肾癌中VHL基因的研究进展

抑癌基因VHL(von Hippel-Lindau)的突变可导致VHL综合征。其所编码的蛋白产物——肿瘤抑制蛋白VHL(von Hippel-Lindau tumor suppressor protein,p VHL)可与多种底物特别是低氧诱导因子(hipoxia inducible factor,HIF)相互作用。p VHL在有氧状态下主要通过参与组成泛素连接酶复合体作用于HIF,从而介导其泛素化降解。VHL突变所致的HIF活化,导致肿瘤血管生成、肿瘤细胞增多,与肾细胞癌的发生、发展密切相关,可作为肾细胞癌潜在治疗靶点之一。     

VHL基因的研究进展及其在肾癌基因治疗中的应用

VHL基因是抑癌基因,定位于染色体3p25-26,其产物pVHL与Wnt-β-catenin信号通路、缺氧诱导因子、氧化磷酸化的调控有关。VHL基因的失活会导致VHL蛋白不能正常合成,这与散发性肾透明细胞癌的发生、发展有着密切的关系。VHL基因的失活机制主要包括基因突变,杂合性缺失和甲基化。通过对VHL基因失活机制的研究有助于筛选用于肾透明细胞癌早期诊断与预后的新分子标志物。目前利用VHL基因开展了肾癌基因治疗的试验探索。     

缺氧诱导因子与肾细胞癌关系的研究进展

缺氧诱导因子(hypoxia inducible factor,HIF)对维持肿瘤细胞的能量代谢、肿瘤血管生成、促进肿瘤细胞增殖和转移起着重要作用,是肿瘤细胞低氧条件下产生的关键信号分子。本综述旨在总结前人研究,阐述HIF与肾癌细胞之间的内在关系。HIF成员是参与肾癌细胞对缺氧应答反应中的关键因子,并通过靶基因的调节,促进新生血管的生成,导致肿瘤生长。其中,HIF-1α及HIF-2α在促进新生血管的生成方面发挥着主要作用。HIF-1α及HIF-2α与VEGF密切相关,随着其的表达增高,VEGF在数量上及m RNA水平上均显著增高,显示其可通过调控VEGF参与肾癌血管生成,而HIF-2α转录激活VEGF m RNA的特异性较HIF-1α更强。HIF-3α可能存在的负性调控作用,其异构体-4的作用可能与HIF-lα的负性调节有关,其可以阻止HIF-lα与下游靶基因的缺氧反应元件(hypoxia response elements,HRE)结合,同时可在转录水平抑制HIF-lα。HIF在未来可能有成为肾细胞癌治疗的靶点。     

VHL综合征遗传学研究

VHL综合征(von Hippel-Lindau syndrome,VHL;MIM 193300)是一种常染色体显性遗传的多系统肿瘤综合征,最常见临床表现是视网膜或中枢神经系统(central nervous system,CNS)血管母细胞瘤.CNS血管母细胞瘤和肾细胞癌(renal cell carcinoma,RCC)的并发症是VHL患者最主要的死因.VHL综合征主要因VHL基因(the vonHipple-Lindau gene,VHL)突变所致,细胞周期素D1基因(the cyclin D1 gene,CCND1)突变和蛋白异常也可能参与其发生.目前已建立了多个VHL基因缺陷动物模型.在此就VHL综合征的遗传学研究进展作一概述.     

一个在肝癌中表达下调的基因syap1的克隆和鉴定

肿瘤细胞区别于正常细胞的最基本特征是细胞生长失控和分化受阻。这种细胞生长失控和分化受阻是由于多种遗传性缺陷积累的结果,这主要表现在两个方面:一是癌基因的激活或过度表达,阻止细胞分化,促进细胞生长;另一方面是肿瘤抑制基因的失活。在肝癌研究中人们发现有多处染色体DNA发生缺失如染色体1p、4q、5q、6q、8p、10p、11p、13q、16q、17p和22q区域,提示这些区域可能存在肿瘤抑制基因。其中13q、17p和8p区域的肿瘤抑制     

