A case-control study of polymorphisms in xenobiotic and arsenic metabolism genes and arsenic-related bladder cancer in New Hampshire

Arsenic is associated with bladder cancer risk even at low exposure levels. Genetic variation in enzymes involved in xenobiotic and arsenic metabolism may modulate individual susceptibility to arsenic-related bladder cancer. Through a population-based case-control study in NH (832 cases and 1191 controls), we investigated gene-environment interactions between arsenic metabolic gene polymorphisms and arsenic exposure in relation to bladder cancer risk. Toenail arsenic concentrations were used to classify subjects into low and high exposure groups. Single nucleotide polymorphisms (SNPs) in GSTP1, GSTO2, GSTZ1, AQP3, AS3MT and the deletion status of GSTM1 and GSTT1 were determined. We found evidence of genotype-arsenic interactions in the high exposure group; GSTP1 Ile105Val homozygous individuals had an odds ratio (OR) of 5.4 [95% confidence interval (CI): 1.5–20.2; P for interaction = 0.03] and AQP3 Phe130Phe carriers had an OR = 2.2 (95% CI: 0.8–6.1; P for interaction = 0.10). Bladder cancer risk overall was associated with GSTO2 Asn142Asp (homozygous; OR = 1.4; 95% CI: 1.0–1.9; P for trend = 0.06) and GSTZ1 Glu32Lys (homozygous; OR = 1.3; 95% CI: 0.9–1.8; P for trend = 0.06). Our findings suggest that susceptibility to bladder cancer may relate to variation in genes involved in arsenic metabolism and oxidative stress response and potential gene-environment interactions requiring confirmation in other populations.     

清肺化痰胶囊对慢性阻塞性肺疾病大鼠气道上皮水通道蛋白-5表达的实验研究

[目的] 通过用清肺化痰胶囊治疗慢性阻塞性肺疾病(COPD)大鼠探讨其对大鼠气道上皮水通道蛋白-5(AQP-5)表达的影响进而探讨中药治疗COPD的作用机制。[方法] 36只雄性Wistar成年大鼠随机分为模型组、空白组、清肺化痰组、氨溴索组、痰热清组、红霉素组。造模并干预后, 免疫组化及图像分析法观察并测定各组AQP-5水平, 酶联免疫吸附测定法(ELISA法)测定各组肺组织匀浆中性粒细胞弹性蛋白酶(NE)水平。[结果] 肺细支气管上皮细胞AQP-5蛋白面积百分比、积分光密度、肺组织匀浆NE水平模型组明显低于清肺化痰组、沐舒坦组、红霉素组、痰热清组和空白组(P<0.05);清肺化痰组与空白组比较差异无统计学意义(P>0.05).[结论] 清肺化痰胶囊能降低NE的含量, 调节AQP-5的表达, 调节黏蛋白分泌, 从而改善黏液高分泌状态, 起到缓解COPD临床症状、促进排痰、提高生活质量的目的。     

Immunohistochemical Localization of the Water Channels AQP4 and AQP5 in the Rat Pituitary Gland

The pituitary gland is composed of the adenohypophysis and neurohypophysis. The adenohypophysis contains endocrine cells, folliculo-stellate (FS) cells, and marginal layer cells, whereas the neurohypophysis mainly comprises axons and pituicytes. To understand the molecular nature of water transfer in the pituitary gland, we examined the immunohistochemical localization of the membrane water channels aquaporin-4 (AQP4) and AQP5 in rat tissue. Double immunofluorescence analysis of AQP4 and S100 protein, a known marker for FS cells, marginal layer cells, and pituicytes, clearly revealed that FS cells and marginal layer cells in the adenohypophysis and the pituicytes in pars nervosa are positive for AQP4. AQP5 was found to be localized at the apical membrane in some marginal layer cells surrounding the Rathke's residual pouch, in which AQP4 was observed to be localized on the basolateral membranes. These results suggest the following possibilities: 1) FS cells especially require water for their functions and 2) transepithelial water transfer could occur between the lumen of Rathke's residual pouch and the interstitial fluid in the adenohypophysis through the AQP4 and AQP5 channels in the marginal layer cells.     

