beta-Hydroxybutyrate fuels synaptic function during development. Histological and physiological evidence in rat hippocampal slices.

To determine whether ketone bodies sustain neuronal function as energy substrates, we examined the effects of beta-hydroxybutyrate (betaHB) on synaptic transmission and morphological integrity during glucose deprivation in rat hippocampal slices. After the depression of excitatory postsynaptic potentials (EPSPs) by 60 min of glucose deprivation, administration of 0.5-10 mM D-betaHB restored EPSPs in slices from postnatal day (PND) 15 rats but not in slices from PND 30 or 120 rats. At PND 15, adding D-betaHB to the media allowed robust long-term potentiation of EPSPs triggered by high frequency stimulation, and prevented the EPSP-spike facilitation that suggests hyperexcitability of neurons. Even after PND 15,D-betaHB blocked morphological changes produced by either glucose deprivation or glycolytic inhibition. These results indicate that D-betaHB is not only able to substitute for glucose as an energy substrate but is also able to preserve neuronal integrity and stability, particularly during early development.     

丹参酮ⅡA对神经祖细胞系C17．2的保护作用

目的:了解丹参酮ⅡA对神经祖细胞系C17.2的保护作用,探讨其可能的作用机制。方法:本实验于2005年起在广州血液中心器官移植配型中心实验室进行。C17.2祖细胞系由澳大利亚新南威尔士大学解剖教研室David Walsh博士惠赠。将C17.2细胞以1×109L-1的密度接种,用含10%胎牛血清IMDM,37℃、体积分数为0.05CO2、饱和湿度的CO2培养箱培养,接近融合的C17.2细胞用含0.1mmol/LEDTA的胰酶室温消化,按1∶3的比例传代。C17.2细胞以5×107L-1的密度接种于96孔板或25cm2的培养瓶中,用含10%胎牛血清IMDM培养过夜后,加入含4g/L AAPH(水溶性偶氮引发剂2,2'-偶氮二(2-脒基丙烷)二盐酸盐)无血清的IMDM培养基培养建立神经细胞凋亡模型。C17.2细胞以5×103/孔的密度接种于96孔板中,用含10%胎牛血清IMDM培养过夜后,加入含4g/LAAPH无血清的IMDM培养基培养。对照组不加入丹参酮ⅡA,实验组分别加入0.02,0.05,0.1,0.2mg/L丹参酮ⅡA培养8h,噻唑蓝法检测细胞活性:细胞活性的相对值=(实验组吸光度值/对照组吸光度值)×100%,流式细胞仪检测细胞凋亡。结果:①AAPH处理8h后,C17.2细胞被过氧化损害,大多数细胞失去正常的形态,细胞呈圆形,脱落。加入丹参酮ⅡA后,细胞形态基本保持正常,少数细胞呈圆形。②C17.2细胞在IMDM的培养液中,细胞数量是含4g/L AAPH无血清的IMDM培养基条件下的2.5～3倍。浓度为0.02,0.05,0.1mg/L的丹参酮ⅡA对C17.2细胞有保护作用,质量浓度大于0.2mg/L丹参酮ⅡA对C17.2细胞保护作用降低。③AAPH作用前大部分C17.2细胞的线粒体完整,有少量的早期凋亡细胞和凋亡细胞,AAPH作用后凋亡细胞总数、凋亡细胞明显增加。丹参酮ⅡA处理组可以明显减少早期凋亡细胞。结论:在体外丹参酮ⅡA对神经细胞具有抗凋亡的作用,可以保护神经细胞。     

低氧训练对下丘脑-垂体-肾上腺皮质轴内分泌相关激素的影响

目的:总结低氧训练对下丘脑-垂体-肾上腺皮质轴内分泌相关激素的影响,为科学运动训练提供依据。资料来源:应用计算机检索中国期刊全文数据库1994-01/2006-10的相关文章,检索词"低氧,低氧训练,下丘脑-垂体-肾上腺,激素",并限定文章语言种类为中文。并应用计算机检索美国国立医学图书馆NCBI1980-01/2006-10的相关文章,检索词"Hypoxic Training,organism endocrine system,hormone",并限定文章语言种类为English。资料选择:对资料进行初审,选取低氧训练与下丘脑-垂体-肾上腺分泌的相关激素有关的文献,并作初步分类,同类文献首选近年发表的核心期刊文章。排除重复及综述类文献。资料提炼:共收集到95篇相关文章,其中56篇属于重复及综述类文献,对符合标准38篇文献进行分析整理。资料综合:①高海拔状态下机体对低氧产生应激反应,表现为下丘脑-垂体-肾上腺皮质轴的适应性运转,血中促肾上腺皮质激素浓度增加,以调节机体对应激刺激的适应能力,同时使促肾上腺皮质激素释放因子分泌增加。②高原训练后,睾酮和皮质醇的变化都较明显,其总体变化均趋于降低,睾酮/皮质醇值有升有降,从一定意义上反映了机体的机能状况与疲劳积累程度。③低氧还引起大鼠血浆β-内啡肽浓度升高,可使心房钠尿素增加、前列腺素增加、血管内皮素分泌增加及抑制血管内皮舒张因子的分泌。结论:激素对机体的新陈代谢、生长发育、各种功能活动以及维持内环境稳态等方面发挥重要的调节作用,低氧训练对机体激素的影响一直应该受到人们的关注。     