hepaCAM和VEGF基因表达与肾透明细胞癌侵袭转移关系的探讨

研究肾癌细胞株786-0,RC-2及肾透明细胞癌组织中肝细胞黏附分子(hepatocyte cell adhesion molecule,hepaC-AM)和血管内皮生长因子(VEGF)mRNA表达及其与肾透明细胞癌侵袭转移的关系。应用逆转录聚合酶链反应(RT-PCR)检测786-0、RC-2、正常肾组织hepaCAM和VEGFmRNA表达,73例肾透明细胞癌组织及相应癌旁组织中hepaCAMmRNA表达,43例肾透明细胞癌组织及相应癌旁组织VEGFmRNA表达,并比较它们之间的差异性和相关性。与正常肾组织比较786-0,RC-2的hepaCAMmRNA显著降低(P0.05);VEGFmRNA显著升高(P0.05)。肾透明细胞癌组织hepaCAMmRNA显著低于癌旁组织(P0.05);VEGFmRNA显著高于癌旁组织(P0.05)。在肾透明细胞癌组织中临床Ⅰ+Ⅱ期和Ⅲ+Ⅳ期两组VEGFmRNA表达差异具有统计学意义(P0.05),hepaCAM与VEGFmRNA呈负相关(r=-0.329,P0.05)。提示hepaC-AM基因缺失可能参与肾透明细胞癌侵袭转移,其机制可能与调节VFGF表达改变有关,hepaCAM有望成为一种新的肾癌基因治疗的靶分子。     

缺氧诱导因子(HIFs)在肾癌发生中的作用及其分子机制

肾癌是一种常见的泌尿系统肿瘤,但在临床上对转移性肾癌的治疗手段还非常有限。缺氧是实体肿瘤微环境的一个重要的基本特征。近年来基于分子机制和临床研究的数据表明,低氧诱导因子(hypoxia-inducible factors, HIFs)在肾细胞癌(renal cell carcinoma, RCC)的发生发展中发挥着至关重要的作用。HIF是一类介导细胞适应低氧状况必需的转录激活因子,由α亚基和β亚基组成。研究已经证实,在RCC中HIF-1α和HIF-2α具有相反的作用,前者作为肿瘤抑制因子,而后者作为癌基因发挥功能。本文综述了HIF信号通路在RCC发生发展中的作用及其分子机制,并对靶向HIF信号通路治疗RCC的进行了探讨,以期指导临床肾细胞癌的精准化治疗和进一步的研究。     

细胞如何适应外界变化的氧环境——解读2019年诺贝尔生理学或医学奖

人的生命活动时刻离不开氧气,在低氧环境或者高氧环境中,机体不断对代谢过程进行调节,以适应环境。缺氧条件下,机体可产生促红细胞生成素(EPO),美国塞门扎教授发现了可对EPO基因转录进行调控的缺氧诱导因子(HIF)。但在正常氧气条件下,HIF1-α在细胞中几乎不存在,威廉·凯林发现了VHL蛋白通过给HIF-1α泛素化以调控其降解和代谢。凯林和拉特克利夫进而在HIF-1α的分子结构中发现了一个氧依赖性降解区(ODD),当氧气浓度较高时,这个部位可被VHL结合。有关此通路的研究临床价值极大,诺贝尔奖实至名归。     

免疫系统防御强,遇到缺氧HIF帮（英文）

缺氧诱导因子(hypoxia-inducible factor,HIF)是一类受氧调控的转录因子。其α亚基是氧敏感性亚基,包括HIF-1α、HIF-2α和HIF-3α,与β亚基形成异源二聚体,活化目标基因的表达以调节细胞对低氧的反应。HIF本身受到精细调节,包括转录组水平的调节,以及通过蛋白质翻译后修饰所进行的蛋白质水平的调节,以确保细胞对低氧压力产生适当反应。免疫应答常伴随局部组织的低氧状况,HIF是低氧环境中先天免疫和适应性免疫应答的重要调节因子。在天然免疫系统,HIF激活一系列与代谢相关的基因表达,调节中性粒细胞、巨噬细胞和树突状细胞的发育、极化和功能。对于适应性免疫,近年来的研究确立了HIF在CD4+T细胞分化和功能中的重要作用。本综述将重点讨论近年来有关HIF调节机制,及其在免疫细胞功能研究的进展。     

Von Hippel—Lindau（VHL）基因

Von Hippel-Lindau(VHL)病虽然发病率较低,但受影响的个体容易产生多种肿瘤,如眼部肿瘤,肾和脑肿瘤等,最近已发现了VHL基因,将其定位在染色体3p25区,很可能是一个新的肿瘤抑制基因,这将对VHL病或肿瘤的诊断和治疗都有重要意义。     

