Bivariate genome-wide association study suggests fatty acid desaturase genes and cadherin DCHS2 for variation of both compressive strength index and appendicular lean mass in males

Compressive strength index (CSI) is a newly established index for predicting hip fracture, the most serious consequence of osteoporosis. Appendicular lean mass (ALM), which influences skeletal strength of the lower limbs, is another trait associated with the risk of hip fracture. In this study, we performed a bivariate genome-wide association study (GWAS) to identify new candidate genes responsible for both CSI and ALM. In our discovery sample of 1627 unrelated Chinese subjects (802 males and 825 females), we scanned 909,509 SNPs using the Affymetrix Human Genome SNP 6.0 genotyping array. We successfully replicated our results in a sample of 2286 Caucasian subjects (558 males and 1728 females). The results indicated that five SNPs (rs174583, rs174577, rs174549, rs174548, rs7672337) in the FADS1, FADS2, and DCHS2 genes had significant bivariate associations with CSI and ALM in male subjects for both the GWAS discovery (with P < 8.42 × 10^? 6) and the Caucasian sample (with P < 0.07). We performed further replication analysis in a 2nd Caucasian sample with 501 Caucasian male subjects, using Affymetrix 500 k arrays, and found that two of the above SNPs (rs174548 and rs174549, P = 0.07) had bivariate associations with both CSI and ALM in males; the other 3 SNPs were not typed with the 500 k array. The above findings suggest that the 3 genes, FADS1, FADS2, and DCHS2, containing these SNPs might play dual roles influencing both CSI and ALM in males. Our findings provide new insights into our understanding of the genetic basis of bone metabolism and the pathogenesis of osteoporosis.     

microRNAs调控消化系肿瘤多药耐药的研究进展

肿瘤多药耐药(multidrug resistance,MDR)是影响化疗效果的最大障碍,尤其是消化系肿瘤发生耐药的现象最为突出.因此,如何逆转MDR已经成为抗肿瘤研究的热点问题.近年来,有关研究发现微小RNA(microRNAs)与多种肿瘤耐药的发生密切相关.microRNAs是一类内源性非编码RNA分子,通过降解mRNA或抑制mRNA翻译的方式调控着众多基因的表达.本综述重点阐述了microRNAs的生物学特性,与胃癌、肠癌、肝癌、胆管癌及胰腺癌等消化系肿瘤MDR的关系及其潜在的信号调控通路,以期为消化系肿瘤耐药的预防和靶向治疗提供新的思路和手段.     

Down-regulation of GFRalpha-1 expression by antisense oligodeoxynucleotide aggravates thermal hyperalgesia in a rat model of neuropathic pain

Glial cell line-derived neurotrophic factor (GDNF) has been hypothesized to play an important role in the modulation of nociceptive signals especially during neuropathic pain. The present study examined the expression of GDNF and GFRalpha-1 (the high-affinity receptor of GDNF) in dorsal root ganglions (DRG) in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. In order to address the role of GDNF and GFRalpha-1 in neuropathic pain, antisense oligodeoxynucleotide (ODN) specifically against GFRalpha-1 was intrathecally administered to result in down-regulation of GFRalpha-1 expression. The results showed that both the protein and mRNA levels of GDNF and GFRalpha-1 were significantly increased after CCI, while the thermal hyperalgesia of neuropathic pain rats could be significantly aggravated by antisense ODN treatment, but not by normal saline (NS) or mismatch ODN treatment. The present study demonstrated that endogenous GDNF and GFRalpha-1 might play an anti-hyperalgesic role in neuropathic pain of rats. In addition, we found a down-regulation of somatostatin (SOM) in DRG and spinal dorsal horn after expression of GFRalpha-1 was knocked down, which suggested the possible relationship between the anti-hyperalgesic effect of GDNF and GFRalpha-1 on neuropathic pain and endogenous SOM.     

