Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which mi...Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury,we performed single-cell RNA sequencing dataset analysis,focusing on changes in microglial subpopulations.We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis,sphingomyelin metabolism,and neuroinflammation at high levels.Subsequently,we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury.Finally,we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells.Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis.Furthermore,ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway.Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function.Pla2g7 formed a“bridge”between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway.Collectively,these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3,thereby exerting neuroprotective effects.展开更多
Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases,posing a significant global public health challenge.Al-though the association between ceramides(Cers)and metabolic disease...Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases,posing a significant global public health challenge.Al-though the association between ceramides(Cers)and metabolic diseases is well-established,the role of the acid sphingomyelinase(ASMase)/Cer pathway in these diseases remains underexplored.This review synthesizes recent research on the biological functions,regulatory mechanisms,and targeted therapies related to the ASMase/Cer pathway in metabolic conditions,including obesity,diabetes,non-alcoholic fatty liver disease,and cardiovascular disease.The effects of the ASMase/Cer pathway on metabolic disease-related indicators,such as glycolipid metabolism,insulin resistance,inflammation,and mitochondrial homeostasis are elucidated.Moreover,this article discusses the therapeutic strategies using ASMase/Cer inhibitors for inverse prevention and treatment of these metabolic diseases in light of the possible efficacy of blockade of the ASMase/Cer pathway in arresting the progression of metabolic diseases.These insights offered herein should provide insight into the contribution of the ASMase/Cer pathway to metabolic diseases and offer tools to develop therapeutic interventions for such pathologies and their severe complications.展开更多
Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and t...Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.展开更多
OBJECTIVE:To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription(慈菇消脂方,CGXZ)in the treatment of the non-alcoholic fatty liver disease(NAFLD)by detoxification and phlegm-reducing,the effect of ...OBJECTIVE:To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription(慈菇消脂方,CGXZ)in the treatment of the non-alcoholic fatty liver disease(NAFLD)by detoxification and phlegm-reducing,the effect of CGXZ prescription on ceramide-mediated lipid apoptosis in Hep G2 cells with NAFLD.METHODS:The experiment was randomly divided into 6groups:normal control group,model group,CGXZ prescription medicated serum high,medium,and low dose groups,and pioglitazone positive control group.Using 500μmol/L free fatty acid(FFA)mixture to induce Hep G2 cells to establish NAFLD cell model,respectively,with 2%,4%,and 6%concentration of CGXZ prescription medicated serum intervention for 24 h.The changes in organelles and lipid droplet accumulation were observed under the electron microscope.Furthermore,Td T-mediated d UTP Nick-End Labeling method was used to assay hepatocyte apoptosis;Biochemical determination of glutamic-pyruvic transaminase,glutamic oxalacetic transaminase,triglycerides,and FFA levels in Hep G2cells;the content of ceramide was determined by highperformance thin-layer chromatography.Finally,Western Blot and quantitative real-time polymerase chain reaction(q RT-PCR)were used to determine the protein and gene expression levels,such as inducible nitric oxide synthase(i NOS),nuclear factorκB(NF-κB),B cell lymphoma 2(Bcl-2)and Bcl-2-associated X(Bax).RESULTS:Under the electron microscope,the cells in the model group showed moderate-to-severe steatosis,and apoptotic bodies could be seen.The model group had greater improvements in the apoptosis rate(P<0.01),and the levels of ceramide C2 and FFA in the cytoplasm(P<0.01)than the normal control group.The protein expressions of NF-κB,i NOS,and Bax were significantly up-regulated(P<0.05),while the Bcl-2 had no significant change(P>0.05).Compared with the model group,the levels of ceramide C2 and FFA(P<0.01),the protein expressions of NF-κB,i NOS,and Bax(P<0.05)in the CGXZ prescription treatment group and pioglitazone positive control group were significantly decreased;Only the Bcl-2 protein was significantly up-regulated in the high-dose Chinese medicine group(P<0.05).The downregulation of Bax m RNA expression in each Chinese medicine treatment group was significantly better than in the pioglitazone positive control group(P<0.01).CONCLUSIONS:The CGXZ prescription,formulated with the method of detoxification and phlegm,can inhibit lipoapoptosis in the NAFLD cell model by downregulating the levels of ceramide C2 and FFA,which may be achieved by regulating ceramide/i NOS/NF-κB signaling pathway.展开更多
Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and ...Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.展开更多