阿霉素肾病大鼠表皮生长因子及其受体的表达

目的研究阿霉素肾病大鼠肾组织中表皮生长因子(EGF)及其受体EGFR的表达分布以及表达量与尿蛋白之间关系。方法选择第5天、14天、28天作为动态观察的时点,同期设立正常对照。采用荧光定量RT-PCR、免疫组织化学及计算机图像定量分析EGF mRNA以及EGF、EGFR蛋白在肾组织的表达,同时测定24 h尿蛋白定量。WT1和EGFR双重免疫组化确定EGFR在肾小球内确切细胞定位。结果阿霉素注射后第5天,EGFmRNA即较正常增高,28 d明显增高并高于5 d和14 d。正常对照组EGF阳性细胞主要分布于远曲小管和髓袢,阿霉素组EGF还在集合管和近曲小管上表达;EGF阳性表达范围和强度随尿蛋白增加而增加;EGFmRNA表达量以及EGF在肾小管中的表达强度与24 h尿蛋白量呈正相关。肾小管上皮细胞广泛表达EGFR,阿霉素组EGFR在小管表达均高于正常,但组间各时点差异无显著性;随尿蛋白增加EGFR在肾小球内表达逐渐增多。EGFR在肾小球和肾小管中的表达强度均与24 h尿蛋白量呈正相关。WT1和EGFR双重免疫组化显示阿霉素肾病组EGFR可在足突细胞上表达,正常组则无。结论阿霉素肾病大鼠的肾小球脏层上皮有EGFR的表达。EGF/EGFR可能参与了阿霉素肾病的发病过程以及蛋白尿的形成。     

Role of N-glycans in growth factor signaling

Secreted proteins and membrane proteins are frequently post-translationally modified by oligosaccharides. Therefore, many glycoproteins are involved in signal transduction. One example is growth factor receptors, which are membrane proteins that often contain oligosaccharides. The oligosaccharides in those growth factor receptors play crucial roles in receptor functions. An analysis of glycosyltransferase-transfectants revealed that the branching structures of oligosaccharide also serve as important determinants. For example, N-glycans of epidermal growth factor receptor (EGFR) are involved in receptor sorting, ligand binding and dimerization. The addition of a bisecting GlcNAc to N-glycans increases the endocytosis of EGFR. N-glycans of Trk, a high affinity nerve growth factor receptor, also affect its function. Thus, oligosaccharides play an important role in growth factor signaling. Published in 2004. This revised version was published online in August 2006 with corrections to the Cover Date.     

神经营养因子NGF、BDNF与围绝经期妇女认知功能关系的研究进展

神经营养因子(NTFs)是近几年神经科学研究的热点,研究显示它在神经系统中发挥独特的作用,尤其是神经生长因子(NGF)、脑源性神经营养因子(BDNF)在脑内功能及其表达调控方面具有重要作用。围绝经期妇女随着雌激素水平的降低会产生认知功能的减退,有研究发现去卵巢动物(OVX)雌激素水平降低可以导致某些NGF、BDNF的丢失。通过启动内源性NGF和BDNF的表达而实现对神经元的保护可能为雌激素替代治疗(ERT)脑保护作用的一种机制。本文就近几年的研究进展做一简要综述。     

Effects of GDNF and LIF on mouse spermatogonial stem cells proliferation in vitro

Spermatogonial stem cells (SSCs) are the only type of cells that transmit genes to the subsequent generations. The proliferation, cultivation and identification of SSCs in vitro are critical to understanding of male infertility, genetic resources and conservation of endangered species. To investigate the effects of glial cell-derived neurotrophic factor (GDNF) and leukemia inhibitory factor (LIF) on the proliferation of mouse SSCs in vitro, supplement of GDNF and/or LIF were designed to culture SSCs. The testes of 6–8 d mouse were harvested and digested by two-step enzyme digestion method. The SSCs and Sertoli cells were separated by differential plating. Then the SSCs were identified by alkaline phosphatase staining, RT-PCR and indirect immunofluorescence cell analysis. The cellular proliferation capacity was measured by methyl thiazolyl tetrazolium assay. The results showed that addition of 20 and 40 ng/ml of GDNF could strongly promote growth of mouse SSCs (p < 0.05). There was no significant difference between LIF treatment groups and the control group in promoting proliferation of the mouse SSCs (p > 0.05). However, the combination of 20 ng/ml GDNF and 1,000 U/ml LIF could significantly enhance the invitro proliferation of mouse SSCs (p < 0.05), and the OD₄₉₀ value was 0.696 at day 5 of culture when the density of SSCs was 5–10 × 10⁴ cells/ml.     

