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。     

Histopathological effects of tannins on the midgut epithelium of Papilio polyxenes and Papilio glaucus

The effects of dietary tannin on midgut epithelial structures were compared in two closely related species of swallowtail caterpillars — Papilio polyxenes, a species restricted to the tannin-free Umbelliferae, and P. glaucus, which feeds on tanniniferous tree species in several families. The effects of tannin ingestion were compared in second and fifth instar caterpillars. While large numbers of lesions were found in the guts of P. polyxenes ingesting tannins, only one small lesion was found in any P. glaucus ingesting tannins. No such lesions could be found in larvae of either species raised on tannin-free leaves. The observed histopathological changes, discussed in detail, resemble those previously reported in several species of Lepidoptera in response to a variety of substances and may represent a general degenerative response to the presence of toxins in the gut.

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Résumé L'étude à porté sur les effets de tanins dans l'alimentation sur les structures épithéliales de l'intestin moyen des chenilles de second et cinquième stades, de deux espèces très voisines: Papilio polyxenes-espèce ne consommant que des ombellifères sans tanins-et P. glaucus qui s'alimente sur des arbres contenant des tanins et appartenant à plusieurs familles. Alors qu'après ingestion de tanins, de nombreuses lésions ont été observées sur l'intestin de P. polyxenes, seulement quelques petites lésions ont été trouvées sur l'intestin de P. glaucus. Aucune lésion de même type n'a été observée dans les chenilles de ces espèces élevées sur feuilles sans tanin. Les modifications histopathologiques, discutées en détail, correspondent à la mortalité induite par le tanin due à une septicémie bactérienne et peut représenter une réponse dégénérative à la présence de substances toxiques dans l'intestin.

     

重症蜂螫伤患者的肾脏病理表现

目的:探讨重症蜂螫伤患者的肾脏病理改变,以指导临床针对性的治疗提供参考依据。方法:通过对4例重症蜂螫伤患者的临床表现及肾脏病理做病例报告,初步了解重症蜂螫伤患者的肾脏病理改变。记录所有患者的一般情况、实验室结果、治疗过程及预后,并进行肾穿刺活检以明确病理改变。结果:所有患者均为青壮年,均出现了MODS,包括急性肾衰竭、中毒性心肌炎及急性肝损伤。3例患者的肾组织病理为急性肾小管坏死及急性过敏性间质性肾炎,病理切片中可见少量嗜酸性粒细胞及大量淋巴细胞浸润。1例患者为急性肾小管坏死,未见嗜酸性粒细胞浸润。有急性过敏性间质性肾炎的患者使用小剂量激素反应较好,使用激素后肾功能恢复时间更短。结论:在重症蜂螫伤患者肾脏损伤的过程中,除了常见的急性肾小管坏死、血管内溶血、横纹肌溶解及休克等原因外,急性过敏性间质性肾炎也起着重要的作用,对于此类患者,及时使用激素治疗可能是减轻肾脏损伤、促进肾功能恢复的有效方法。     

术前外周血中性粒细胞/淋巴细胞比值与肾癌临床病理特点及预后关系的研究

目的:分析术前外周血中性粒细胞/淋巴细胞比值(NLR)与肾癌临床病理特征及预后的关系。方法:回顾性分析2007年1月~2011年12月在哈尔滨医科大学附属第一医院泌尿外科接受根治性手术且病理证实为非转移肾癌患者的临床病例及随访资料。根据ROC曲线确定NLR最佳截点,并以此截点将患者分为高NLR组和低NLR组。分析两组间临床病理特征的差异。应用Kaplan-Meier法、Log-rank法进行单因素生存分析,应用Cox风险回归模型进行多因素生存分析。结果:460例患者中,男性306例,女性154例,中位年龄56岁。NLR平均值为2.34±1.77,中位值为2.45。根据ROC曲线分析,当NLR为2.5时,曲线下面积(AUC=0.628,p0.001)最大。以此截点将患者分为高NLR(≥2.5)组154例,低NLR(2.5)组306例。两组间年龄、Fuhrman分期、T分期上差异具有统计学意义(p0.05)。单因素生存分析显示Fuhrman、T分期、NLR值是肾癌预后因素,Cox多因素回归分析显示T分期、NLR值是肾癌的独立预后因素。结论:术前外周血中性粒细胞/淋巴细胞比值(NLR)是肾癌患者预后不良的独立危险因素。     

益肾和络合剂对慢性肾衰竭实验室指标的影响(英文)

目的:观察益肾和络合剂对慢性肾衰竭(CRF)实验室指标的影响。方法:将60例CRF患者随机分为两组,治疗组30例给予益肾和络合剂,对照组30例给予尿毒清颗粒,6个月后观察两组的实验室指标。结果:治疗组在用药后血肌酐(Scr)、尿素氮(BUN)、胆固醇(CH)、低密度脂蛋白(LDL)下降,高密度脂蛋白(HDL)、血清清蛋白(ALB)升高,与治疗前比较差异均有显著性(P0.05),与对照组比较差异均有显著性(P0.05)。结论:益肾和络合剂可以明显改善CRF患者的实验室指标,延缓CRF的进展。     