The skin’s primary function is to protect the body against a spectrum of environmental stressors, including mechanical insults, microorganisms, chemicals, and allergens. Located in the outermost layers, the primary s...The skin’s primary function is to protect the body against a spectrum of environmental stressors, including mechanical insults, microorganisms, chemicals, and allergens. Located in the outermost layers, the primary structures and components responsible for the skin’s barrier function are susceptible to environmental variables, dermatological conditions, and the aging process. The ensuing alterations to structure, composition, and organizational attributes of the epidermal barrier can impact its integrity and functionality. The aim of this study was to assess the effect of a novel complex composed of a ceramide, energizing peptide, and Camu Camu extract (SUPCERAT<sup>TM</sup> complex) on specific markers of epidermal barrier integrity, as well as epidermal and dermal function. All the experiments were conducted on fresh human abdominal skin explants. Intradermal production of hyaluronic acid, epidermal claudin-1, and ceramide synthase 3 expressions, as well as epidermal lipids content were assessed using specific fluorescent stainings on ex vivo skin after the application of the complex or placebo. Additionally, dermal elastase and collagenase activities were assessed using in tubo enzymatic assays. Lastly, the effect of a cosmetic cream containing SUPCERAT<sup>TM</sup> complex was assessed using subjective Global Aesthetic Improvement Scale (GAIS) in a small cohort of patients after 60 days of use. The application of the SUPCERAT<sup>TM</sup> complex on ex vivo skin led to significant increase in dermal hyaluronic acid content and epidermal activity of claudin-1, ceramide synthase 3 and epidermal ceramide content. Furthermore, in tubo enzymatic assays demonstrated inhibition of both dermal elastase and collagenase activities. In addition, the patient-reported results indicated significant improvements in skin quality and appearance. .展开更多
Physical stresses such as high temperature or hyper- osmosis are known causes of intracellular ceramide (Cer) accumulation in mammalian epithelial cells;these stresses also result in the activation of the biosy- nthes...Physical stresses such as high temperature or hyper- osmosis are known causes of intracellular ceramide (Cer) accumulation in mammalian epithelial cells;these stresses also result in the activation of the biosy- ntheses of glucosylceramide (GlcCer) or galactosyl- ceramide via ceramide glycosylation. We confirmed that intracellular Cer and GlcCer increased in mouse fibroblast Mop 8 cells under conditions of heat stress. When molecular species of Cer, GlcCer and sphingo- myelin (SM) were analyzed by matrix assisted laser desorption ionization time of flight mass spectrome- try (MALDI-TOF MS), the molecular ion peaks of Cer (d18:1 - C16:0, Na+) and Cer (d18:1 - C22:0, Na+) increased under heat stress compared with those of Cer (d18:1 - C24:1, Na+) and Cer (d18:1 - C24:0, Na+). GlcCer and SM demonstrated the wide spectra of fatty acyl chains compared with that of Cer. The ratio of GlcCer consisted of hydroxy fatty acid to that con- sisted of non-hydroxy fatty acid increased 2-5-fold in heat stressed cells. Cer metabolism-related genes, se- rine palmitoyltransferase (Spt), ceramide synthase-1, -2, -4, -5 and -6 (CerS1, -2, -4, -5 and -6), neutral sphingomyelinase-1 and -2 (nSMase1 and nS-Mase2), sphingomyelin synthase-1 (SgmS1), and ceramide glu- cosyltransferase (GlcT), were activated after 16 h un- der heat stress at 42?C. Activation of Sg-mS1 and GlcT genes played a role as Cer scavengers in the decrease of intracellular Cer levels. Activation of Cer- S5 and/or CerS6 gene may contribute to the accu- mulation of Cer species of (d18:1 - C16:0) under heat stress.展开更多
Ceramides are significant metabolic products of sphingolipids in lipid metabolism and are associated with insulin resistance and hepatic steatosis. In chronic inflammatory pathological conditions, hypoxia occurs, the ...Ceramides are significant metabolic products of sphingolipids in lipid metabolism and are associated with insulin resistance and hepatic steatosis. In chronic inflammatory pathological conditions, hypoxia occurs, the metabolism of ceramide changes, and insulin resistance arises. Hypoxia-inducible factors(HIFs)are a family of transcription factors activated by hypoxia. In hypoxic adipocytes,HIF-1α upregulates pla2 g16(a novel HIF-1α target gene) gene expression to activate the NLRP3 inflammasome pathway and stimulate insulin resistance, and adipocyte-specific Hif1 a knockout can ameliorate homocysteine-induced insulin resistance in mice. The study on the HIF-2α-NEU3-ceramide pathway also reveals the role of ceramide in hypoxia and insulin resistance in obese mice.Under obesity-induced intestinal hypoxia, HIF-2α increases the production of ceramide by promoting the expression of the gene Neu3 encoding sialidase 3,which is a key enzyme in ceramide synthesis, resulting in insulin resistance in high-fat diet-induced obese mice. Moreover, genetic and pathophysiologic inhibition of the HIF-2α-NEU3-ceramide pathway can alleviate insulin resistance, suggesting that these could be potential drug targets for the treatment of metabolic diseases. Herein, the effects of hypoxia and ceramide, especially in the intestine, on metabolic diseases are summarized.展开更多
A new C-18 phytosphingosine derivative (1) was isolated from the fruiting bodies of Tuber indicum. Its structure was established as (2S, 3S, 4R, 2R)-2-N-(2-hydroxytricosano- yl)-octadecan-1, 3, 4-triol by spectral a...A new C-18 phytosphingosine derivative (1) was isolated from the fruiting bodies of Tuber indicum. Its structure was established as (2S, 3S, 4R, 2R)-2-N-(2-hydroxytricosano- yl)-octadecan-1, 3, 4-triol by spectral and chemical methods.展开更多