Ixodid tick salivary gland products target host wound healing growth factors

For successful blood-feeding, ticks must confront the host immune system comprising many cells and signaling molecules, mainly cytokines and growth factors. These factors bind to specific receptors on the cell membranes, thereby initiating a signaling cascade that leads to distinct cellular activities. Ticks are able to manipulate host immune responses via molecules secreted from their salivary glands. Saliva of ixodid ticks contains factors binding important cytokines and their subgroup, chemokines. Here we demonstrate that constituents of tick salivary gland extract (SGE) also appear to bind growth factors: transforming growth factor beta (TGF-β1), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF-2), and hepatocyte growth factor (HGF), depending on tick species. SGE derived from Amblyommavariegatum reacted with TGF-β1, PDGF, FGF-2 and HGF; Dermacentorreticulatus and Rhipicephalusappendiculatus with TGF-β1, FGF-2 and HGF; and Ixodes ricinus and Ixodesscapularis with PDGF. SGE from the species targeting PDGF (A. variegatum and I. ricinus) also inhibited cell proliferation in vitro and induced a change in morphology of different cell lines. These effects correlated with disruption of the actin cytoskeleton. Such effects were not observed with SGE of the two species that did not target PDGF. Targeting of wound healing growth factors appears to be yet another strategy ixodid ticks adopt for suppression of inflammation and successful haematophagy.     

乌司他丁对大鼠毛细血管渗漏综合征肺毛细血管通透性的影响

目的:观察乌司他丁(UTI)注射液对毛细血管渗漏综合征(CLS)大鼠肺毛细血管通透性及肺血管内皮生长因子(VEGF)表达的影响,探讨UTI降低CLS大鼠肺毛细血管通透性的机制。方法:雄性SD大鼠120只,随机均分为三组。其中正常对照组(C组)20只,UTI干预组(U组)40只,模型组(M组)60只。实验动物观察12小时,处死前取静脉血ELISA法测血清VEGF;处死动物后取肺组织分别行病理学检查、干湿比重法测肺含水量、伊文思兰法测肺毛细血管通透性。结果:M组血清VEGF明显高于C组和U组(P<0.05),M组肺组织损伤较重,肺含水量及组织通透性均高于C组和U组(P<0.05)。结论:UTI可降低大鼠CLS肺毛细血管通透性,其作用机制可能是通过降低血中的VEGF表达。     

Assessment of potential indigenous plant species for the phytoremediation of arsenic-contaminated areas of Bangladesh

Soil and water contaminated with arsenic (As) pose a major environmental and human health problem in Bangladesh. Phytoremediation, a plant-based technology, may provide an economically viable solution for remediating the As-polluted sites. The use of indigenous plants with a high tolerance and accumulation capacity for As may be a very convenient approach for phytoremediation. To assess the potential of native plant species for phytoremediation, plant and soil samples were collected from four As-contaminated (groundwater) districts in Bangladesh. The main criteria used for selecting plants for phytoremediation were high bioconcentration factors (BCFs) and translocation factors (TFs) of As. From the results of a screening of 49 plant species belonging to 29 families, only one species of fern (Dryopteris filix-mas), three herbs (Blumea lacera, Mikania cordata, and Ageratum conyzoides), and two shrubs (Clerodendrum trichotomum and Ricinus communis) were found to be suitable for phytoremediation. Arsenic bioconcentration and translocation factors > 1 suggest that these plants are As-tolerant accumulators with potential use in phytoextraction. Three floating plants (Eichhornia crassipes, Spirodela polyrhiza, and Azolla pinnata) and a common wetland weed (Monochoria vaginalis) also showed high BCF and TF values; therefore, these plants may be promising candidates for cleaningup As-contaminated surface water and wetland areas. The BCF of Oryza sativa, obtained from As-contaminated districts was > 1, which highlights possible food-chain transfer issues for As-contaminated areas in Bangladesh.     

