、骨碎补总黄酮组+ER阻断剂组97.5 mg/(kg·d)+0.072 mg/(kg·d)。观察小鼠的学习记忆能力,HE染色观察海马病理形态;Western blot法观察海马区淀粉样蛋白前体蛋白(amyloid precursor protein,APP)、淀粉样前体蛋白β-分泌酶(amyloid precursor proteinβ-secretory enzyme,BACE1)、过度磷酸化tau蛋白(over-phosphorylated tau protein,P-Tau^(396))和细胞周期素依赖蛋白激酶5(cyclin-dependent protein kinase 5,CDK5)蛋白含量。结果:模型组学习行为能力降低,海马区颗粒细胞明显坏死,海马区APP、BACE1、P-Tau^(396)和CDK5表达水平升高(P<0.01)。骨碎补总黄酮能够改善模型小鼠的行为学表现,降低APP、BACE1、P-Tau^(396)和CDK5的表达(P<0.01)。ER阻断剂能够反转骨碎补总黄酮在以上指标蛋白中的作用。结论:骨碎补总黄酮对亚硝酸钠模型小鼠学习记忆能力具有改善作用,此效应与调节APP代谢途径相关蛋白的影响相关。

Vitamin D-Binding Protein is Involved in the Pathogenesis of Preeclampsia by Inhibiting the Tyrosine Phosphorylation of Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells

Objective::The role of Vitamin D-binding protein(DBP)in preeclampsia(PE)pathogenesis is unknown.In this study,we compared the expression of DBP in the placentas of PE patients with the placentas of normotensive pregnant women with placenta previa controls,and aimed to explore the effect of DBP on endothelial cells(ECs)and the underlying mechanism.Methods::DBP expression in placental tissues collected from PE patients and controls was evaluated by immunohistochemistry.The downregulation and upregulation of DBP expression in HTR-8/SVneo cells were examined using DBP-targeting small interfering RNA(siRNA)and DBP-expression vector,respectively.The conditioned media of these DBP-overexpressing and DBP-siRNA HTR-8/SVneo cells were collected and added to human umbilical vein EC(HUVEC)cultures.Angiogenic effects on HUVECs were assessed by tube formation assays,and the proliferation and migration of HUVECs were examined using the Real-Time Cell Analyzer.The expression of vascular endothelial growth factor(VEGF)and VEGF receptor(VEGFR)-2,as well as the phosphorylation of different residues of VEGFR-2 in HUVECs,were determined by western blotting.Results::DBP expression was significantly increased in the placental tissues collected from PE patients.The conditioned medium of DBP-overexpressing HTR-8/SVneo cells potently inhibited tube formation by HUVECs,in addition to their proliferation and migration.Furthermore,treatment of HUVECs with the conditioned medium of DBP-overexpressing HTR-8/SVneo cells decreased the phosphorylation of VEGFR-2 at tyrosine 996,whereas the treatment of these cells with the conditioned medium of DBP-siRNA HTR-8/SVneo cells increased the phosphorylation of VEGFR-2 at tyrosine 951,996,and 1,175.Conclusions::The expression of DBP is increased in the placentas of PE patients.DBP plays potential roles in endothelial dysfunction,which contributes to PE development,by inhibiting tyrosine phosphorylation of VEGFR-2 in ECs.

雌激素介导的HSP27在动脉粥样硬化中作用的研究进展

热休克蛋白27(HSP27)是人体内一种在应激状态下大量表达的蛋白,其对机体一系列生理、病理过程有着重要作用。近年研究表明,雌激素通过多种途径调控HSP27的表达对动脉起到了完美的"三重保护"作用。血管内皮损伤早期雌激素通过PI3K/Akt信号通路诱导HSP27磷酸化,磷酸化的HSP27则通过抗氧化、调控凋亡通路、抑制细胞色素C(cyt-C)等作用,抵抗血管内皮细胞(VECs)凋亡;泡沫细胞形成期,雌激素通过刺激雌激素受体β(ERβ)诱导巨噬细胞表达和释放HSP27,后者则与巨噬细胞表面的清道夫受体A(SR-A)结合,阻止低密度脂蛋白(LDL)的摄取和促炎因子的释放;血管平滑肌细胞(VSMCs)增殖、迁移期,雌激素诱导雌激素受体α(ERα)与蛋白磷酸酶2(PP2A)形成复合物,增强PP2A的活性,引起下游HSP27脱磷酸,抑制VSMCs增殖、迁移。综上,雌激素抗动脉粥样硬化(atherosclerosis,AS)作用与HSP27密切相关,而雌激素替代疗法(MHT)防治绝经女性心血管疾病的副作用不容小觑,故借鉴雌激素的调控机制,研发药物调控HSP27对防治AS有着重要意义。

