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1.
Ceramide synthases (CerS) synthesise ceramides of defined acyl chain lengths, which are thought to mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed a significant elevation of CerS2 and its products, C24-ceramides, in CD11b+ cells (monocytes and neutrophils) isolated from blood. This result correlates with the clinical finding that CerS2 mRNA expression and C24-ceramide levels were significantly increased by 2.2- and 1.5-fold, respectively, in white blood cells of MS patients. The increased CerS2 mRNA/C24-ceramide expression in neutrophils/monocytes seems to mediate pro-inflammatory effects, since a specific genetic deletion of CerS2 in blood cells or a total genetic deletion of CerS2 significantly delayed the onset of clinical symptoms, due to a reduced infiltration of immune cells, in particular neutrophils, into the central nervous system. CXCR2 chemokine receptors, expressed on neutrophils, promote the migration of neutrophils into the central nervous system, which is a prerequisite for the recruitment of further immune cells and the inflammatory process that leads to the development of MS. Interestingly, neutrophils isolated from CerS2 null EAE mice, as opposed to WT EAE mice, were characterised by significantly lower CXCR2 receptor mRNA expression resulting in their reduced migratory capacity towards CXCL2. Most importantly, G-CSF-induced CXCR2 expression was significantly reduced in CerS2 null neutrophils and their migratory capacity was significantly impaired. In conclusion, our data strongly indicate that G-CSF-induced CXCR2 expression is regulated in a CerS2-dependent manner and that CerS2 thereby promotes the migration of neutrophils, thus, contributing to inflammation and the development of EAE and MS. 相似文献
2.
目的 观察丝裂霉素C(MMC)与C2-神经酰胺(C2-cer)联合应用对人膀胱癌细胞的作用效果,并探讨其机制。方法 不同浓度MMC与C2-cer单独及联合作用于人膀胱癌BIU-87细胞后,应用噻唑蓝(MTT)比色法检测细胞生长抑制率,计算合用指数(CI),流式细胞仪(FCM)检测BIU-87细胞凋亡率,吖啶橙(AO)荧光染色观察凋亡形态学变化,Western blot检测细胞色素C在细胞内分布变化,并检测Caspase-3活性改变。结果 单独应用时MMC与C2-cer的中效浓度分别是159和28μmol/L,联合用药时下降为55和11μmol/L,CI=0.74。MMC与C2-cer单独及联合应用均可导致BIU-87细胞出现凋亡的形态学变化。两种药物联合应用时的凋亡率高于各自单用(P<0.05)。线粒体细胞色素C含量在MMC与C2-cer单独及联合应用时均较对照组减少,联合用药时减少最为明显,细胞质内细胞色素C含量在联合用药时增加也最为明显(P<0.05)。Caspase-3活性在MMC与C2-cer单独及联合应用时均较对照组升高,联合用药时升高最为明显(P<0.05)。结论 MMC与C2-cer联合应用可以通过共同诱导细胞凋亡,协同抑制膀胱癌细胞生长。线粒体细胞色素C释放和Caspase-3活性变化可能发挥重要作用。 相似文献
3.
目的:对毛鱼藤根化学成分进行分离和鉴定。方法:通过多种层析方法分离纯化化合物,用波谱解析方法进行结构鉴定。结果:从毛鱼藤根中分离到4个脂质化合物,包含3个神经酰胺:(2S,3S,4R,8E)-2N-[(2′R,3′)-2′,3′-dihydroxy-hexacosanoyl]-1,3,4-trihydroxy-8-octadecene(1),(2S,3S,4R,8E)-2N-[(2′R)-2′-hydroxyhexacosanoyl]-1,3,4-trihydroxy-8-octadecene(2),1-O-β-D-glucopyranosyl-(2S,3S,4R,8E)-2N-[(2′R)-2′-hydroxytetracosanoyl]-3,4-dihydroxy-8-octadecene(3),和1个多羟基十八烷酸:12,13,15-trihydroxy-9-octadecenoicacid(4)。结论:化合物1为新化合物,也是首个C-3′有羟基取代的新神经酰胺。化合物2-4为鱼藤属植物中首次发现的化合物。 相似文献
4.
