Background Sphingolipids(SL)are key regulators of inflammatory processes,yet their roles in dairy cows remain poorly understood.This study investigated the effects of inflammation(plasma haptoglobin concentration),ket...Background Sphingolipids(SL)are key regulators of inflammatory processes,yet their roles in dairy cows remain poorly understood.This study investigated the effects of inflammation(plasma haptoglobin concentration),ketosis,and mastitis on plasma SL profiles in Holstein cows sampled seven days postpartum.From a cohort of 427 cows across 25 farms,80 animals were classified into four groups:inflammation(n=20),ketosis(n=19),mastitis(n=21),and healthy controls(n=20).Plasma SL were quantified by targeted HPLC-MS/MS,while cytokines were quantified with a 15-plex bead-based assay.Both univariate and multivariate analyses were applied to assess pathological effects,along with SL ratios and correlations between SL and cytokines.Results Systemic inflammation detected through the haptoglobin measure induced the most pronounced alterations in SL metabolism,characterized by elevated dihydrosphingomyelins(DHSM)and lactosylceramides(Lac Cer),higher C22-24:C16 ratios,and lower unsaturated:saturated ratios in ceramides(Cer)and sphingomyelins(SM).Although total Cer,SM,and the Cer:SM ratio remained unchanged,specific reductions were observed in both Cer and SM in C14,Cer C18:1,SM C16:1,and SM C23:1,whereas SM C25:0 and C26:0 increased.Sphingosine-1-phosphate(So1P)was positively correlated with IL-10 as well as IL-1α and TNFα,while C18-20 Cer correlated positively with multiple pro-inflammatory cytokines and chemokines such as CXCL8 and CCL2.Ketosis induced subtler changes,primarily an increase in plasma DHSM and DHSM:SM ratio(driven by C16:0),an increase in C22-24:C16 DHCer ratio,and a decrease in both Lac So:Lac Cer and unsaturated:saturated ratios in C23-SM.In this group,So1P correlated positively with CXCL8 and CCL2.Moreover C18-20 Cer and DHCer were positively associated with CXCL8,CCL2,CCL3,and CCL4,which also showed correlations with most Lac Cer species.Analysis of chronic mastitis cases yielded a clear separation from controls in multivariate analysis but only minimal changes in SL concentrations and ratios,maybe due to the localized nature of the inflammatory response.Conclusions In summary,heightened inflammatory response in early post-partum is associated with the strongest systemic effects on SL metabolism,followed by ketosis,while mastitis induced only modest alterations.These findings highlight condition-specific patterns of SL regulation postpartum and suggest potential immunometabolic biomarkers of disease.展开更多
Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play...Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation,apoptosis,and metastasis through metabolic interconversions,including phosphorylation,glycosylation,and the generation of sphingosine-1-phosphate.This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression.Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites,such as sphingosine-1-phosphate,which collectively influence tumor growth and the therapeutic response.Additional sphingolipid species,including glucosylceramide and gangliosides(GD2,GD3,GM1,and GM3),have also been implicated in promoting breast cancer development.Furthermore,sphingolipid-based therapeutic strategies,including immunotherapy and antibody therapy,are discussed.By providing a comprehensive overview of sphingolipid metabolism,this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmito...A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmitoyldihydrosphingosine （C）, were isolated from two marine-derived mangrove endophytic fungal strains （strains No. 1924 and 3893） from the South China Sea. Their structures were elucidated by 2D NMR and FABMS methods. It is the first time that these sphingolipids were separated and obtained from marine-derived mangrove endophytic fungus from the South China Sea.展开更多
Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphing...Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases.Moreover,blood sphingolipids can also be used as biomarkers for disease diagnosis.This review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains.The possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also discussed.Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.展开更多
8-Sphingolipid desaturase is the key enzyme that catalyses desaturation at the C8 position of the long-chain base of sphingolipids in higher plants. There have been no previous studies on the genes encoding AS-sphingo...8-Sphingolipid desaturase is the key enzyme that catalyses desaturation at the C8 position of the long-chain base of sphingolipids in higher plants. There have been no previous studies on the genes encoding AS-sphingolipid desaturases in Brassica rapa. In this study, four genes encoding AS-sphingolipid desaturases from B. rapa were isolated and characterised. Phylogenetic analyses indicated that these genes could be divided into two groups： BrD8A, BrD8C and BrD8D in group I, and BrD8B in group II. The two groups of genes diverged before the separation of Arabidopsis and Brassica. Though the four genes shared a high sequence similarity, and their coding desaturases all located in endoplasmic reticulum, they exhibited distinct expression patterns. Heterologous expression in Saccharomyces cerevisiae revealed that BrD8A/B/C/D were functionally diverse AS-sphingolipid desaturases that catalyse different ratios of the two products 8（Z）- and 8（E）-C18-phytosphingenine. The aluminium tolerance of transgenic yeasts expressing BrD8A/B/C/D was enhanced compared with that of control cells. Expression of BrD8A in Arabidopsis changed the ratio of 8（Z）：8（E）-C 18-phytosphingenine in transgenic plants. The information reported here provides new insights into the biochemical functional diversity and evolutionary relationship of AS-sphingolipid desaturase in plants and lays a foundation for further investigation of the mechanism of 8（Z）- and 8（E）-C18- phytosphingenine biosynthesis.展开更多