Sucrose preference is restored by electro-acupuncture combined with chlorimipramine in the depression-model rats

The present study was to investigate the effect of electroacupuncture (EA) combined with chlorimipramine on the sucrose preference of depressive rats induced by chronic mild stress (CMS). Rats were exposed chronically (1st - 4th week) to a variety of mild unpredictable stresses. The tricyclic antidepressant chlorimipramine and EA were administrated on these depressive rats for 6 weeks (5th - 11th week). EA was applied at points of "Bai-Hui" (Du 20) and "An-Mian" (EX 17) (right side), by EA apparatus (Model 6805-2, Shanghai). Dense (60Hz/5sec)-sparse (4Hz/2.5sec) frequency of the wave was selected and the current intensity (< or = 1mA) was adjusted to provoke slight twitches of the rat's ear. The preference for 1% sucrose solution and the immobility time in the forced swimming test were measured as the symptoms of anhedonia and depressed mood, which were central features of major depression. The preference for 1% sucrose solution was reduced by CMS, but could be restored to normal level after 6 weeks treatment with chlorimipramine at 5mg/kg or EA combined with chlorimipramine at 2.5mg/kg. In the forced swimming test, the immobility time of depressive rats was decreased in both groups. However, the preference for sucrose and the immobility time in the depressive rats were not significantly changed by the treatment with only EA or chlorimipramine at 2.5 mg/kg. The results suggested that EA could potentiate the antidepressant effect of chlorimipramine in low dose, and EA combined with antidepressant might be a better method in treating depression.     

哮喘小鼠CD4~+CD25~+Foxp3~+调节T细胞和Foxp3蛋白的变化及淫羊藿苷干预作用

目的:研究哮喘小鼠CD4+CD25+Foxp3+调节T(Treg)细胞和Foxp3蛋白的变化,探讨淫羊藿苷对哮喘干预机制。方法:将BALB/c小鼠32只随机分为正常对照组、哮喘模型组、淫羊藿苷组、地塞米松阳性对照组,每组8只。哮喘模型制备用卵白蛋白(OVA)致敏大鼠并雾化吸入刺激,治疗组采用相应药物灌胃给药,对照组用等量生理盐水代替。最后一次激发24小时后,采用Buxco肺功能仪有创法检测小鼠气道反应性;HE染色评价观察小鼠肺组织病理形态学改变;流式细胞术检测脾脏CD4+CD25+Foxp3+Treg细胞比例及Foxp3蛋白表达量;免疫印迹法测定肺组织Foxp3蛋白表达量;ELISA法测定血清及肺泡灌洗液(BALF)IL-10水平。结果:与正常对照组比较:模型组气道阻力及气道炎症指数显著增加(P<0.05);脾Treg细胞比例无明显变化(P>0.05);脾Foxp3蛋白表达显著下降(P<0.05),肺组织Foxp3蛋白表达显著升高(P<0.05),外周血IL-10水平显著下降(P<0.05),BALF中IL-10无显著差异(P>0.05);与模型组比较:淫羊藿苷组气道阻力和气道炎症明显减轻(P<0.05);脾Treg细胞比例和脾Foxp3蛋白表达水平无显著变化(P>0.05),但淫羊藿苷可进一步上调哮喘小鼠肺组织Foxp3蛋白表达量(P<0.05),并增加外周血IL-10水平(P<0.05)。结论:哮喘小鼠脾脏CD4+CD25+Foxp3+Treg细胞Foxp3蛋白表达水平下降,淫羊藿苷可显著改善哮喘小鼠气道炎症和气道高反应,可能与其上调肺组织Foxp3蛋白表达和增加外周血IL-10水平相关。     

去甲斑蝥素诱导人鼻咽癌细胞CNE1凋亡的实验研究

目的检测去甲斑蝥素对人鼻咽癌细胞CNE1增殖、凋亡的影响,为临床应用NCTD治疗鼻咽癌细胞提供实验基础。方法体外常规培养CNE1细胞用于实验,经NCTD作用后,采用MTT比色法检测细胞增殖情况,流式细胞仪观察鼻咽癌细胞凋亡、细胞周期。结果 NCTD对鼻咽癌细胞的生长有明显的抑制作用,呈剂量依赖性,与对照组比较差异有统计学意义（P〈0.01）;NCTD可剂量和时间依赖性地诱导肿瘤细胞凋亡;NCTD可剂量依赖性地诱导肿瘤细胞周期发生改变,将鼻咽癌细胞阻滞在G2期。结论 NCTD对体外培养的CNE1细胞的生长有明显抑制作用和诱导凋亡的作用。