2,4-Dichlorophenoxyacetic acid disrupts the cytoskeleton and disorganizes the Golgi apparatus of cultured neurons.

2,4-Dichlorophenoxyacetic acid (2,4-D) is a potent neurotoxic herbicide widely used in agriculture. The basic mechanisms by which 2,4-D produces cell damage have not yet been determined. In this study we have examined the effects of 2,4-D in primary cultures of cerebellar granule cells in order to obtain insights into the possible mechanisms underlying the toxic effects of this herbicide. The results obtained indicate that a 24-hour exposure to 2,4-D produces a striking and dose-dependent inhibition of neurite extension. This phenomenon is paralleled by a significant reduction in the cellular content of both dynamic and stable microtubules, a disorganization of the Golgi apparatus, and an inhibition in the synthesis of complex gangliosides. Interestingly, 2,4-D inhibits the in vitro polymerization of purified tubulin. Taken together, the present observations raise the possibility that at least one basic mechanism underlying 2,4-D neurotoxicity involves an inhibition of microtubule assembly. That event may cause a decreased neurite outgrowth response, and could also explain the observed differences in the pattern of ganglioside biosynthesis and/or the disorganization of the Golgi apparatus.     

Factors defining target specificity in antibody-mediated neuropathy: Density-dependent binding of anti-GD1a polyclonal IgG from a neurological patient

IgM and IgG antibodies reacting with components of human brain gangliosides were detected in a patient bearing severe sensory ataxy. Using different chemical and immunological methods, the antigen was identified as the GD_1a ganglioside. The antibodies showed antigen “density-dependent” binding, a property only observed in tumor-specific monoclonal antibodies. The relevance of this result in regard with target specificity of neuropathy-associated antibodies directed to ubiquitous glycolipids is discussed. J. Neurosci. Res. 47: 636–641, 1997. © 1997 Wiley-Liss, Inc.     

Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance

Cancer development is a multistep process in which cells must overcome a series of obstacles before they can become fully developed tumors. First, cells must develop the ability to proliferate unchecked. Once this is accomplished, they must be able to invade the neighboring tissue, as well as provide themselves with oxygen and nutrients. Finally, they must acquire the ability to detach from the newly formed mass in order to spread to other tissues, all the while evading an immune system that is primed for their destruction. Furthermore, increased levels of inflammation have been shown to be linked to the development of cancer, with sites of chronic inflammation being a common component of tumorigenic microenvironments. In this Review, we give an overview of the impact of sphingolipid metabolism in cancers, from initiation to metastatic dissemination, as well as discussing immune responses and resistance to treatments. We explore how sphingolipids can either help or hinder the progression of cells from a healthy phenotype to a cancerous one.     

Sialidase NEU3 contributes neoplastic potential on colon cancer cells as a key modulator of gangliosides by regulating Wnt signaling

The plasma membrane‐associated sialidase NEU3 is a key enzyme for ganglioside degradation. We previously demonstrated remarkable up‐regulation of NEU3 in various human cancers, with augmented malignant properties. Here, we provide evidence of a close link between NEU3 expression and Wnt/β‐catenin signaling in colon cancer cells by analyzing tumorigenic potential and cancer stem‐like characteristics. NEU3 silencing in HT‐29 and HCT116 colon cancer cells resulted in significant decrease in clonogenicity on soft agar and in vivo tumor growth, along with down‐regulation of stemness and Wnt‐related genes. Analyses further revealed that NEU3 enhanced phosphorylation of the Wnt receptor LRP6 and consequently β‐catenin activation by accelerating complex formation with LRP6 and recruitment of GSK3β and Axin, whereas its silencing exerted the opposite effects. NEU3 activity‐null mutants failed to demonstrate the activation, indicating the requirement of ganglioside modulation by the sialidase for the effects. Under sphere‐forming conditions, when stemness genes are up‐regulated, endogenous NEU3 expression was found to be significantly increased, whereas NEU3 silencing suppressed sphere‐formation and in vivo tumor incidence in NOD‐SCID mice. Increased ability of clonogenicity on soft agar and sphere formation by Wnt stimulation was abrogated by NEU3 silencing. Furthermore, NEU3 was found to regulate phosphorylation of ERK and Akt via EGF receptor and Ras cascades, thought to be additionally required for tumor progression. The results indicate an essential contribution of NEU3 to tumorigenic potential through maintenance of stem‐like characteristics of colon cancer cells by regulating Wnt signaling at the receptor level, in addition to tumor progression via Ras/MAPK signaling.     