The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an a...The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an altered SL pathway exists, and contributes to the pathogenesis of hepatic steatosis associated with obesity. Steatotic and non-steatotic livers were procured from Zucker Obese female rats and their lean counterparts in this pre-clinical study, and assessed for enzymes involved in degradation as well as in phos-phorylation of proapoptotic SLs. The expression of enzymes [sphingo-myelinase (SMase), ceramidase, and sphingosine kinase-1 (SK1)] and apoptotic proteins (Bax and Bcl-2) was quantified by ELISA and by Western Blot. Sphingomyelin (SM), ceramide, ceramide-1 phosphate (C1P), sphingosine (SPH), and sphingosine-1-phosphate (S1P) levels were quantified by high-performance liquid chroma-tography (HPLC)-tandem mass spectroscopy (MS). Obese steatotic livers exhibited significantly upregulated ceramidase and down-regulated SK1 and C1P levels (P < 0.05), as well as significantly lower levels of SM and higher levels of ceramide species containing long chain fatty acids, compared to their lean counterparts. These findings demonstrate that obese liver harbours SLs that favour a proapoptotic environment. Moreover, accumulation of ceramides containing long chain fatty acids could be involved in the pathogenesis of hepatic steatosis.展开更多
The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell ...The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.展开更多
Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16...Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.展开更多
The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases...The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to theplasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.展开更多
Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly eleva...Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids(CBAs),which are correlated with bile duct obstruction.展开更多
Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune ...Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune response,and drug sensitivity.Methods:Data were obtained from The Cancer Genome Atlas(TCGA)-Hepatocellular Carcinoma(LIHC)and Gene Expression Omnibus(GEO,GSE14520 datasets).47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database.After classifying HCC samples using the Non-negative Matrix Factorization(NMF)clustering method,differentially expressed genes were screened.Then,8 risk genes were obtained by univariate analysis,survival random forest reduction and lasso analysis.The expression of 8 risk genes was verified in vitro.Results:8 risk genes were used to construct the Sphingolipid score model.High-Sphingolipid score predicted poor prognosis of HCC patients.Sphingolipid score was associated with immune checkpoints(IL-1B,TLR4,TGFB1,and IL-10),immune cells(Th2,Treg,MDSC,Neutrophil,Fibroblasts and macrophage),and MAPK Cascade.In the High-Sphingolipid score group,a significantly higher proportion of patients with TP53(p53)mutations was significantly higher(56%).Furthermore,patients with a high-Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs.In vitro validation showed that compared with normal liver cells LX-2,TRIM47,and S100A9 significantly increased in liver cancer cells Hep G2,MHCC-97H,and Hep3B2.1-7,while SLC1A7,LPCAT1,and CFHR4 significantly decreased.Silencing TRIM47 reduced the proliferation and promoted apoptosis.The levels of ceramide synthesis-related indexes(CERS1,CERS6,CERS5,and SPTLC2)increased,and the ACER3 related to catalytic hydrolysis decreased.Conclusion:We constructed a sphingolipid metabolism-related prognostic signature(Sphingolipid score)based on 8 risk genes.TRIM47 may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis.展开更多
Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a high...Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes.Ceramide(Cer),which is the central molecule of this network,has been established to induce apoptosis.However,another molecule,sphingosine-1-phosphate(S1P),exerts the opposite function,i.e.,serves as a regulator of pro-survival.Other sphingolipid molecules,including dihydroceramide,ceramide-1-phosphate,glucosylceramide(Glu Cer),and sphingosine(Sph),or sphingolipid catalytic enzymes such as Sph kinase(Sph K),Cer synthase(Cer S),and S1 P lyase,have also attracted considerable attention,particularly Cer,Glu Cer,Sph K,Cer S,and S1 P lyase,which have been implicated in cisplatin resistance.This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin,particularly in relation to induction of apoptosis and drug resistance.展开更多
Decades of international research highlight the dynamic interplay between dietary patterns and systemic metabolism.Emerging evidence underscores the central role of sphingolipids and their metabolic pathways in regula...Decades of international research highlight the dynamic interplay between dietary patterns and systemic metabolism.Emerging evidence underscores the central role of sphingolipids and their metabolic pathways in regulating diverse physiological processes.However,the links between specific diets,sphingolipidomic remodeling,and metabolic outcomes remain underexplored.This study employed transcriptomic and sphingo-lipidomic analyses to profile diet-specific sphingolipid signatures and metabolic alterations in the liver,serum,and hypothalamus of mice fed Mediterranean(MD),ketogenic(KD),intermittent fasting(IF),or Western(WD)diets,with standard chow(CD)as the control group.Notably,substantial remodeling of sphingolipid metabolism was observed across dietary interventions,particularly in the salvage and de novo synthesis pathways.The MD and KD groups revealed reduced hepatic and serum levels of pro-inflammatory long-chain ceramides,e.g.,Cer(d18:1/16:0),Cer(d18:1/18:0),while increasing cardioprotective ultra-long-chain ceramides,e.g.,Cer(d18:1/26:0).In contrast,WD was associated with widespread ceramide accumulation in these tissues,along with upregulation of DEGS1/2.IF and WD uniquely enriched 1-deoxyceramides,e.g.,1-deoxyCer(m18:0/16:0),lipids associated with metabolic dysfunction.Given the role of the hypothalamus in metabolic regulation,its tran-scriptome analysis revealed diet-specific modulation of sphingolipid-related genes.Taken together,MD and KD emerged as favorable dietary patterns for restoring sphingolipid homeostasis,whereas WD exacerbated patho-logical lipid signatures.This study provides a resource for clarifying potential mechanistic links between dietary patterns and lipid metabolism,offering insights into metabolic disease prevention.展开更多