雌激素对AD模型大鼠脑内P-Tau、ChAT和神经生长因子蛋白表达的影响、

目的探讨雌激素治疗阿尔茨海默病(AD)动物模型后脑组织中磷酸化Tau(P-Tau)、乙酰胆碱转移酶(ChAT)和神经生长因子(NGF)蛋白的变化。方法大鼠右侧脑室注射Aβ1-42蛋白片段制作AD模型,2周后颈部皮下植入17β-雌二醇片剂30d。HE染色观察大鼠脑组织神经元的病理改变,免疫组化法观察P-Tau、ChAT和NGF蛋白的表达变化。结果 AD组大鼠脑组织出现神经纤维缠结,雌激素治疗组比AD组明显减少;治疗组磷酸化Tau蛋白表达比模型组明显减少(P<0.01),ChAT和NGF蛋白的表达比模型组明显增多(P<0.01)。结论雌激素能够上调NGF和ChAT蛋白的表达及抑制tau蛋白的异常磷酸化,对AD模型大鼠有明显的治疗作用。

表皮生长因子促进子宫内膜腺癌细胞系Ishikawa增殖

目的研究表皮生长因子(EGF)对子宫内膜腺癌细胞系Ishikawa增殖的影响,并探讨雌激素受体α(ERα)和Ack1在其调控机制中的作用。方法无雌激素环境下,EGF作用于Ishikawa细胞,CCK-8法检测子宫内膜腺癌细胞增殖;Western blot检测细胞ERα及Ack1磷酸化;用酪氨酸激酶抑制剂达沙替尼处理细胞后,检测Ishikawa细胞增殖和ERα及Ack1磷酸化状态。结果 EGF可增强Ishikawa细胞增殖(P<0.05),并促进ERαTyr-537特异位点磷酸化和Ack1磷酸化;用达沙替尼后,细胞增殖能力下降(P<0.05),ERαTyr-537特异位点磷酸化和Ack1磷酸化水平下调。结论 EGF促进Ishikawa细胞增殖,其机制可能与诱导ERαTyr-537特异位点磷酸化和激活Ack1激酶通路有关。

王不留行对奶牛乳腺上皮细胞磷酸化雌激素受体的影响

通过研究王不留行对奶牛乳腺上皮细胞中磷酸化ERα的影响揭示王不留行促进乳腺泌乳的分子机制。应用Western blot和实时荧光RT-PCR检测P-ERα的变化;免疫荧光观察P-ERα定位表达变化。结果表明,中药王不留行增乳活性成分可通过调控奶牛乳腺上皮细胞雌激素信号转导途径中P-ERα的表达来增强其泌乳功能,但详细机制尚需进一步研究。