Objective To investigate the potential mechanisms of cell death after the treatment with ceramide. Methods MTT assay, DNA ladder, reporter assay, FACS and Western blot assay were employed to investigate the potential ...Objective To investigate the potential mechanisms of cell death after the treatment with ceramide. Methods MTT assay, DNA ladder, reporter assay, FACS and Western blot assay were employed to investigate the potential mechanisms of cell death after the treatment with C2-ceramide. Results A short-time treatment with C2-ceramide induced cell death, which was associated with p38 MAP kinase activation, but had no links with typical caspase activation or PARP degradation. Rather than caspase inhibitor, Inhibitor of p38 MAP kinase blocked cell death induced by a short-time treatment with ceramide （〈12 h）. However, inhibition of p38 MAP kinase could not block cell death induced by a prolonged treatment with ceramide （〉12 h）. Moreover, incubation of cells with ceramide for a long time （〉12 h） increased subG1, but reduced S phase accompanied by caspase-dependent and caspase-independent changes including NFr, B activation. Conclusion Ceramide-induced cell apoptosis involves both caspase-dependent and -independent signaling pathway. Caspase-independent cell death occurring in a relatively early stage, which is mediated via p38 MAP kinase, can progress into a stage involving both caspase-dependent and -independent mechanisms accompanied by cell signaling of MAPKs and NFκB.展开更多
AIM： To investigate the effect of exogenous ceramideinduced apoptosis on human colon carcinoma HT-29 cells. METHODS： Light microscope, transmission electron microscope and fluorescence microscope were used to observ...AIM： To investigate the effect of exogenous ceramideinduced apoptosis on human colon carcinoma HT-29 cells. METHODS： Light microscope, transmission electron microscope and fluorescence microscope were used to observe the morphology change of apoptosis in HT-29 cells. Agarose gel electrophoresis was performed to detect the DNA fragment. Mitochondrial function was detected by MTT assay, mRNA expression of Bcl-2 family gene members was determined by reverse transcription polymerase chain reaction （RT-PCR） assay. RESULTS： After C2-ceramide treatment, typical characteristics of apoptosis, such as nuclear chromatin breakage, apoptotic body and DNA ladder, could be observed. After exposure to 50μmol/L C2-ceramide for 12 and 24 h, cell apoptosis was 64.1% and 81.3% respectively, which had a time-and dose-effect relationship. Mitochondrial function started to decrease from 6 h after exposure to ceramide. Meanwhile, ceramide up-regulated or down-regulated the mRNA expression of Bcl-2 family gene members. CONCLUSION： Ceramide induces apoptosis of human colon carcinoma HT-29 cells by affecting the expression of Bcl-2 family gene members and impacting the mitochondrial function.展开更多
A new phytosphingosine-type ceramide, armillaramide 1, has been isolated from the fruiting bodies of Basidiomycetes Armillaria mellea (Vahl ex Fr.) Quel. Its structure was established as (2S, 3S. 4R)-2-N-(palmitoyl)-p...A new phytosphingosine-type ceramide, armillaramide 1, has been isolated from the fruiting bodies of Basidiomycetes Armillaria mellea (Vahl ex Fr.) Quel. Its structure was established as (2S, 3S. 4R)-2-N-(palmitoyl)-phytosphingosine by spectroscopic and chemical methods.展开更多
In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions...In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.展开更多
A new ceramide, humesamide, was isolated from the soft coral Cladiella humesi Verseveldt, which was collected from Linshui County of Hainan Province. Its structure was established by spectroscopic analysis and chemica...A new ceramide, humesamide, was isolated from the soft coral Cladiella humesi Verseveldt, which was collected from Linshui County of Hainan Province. Its structure was established by spectroscopic analysis and chemical degradation methods.展开更多
A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as (25,35,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-l,3,4-triol(I)and 1-O-β-...A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as (25,35,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-l,3,4-triol(I)and 1-O-β-D-glucopyranosy1-(2S,3S,4R,8E)-2-[(2'R)-hydroxy-hexade-canoylamino]-8-tetracosene-1,3,4-triol (II) on the basis of chemical and spectroscopic studies.展开更多
AIM： To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells. Possible molecular mechanisms were explored. METHODS： [3- （4, 5）-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium ...AIM： To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells. Possible molecular mechanisms were explored. METHODS： [3- （4, 5）-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide （MTT） assay, plasmid transfection, reporter assay, FACS and Western blotting analyses were employed to investigate the effect and the related molecular mechanisms of C2-ceramide on the cell cycle of Bel7402 cells. RESULTS： C2-ceramide was found to inhibit the growth of Bel7402 cells by indudng cell cycle arrest. During the process, the expression of p21 protein increased, while that of cyclinD1, phospho-ERKl/2 and c-myc decreased. Furthermore, the level of CDK7 was downregulated, while the transcriptional activity of PPARy was upregulated. Addition of GW9662, which is a PPARy specific antagonist, could reserve the modulation action on CDK7. CONCLUSION： Our results support the hypothesis that cell cycle arrest induced by C2-ceramide may be mediated via accumulation of p21 and reduction of cyclinD1 and CDK7, at least partly, through PPARy activation. The ERK signaling pathway was involved in this process.展开更多