Juvenile dietary-induced glucolipid metabolic disruption impairs cognitive development,though the underlying molecular mechanisms remain unclear.3-week old mice were subjected to a 12-week dietary intervention with se...Juvenile dietary-induced glucolipid metabolic disruption impairs cognitive development,though the underlying molecular mechanisms remain unclear.3-week old mice were subjected to a 12-week dietary intervention with sequentially decreasing glucose-to-fat ratios.Behavioral tests demonstrated generalized cognitive dysfunction in high-sugar diet(HSD)mice and selective NORT deficits in medium-sugar diet(MSD)mice.Serum metabolomics indicated enriched sphingolipid metabolism in HSD(p=0.14)and MSD(p=0.03)groups,marked by elevated dihydrosphingosine levels.These changes,associated with Sptlc1 upregulation and CerS/SPHK1 downregulation,ultimately enhanced hippocampal inflammatory responses,as evidenced by the increased mRNA expression of TNF-α,IL-6 and IL-β.HSD-induced AMPK inhibition indirectly upregulated Sptlc1 expression,as evidenced by a significant correlation between them(ρ=-0.69,p<0.01).Moreover,the upregulated short-chain sphingomyelins in HSD mice may impair neuronal membrane function,thereby amplifying the neurotoxic effects of sphingolipid imbalance.Collectively,this study demonstrates that a high-glucose diet impairs cognitive development through sphingolipid dysregulation and reveals the neurotoxicity of specific intermediate metabolites,offering new insights into optimal carbohydrate intake.展开更多
Insulin resistance is connection to immoderate glucose producing and unusual lipid metabolism,which is principal to diabetes.Rhinacanthus nasutus(L.)Kurz(R.nasutus)is a medicinal and edible plant used for thou-sands o...Insulin resistance is connection to immoderate glucose producing and unusual lipid metabolism,which is principal to diabetes.Rhinacanthus nasutus(L.)Kurz(R.nasutus)is a medicinal and edible plant used for thou-sands of years,and the R.nasutus“tea bags”is widely used as an edible material to treat diabetes.Rhinacanthin C(RC)was reported to be the main active components of R.nasutus,which has the effect of treating diabetes.The study aims to explore the effects and mechanism of RC and Rhinacanthins-rich extract(RRE)on the glycolipid metabolism of HepG2 cells under insulin resistance via network pharmacology,untargeted metabolomics and molecular pharmacology.As a result,network pharmacology analysis predicted that RRE could anti-diabetes by insulin resistance signal pathway.In vitro studies indicated that RC and RRE ameliorated the strangeness of glycolipid metabolism and inhibited the activation of IRS1/PI3K/Akt/GSK 3βsignal pathway in insulin resistant HepG2(IR-HepG2)cells.Untargeted metabolomics analysis showed that RC and RRE could affect sphingolipid metabolism and other metabolic pathways.Furthermore,RC and RRE were found to regulate insulin resistance through sphingolipid metabolism proved by Western blot analysis.Hence,it was suggested that RC and RRE might be involved in the glycolipid metabolism of IR-HepG2 cells through the IRS1/PI3K/AKT/GSK 3βsignal pathway and the sphingolipid metabolic pathway.Overall,this study could provide the active mechanism of the components RC and RRE from R.nasutus in regulating insulin resistance,also it could providenew ideas for the development of functional foods derived from R.nasutus.展开更多
Lung cancer remains a leading cause of cancer-related mortality worldwide.Sphingolipids,a diverse class of lipids featuring a sphingoid base backbone,play essential roles in cellular processes and membrane structure.C...Lung cancer remains a leading cause of cancer-related mortality worldwide.Sphingolipids,a diverse class of lipids featuring a sphingoid base backbone,play essential roles in cellular processes and membrane structure.Complex sphingolipids such as sphingomyelins and glycosphingolipids maintain membrane integrity,while their metabolites—ceramide,sphingosine,and their phosphorylated forms,ceramide-1-phosphate(C1P)and sphingosine-1-phosphate(S1P)—act as bioactive lipids involved in regulating key cellular functions.Ceramide and sphingosine are generally tumor-suppressive,promoting apoptosis and inhibiting cell proliferation,whereas C1P and S1P support tumor progression through enhanced cell survival,proliferation,angiogenesis,and metastasis.S1P exerts its effects via G protein-coupled S1P receptors(S1PRs)and intracellular pathways,while C1P acts primarily through intracellular signaling.Dysregulation of these metabolites contributes to lung cancer pathogenesis,influencing tumor survival and resistance to therapy.Targeting sphingolipid metabolism—either by enhancing ceramide and sphingosine levels or inhibiting C1P and S1P—has shown promise in preclinical models.Moreover,these sphingolipid metabolites hold potential as biomarkers for diagnosis and prognosis in lung cancer.This review explores the roles of sphingolipids in lung cancer biology,their impact on tumor progression,and their therapeutic potential.展开更多