雌激素受体β与磷酸化细胞外信号调控蛋白激酶1、2在卵巢癌中的表达及其临床意义

目的:探讨上皮性卵巢癌组织中雌激素受体β(ERβ)与磷酸化细胞外信号调控蛋白激酶1、2(p-ERK1/2)的表达及其与临床病理参数的关系。方法:选取2010年10月至2011年12月青岛大学医学院附属医院经病理证实的上皮性卵巢癌组织标本70例,卵巢良性肿瘤24例,正常卵巢组织24例。采用RT-PCR和免疫组织化学SP法检测上述组织中ERβ和p-ERK1/2的表达。结果:(1)卵巢癌组织中ERβmRNA相对表达水平(0.3764±0.9826)显著低于卵巢良性肿瘤(0.4900±0.3742)及正常卵巢组织(0.4980±0.0434)(P<0.05)。卵巢癌组织中ERβ表达与组织学分型、细胞学分级及淋巴转移有关(P<0.05);ERβ蛋白阳性表达率及其与临床病理特征关系与ERβmRNA一致;(2)ERK1/2 mRNA相对表达水平(0.6007±0.1554、0.6951±1.3694)显著高于卵巢良性肿瘤(0.3575±0.0479、0.5125±0.0411)及正常卵巢组织(0.3027±0.1024、0.5431±0.0811)(P<0.05);ERK1/2表达与细胞学分级、临床分期及腹水有关(P<0.05);p-ERK1/2蛋白阳性表达率及其与临床病理特征与p-ERK1/2 mRNA一致。ERβ蛋白与p-ERK1/2蛋白表达呈负相关(r=-0.282,P<0.05)。结论:ERβ低表达和p-ERK1/2高表达于卵巢癌组织,可能在卵巢癌的发生、发展中有重要作用。

不同时期阿尔茨海默病小鼠脑中GnRH表达的变化

目的:观察不同时期阿尔茨海默病(AD)小鼠脑中促性腺激素释放激素(GnRH)表达的变化,探讨其与AD的内在关系。方法:140只昆明鼠随机分为对照组和AD模型组,每组又按取样时间不同分为0、15、30、45、60、75和90d七个亚组,每亚组10只。采用D-半乳糖联合氯化铝构建AD小鼠模型,跳台实验观察各组小鼠认知功能;Westernblot法测定海马苏氨酸231位点磷酸化tau蛋白(Tau-pThr231)水平;ELISA法测定血清中雌二醇(E2)水平;免疫组化观察脑组织中GnRH的表达。结果:AD模型组45、60、75、90d小鼠的认知功能减退,Tau-pThr231表达增高(P<0.05),其中60、75、90d的AD模型组小鼠GnRH水平低于对照组(P<0.01),90d的AD模型组小鼠E2水平低于对照组(P<0.05)。结论:GnRH表达与AD的严重程度正相关,GnRH表达减少可能是比雌激素更早影响AD发病的因素。

肝组织内性甾体激素受体与慢性乙型肝炎病毒复制及其抗原表达的相关性

目的探讨肝组织内雄激素受体(AR)和雌激素受体-α(ERα)含量对慢性乙型肝炎(CHB)患者血清HBV DNA载量、HBsAg水平和肝组织内HBsAg、HBcAg表达水平影响。方法 135例经肝活组织检查的CHB患者入选本研究,其中HBeAg阳性80例,HBeAg阴性55例。肝组织内AR mRNA和ERαmRNA采用反转录定量PCR检测。结果HBeAg阳性患者,血清HBV DNA载量与肝组织内AR mRNA和ERαmRNA含量均无显著相关性(r=0.132,P=0.241和r=0.130,P=0.249),血清HBsAg水平与肝组织内AR mRNA和ERαmRNA含量均呈显著正相关(r=0.355,P=0.001和r=0.246,P=0.028);肝组织内HBcAg表达水平与肝组织内AR mRNA和ERαmRNA含量均呈显著正相关(rs=0.438,P=0.000和rs=0.352,P=0.002),肝组织内HBsAg表达水平与肝组织内AR mRNA和ERαmRNA含量无显著相关性(rs=0.112,P=0.333和rs=0.024,P=0.836)。HBeAg阴性患者,血清HBV DNA载量与肝组织内AR mRNA和ERαmRNA含量均无显著相关性(r=-0.256,P=0.061和r=-0.121,P=0.385),血清HBsAg水平与肝组织内AR mRNA和ERαmRNA含量均无显著相关性(r=0.130,P=0.348和r=0.165,P=0.234);肝组织内HBcAg表达水平与肝组织内AR mRNA和ERαmRNA含量均无显著相关性(rs=-0.053,P=0.701和rs=-0.203,P=0.137),肝组织内HBsAg表达水平与肝组织内AR mRNA和ERαmRNA含量无显著相关性(rs=0.159,P=0.247和rs=0.192,P=0.160)。多因素方差分析和有序Logistic回归分析的结果显示,肝组织内AR mRNA为影响HBeAg阳性患者血清HBsAg水平和肝组织内HBcAg表达水平的独立因素。结论肝组织内AR表达水平是影响CHB患者HBV抗原表达的一个独立因素。