Objective:To explore the role that ceramide plays in the activation of mitogen-activated protein kinases(MAPKs)during cerebral ischemia and reperfusion.Methods:Rats were subjected to ischemia by the fourvessel occlusi...Objective:To explore the role that ceramide plays in the activation of mitogen-activated protein kinases(MAPKs)during cerebral ischemia and reperfusion.Methods:Rats were subjected to ischemia by the fourvessel occlusion(4-VO)method.The sphingomyelinase inhibitor TPCK was administered to the CA1 subregion of the rat hippocampus before inducing ischemia.Western blot was used to examine the activity of extracellular-signal regulated kinase(ERK)and c-Jun N-terminal protein kinase(JNK)using antibodies against ERK,JNK and diphosphorylated ERK and JNK.Results:At lh reperfusion post-ischemia,JNK reached its peak activity while ERK was undergoing a sharp inactivation(P〈0.05).The level of diphosphorylated JNK was significantly reduced but the sharp inactivation of ERK was visibly reversed(P〈0.05)by the sphingomyelinase inhibitor.Conclusion:The ceramide signaling pathway is up-regulated through sphingomyelin hydrolysis in brain ischemia,promoting JNK activation and suppressing ERK activation,culminating in the ischemic lesion.展开更多
Two new ceramides,(2S,3S,4R)-2-N-[(2 R)-2 -hydroxypentacosanoylamino]-nonacosane-1,3,4-triol(1) and(2S,3S,4R,8E)-2- N-[(2 R)-2 -hydroxytetracosanoylamino]-8-eicosylene-1,3,4-triol(2) have been isolated from the stems ...Two new ceramides,(2S,3S,4R)-2-N-[(2 R)-2 -hydroxypentacosanoylamino]-nonacosane-1,3,4-triol(1) and(2S,3S,4R,8E)-2- N-[(2 R)-2 -hydroxytetracosanoylamino]-8-eicosylene-1,3,4-triol(2) have been isolated from the stems of Piper betle L.collected from Baoshan city of Yunnan Province in China.Their structures were determined by spectroscopic and chemical methods.展开更多
Prenatal alcohol exposure, especially during early pregnancy, can lead to fetal alcohol syndrome. The pharmacological and toxicological mechanisms of ethanol are related to the effects of ceramide In this study, we es...Prenatal alcohol exposure, especially during early pregnancy, can lead to fetal alcohol syndrome. The pharmacological and toxicological mechanisms of ethanol are related to the effects of ceramide In this study, we established an alcohol exposure model in wild-type mice and in knockout mice for the key enzyme involved in ceramide metabolism, sphingomyelin synthase 2. This model received daily intragastric administration of 25% ethanol, and pups were used at postnatal days 0, 7, 14, 30 for experiments. Serology and immunofluorescence staining found that ethanol exposure dose-dependently reduced blood sphingomyelin levels in two genotypes of pups, and increased neural cell proliferation and the number of new neurons in the hippocampal dentate gyrus. Western blot analysis showed that the relative expression level of protein kinase C e increased in two genotypes of pups after ethanol exposure. Compared with witd-type pups, the expression level of the important activator protein of the ceramide/ceramide-l-phosphate pathway, protein kinase C a, was reduced in the hippocampus of sphingomyelin synthase 2 knockouts. Our findings illustrate that ceramide is involved in alcohol-induced neural proliferation in the hippocampal dentate gyrus of pups after prenatal ethanol exposure, and the mechanism may be associated with increased ex- pression of protein kinase C a activating the ceramide/ceramide-l-phosphate pathway.展开更多
In the present study, a new ceramide, namely 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diol(1), along with four known steroids, including 24-methylcholesta-5, 24(28)-diene-3β-ol(2), 24-methylchol...In the present study, a new ceramide, namely 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diol(1), along with four known steroids, including 24-methylcholesta-5, 24(28)-diene-3β-ol(2), 24-methylcholesta-5, 24(28)-diene-3β-acetate(3), 4-methyl-24-methylcholesta- 22-ene-3-ol(4), and cholesterol, was isolated and characterized from CH2Cl2/Me OH extract of Cespitularia stolonifera. A new acetate derivative of compound 1, termed 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diacetate(1a), was also prepared in the present study. All the structures were established on the basis of modern spectroscopic techniques, including FT-IR, 1D, 2D-NMR, HRESI-MS, and GC-MS, in addition of chemical methods.(-)-Alloaromadendren, ledane,(1)-alloaromadendren oxide, isoaromadendrene epoxide and(-)-caryophellen oxide were identified from the n-hexane fraction using GC-MS. The extract and the two ceramides(1) and(1a) exhibited significant cytotoxic activity against lung cancer A549 cells, while the extract and the two steroids(2) and(3) exhibited significant cytotoxic activity against breast cancer MCF-7 cells. The CH_2Cl_2/MeOH extract exhibited significant antiulcer activity in both ethanol and acetic acid induced ulcer models in rats, as evidenced by histopathological, histochemical, and biochemical examinations.展开更多
基金supported by grants from the National Key Research and Development Program of China,No.2017YFA0105400(to LR)the Key Research and Development Program of Guangdong Province,No.2019B020236002(to LR)the National Natural Science Foundation of China,Nos.81972111(to LZ),81772349(to BL).