我国落叶松林生物量碳计量参数的初步研究

通过整理归纳落叶松(Larix)天然林和人工林的生物量文献数据,研究探讨了有关生物量碳计量参数,结果表明:1) 落叶松生物量转化与扩展因子(Biomass conversion and expansion factor, BCEF)的平均值为0.683 4 Mg·m^-3 (n=113, SD=0.355 1),其中天然林为0.555 1 Mg·m^-3 (n=56, SD=0.058 2),明显小于人工林的0.809 5 Mg·m^-3 (n=57, SD=0.465 0)(p<0.05);生物量扩展因子(Biomass expansion factor,BEF)的平均值为1.349 3 (n=134, SD=0.384 4),其中天然林为1.176 3 (n=63, SD=0.039 9),也明显小于人工林的1.502 9 (n=71, SD=0.478 0)(p<0.05)。天然林与人工林的BCEF和BEF随林龄(Stand age, A)、平均胸径(Diameter at breast height, DBH)和林分密度(Stand density, D)的增加呈现相反的变化趋势。天然林的BCEF和BEF随A和DBH的增加而增加,随D的增加而呈降低趋势。人工林随A和DBH的增加呈指数降低并趋于稳定值,随D的增加而呈增加趋势。2) 根茎比(Root∶shoot ratio,R)的平均值为0.245 6 (n=156, SD=0.092 6),其中天然林为0.237 6 (n=64, SD=0.061 8)),人工林为0.251 1 (n=92, SD=0.109 0),二者无明显差异(p<0.05)。天然林的R随A和DBH的增加分别呈明显的指数和幂函数增加,而随D的增加呈幂函数下降,而人工林的R与A、DBH和D没有显著相关性(p<0.05)。3) 群落生物量扩展因子(Community biomass expansion factor,CBEF)的平均值为1.079 2 (n=49, SD=0.100 5),其中天然林为1.103 9 (n=29, SD=0.114 9),明显大于人工林的1.043 4 (n=20, SD=0.061 4) (p<0.05)。由于天然林和人工林的某些碳计量参数(如BCEF、BEF、CBEF)间存在明显差异,在进行落叶松林生物量碳计量时需分别天然林和人工林计算,在使用有关参数时还需考虑A、DBH和D等因素,有利于降低计量中的不确定性。但是人工林的有些参数(如人工林BCEF和BEF与D的关系、天然林和人工林的CBEF等)尚需进一步研究。     

Nrf2在阿尔茨海默病中的研究现状

阿尔茨海默病(Alzheimer's disease,AD)是最常见的神经系统变性疾病,主要病理特征为细胞外老年斑(senile plaques,SP)和细胞内神经原纤维缠结(neurofibrillary tangles,NFT)形成.但其发病机制不清,涉及多种病理学变化如炎症反应、氧化应激、线粒体功能障碍、细胞凋亡以及突触功能障碍等.核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)是经典的调控机体抗氧化应激反应的核转录因子.Nrf2激活后诱导抗氧化蛋白的表达,提高机体的抗氧化应激能力.随着Nrf2抗氧化应激作用研究的深入,发现Nrf2不仅能够通过抗氧化应激延缓AD的发生发展,且在AD的病理性沉积物的清除、抗炎、抗凋亡、神经营养等方面扮演着重要的角色.近年来,由于多种针对单一靶点的抗AD药物临床试验的失败,有学者提出Nrf2可能是实现AD多靶点疗法的重要因子.因此,本文对Nrf2在AD中的研究现状做一综述,为寻找治疗AD潜在的生物学靶点提供理论依据.     

Phytoremedial Potential of Typha latifolia,Eichornia crassipes and Monochoria hastata found in Contaminated Water Bodies Across Ranchi City (India)

Phytoremediation is an emerging technology that uses green plants (living machines) for removal of contaminants of concern (COC). These plant species have the potential to remove the COC, thereby restoring the original condition of soil or water environment. The present study focuses on assessing the heavy metals (COC) present in the contaminated water bodies of Ranchi city, Jharkhand, India. Phytoremedial potential of three plant species: Typha latifolia, Eichornia crassipes and Monochoria hastata were assessed in the present study. Heterogenous accumulation of metals was found in the three plant species. It was observed that the ratio of heavy metal concentration was different in different parts, i.e., shoots and roots. Positive results were also obtained for translocation factor of all species with minimum of 0.10 and maximum of 1. It was found experimentally that M. hastata has the maximum BFC for root as 4.32 and shoot as 2.70 (for Manganese). For T. latifolia, BCF of maximum was observed for root (163.5) and respective shoot 86.46 (for Iron), followed by 7.3 and 5.8 for root and shoot (for Manganese) respectively. E. crassipes was found to possess a maximum BCF of 278.6 (for Manganese and 151 (for Iron) and shoot as 142 (for Manganese) and 36.13 (for Iron).