Background:Renal osteodystrophy(ROD)is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder(CKD-MBD)that is characterized by aberrant bone mineralization and remodeling.ROD increases t...Background:Renal osteodystrophy(ROD)is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder(CKD-MBD)that is characterized by aberrant bone mineralization and remodeling.ROD increases the risk of fracture and mortality in CKD patients.The underlying mechanisms of ROD remain elusive,partially due to the absence of an appropriate animal model.To address this gap,we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing(RNA-seq).Methods:Eight-week-old male C57BL/6J mice were randomly allocated into three groups:control group(n=5),adenine and high-phosphate(HP)diet group(n=20),and the optimized adenine-containing diet group(n=20)for 12 weeks.We assessed the skeletal characteristics of model mice through blood biochemistry,microcomputed tomography(micro-CT),and bone histomorphometry.RNA-seq was utilized to profile gene expression changes of ROD.We elucidated the functions of differentially expressed genes(DEGs)using gene ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis,and gene set enrichment analysis(GSEA).DEGs were validated via quantitative real-time polymerase chain reaction(qRT-PCR).Results:By the fifth week,adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group,precluding further model development.Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels,accompanied by pronounced hyperparathyroidism and hyperphosphatemia.The femur bone mineral density(BMD)of the model mice was lower than that of control mice,with substantial bone loss and cortical porosity.ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers.Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice.Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway.The significant upregulation of alkaline ceramidase 1(Acer1),alkaline ceramidase 2(Acer2),prosaposin-like 1(Psapl1),adenosine A1 receptor(Adora1),and sphingosine-1-phosphate receptor 5(S1pr5)were successfully validated in mouse femurs by qRT-PCR.Conclusions:Optimized adenine diet mouse model may be a valuable proxy for studying ROD.RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis,thereby providing new avenues for therapeutic intervention.展开更多
Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in...Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in plant signal transduction in response to environmental cues are yet to be investigated in detail. In this review,we discuss the signaling roles of sphingolipid metabolites with a focus on plant sphingolipids.We also mention some microbial sphingolipids that initiate signals during their interaction with plants, because of the limited literatures on their plant analogs.The equilibrium of nonphosphorylated and phosphorylated sphingolipid species determine the destiny of plant cells,whereas molecular connections among the enzymes responsible for this equilibrium in a coordinated signaling network are poorly understood.A mechanistic link between the phytohormone-sphingolipid interplay has also not yet been fully understood and many key participants involved in this complex interaction operating under stress conditions await to be identified.Future research is needed to fill these gaps and to better understand the signal pathways of plant sphingolipids and their interplay with other signals in response to environmental stresses.展开更多
Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter rel...Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.展开更多
基金partly funded by APIS-GENEsupported by a grant Bonus QualitéRecherche(BQR)s from ENVT。
文摘Background Sphingolipids(SL)are key regulators of inflammatory processes,yet their roles in dairy cows remain poorly understood.This study investigated the effects of inflammation(plasma haptoglobin concentration),ketosis,and mastitis on plasma SL profiles in Holstein cows sampled seven days postpartum.From a cohort of 427 cows across 25 farms,80 animals were classified into four groups:inflammation(n=20),ketosis(n=19),mastitis(n=21),and healthy controls(n=20).Plasma SL were quantified by targeted HPLC-MS/MS,while cytokines were quantified with a 15-plex bead-based assay.Both univariate and multivariate analyses were applied to assess pathological effects,along with SL ratios and correlations between SL and cytokines.Results Systemic inflammation detected through the haptoglobin measure induced the most pronounced alterations in SL metabolism,characterized by elevated dihydrosphingomyelins(DHSM)and lactosylceramides(Lac Cer),higher C22-24:C16 ratios,and lower unsaturated:saturated ratios in ceramides(Cer)and sphingomyelins(SM).Although total Cer,SM,and the Cer:SM ratio remained unchanged,specific reductions were observed in both Cer and SM in C14,Cer C18:1,SM C16:1,and SM C23:1,whereas SM C25:0 and C26:0 increased.Sphingosine-1-phosphate(So1P)was positively correlated with IL-10 as well as IL-1α and TNFα,while C18-20 Cer correlated positively with multiple pro-inflammatory cytokines and chemokines such as CXCL8 and CCL2.Ketosis induced subtler changes,primarily an increase in plasma DHSM and DHSM:SM ratio(driven by C16:0),an increase in C22-24:C16 DHCer ratio,and a decrease in both Lac So:Lac Cer and unsaturated:saturated ratios in C23-SM.In this group,So1P correlated positively with CXCL8 and CCL2.Moreover C18-20 Cer and DHCer were positively associated with CXCL8,CCL2,CCL3,and CCL4,which also showed correlations with most Lac Cer species.Analysis of chronic mastitis cases yielded a clear separation from controls in multivariate analysis but only minimal changes in SL concentrations and ratios,maybe due to the localized nature of the inflammatory response.Conclusions In summary,heightened inflammatory response in early post-partum is associated with the strongest systemic effects on SL metabolism,followed by ketosis,while mastitis induced only modest alterations.These findings highlight condition-specific patterns of SL regulation postpartum and suggest potential immunometabolic biomarkers of disease.