文摘Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury,we performed single-cell RNA sequencing dataset analysis,focusing on changes in microglial subpopulations.We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis,sphingomyelin metabolism,and neuroinflammation at high levels.Subsequently,we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury.Finally,we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells.Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis.Furthermore,ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway.Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function.Pla2g7 formed a“bridge”between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway.Collectively,these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3,thereby exerting neuroprotective effects.
基金Supported by Ganzhou City’s“Light of the Soviet Area”Talent Project,No.GZSQZG202301009。
文摘Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases,posing a significant global public health challenge.Al-though the association between ceramides(Cers)and metabolic diseases is well-established,the role of the acid sphingomyelinase(ASMase)/Cer pathway in these diseases remains underexplored.This review synthesizes recent research on the biological functions,regulatory mechanisms,and targeted therapies related to the ASMase/Cer pathway in metabolic conditions,including obesity,diabetes,non-alcoholic fatty liver disease,and cardiovascular disease.The effects of the ASMase/Cer pathway on metabolic disease-related indicators,such as glycolipid metabolism,insulin resistance,inflammation,and mitochondrial homeostasis are elucidated.Moreover,this article discusses the therapeutic strategies using ASMase/Cer inhibitors for inverse prevention and treatment of these metabolic diseases in light of the possible efficacy of blockade of the ASMase/Cer pathway in arresting the progression of metabolic diseases.These insights offered herein should provide insight into the contribution of the ASMase/Cer pathway to metabolic diseases and offer tools to develop therapeutic interventions for such pathologies and their severe complications.
基金supported by the National Natural Science Foundation of China(Grant No.:82374552)Hunan Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.:2024JJ2086)+1 种基金the Science and Technology Innovation Program of Hunan Province,China(Grant No.:2022RC1220)Support Plan for High-level Health and Medical Talents in Hunan Province,China.
文摘Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
基金Natural Science Foundation-funded Project:the Interaction of mi RNAs and Hh Signaling Pathway in NASH Related Liver Fibrosis and the Intervention of Sagittaria Xiaozhi Pill(No.81860821)Toxin and Eliminating Phlegm Intervention Ceramide and Induced iNOS Nonalcoholic Fatty Liver Disease Fat Research of Apoptosis Signaling(No.81460710)。
文摘OBJECTIVE:To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription(慈菇消脂方,CGXZ)in the treatment of the non-alcoholic fatty liver disease(NAFLD)by detoxification and phlegm-reducing,the effect of CGXZ prescription on ceramide-mediated lipid apoptosis in Hep G2 cells with NAFLD.METHODS:The experiment was randomly divided into 6groups:normal control group,model group,CGXZ prescription medicated serum high,medium,and low dose groups,and pioglitazone positive control group.Using 500μmol/L free fatty acid(FFA)mixture to induce Hep G2 cells to establish NAFLD cell model,respectively,with 2%,4%,and 6%concentration of CGXZ prescription medicated serum intervention for 24 h.The changes in organelles and lipid droplet accumulation were observed under the electron microscope.Furthermore,Td T-mediated d UTP Nick-End Labeling method was used to assay hepatocyte apoptosis;Biochemical determination of glutamic-pyruvic transaminase,glutamic oxalacetic transaminase,triglycerides,and FFA levels in Hep G2cells;the content of ceramide was determined by highperformance thin-layer chromatography.Finally,Western Blot and quantitative real-time polymerase chain reaction(q RT-PCR)were used to determine the protein and gene expression levels,such as inducible nitric oxide synthase(i NOS),nuclear factorκB(NF-κB),B cell lymphoma 2(Bcl-2)and Bcl-2-associated X(Bax).RESULTS:Under the electron microscope,the cells in the model group showed moderate-to-severe steatosis,and apoptotic bodies could be seen.The model group had greater improvements in the apoptosis rate(P<0.01),and the levels of ceramide C2 and FFA in the cytoplasm(P<0.01)than the normal control group.The protein expressions of NF-κB,i NOS,and Bax were significantly up-regulated(P<0.05),while the Bcl-2 had no significant change(P>0.05).Compared with the model group,the levels of ceramide C2 and FFA(P<0.01),the protein expressions of NF-κB,i NOS,and Bax(P<0.05)in the CGXZ prescription treatment group and pioglitazone positive control group were significantly decreased;Only the Bcl-2 protein was significantly up-regulated in the high-dose Chinese medicine group(P<0.05).The downregulation of Bax m RNA expression in each Chinese medicine treatment group was significantly better than in the pioglitazone positive control group(P<0.01).CONCLUSIONS:The CGXZ prescription,formulated with the method of detoxification and phlegm,can inhibit lipoapoptosis in the NAFLD cell model by downregulating the levels of ceramide C2 and FFA,which may be achieved by regulating ceramide/i NOS/NF-κB signaling pathway.
文摘Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.
