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
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
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
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
BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile...BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile acids in the peripheral circulation reflect the amount of bile acids in the gut.Therefore,a further investigation of luminal bile acids following DJB is of great significance.AIM To investigate changes of luminal bile acids following DJB.METHODS Salicylhydroxamic acid(SHAM),DJB,and DJB with oral chenodeoxycholic acid(CDCA)supplementation were performed in a high-fat-diet/streptozotocininduced diabetic rat model.Body weight,energy intake,oral glucose tolerance test,luminal bile acids,serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTS Compared to SHAM,DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor(FXR)-inhibitory bile acids within the common limb.Intestinal ceramide synthesis was repressed with decreased serum ceramides,and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSION DJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels.There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.展开更多
The nucleus-initiated augmentation of ER membrane is reflected in a coordinated synthesis and intercalation of the explicit proteins and lipids required for the replacement, repair and function of the cell and its org...The nucleus-initiated augmentation of ER membrane is reflected in a coordinated synthesis and intercalation of the explicit proteins and lipids required for the replacement, repair and function of the cell and its organelles. The direct connection between nucleus and the membranes containing labeled sphingosine (SphN) and ceramide (Cer) was affirmed by determining synthetic activity of serine palmitoyltransferase (SPT). The SPT and the newly synthesized serine-labeled lipid products were identified in the Outer- and Inner-Nuclear Membrane (ONM, INM) and ER. The pulse-chase experiments disclosed that the incorporation of radiolabeled lipids into both nuclear membranes declined upon their simultaneous increase in Endoplasmic Reticulum (ER). These results, and prior findings regarding metabolic transfer of nuclear membrane phosphoinositides to the outer leaflet of ER [Slomiany and Slomiany, Health, 2011, 3, 187-199], allowed us to reason that INM and ONM are not distinct entities, but uninterrupted continuum facing nucleosol and then cytosol when protracted into segment known as ER. Consequently, the identification of SPT and its products in the inner leaflet of nuclear and ER microsomes lent credence to the luminal presence of Cer in Golgi, luminal synthesis of glycosphingolipids (GSphLs), sphingomyelin (SM), and their delivery to the outer leaflet of apical and basolateral cell membrane, respectively. The findings presented in this communication provide further support to our concept that the factual intercalation of proteins and lipids into the cell membranes can only take place during their simultaneous synthesis that is guided by the nuclear and cytosolic processes enacted in nuclear-ER membrane continuum. At the nuclear stage, the signal-specific genes expression promotes active synthesis and intercalation of lipids into the organelles’ customized membrane that is protracted and articulated in ER in form of transport vesicles.展开更多
A new ceramide, biemnamide, was isolated from the marine sponge Biemne sp. collected from the South China Sea and Its structure was established by spectroscopic analysis.
A new ceramide （1） was isolated from transgenic crown galls of Panax quinquefolium. The structure was elucidated as （2S, 3S, 4R, 20E）-2-[（2＇R）-2＇-hydroxylpalmitoylamino]-20-hexacosene- 1, 3, 4-triol on the bas...A new ceramide （1） was isolated from transgenic crown galls of Panax quinquefolium. The structure was elucidated as （2S, 3S, 4R, 20E）-2-[（2＇R）-2＇-hydroxylpalmitoylamino]-20-hexacosene- 1, 3, 4-triol on the basis of spectroscopic and chemical methods.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 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 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.
文摘BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile acids in the peripheral circulation reflect the amount of bile acids in the gut.Therefore,a further investigation of luminal bile acids following DJB is of great significance.AIM To investigate changes of luminal bile acids following DJB.METHODS Salicylhydroxamic acid(SHAM),DJB,and DJB with oral chenodeoxycholic acid(CDCA)supplementation were performed in a high-fat-diet/streptozotocininduced diabetic rat model.Body weight,energy intake,oral glucose tolerance test,luminal bile acids,serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTS Compared to SHAM,DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor(FXR)-inhibitory bile acids within the common limb.Intestinal ceramide synthesis was repressed with decreased serum ceramides,and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSION DJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels.There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.
文摘The nucleus-initiated augmentation of ER membrane is reflected in a coordinated synthesis and intercalation of the explicit proteins and lipids required for the replacement, repair and function of the cell and its organelles. The direct connection between nucleus and the membranes containing labeled sphingosine (SphN) and ceramide (Cer) was affirmed by determining synthetic activity of serine palmitoyltransferase (SPT). The SPT and the newly synthesized serine-labeled lipid products were identified in the Outer- and Inner-Nuclear Membrane (ONM, INM) and ER. The pulse-chase experiments disclosed that the incorporation of radiolabeled lipids into both nuclear membranes declined upon their simultaneous increase in Endoplasmic Reticulum (ER). These results, and prior findings regarding metabolic transfer of nuclear membrane phosphoinositides to the outer leaflet of ER [Slomiany and Slomiany, Health, 2011, 3, 187-199], allowed us to reason that INM and ONM are not distinct entities, but uninterrupted continuum facing nucleosol and then cytosol when protracted into segment known as ER. Consequently, the identification of SPT and its products in the inner leaflet of nuclear and ER microsomes lent credence to the luminal presence of Cer in Golgi, luminal synthesis of glycosphingolipids (GSphLs), sphingomyelin (SM), and their delivery to the outer leaflet of apical and basolateral cell membrane, respectively. The findings presented in this communication provide further support to our concept that the factual intercalation of proteins and lipids into the cell membranes can only take place during their simultaneous synthesis that is guided by the nuclear and cytosolic processes enacted in nuclear-ER membrane continuum. At the nuclear stage, the signal-specific genes expression promotes active synthesis and intercalation of lipids into the organelles’ customized membrane that is protracted and articulated in ER in form of transport vesicles.
文摘A new ceramide, biemnamide, was isolated from the marine sponge Biemne sp. collected from the South China Sea and Its structure was established by spectroscopic analysis.
基金supported by the grants from Ministry of Education of China(No.104180)Natural Sciences Foundation of Guangdong(No.31891)Chinese Traditional Medicine Administration of Guangdong,China(No.103041).
文摘A new ceramide （1） was isolated from transgenic crown galls of Panax quinquefolium. The structure was elucidated as （2S, 3S, 4R, 20E）-2-[（2＇R）-2＇-hydroxylpalmitoylamino]-20-hexacosene- 1, 3, 4-triol on the basis of spectroscopic and chemical methods.