Modulation of cystic fibrosis lung disease by variants in interleukin-8

Cystic fibrosis pulmonary disease is characterized by excessive and prolonged inflammation. CF Pulmonary disease severity exhibits considerable variation that, to some extent, appears to be due to the presence of modifier genes. Several components of the inflammatory response are known to have altered regulation in the CF lung. Genetic variants in 52 inflammatory genes were tested for associations with lung disease indices in a CF patient population (n=737) homozygous for the DeltaF508 cystic fibrosis transmembrane conductance regulator mutation. Variants in three inflammatory genes showed significant genotypic associations with CF lung disease severity, including IL8 and previously reported TGFbeta1 (P< or =0.05). When analyzed by gender, it was apparent that IL8 variant associations were predominantly due to males. The IL8 variants were tested in an additional CF population (n=385) and the association in males verified (P< or =0.01). The IL8 variants were in strong linkage disequilibrium with each other (R2> or =0.82), while variants in neighboring genes CXCL6, RASSF6 and PF4V1 did not associate (P> or =0.26) and were in weaker LD with each other and with the IL8 variants (0.01< or =R2< or =0.49). Studies revealed differential expression between the IL8 promoter variant alleles (P<0.001). These results suggest that IL8 variants modify CF lung disease severity and have functional consequences.     

Effects of fructose-1,6-bisphosphate on morphological and functional neuronal integrity in rat hippocampal slices during energy deprivation

D-fructose-1,6-bisphosphate, a high energy glycolytic intermediate, attenuates ischemic damage in a variety of tissues, including brain. To determine whether D-fructose-1,6-bisphosphate serves as an alternate energy substrate in the CNS, rat hippocampal slices were treated with D-fructose-1,6-bisphosphate during glucose deprivation. Unlike pyruvate, an endproduct of glycolysis, 10 mM D-fructose-1,6-bisphosphate did not preserve synaptic transmission or morphological integrity of CA1 pyramidal neurons during glucose deprivation. Moreover, during glucose deprivation, 10-mM D-fructose-1,6-bisphosphate failed to maintain adenosine triphosphate levels in slices. D-fructose-1,6-bisphosphate, however, attenuated acute neuronal degeneration produced by 200 microM iodoacetate, an inhibitor of glycolysis downstream of D-fructose-1,6-bisphosphate. Because (5S, 10R)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine, an antagonist of N-methyl-D-aspartate receptors, exhibited similar protection against iodoacetate damage, we examined whether (5S, 10R)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine and D-fructose-1,6-bisphosphate share a common neuroprotective mechanism. Indeed, D-fructose-1,6-bisphosphate diminished N-methyl-D-aspartate receptor-mediated synaptic responses and partially attenuated neuronal degeneration induced by 100-microM N-methyl-D-aspartate.Taken together, these results indicate that D-fructose-1,6-bisphosphate is unlikely to serve as an energy substrate in the hippocampus, and that neuroprotective effects of D-fructose-1,6-bisphosphate are mediated by mechanisms other than anaerobic energy supply.     

Inflamed fibronectin: an altered fibronectin enhances neutrophil adhesion

Recent investigations have emphasized the role of activated granulocytes in mediating vascular endothelial injury in the pathogenesis of shock lung. In vitro studies have indicated that tight adherence of the neutrophil to the endothelium is crucial for the development of cellular injury. Fibronectin is critical to cell-to- substratum and cell-to-cell interactions. Since fibronectin resides in plasma, on endothelial cell surfaces and is secreted into cell matrices, the adhesive properties of fibronectin must be modulated, lest universal cell agglomeration occur, yet be enhanced when cell attachment is appropriate. In these studies, treatment of fibronectin- coated surfaces with neutrophil release products increased the adhesion of activated neutrophils. Similarly, endothelial cells treated with neutrophil release products become a more adherent substrate for neutrophils. This enhanced adherence generated by treatment of fibronectin with neutrophil supernatants is inhibitable by heat and the lysosomal proteinase inhibitor, pepstatin-A. Neutrophil release products cause proteolytic fragmentation of fibronectin and enhanced fibronectin immunofluorescence on endothelial cells. In addition, neutrophils are more injurious to endothelial cells that have been pretreated with neutrophil release products. Neutrophils may enhance their own adherence to endothelial cells by altering fibronectin, and this altered, or "inflamed," fibronectin may serve as an amplifier of inflammation.     

Arachidonic acid rescues hippocampal long-term potentiation blocked by group I metabotropic glutamate receptor antagonists

Although there is evidence that group I metabotropic glutamate receptors participate in long-term potentiation, the role of these receptors remains unclear. Among antagonists of group I metabotropic glutamate receptors, the mGluR5-selective 6-methyl-2-(phenylethynyl)-pyridine inhibited long-term potentiation in the CA1 region of hippocampal slices from 30-day-old rats, whereas (RS)-1-aminoindan-1,5-dicarboxylic acid and cyclopropan[b]chromen-1a-carboxylic acid ethylester, which are more selective for mGluR1, failed to inhibit long-term potentiation. Evidence also indicates that arachidonic acid is required for long-term potentiation, as inhibition of phospholipase A(2) blocks long-term potentiation. Administration of arachidonic acid immediately after tetanic stimulation restored long-term potentiation that had been inhibited by group I antagonists. Furthermore, arachidonic acid overcame inhibition of long-term potentiation by xestospongin C, an inositol triphosphate receptor channel blocker, or by thapsigargin, an agent that depletes intracellular calcium stores. However, arachidonic acid did not restore long-term potentiation blocked by N-methyl-D-aspartate receptor antagonists.Although it has been assumed that the source of the arachidonic acid necessary for long-term potentiation is N-methyl-D-aspartate receptor activation, our results suggest that during long-term potentiation group I metabotropic glutamate receptors cause arachidonic acid release by mobilization of intracellular calcium.