文摘The skin’s primary function is to protect the body against a spectrum of environmental stressors, including mechanical insults, microorganisms, chemicals, and allergens. Located in the outermost layers, the primary structures and components responsible for the skin’s barrier function are susceptible to environmental variables, dermatological conditions, and the aging process. The ensuing alterations to structure, composition, and organizational attributes of the epidermal barrier can impact its integrity and functionality. The aim of this study was to assess the effect of a novel complex composed of a ceramide, energizing peptide, and Camu Camu extract (SUPCERAT<sup>TM</sup> complex) on specific markers of epidermal barrier integrity, as well as epidermal and dermal function. All the experiments were conducted on fresh human abdominal skin explants. Intradermal production of hyaluronic acid, epidermal claudin-1, and ceramide synthase 3 expressions, as well as epidermal lipids content were assessed using specific fluorescent stainings on ex vivo skin after the application of the complex or placebo. Additionally, dermal elastase and collagenase activities were assessed using in tubo enzymatic assays. Lastly, the effect of a cosmetic cream containing SUPCERAT<sup>TM</sup> complex was assessed using subjective Global Aesthetic Improvement Scale (GAIS) in a small cohort of patients after 60 days of use. The application of the SUPCERAT<sup>TM</sup> complex on ex vivo skin led to significant increase in dermal hyaluronic acid content and epidermal activity of claudin-1, ceramide synthase 3 and epidermal ceramide content. Furthermore, in tubo enzymatic assays demonstrated inhibition of both dermal elastase and collagenase activities. In addition, the patient-reported results indicated significant improvements in skin quality and appearance. .
文摘Physical stresses such as high temperature or hyper- osmosis are known causes of intracellular ceramide (Cer) accumulation in mammalian epithelial cells;these stresses also result in the activation of the biosy- ntheses of glucosylceramide (GlcCer) or galactosyl- ceramide via ceramide glycosylation. We confirmed that intracellular Cer and GlcCer increased in mouse fibroblast Mop 8 cells under conditions of heat stress. When molecular species of Cer, GlcCer and sphingo- myelin (SM) were analyzed by matrix assisted laser desorption ionization time of flight mass spectrome- try (MALDI-TOF MS), the molecular ion peaks of Cer (d18:1 - C16:0, Na+) and Cer (d18:1 - C22:0, Na+) increased under heat stress compared with those of Cer (d18:1 - C24:1, Na+) and Cer (d18:1 - C24:0, Na+). GlcCer and SM demonstrated the wide spectra of fatty acyl chains compared with that of Cer. The ratio of GlcCer consisted of hydroxy fatty acid to that con- sisted of non-hydroxy fatty acid increased 2-5-fold in heat stressed cells. Cer metabolism-related genes, se- rine palmitoyltransferase (Spt), ceramide synthase-1, -2, -4, -5 and -6 (CerS1, -2, -4, -5 and -6), neutral sphingomyelinase-1 and -2 (nSMase1 and nS-Mase2), sphingomyelin synthase-1 (SgmS1), and ceramide glu- cosyltransferase (GlcT), were activated after 16 h un- der heat stress at 42?C. Activation of Sg-mS1 and GlcT genes played a role as Cer scavengers in the decrease of intracellular Cer levels. Activation of Cer- S5 and/or CerS6 gene may contribute to the accu- mulation of Cer species of (d18:1 - C16:0) under heat stress.
基金Supported by the National Natural Science Foundation of China,No.81904158TCM Modernization Research of National Key Research and Development Program,No.2018YFC1704202。
文摘Ceramides are significant metabolic products of sphingolipids in lipid metabolism and are associated with insulin resistance and hepatic steatosis. In chronic inflammatory pathological conditions, hypoxia occurs, the metabolism of ceramide changes, and insulin resistance arises. Hypoxia-inducible factors(HIFs)are a family of transcription factors activated by hypoxia. In hypoxic adipocytes,HIF-1α upregulates pla2 g16(a novel HIF-1α target gene) gene expression to activate the NLRP3 inflammasome pathway and stimulate insulin resistance, and adipocyte-specific Hif1 a knockout can ameliorate homocysteine-induced insulin resistance in mice. The study on the HIF-2α-NEU3-ceramide pathway also reveals the role of ceramide in hypoxia and insulin resistance in obese mice.Under obesity-induced intestinal hypoxia, HIF-2α increases the production of ceramide by promoting the expression of the gene Neu3 encoding sialidase 3,which is a key enzyme in ceramide synthesis, resulting in insulin resistance in high-fat diet-induced obese mice. Moreover, genetic and pathophysiologic inhibition of the HIF-2α-NEU3-ceramide pathway can alleviate insulin resistance, suggesting that these could be potential drug targets for the treatment of metabolic diseases. Herein, the effects of hypoxia and ceramide, especially in the intestine, on metabolic diseases are summarized.
基金supported by the Natural Science Foundation of Yunnan Province(2000B0066M)
文摘A new C-18 phytosphingosine derivative (1) was isolated from the fruiting bodies of Tuber indicum. Its structure was established as (2S, 3S, 4R, 2R)-2-N-(2-hydroxytricosano- yl)-octadecan-1, 3, 4-triol by spectral and chemical methods.
基金supported by the Knowledge Innovation Program of the Chinese Academy of Sciences(RCEES-QN-200712)the Special Funds for Young Scholars of RCEES,CAS.