基金supported by National Research Foundation(NRF)of Korea grants funded by the Korean government,the Ministry of Science and ICT[NRF-2022R1A2C1006737 to Joo-Won Park,NRF-2022R1I1A1A0106408112 to Min Hee Kim].
文摘Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors.Among various regulatory molecules,sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation,apoptosis,and metastasis through metabolic interconversions,including phosphorylation,glycosylation,and the generation of sphingosine-1-phosphate.This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression.Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites,such as sphingosine-1-phosphate,which collectively influence tumor growth and the therapeutic response.Additional sphingolipid species,including glucosylceramide and gangliosides(GD2,GD3,GM1,and GM3),have also been implicated in promoting breast cancer development.Furthermore,sphingolipid-based therapeutic strategies,including immunotherapy and antibody therapy,are discussed.By providing a comprehensive overview of sphingolipid metabolism,this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
基金the National ＂863＂ Program of China （No. 2001AA624010）the Guangdong Provincial Natural Science Foundation of China （No. 04300674）+1 种基金 the Guangdong Provincial Science and Technology Program Foundation of China （No.2004B30101017） the Foshan City Foundation for the Development of Science and Technology （No. 2005081871）.
文摘A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmitoyldihydrosphingosine （C）, were isolated from two marine-derived mangrove endophytic fungal strains （strains No. 1924 and 3893） from the South China Sea. Their structures were elucidated by 2D NMR and FABMS methods. It is the first time that these sphingolipids were separated and obtained from marine-derived mangrove endophytic fungus from the South China Sea.
基金supported by grants from National Key R&D Program of China(2018YFA0506900,2018YFA0800901)the National Natural Science Foundation of China(NSFC92057202)the Chinese Academy of Sciences(XDB39050900).
文摘Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases.Moreover,blood sphingolipids can also be used as biomarkers for disease diagnosis.This review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains.The possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also discussed.Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.
基金supported by the National High-tech R&D Program(863 Program,No.2006AA10A113) of the Ministry of Science and Technology of Chinathe projects of Ministry of Agriculture of China for Transgenic Research (Nos.2009ZX08009-098B and 2008ZX08009-003)
文摘8-Sphingolipid desaturase is the key enzyme that catalyses desaturation at the C8 position of the long-chain base of sphingolipids in higher plants. There have been no previous studies on the genes encoding AS-sphingolipid desaturases in Brassica rapa. In this study, four genes encoding AS-sphingolipid desaturases from B. rapa were isolated and characterised. Phylogenetic analyses indicated that these genes could be divided into two groups： BrD8A, BrD8C and BrD8D in group I, and BrD8B in group II. The two groups of genes diverged before the separation of Arabidopsis and Brassica. Though the four genes shared a high sequence similarity, and their coding desaturases all located in endoplasmic reticulum, they exhibited distinct expression patterns. Heterologous expression in Saccharomyces cerevisiae revealed that BrD8A/B/C/D were functionally diverse AS-sphingolipid desaturases that catalyse different ratios of the two products 8（Z）- and 8（E）-C18-phytosphingenine. The aluminium tolerance of transgenic yeasts expressing BrD8A/B/C/D was enhanced compared with that of control cells. Expression of BrD8A in Arabidopsis changed the ratio of 8（Z）：8（E）-C 18-phytosphingenine in transgenic plants. The information reported here provides new insights into the biochemical functional diversity and evolutionary relationship of AS-sphingolipid desaturase in plants and lays a foundation for further investigation of the mechanism of 8（Z）- and 8（E）-C18- phytosphingenine biosynthesis.