神经酰胺诱导人结肠癌细胞凋亡作用 总被引:1,自引:2,他引:1
目的探讨外源性神经酰胺诱导人结肠癌HT-29细胞的凋亡作用。方法采用光镜、电镜、荧光显微镜和琼脂糖凝胶电泳方法检测C2-神经酰胺诱导HT-29细胞凋亡。MTT法检测C2-神经酰胺对HT-29细胞线粒体功能的影响。结果C2-神经酰胺使HT-29细胞发生核染色质断裂、DNA Ladder、凋亡小体等典型凋亡表现,12和24 h凋亡细胞率分别为64.1%和81.3%,呈现时间-剂量依赖关系。同时C2-神经酰胺处理细胞6 h后,细胞线粒体功能即出现损伤。结论外源性神经酰胺能诱导人结肠癌HT-29细胞凋亡,参与其凋亡调控。 相似文献
5.
Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology. 相似文献
6.
Masaru Kubota Koji Narita Tadayoshi Nakagomi Akira Tamura Hiroyuki Shimasaki Nobuo Ueta 《Neurological research》2013,35(4):337-341
AbstractTo better define the sphingolipid metabolism during focal brain ischemia, levels of ceramide, sphingomyelin, cerebroside and gangliosides were determined in rat cerebral cortex during focal ischemia produced by occlusion of the middle cerebral artery. Sphingomyelin began to decrease at 2 hours of ischemia and continued to decrease for 96 hours. In contrast, ceramide increased at 6 hours and increased to 4.2-fold at 96 hours after ischemia, and the fatty acid composition of ceramide was solely nonhydroxylated fatty acid similar to sphingomyelin. Hydroxylated fatty acid-linked cerebroside decreased at 6 hours of ischemia, whereas any significant decrease of nonhydroxylated fatty acid-linked cerebroside didn't occur for 96 hours of ischemia. There were no measurable changes in the levels of gangliosides. These results suggested that ceramide was produced in the cerebral cortex by the breakdown of sphingomyelin during early ischemia. [Neurol Res 1996; 18: 337-341] 相似文献
7.
8.
《Brain & development》2022,44(6):391-400
IntroductionNext generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; ≥C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (MIM: 618527) stem from ELOVL1 gene deficiency in human.MethodsWe have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC–MS/MS). ELOVL1 protein structure was computationally modelled.ResultsThe novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC–MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides.DiscussionIt has recently been shown that disease associated variants of ELOVL1 segregate in an autosomal dominant manner. However, our study for the first time demonstrates an alternative autosomal recessive inheritance model for ELOVL1. In conclusion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes can be an important guide to identifying the molecular mechanism of genetic cerebral palsy. 相似文献
9.
Young MR Neville BW Chi AC Lathers DM Gillespie MB Day TA 《Clinical & experimental metastasis》2007,24(2):131-139
Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose
aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility
characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional
analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion
cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of
the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This
was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity
and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion
cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity. 相似文献
10.
Tang N Ong WY Zhang EM Chen P Yeo JF 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2007,183(2):241-247
Increases in several ceramide species have been shown by non-targeted lipid profiling (lipidomics) of the rat hippocampus
after kainate lesions (Guan et al. FASEB J 20:1152–1161, 2006). This study was carried out to examine possible effects of ceramide species on exocytosis. Significant increase in membrane
capacitance in voltage-clamped rat pheochromocytoma (PC12) cells, an indication of exocytosis, was detected immediately after
external application of C2, C6, and C18 ceramide. In contrast, no increase in capacitance was found after addition of C16
and C20 ceramide, or DMSO vehicle. The effect of ceramide on exocytosis was dependent on the integrity of lipid rafts. Treatment
of cells with the cholesterol binding agent/disruptor of lipid rafts, methyl β cyclodextrin, prior to addition of C18 ceramide
suppressed the increase in capacitance induced by this lipid species. The ability of C2, C6 and C18 ceramide to trigger exocytosis
was confirmed using total internal reflection fluorescence microscopy (TIRFM) experiments. External application of these species
caused an exponential decrease in the number of subplasmalemmal neuropeptide Y (NPY)-enhanced green fluorescence protein (EGFP)
labeled vesicles, indicating exocytosis. Interestingly, C18 is also the ceramide species that showed the greatest increase
in the rat hippocampus after kainate excitotoxicity. It is postulated that C18 ceramide might facilitate exocytosis of glutamate
from damaged neurons, thus propagating neuronal injury. 相似文献