文摘Objective To investigate the potential mechanisms of cell death after the treatment with ceramide. Methods MTT assay, DNA ladder, reporter assay, FACS and Western blot assay were employed to investigate the potential mechanisms of cell death after the treatment with C2-ceramide. Results A short-time treatment with C2-ceramide induced cell death, which was associated with p38 MAP kinase activation, but had no links with typical caspase activation or PARP degradation. Rather than caspase inhibitor, Inhibitor of p38 MAP kinase blocked cell death induced by a short-time treatment with ceramide （〈12 h）. However, inhibition of p38 MAP kinase could not block cell death induced by a prolonged treatment with ceramide （〉12 h）. Moreover, incubation of cells with ceramide for a long time （〉12 h） increased subG1, but reduced S phase accompanied by caspase-dependent and caspase-independent changes including NFr, B activation. Conclusion Ceramide-induced cell apoptosis involves both caspase-dependent and -independent signaling pathway. Caspase-independent cell death occurring in a relatively early stage, which is mediated via p38 MAP kinase, can progress into a stage involving both caspase-dependent and -independent mechanisms accompanied by cell signaling of MAPKs and NFκB.
基金the National Natural Science Foundation of China, No. 30471447
文摘AIM： To investigate the effect of exogenous ceramideinduced apoptosis on human colon carcinoma HT-29 cells. METHODS： Light microscope, transmission electron microscope and fluorescence microscope were used to observe the morphology change of apoptosis in HT-29 cells. Agarose gel electrophoresis was performed to detect the DNA fragment. Mitochondrial function was detected by MTT assay, mRNA expression of Bcl-2 family gene members was determined by reverse transcription polymerase chain reaction （RT-PCR） assay. RESULTS： After C2-ceramide treatment, typical characteristics of apoptosis, such as nuclear chromatin breakage, apoptotic body and DNA ladder, could be observed. After exposure to 50μmol/L C2-ceramide for 12 and 24 h, cell apoptosis was 64.1% and 81.3% respectively, which had a time-and dose-effect relationship. Mitochondrial function started to decrease from 6 h after exposure to ceramide. Meanwhile, ceramide up-regulated or down-regulated the mRNA expression of Bcl-2 family gene members. CONCLUSION： Ceramide induces apoptosis of human colon carcinoma HT-29 cells by affecting the expression of Bcl-2 family gene members and impacting the mitochondrial function.
基金Natural Science Foundation of Yunnan Province (98C086M, 98C008Z) and the National Natural Science Foundation of China (39969005)
文摘A new phytosphingosine-type ceramide, armillaramide 1, has been isolated from the fruiting bodies of Basidiomycetes Armillaria mellea (Vahl ex Fr.) Quel. Its structure was established as (2S, 3S. 4R)-2-N-(palmitoyl)-phytosphingosine by spectroscopic and chemical methods.
基金Supported by INSERM,the SociétéFrancophone du Diabètean Agence Nationale de la Recherche grant project(Crisalis)
文摘In healthy people,balance between glucose production and its utilization is precisely controlled.When circulating glucose reaches a critical threshold level,pancreaticβcells secrete insulin that has two major actions:to lower circulating glucose levels by facilitating its uptake mainly into skeletal muscle while inhibiting its production by the liver.Interestingly,dietary triglycerides are the main source of fatty acids to fulfill energy needs of oxidative tissues.Normally,the unconsumed fraction of excess of fatty acids is stored in lipid droplets that are localized in adipocytes to provide energy during fasting periods.Thus,adipose tissue acts as a trap for fatty acid excess liberated from plasma triglycerides.When the buffering action of adipose tissue to store fatty acids is impaired,fatty acids that build up in othertissues are metabolized as sphingolipid derivatives such as ceramides.Several studies suggest that ceramides are among the most active lipid second messengers to inhibit the insulin signaling pathway and this review describes the major role played by ceramide accumulation in the development of insulin resistance of peripherals tissues through the targeting of specific proteins of the insulin signaling pathway.
基金This work was supported by the National Science Foundation of China !(960012).
文摘A new ceramide, humesamide, was isolated from the soft coral Cladiella humesi Verseveldt, which was collected from Linshui County of Hainan Province. Its structure was established by spectroscopic analysis and chemical degradation methods.
文摘A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as (25,35,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-l,3,4-triol(I)and 1-O-β-D-glucopyranosy1-(2S,3S,4R,8E)-2-[(2'R)-hydroxy-hexade-canoylamino]-8-tetracosene-1,3,4-triol (II) on the basis of chemical and spectroscopic studies.