纳络酮预处理对脑出血大鼠脑组织水通道蛋白4及基质金属蛋白酶9表达的影响

目的 探讨纳络酮预处理对脑出血大鼠的保护效应及相关作用机制.方法 将30只雄性Sprague-Dawley大鼠(体质量280～350 g)按随机数字表法随机分为假手术对照组(Sham组)、脑出血(intracerebral hemorrhage,ICH)组和纳络酮预处理(Naloxone preconditioning,NP)组,每组10只大鼠.复制上述动物模型之前,NP组大鼠预先给予盐酸纳络酮(2.0 mg/kg),ICH组给予相同体积的生理盐水,随后制备ICH模型.切取并收集大鼠脑出血灶周围脑组织,分别采用RT-PCR和Western blot检测大鼠病变脑组织中水通道蛋白(aquaporin protein 4,AQP4)在转录水平和蛋白水平上的变化情况;同时采用免疫组织化学检测大鼠病变脑组织中基质金属蛋白酶(matrix metalloproteinase 9,MMP-9)的阳性表达情况.结果 相对于Sham组,ICH组大鼠脑组织中含水量明显增加(P<0.05),而经过纳络酮预处理后,大鼠脑组织中含水量明显减少(P<0.05);相对于ICH组,NP可有效降低脑出血大鼠脑组织中AQP4 mRNA和蛋白水平(P<0.01);同时,NP组大鼠脑组织中MMP-9阳性表达率明显下调(P<0.01).结论 纳络酮作为脑出血的一种有效的保护措施,其具体作用机制可能与其降低脑组织中AQP4的表达,从而减少脑水肿的发生及下调的MMP-9水平密切相关.     

糖性白内障渗透性膨胀期相关机制的研究进展

晶状体具有良好的透光性与适度的折光性,是一个近乎完美的视觉器官。它来源于表皮外胚叶,由外向内依次为晶状体囊、晶状体上皮、皮质及核,其中晶状体上皮细胞是整个晶状体的生命中枢,不仅分泌Ⅳ型胶原形成外层晶状体囊,并在赤道部衍化为纤维细胞,构成皮质与核;而且提供了晶状体代谢所需的全部能量。在长期高糖环境下,醛糖还原酶被激活,造成大量高渗性物质——山梨醇在细胞内堆积,引起皮质高度吸水膨胀;近年来还发现p糖-蛋白、细胞容积型氯离子通道和水通道蛋白也参与了糖性白内障渗透性膨胀期的发生发展。     

Water entry into astrocytes during brain edema formation

The process of brain edema formation has been studied extensively at the macroscopic level. In contrast, little is known about water fluxes and volume changes at the cellular level in the initial phase of brain edema. Insight in these "microscopic" events could pave the way for more efficient prevention and therapy. Here, we report measurements of brain cell volume responses recorded in vivo in a model of systemic hyponatremia. Transgenic mice expressing fluorescent proteins in astrocytes were subjected to hypo-osmotic stress and two photon laser scanning microscopy. Volume measurements of glial cells in the cerebellum and the visual cortex indicate that individual astrocytes undergo a position-dependent increase in cell volume by a factor of two or more during edema formation. Our data are the first to show that volume changes can be monitored at the cellular level in vivo and demonstrate that astrocytes are sites of water entry in the initial phase of brain edema formation. The uptake of water in astrocytes is likely to reflect the strong expression of aquaporin-4 in these cells.     

乙酰唑胺对表达水孔蛋白1的非洲爪蟾卵母细胞转运水功能的影响

目的观察乙酰唑胺对水孔蛋白1(AQP1)水转运功能的影响。方法将AQP1 cRNA 10 ng注射入非洲爪蟾卵母细胞,观察并记录给予1×10^-7～1×10^-5 mol·L^-1乙酰唑胺后卵母细胞在低渗溶液中的膨胀率,并计算其渗透水通透性(Pf)的变化。结果非洲爪蟾卵母细胞表达AQP1蛋白后,在低渗溶液中迅速膨胀,Pf值显著增加至1.82×10^-2 cm·s^-1,而注射水的阴性对照仅为0.25×10^-2 cm·s^-1。AQP抑制剂HgCl₂使Pf值降至0.64×10^-2 cm·s^-1;1×10^-7～1×10^-5 mol·L^-1乙酰唑胺处理后,Pf值分别降至1.43,1.24和0.93×10^-2 cm·s^-1。结论乙酰唑胺剂量依赖性地降低AQP1介导的渗透水通透性,抑制AQP1转运水的功能。