神经节苷脂对大鼠坐骨神经损伤后Wallerian变性的预防作用

神经节苷脂对大鼠坐骨神经损伤后Ｗａｌｅｒｉａｎ变性的预防作用１马鸣超王捷（沈阳军区军事医学研究所，沈阳１１００３１）神经节苷脂（ｇａｎｇｌｉｏｓｉｄｅｓ，Ｇａｎ）是一类存在于大多数细胞膜上的糖鞘脂，特别存在于神经细胞膜上．有关其作用已有大量文献报道，...     

Protective effects of exogenous gangliosides on ROS-induced changes in human spermatozoa

This article summarizes the available evidence on the efficacy of gangliosides to reduce the degree of reactive oxygen species (ROS)-mediated damage. The antioxidative efficacy of exogenous gangliosides in protecting different cells encouraged us to examine their ability to protect human spermatozoa. Gangliosides are sialic acid-containing glycosphingolipids with strong amphiphilic character due to the bulky headgroup made of several sugar rings with sialic acid residues and the double-tailed hydrophobic lipid moiety. The amphiphilicity of gangliosides allows them to exist as micelles in aqueous media when they are present at a concentration above their critical micellar concentration. The protective effect of ganglioside micelles on spermatozoa is believed to stem from their ability to scavenge free radicals and prevent their damaging effects. In our study, we particularly focused our attention on the protective effect of ganglioside micelles on DNA in human spermatozoa exposed to cryopreservation. The results indicate that ganglioside micelles can modulate the hydrophobic properties of the sperm membrane to increase tolerance to DNA fragmentation, thus protecting the DNA from cryopreservation-induced damage. Further actions of ganglioside micelles, which were documented by biochemical and biophysical studies, included (i) the modulation of superoxide anion generation by increasing the diffusion barrier for membrane events responsible for signal translocation to the interior of the cell; (ii) the inhibition of iron-catalysed hydroxyl radical formation due to the iron chelation potential of gangliosides; and (iii) inhibition of hydrogen peroxide diffusion across the sperm membrane.     

β-淀粉样蛋白对培养神经细胞的毒性作用及神经节苷脂的保护作用

向培养液中加入15mmol／L的β-AP1-40，48h后，发现原代培养的海马细胞内Ca2+的浓度明显增高，对照组为23．9±3．6（n=51）而β-AP组为36．5±15．8（n=30），两组比较P＜0．001，有非常显著性的差别。对照组的乳酸脱氢酶没有明显变化，而β－AP组在加β－AP1－4048h后乳酸脱氢酶明显增加，从52iu／L增加到105iu／L，实增加了101％。实验结果表明，β－AP1-40对培养的神经细胞有明显的毒性作用，但没有发现形态学的变化和对细胞的特异性。如在培养液中加β－AP1-40的同时再加25mg／ml的神经节苷脂（GAs）可明显减弱β-AP1-40引发的胞内Ca2+浓度和培养液中LDH浓度的升高。β-AP＋GAs组胞内Ca2+浓度为27.7±5.58，与β-AP组比较，有显著性差异（P＜0．01）。β-AP组海马细胞培养液中乳酸脱氢酶的浓度增高为101％，而β-AP-GAs组培养液中乳酸脱氢酶的浓度增高仅为67％。在NG108－15细胞上也获得了相同的结果。单唾液酸神经节苷脂虽有与GAs类似的作用，但较弱。这些实验结果指出，神经节苷脂和单唾液酸神经节苷脂均能拮抗β-AP1-40的毒性作用，从而对细胞可起到保护作用。     