Fluorescence correlation spectroscopy reveals topological segregation of the two tumor necrosis factor membrane receptors

The proinflammatory cytokine tumor necrosis factor (TNF) binds two distinct plasma membrane receptors, TNFR1 and TNFR2. We have produced different receptor mutants fused with enhanced green fluorescent protein to study their membrane dynamics by fluorescence correlation spectroscopy (FCS). TNFR1 mutants show diffusion constants of approximately 1.2 × 10^− 9 cm²/s and a broad distribution of diffusion times, which is hardly affected by ligand binding. However, cholesterol depletion enhances their diffusion, suggesting a constitutive affinity to cholesterol rich membrane microdomains. In contrast, TNFR2 and mutants thereof diffuse rather fast (D? = 3.1 × 10^− 9 cm²/s) with a marked reduction after 30 min of TNF treatment (D? = 0.9 × 10^− 9 cm²/s). This reduction cannot be explained by the formation of higher ordered receptor clusters, since the fluorescence intensity of TNF treated receptors indicate the presence of a few receptor molecules per complex only. Together, these data point to a topological segregation of the two TNF receptors in different microcompartments of the plasma membrane independent of the cytoplasmic signaling domains of the receptors.     

Urinary markers of nephrotoxicity following administration of 2 bromoethanamine hydrobromide a comparison with hexachlorobutadiene

2 bromoethanamine hydrobromide (BEA) has been widely considered to be a target selective nephrotoxin that causes necrosis of the medulla in 24-48 h, but recent reports suggest that early cortical injury is also associated with this lesion. In order to assess the cortical effects of BEA (100 mg kg^-1 bw single ip injection), several urinary markers of renal injury were evaluated over a 7 day period in male Wistar Albino rats. Hexachlorobutadiene (HCBD 150 mg kg^-1 bw in peanut oil ip), a renal toxin which targets selectively for the proximal tubule, was used as a comparison. After BEA treatment, urinary levels of alanine aminopeptidase, gamma-glutamyl-transpeptidase, alkaline phosphatase and glucose increased transiently. Each of the proximal tubule marker enzymes peaked earlier following HCBD treatment and elevation of alanine aminopeptidase and gamma glutamyl transpeptidase was sustained for longer periods than for BEA. Following BEA treatment, lactate dehydrogenase rose prominently on day 1 followed by a return to control values on day 2 and a further rise on day 3 and remained high until the end of the study. BEA also increased the urinary excretion of total protein and albumin. After HCBD treatment, lactate dehydrogenase showed a transient elevation and glucose levels were slightly increased. Based on the present observations the changes induced by BEA administration on urinary markers of renal injury are different from those observed following HCBD treatment. These findings suggest that BEA toxicity also involves other parts of the kidney besides the papilla.     

Significant alterations of the novel 15 gene signature identified from macrophage-tumor interactions in breast cancer

Background

Tumor microenvironment is composed of a largely altered extracellular matrix with different cell types. The complex interplay between macrophages and tumor cells through several soluble factors and signaling is an important factor in breast cancer progression.

TNF-α mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-κB activation in liver cells

Development of hepatocellular carcinoma (HCC) is accompanied by a continuous increase in reactive oxygen species (ROS) levels. To investigate the primary source of ROS in liver cells, we used tumor necrosis factor-alpha (TNF-α) as stimulus. Applying inhibitors against the respiratory chain complexes, we identified mitochondria as primary source of ROS production. TNF-α altered mitochondrial integrity by mimicking a mild uncoupling effect in liver cells, as indicated by a 40% reduction in membrane potential and ATP depletion (35%). TNF-α-induced ROS production activated NF-κB 3.5-fold and subsequently enhanced migration up to 12.7-fold. This study identifies complex I and complex III of the mitochondrial respiratory chain as point of release of ROS upon TNF-α stimulation of liver cells, which enhances cell migration by activating NF-κB signalling.     

Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes

B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations and has been associated with autoimmune disease. BAFF is known to interact with three receptors, BCMA, TACI and BAFF-R, that have distant similarities with other receptors of the TNF family. We have determined the crystal structure of the TNF-homologous domain of BAFF at 2.8 A resolution. The structure reveals significant differences when compared to other TNF family members, including an unusually long D-E loop that participates in the formation of a deep, concave and negatively charged region in the putative receptor binding site. The BAFF structure was further used to generate a homology model of APRIL, a closely related TNF family ligand that also binds to BCMA and TACI, but not BAFF-R. Analysis of the putative receptor binding sites of BAFF and APRIL suggests that differences in the D-E loop structure and electrostatic surface potentials may be important for determining binding specificities for BCMA, TACI and BAFF-R.