文摘AIM： To investigate the effect of ceramide on the cell cycle in human hepatocarcinoma Bel7402 cells. Possible molecular mechanisms were explored. METHODS： [3- （4, 5）-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide （MTT） assay, plasmid transfection, reporter assay, FACS and Western blotting analyses were employed to investigate the effect and the related molecular mechanisms of C2-ceramide on the cell cycle of Bel7402 cells. RESULTS： C2-ceramide was found to inhibit the growth of Bel7402 cells by indudng cell cycle arrest. During the process, the expression of p21 protein increased, while that of cyclinD1, phospho-ERKl/2 and c-myc decreased. Furthermore, the level of CDK7 was downregulated, while the transcriptional activity of PPARy was upregulated. Addition of GW9662, which is a PPARy specific antagonist, could reserve the modulation action on CDK7. CONCLUSION： Our results support the hypothesis that cell cycle arrest induced by C2-ceramide may be mediated via accumulation of p21 and reduction of cyclinD1 and CDK7, at least partly, through PPARy activation. The ERK signaling pathway was involved in this process.
基金supported by grants from the National Natural Science Foundation of China (No.30871200)the Practice and Innovation Training Program for Students in Colleges and Universities of Jiangsu Province (NO.20090370)
文摘Objective:To explore the role that ceramide plays in the activation of mitogen-activated protein kinases(MAPKs)during cerebral ischemia and reperfusion.Methods:Rats were subjected to ischemia by the fourvessel occlusion(4-VO)method.The sphingomyelinase inhibitor TPCK was administered to the CA1 subregion of the rat hippocampus before inducing ischemia.Western blot was used to examine the activity of extracellular-signal regulated kinase(ERK)and c-Jun N-terminal protein kinase(JNK)using antibodies against ERK,JNK and diphosphorylated ERK and JNK.Results:At lh reperfusion post-ischemia,JNK reached its peak activity while ERK was undergoing a sharp inactivation(P〈0.05).The level of diphosphorylated JNK was significantly reduced but the sharp inactivation of ERK was visibly reversed(P〈0.05)by the sphingomyelinase inhibitor.Conclusion:The ceramide signaling pathway is up-regulated through sphingomyelin hydrolysis in brain ischemia,promoting JNK activation and suppressing ERK activation,culminating in the ischemic lesion.
基金supported by the Key Project of Chinese Ministry of Education(No.209116)
文摘Two new ceramides,(2S,3S,4R)-2-N-[(2 R)-2 -hydroxypentacosanoylamino]-nonacosane-1,3,4-triol(1) and(2S,3S,4R,8E)-2- N-[(2 R)-2 -hydroxytetracosanoylamino]-8-eicosylene-1,3,4-triol(2) have been isolated from the stems of Piper betle L.collected from Baoshan city of Yunnan Province in China.Their structures were determined by spectroscopic and chemical methods.
基金supported by the Technological Project of Science and Technology Department of Henan Province in China,No.122102310205the National Natural Science Foundation of China,No.30771140,31070952,U1204311
文摘Prenatal alcohol exposure, especially during early pregnancy, can lead to fetal alcohol syndrome. The pharmacological and toxicological mechanisms of ethanol are related to the effects of ceramide In this study, we established an alcohol exposure model in wild-type mice and in knockout mice for the key enzyme involved in ceramide metabolism, sphingomyelin synthase 2. This model received daily intragastric administration of 25% ethanol, and pups were used at postnatal days 0, 7, 14, 30 for experiments. Serology and immunofluorescence staining found that ethanol exposure dose-dependently reduced blood sphingomyelin levels in two genotypes of pups, and increased neural cell proliferation and the number of new neurons in the hippocampal dentate gyrus. Western blot analysis showed that the relative expression level of protein kinase C e increased in two genotypes of pups after ethanol exposure. Compared with witd-type pups, the expression level of the important activator protein of the ceramide/ceramide-l-phosphate pathway, protein kinase C a, was reduced in the hippocampus of sphingomyelin synthase 2 knockouts. Our findings illustrate that ceramide is involved in alcohol-induced neural proliferation in the hippocampal dentate gyrus of pups after prenatal ethanol exposure, and the mechanism may be associated with increased ex- pression of protein kinase C a activating the ceramide/ceramide-l-phosphate pathway.
基金supported by the Science and Technology Development Fund(STDF)(No.6554)
文摘In the present study, a new ceramide, namely 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diol(1), along with four known steroids, including 24-methylcholesta-5, 24(28)-diene-3β-ol(2), 24-methylcholesta-5, 24(28)-diene-3β-acetate(3), 4-methyl-24-methylcholesta- 22-ene-3-ol(4), and cholesterol, was isolated and characterized from CH2Cl2/Me OH extract of Cespitularia stolonifera. A new acetate derivative of compound 1, termed 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diacetate(1a), was also prepared in the present study. All the structures were established on the basis of modern spectroscopic techniques, including FT-IR, 1D, 2D-NMR, HRESI-MS, and GC-MS, in addition of chemical methods.(-)-Alloaromadendren, ledane,(1)-alloaromadendren oxide, isoaromadendrene epoxide and(-)-caryophellen oxide were identified from the n-hexane fraction using GC-MS. The extract and the two ceramides(1) and(1a) exhibited significant cytotoxic activity against lung cancer A549 cells, while the extract and the two steroids(2) and(3) exhibited significant cytotoxic activity against breast cancer MCF-7 cells. The CH_2Cl_2/MeOH extract exhibited significant antiulcer activity in both ethanol and acetic acid induced ulcer models in rats, as evidenced by histopathological, histochemical, and biochemical examinations.