p-Ser^(118)-ERα在乳腺癌组织中的表达及其意义

目的研究乳腺癌组织中丝氨酸118磷酸化的雌激素受体α(p-Ser118-ERα)的表达情况、与ERα、PR表达的关系及临床价值。方法应用免疫组织化学的方法,检测5年前治疗的70例原发性乳腺癌组织中p-Ser118-ERα、ERα、PR的表达情况,进行相关分析,并用Kaplan-Meier法分析其与三苯氧胺(TAM)疗效的关系。结果70例ERα阳性的乳腺癌组织标本中,p-Ser118-ERα的表达与ERα的表达正相关(r=0.348P=0.003),p-Ser118-ERα的表达与PR的表达正相关(r=0.241P=0.044)。p-Ser118-ERα阳性患者的无病生存率高于阴性患者(P=0.013);PR阳性的患者中,p-Ser118-ERα阳性的患者的无病生存率高于阴性的患者(P=0.021)。结论p-Ser118-ERα联合PR检测有可能为三苯氧胺疗效的评价提供一个更精确的生物指标。

雌激素对SH-SY5Y细胞tau蛋白磷酸化的影响

目的研究雌激素对冈田酸诱导的人神经母细胞瘤系(SH-SY5Y)细胞tau蛋白磷酸化的影响。方法四甲基偶氮唑盐观察冈田酸对SH-SY5Y细胞活力的影响,模拟AD时tau蛋白过度磷酸化细胞模型;Western blot检测冈田酸及雌激素对Thr231 tau蛋白磷酸化的影响。结果四甲基偶氮唑盐结果表明,当冈田酸浓度>40 nmol/L时,细胞活力受到明显抑制,<40 nmol/L的冈田酸对细胞活力没有明显的影响;Western blot结果表明,SH-SY5Y细胞经冈田酸处理后,tau蛋白磷酸化的水平明显增加,这种作用可被雌激素所抑制。结论雌激素抑制了冈田酸诱导的SH-SY5Y细胞的tau蛋白磷酸化水平。

雌激素受体α磷酸化位点突变体T224A和S559A的构建及其转录激活活性检测

目的:构建雌激素受体α(ERα)T224A和S559A磷酸化位点突变体载体,在HEK293T细胞中检测其表达及突变体生物活性的改变。方法:以pc DNA3-Flag-ERα为模板,通过重组PCR技术扩增目的基因片段并突变碱基,插入pc DNA3-Flag载体;将构建的质粒转染HEK293T细胞进行瞬时表达,通过Western印迹检测融合蛋白的表达,采用萤光素酶报告基因方法检测ERα突变体的活性改变。结果:T224A和S559A磷酸化位点突变体在HEK293T细胞中得到表达,相对分子质量为66×103。在无雌激素(E2)时,野生型ERα及T224A和S559A突变体的转录活性分别为空载体的1.94、1.49和1.84倍;在雌激素存在时,野生型ERα活性增强了1.57倍,T224A和S559A突变体活性分别增强了0.54和0.61倍。结论:224位Thr磷酸化修饰对ERα的活性起重要作用,且2个磷酸化位点突变体受雌激素调控减弱。

磷酸化P53与ERα在乳头状甲状腺癌中的相关性研究

目的探讨磷酸化P53[p-P53(Ser 6)]与雌激素受体(ER)α在乳头状甲状腺癌(PTC)中的表达及其相关性。方法应用免疫组织化学Elivision plus二步法检测p-P53(Ser 6)、突变P53(mut-p53)、ERα在34例生育期女性乳头状甲状腺癌组织石蜡切片中的表达,并进一步分析p-P53(Ser 6)与ERα表达的相关性。结果生育期女性的PTC组织中均有p-P53(Ser 6)的的表达,阳性率为100%,表现为细胞核或细胞核/质阳性染色,其表达与mut-P53的检测结果有明显不同。生育期女性PTC组织中p-P53(Ser6)的表达水平与ERα呈显著正相关(r=0.334,P=0.053),而mut-P53的表达水平与ERα表达无相关(r=-0.078,P=0.661)。结论 p-P53(Ser6)与ERα的表达呈显著正相关,提示P53磷酸化可能参与促进了生育期女性PTC的发生、发展。