文摘The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an altered SL pathway exists, and contributes to the pathogenesis of hepatic steatosis associated with obesity. Steatotic and non-steatotic livers were procured from Zucker Obese female rats and their lean counterparts in this pre-clinical study, and assessed for enzymes involved in degradation as well as in phos-phorylation of proapoptotic SLs. The expression of enzymes [sphingo-myelinase (SMase), ceramidase, and sphingosine kinase-1 (SK1)] and apoptotic proteins (Bax and Bcl-2) was quantified by ELISA and by Western Blot. Sphingomyelin (SM), ceramide, ceramide-1 phosphate (C1P), sphingosine (SPH), and sphingosine-1-phosphate (S1P) levels were quantified by high-performance liquid chroma-tography (HPLC)-tandem mass spectroscopy (MS). Obese steatotic livers exhibited significantly upregulated ceramidase and down-regulated SK1 and C1P levels (P < 0.05), as well as significantly lower levels of SM and higher levels of ceramide species containing long chain fatty acids, compared to their lean counterparts. These findings demonstrate that obese liver harbours SLs that favour a proapoptotic environment. Moreover, accumulation of ceramides containing long chain fatty acids could be involved in the pathogenesis of hepatic steatosis.
基金Supported by Grants from the National Institutes of Health (NS40516,to Yenari MA)the Veteran's Merit Award(Yenari MA)+3 种基金the Uehara Foundation(2013 Research Fellowship,to Kawabori M)the National Heart,Lung,and Blood Institute/NHLBI(1P01 HL 68738 and R01 HL 090606 to Karliner JS)Grants to Yenari MA and Karliner JS were administered by the Northern California Institute for Research and Educationsupported by resources of the Veterans Affairs Medical Center, San Francisco,California
文摘The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.
基金Supported by the National Natural Science Foundation of China(Nos.42076086,41576166)the Natural Science Foundation of Fujian Province(No.2020J05138)+1 种基金the Education and Research Project for Young and Middle-aged Teachers of Fujian Province(No.JAT190343)the Cultivation Plan for Distinguished Young Scholars in Fujian Universities。
文摘Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.
基金Supported by The James Graham Brown Cancer Center and NIH, No. CA111987
文摘The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to theplasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.
文摘Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids(CBAs),which are correlated with bile duct obstruction.
基金The work was supported by funds from The Science and Technology Project of Hangzhou City(Agriculture and Social Development,No.2016007)&(Agriculture and Social Development,No.20201231Y131)&(Social Development,No.20140633B57)The Science and Technology Project of Yuhang District,Hangzhou City(Nos.2017002&2014003)+2 种基金The Health Science and Technology Project of Hangzhou City(No.2015B32)Zhejiang Provincial Natural Science Foundation of China under Grant(No.LTGY23H160006)The Health Science and Technology Project of Zhejiang Province(No.2023XY009).
文摘Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune response,and drug sensitivity.Methods:Data were obtained from The Cancer Genome Atlas(TCGA)-Hepatocellular Carcinoma(LIHC)and Gene Expression Omnibus(GEO,GSE14520 datasets).47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database.After classifying HCC samples using the Non-negative Matrix Factorization(NMF)clustering method,differentially expressed genes were screened.Then,8 risk genes were obtained by univariate analysis,survival random forest reduction and lasso analysis.The expression of 8 risk genes was verified in vitro.Results:8 risk genes were used to construct the Sphingolipid score model.High-Sphingolipid score predicted poor prognosis of HCC patients.Sphingolipid score was associated with immune checkpoints(IL-1B,TLR4,TGFB1,and IL-10),immune cells(Th2,Treg,MDSC,Neutrophil,Fibroblasts and macrophage),and MAPK Cascade.In the High-Sphingolipid score group,a significantly higher proportion of patients with TP53(p53)mutations was significantly higher(56%).Furthermore,patients with a high-Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs.In vitro validation showed that compared with normal liver cells LX-2,TRIM47,and S100A9 significantly increased in liver cancer cells Hep G2,MHCC-97H,and Hep3B2.1-7,while SLC1A7,LPCAT1,and CFHR4 significantly decreased.Silencing TRIM47 reduced the proliferation and promoted apoptosis.The levels of ceramide synthesis-related indexes(CERS1,CERS6,CERS5,and SPTLC2)increased,and the ACER3 related to catalytic hydrolysis decreased.Conclusion:We constructed a sphingolipid metabolism-related prognostic signature(Sphingolipid score)based on 8 risk genes.TRIM47 may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis.
文摘Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes.Ceramide(Cer),which is the central molecule of this network,has been established to induce apoptosis.However,another molecule,sphingosine-1-phosphate(S1P),exerts the opposite function,i.e.,serves as a regulator of pro-survival.Other sphingolipid molecules,including dihydroceramide,ceramide-1-phosphate,glucosylceramide(Glu Cer),and sphingosine(Sph),or sphingolipid catalytic enzymes such as Sph kinase(Sph K),Cer synthase(Cer S),and S1 P lyase,have also attracted considerable attention,particularly Cer,Glu Cer,Sph K,Cer S,and S1 P lyase,which have been implicated in cisplatin resistance.This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin,particularly in relation to induction of apoptosis and drug resistance.