神经节苷脂治疗儿童病毒性脑炎的疗效观察

目的观察神经节苷脂治疗儿童病毒性脑炎（VE）的疗效。方法98例VE患儿,随机分成对照组49例和治疗组49例,两组性别、病情轻重差异无统计学意义（P〉0．05）。两组均进行常规综合治疗,对照组予在常规治疗基础上给予胞二磷胆碱治疗,治疗组在常规治疗上给予神经节苷脂治疗,对两组治疗效果进行比较。结果治疗组在临床症状及体征恢复时间较对照组缩短,显效率和总有效率明显高于对照组,两组疗效有显著差异（P〈0．01）,治疗组明显优于对照组。结论神经节苷脂辅助治疗VE能提高疗效,减少并发症,具有重要的临床推广应用价值。     

基于NLRP3信号通路探究天麻素注射液联合神经节苷脂辅助治疗脊髓损伤的可能机制

基于NOD样受体热蛋白结构域相关蛋白3（NLRP3）信号通路探究天麻素注射液联合神经节苷脂辅助治疗脊髓损伤（SCI）的可能机制。【方法】 将108例SCI患者随机分为观察组和对照组,每组各54例。2组患者均给予常规康复训练,在此基础上,对照组给予神经节苷脂治疗,观察组给予天麻素注射液联合神经节苷脂治疗。30 d为1个疗程,连续治疗2个疗程。比较2组患者的肌力恢复正常时间、可下地行走时间和留院观察时间,观察2组患者治疗前后美国脊柱损伤协会（ASIA）评分及血清脑源性神经生长因子（BDNF）、中枢神经特异性蛋白（S-100β）、白细胞介素（IL）-1β、IL-18及NLRP3、半胱氨酸蛋白酶1（Caspase-1）、凋亡相关斑点样蛋白（ACS）水平的变化情况,并评价2组患者的临床疗效及安全性。【结果】（1）治疗2个疗程后,观察组的总有效率为 83.33%（45/54）,对照组为 66.67%（36/54）,组间比较（χ2检验）,观察组的疗效明显优于对照组（P＜0.05）。（2）治疗后,观察组的肌力恢复正常时间、可下地行走时间及留院观察时间均较对照组明显缩短（P＜0.01）。（3）治疗 1 个和2个疗程后,2组患者ASIA的痛觉、运动、触觉评分均较治疗前明显升高（P＜0.05）,且治疗2个疗程后又较治疗 1个疗程后升高（P＜0.05）;组间比较,观察组在治疗 1个和 2个疗程后对 ASIA的痛觉、运动、触觉评分的升高幅度均明显优于对照组（P＜0.05）。（4）治疗1个和2个疗程后,2组患者的血清BDNF水平均较治疗前升高（P＜0.05）,NLRP3、ACS、Caspase-1蛋白和血清IL-1β、IL-18、S-100β水平均较治疗前下降（P＜0.05）,且治疗2个疗程后血清BDNF水平又均较治疗1 个疗程后升高（P＜0.05）,NLRP3、ACS、Caspase-1 蛋白和血清 IL-1β、IL-18、S-100β 水平又均较治疗 1 个疗程后下降（P＜0.05）;组间比较,观察组在治疗1个和2个疗程后对血清BDNF水平的升高幅度及对NLRP3、ACS、Caspase-1蛋白和血清IL-1β、IL-18、S-100β水平的下降幅度均明显优于对照组（P＜0.05）。（5）治疗过程中,2组患者均未出现药物相关不良反应。【结论】 天麻素注射液联合神经节苷脂治疗 SCI患者疗效确切,可通过调控炎症小体 NLRP3信号通路,减轻神经炎症反应,促进神经功能恢复,其疗效优于单纯神经节苷脂治疗。