雌激素受体β与女性阿尔茨海默病的关系

阿尔茨海默病(Alzheimer*s Disease,AD)是常见的神经系统变性疾病,以进行性认知功能障碍和行为损害为特征⑴。其主要病理特征为0淀粉样蛋白(amyloid p,Ap)异常沉积和神经原纤维缠结、海马锥体细胞颗粒空泡变性及神经元缺失⑵。

雌激素受体α介导氧化磷酸化通路在肺癌发生中的作用

目的:通过生物信息学方法探讨雌激素受体α(ESRRA)在肺癌发生发展中的作用。方法:利用UALCAN在线平台对人肺癌组织(包括肺腺癌与肺鳞癌)和癌旁正常肺组织中ESRRA基因的表达变化进行分析,并利用Kaplan-Meier Plotter数据库对肺癌中ESRRA及其相关基因的表达进行生存分析。利用GEPIA2在线平台获得与ESRRA表达模式相似的前50个基因,在GeneMANIA在线平台上构建这50个基因编码的蛋白质-蛋白质的相互作用网络,并通过DAVID数据库对该50个基因群进行GO分析和KEGG通路富集。通过TIMER 2.0在线平台分析肺癌组织中ESRRA与富集在氧化磷酸化通路中核心基因表达水平的相关性。利用Western blot法验证ESRRA蛋白在肺癌细胞系中的表达水平。结果:与癌旁正常肺组织相比,ESRRA在肺癌组织中高表达(P<0.01),ESRRA表达水平高的肺癌患者显示出较差的预后(P<0.01)。与ESRRA表达模式相似的前50个基因主要富集在氧化磷酸化通路,包括ATP5B、ATP5G3、COX5A、COX8A、SDHD、UQCRC1和UQCRC2。其中ATP5B、COX8A和UQCRC1在肺癌组织中的表达水平与ESRRA的表达呈正相关(P<0.05)。ATP5B、ATP5G3、COX5A、COX8A、SDHD、UQCRC1和UQCRC2在肺癌组织中均高表达,ATP5B、ATP5G3、COX5A、COX8A表达水平高和SDHD表达水平低的肺癌患者均显示出较差的预后(P<0.01)。Western blot验证结果显示,与正常人支气管上皮16HBE细胞相比,ESRRA蛋白的相对表达水平在肺腺癌NCI-H1975细胞和肺鳞癌SW900细胞中均高表达(P<0.01)。结论:ESRRA介导氧化磷酸化通路中ATP5B和COX8A的表达改变引起能量代谢紊乱可能是其促进肺癌发生和导致肺癌不良预后的原因之一。

Cadmium-induced neurotoxicity: still much ado

Cadmium（Cd） is a highly toxic heavy metal that accumulates in living system and as such is currently one of the most important occupational and environmental pollutants. Cd reaches into the environment by anthropogenic mobilization and it is absorbed from tobacco consumption or ingestion of contaminated substances. Its extremely long biological half-life（approximately 20-30 years in humans） and low rate of excretion from the body cause cadmium storage predominantly in soft tissues（primarily, liver and kidneys） with a diversity of toxic effects such as nephrotoxicity, hepatotoxicity, endocrine and reproductive toxicities. Moreover, a Cd-dependent neurotoxicity has been also related to neurodegenerative diseases such as Alzheimer＇s and Parkinson＇s diseases, amyotrophic lateral sclerosis, and multiple sclerosis. At the cellular level, Cd affects cell proliferation, differentiation, apoptosis and other cellular activities. Among all these mechanisms, the Cd-dependent interference in DNA repair mechanisms as well as the generation of reactive oxygen species, seem to be the most important causes of its cellular toxicity. Nevertheless, there is still much to find out about its mechanisms of action and ways to reduce health risks. This article gives a brief review of the relevant mechanisms that it would be worth investigating in order to deep inside cadmium toxicity.