基金supported by the Youth Cross-innovation Research Program of CFSE-OUC(No.2024104)Youth Talent Project Launch Fund of Ocean University of China(No.862401013170)Post-doctoral Fellowship Program of CPSF(No.GZB20240695).
文摘Decades of international research highlight the dynamic interplay between dietary patterns and systemic metabolism.Emerging evidence underscores the central role of sphingolipids and their metabolic pathways in regulating diverse physiological processes.However,the links between specific diets,sphingolipidomic remodeling,and metabolic outcomes remain underexplored.This study employed transcriptomic and sphingo-lipidomic analyses to profile diet-specific sphingolipid signatures and metabolic alterations in the liver,serum,and hypothalamus of mice fed Mediterranean(MD),ketogenic(KD),intermittent fasting(IF),or Western(WD)diets,with standard chow(CD)as the control group.Notably,substantial remodeling of sphingolipid metabolism was observed across dietary interventions,particularly in the salvage and de novo synthesis pathways.The MD and KD groups revealed reduced hepatic and serum levels of pro-inflammatory long-chain ceramides,e.g.,Cer(d18:1/16:0),Cer(d18:1/18:0),while increasing cardioprotective ultra-long-chain ceramides,e.g.,Cer(d18:1/26:0).In contrast,WD was associated with widespread ceramide accumulation in these tissues,along with upregulation of DEGS1/2.IF and WD uniquely enriched 1-deoxyceramides,e.g.,1-deoxyCer(m18:0/16:0),lipids associated with metabolic dysfunction.Given the role of the hypothalamus in metabolic regulation,its tran-scriptome analysis revealed diet-specific modulation of sphingolipid-related genes.Taken together,MD and KD emerged as favorable dietary patterns for restoring sphingolipid homeostasis,whereas WD exacerbated patho-logical lipid signatures.This study provides a resource for clarifying potential mechanistic links between dietary patterns and lipid metabolism,offering insights into metabolic disease prevention.
基金supported by National Natural Science Foundation of China(No.22278182)the National Food and Strategic Reserves Administration for Young Top Talents Program(QN2022506)the Jiangsu Province“Collaborative Innovation Center of Food Safety and Quality Control”industry development program.
文摘Juvenile dietary-induced glucolipid metabolic disruption impairs cognitive development,though the underlying molecular mechanisms remain unclear.3-week old mice were subjected to a 12-week dietary intervention with sequentially decreasing glucose-to-fat ratios.Behavioral tests demonstrated generalized cognitive dysfunction in high-sugar diet(HSD)mice and selective NORT deficits in medium-sugar diet(MSD)mice.Serum metabolomics indicated enriched sphingolipid metabolism in HSD(p=0.14)and MSD(p=0.03)groups,marked by elevated dihydrosphingosine levels.These changes,associated with Sptlc1 upregulation and CerS/SPHK1 downregulation,ultimately enhanced hippocampal inflammatory responses,as evidenced by the increased mRNA expression of TNF-α,IL-6 and IL-β.HSD-induced AMPK inhibition indirectly upregulated Sptlc1 expression,as evidenced by a significant correlation between them(ρ=-0.69,p<0.01).Moreover,the upregulated short-chain sphingomyelins in HSD mice may impair neuronal membrane function,thereby amplifying the neurotoxic effects of sphingolipid imbalance.Collectively,this study demonstrates that a high-glucose diet impairs cognitive development through sphingolipid dysregulation and reveals the neurotoxicity of specific intermediate metabolites,offering new insights into optimal carbohydrate intake.
基金supported by a grant from the National Natural Sci-ence Foundation of China(Grant No.32372245,32172169)the grant from Tianjin Municipal Science and Technology Foundation(Grant No.22JCYBJC00160)the grant from National Key Research and Development Program of China(Grant No.2021YFE0110000).
文摘Insulin resistance is connection to immoderate glucose producing and unusual lipid metabolism,which is principal to diabetes.Rhinacanthus nasutus(L.)Kurz(R.nasutus)is a medicinal and edible plant used for thou-sands of years,and the R.nasutus“tea bags”is widely used as an edible material to treat diabetes.Rhinacanthin C(RC)was reported to be the main active components of R.nasutus,which has the effect of treating diabetes.The study aims to explore the effects and mechanism of RC and Rhinacanthins-rich extract(RRE)on the glycolipid metabolism of HepG2 cells under insulin resistance via network pharmacology,untargeted metabolomics and molecular pharmacology.As a result,network pharmacology analysis predicted that RRE could anti-diabetes by insulin resistance signal pathway.In vitro studies indicated that RC and RRE ameliorated the strangeness of glycolipid metabolism and inhibited the activation of IRS1/PI3K/Akt/GSK 3βsignal pathway in insulin resistant HepG2(IR-HepG2)cells.Untargeted metabolomics analysis showed that RC and RRE could affect sphingolipid metabolism and other metabolic pathways.Furthermore,RC and RRE were found to regulate insulin resistance through sphingolipid metabolism proved by Western blot analysis.Hence,it was suggested that RC and RRE might be involved in the glycolipid metabolism of IR-HepG2 cells through the IRS1/PI3K/AKT/GSK 3βsignal pathway and the sphingolipid metabolic pathway.Overall,this study could provide the active mechanism of the components RC and RRE from R.nasutus in regulating insulin resistance,also it could providenew ideas for the development of functional foods derived from R.nasutus.
基金supported in part by the National Institutes of Health(NIH)grants(No.R01CA273263 and P01CA097132).
文摘Lung cancer remains a leading cause of cancer-related mortality worldwide.Sphingolipids,a diverse class of lipids featuring a sphingoid base backbone,play essential roles in cellular processes and membrane structure.Complex sphingolipids such as sphingomyelins and glycosphingolipids maintain membrane integrity,while their metabolites—ceramide,sphingosine,and their phosphorylated forms,ceramide-1-phosphate(C1P)and sphingosine-1-phosphate(S1P)—act as bioactive lipids involved in regulating key cellular functions.Ceramide and sphingosine are generally tumor-suppressive,promoting apoptosis and inhibiting cell proliferation,whereas C1P and S1P support tumor progression through enhanced cell survival,proliferation,angiogenesis,and metastasis.S1P exerts its effects via G protein-coupled S1P receptors(S1PRs)and intracellular pathways,while C1P acts primarily through intracellular signaling.Dysregulation of these metabolites contributes to lung cancer pathogenesis,influencing tumor survival and resistance to therapy.Targeting sphingolipid metabolism—either by enhancing ceramide and sphingosine levels or inhibiting C1P and S1P—has shown promise in preclinical models.Moreover,these sphingolipid metabolites hold potential as biomarkers for diagnosis and prognosis in lung cancer.This review explores the roles of sphingolipids in lung cancer biology,their impact on tumor progression,and their therapeutic potential.
基金funded by the National Natural Science Foundation of China(No.82370742)the Key Program of Jiangsu Health and Health Committee(No.ZD2022045).
文摘Background:Renal osteodystrophy(ROD)is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder(CKD-MBD)that is characterized by aberrant bone mineralization and remodeling.ROD increases the risk of fracture and mortality in CKD patients.The underlying mechanisms of ROD remain elusive,partially due to the absence of an appropriate animal model.To address this gap,we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing(RNA-seq).Methods:Eight-week-old male C57BL/6J mice were randomly allocated into three groups:control group(n=5),adenine and high-phosphate(HP)diet group(n=20),and the optimized adenine-containing diet group(n=20)for 12 weeks.We assessed the skeletal characteristics of model mice through blood biochemistry,microcomputed tomography(micro-CT),and bone histomorphometry.RNA-seq was utilized to profile gene expression changes of ROD.We elucidated the functions of differentially expressed genes(DEGs)using gene ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis,and gene set enrichment analysis(GSEA).DEGs were validated via quantitative real-time polymerase chain reaction(qRT-PCR).Results:By the fifth week,adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group,precluding further model development.Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels,accompanied by pronounced hyperparathyroidism and hyperphosphatemia.The femur bone mineral density(BMD)of the model mice was lower than that of control mice,with substantial bone loss and cortical porosity.ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers.Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice.Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway.The significant upregulation of alkaline ceramidase 1(Acer1),alkaline ceramidase 2(Acer2),prosaposin-like 1(Psapl1),adenosine A1 receptor(Adora1),and sphingosine-1-phosphate receptor 5(S1pr5)were successfully validated in mouse femurs by qRT-PCR.Conclusions:Optimized adenine diet mouse model may be a valuable proxy for studying ROD.RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis,thereby providing new avenues for therapeutic intervention.
基金the National Natural Science Foundation of China (31570808)the Fundamental Research Funds for the Central Universities (2662015PY090).
文摘Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in plant signal transduction in response to environmental cues are yet to be investigated in detail. In this review,we discuss the signaling roles of sphingolipid metabolites with a focus on plant sphingolipids.We also mention some microbial sphingolipids that initiate signals during their interaction with plants, because of the limited literatures on their plant analogs.The equilibrium of nonphosphorylated and phosphorylated sphingolipid species determine the destiny of plant cells,whereas molecular connections among the enzymes responsible for this equilibrium in a coordinated signaling network are poorly understood.A mechanistic link between the phytohormone-sphingolipid interplay has also not yet been fully understood and many key participants involved in this complex interaction operating under stress conditions await to be identified.Future research is needed to fill these gaps and to better understand the signal pathways of plant sphingolipids and their interplay with other signals in response to environmental stresses.
基金supported by the National Natural Science Foundation of China,No.82201568(to QQ)Capital’s Funds for Health Improvement and Research,No.2024-2-1031(to QQ)Beijing Nova Program,No.20240484566(to QQ).
文摘Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.
