Dear Editor,Hepatitis B virus(HBV)is a small,enveloped DNA virus and a member of the Hepadnaviridae family(Zhao et al.,2020).It is a major human pathogen causing chronic liver disease,leading to significant morbidity ...Dear Editor,Hepatitis B virus(HBV)is a small,enveloped DNA virus and a member of the Hepadnaviridae family(Zhao et al.,2020).It is a major human pathogen causing chronic liver disease,leading to significant morbidity and mortality worldwide(Xia and Liang,2019).According to the World Health Organization(WHO),an estimated 296 million people live with chronic HBV infection,contributing to around 820,000 deaths annually due to complications such as liver cirrhosis and hepatocellular carcinoma(HCC)(Easterbrook et al.,2021).展开更多
In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation...In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.展开更多
Sphingolipids, a new class of lipid mediators, are involved in a variety of important physiological and pathological processes. Sphingomyelin synthase （SMS） is an enzyme to convert the ceramide （Cer.） and phosphat...Sphingolipids, a new class of lipid mediators, are involved in a variety of important physiological and pathological processes. Sphingomyelin synthase （SMS） is an enzyme to convert the ceramide （Cer.） and phosphatidylcholine into sphingomyelin （SM） and diacylglycerol, which plays a key role in sphingolipid biosynthesis. Two SMS isoforms, SMS1 and SMS2, have been identified with different subceUular localizations and expression level in tissues. Previous studies have shown that SMS may serve as a potential therapeutic target for the treatment of various diseases, such as cardiovascular and metabolic diseases. Thus, there is an urgent need for a rapid and sensitive method for SMS activity analysis. In our study, we developed a novel method for SMS activity by monitoring the appearance of the product, NBD-SM, in the tissue culture medium or blood and applied this method in cells and mice. In Huh7 cells, the interassay coefficient of variation of the SMS activity assay was （3.60±0.07）% . In wild type （WT） mice, we observed accumulation of NBD-SM in blood in a time dependent fashion. In SMS2 KO mice, NBD-SM in plasma collected at 5- （0%, P〈0.01）, 30- （16%, P〈0.01）, and 60 min （21%, P〈0.01） after injection of fluorescence liposome solution was significantly decreased compared with WT mice. However, in SMS1 KO mice, NBD-SM in plasma collected 5- and 30 min is similar to that in WT mice. Our results suggest that this method could be used for SMS activity measurement in vitro and in vivo.展开更多
Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with aci...Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.展开更多
BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methy...BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells.However,its aberrant regulation in GC has not been fully elucidated.AIM To excavate the role of METTL5 in the development of GC.METHODS METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry,western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples.The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays,colony formation assays,scratch healing assays,transwell assays and flow cytometry.The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model.The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification.Next,liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism,which was confirmed by Enzyme-linked immunosorbent assay and rescue tests.In addition,we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments.RESULTS Our research revealed substantial upregulation of METTL5,which suggested a poor prognosis of GC patients.Increased METTL5 expression indicated distant lymph node metastasis,advanced cancer stage and pathological grade.An increased level of METTL5 correlated with a high degree of m6A methylation.METTL5 markedly promotes the proliferation,migration,and invasion of GC cells in vitro.METTL5 also promotes the growth of GC in animal models.METTL5 knockdown resulted in significant changes in sphingomyelin metabolism,which implies that METTL5 may impact the development of GC via sphingomyelin metabolism.In addition,high METTL5 expression led to cisplatin resistance.CONCLUSION METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.展开更多
The interaction of trivalent lanthanide ions and divalent calcium ions with sph-'ngomyelm bilayer has been studied by FT-Raman spectroscopy.The results showed that the bonding of metal ions to the phosphate group ...The interaction of trivalent lanthanide ions and divalent calcium ions with sph-'ngomyelm bilayer has been studied by FT-Raman spectroscopy.The results showed that the bonding of metal ions to the phosphate group of sphingomyelin bi-iayer,either La3+or Ca2+did not change the conformation of the choline group,that is,O-C-C-N+is still in its gauche conformation.The presence of metal ions changed the states of the interfacial region from liquid-like to amorphous state and even to crystalline.They increased the fluidity of acyl chains of sphingomyelin bilaver and made them packed disorderly.展开更多
This report investigated the ordering of the alky chain of sphingomyelin （SMs） monolayers induced by cholesterol at the air/water interface using high-resolution broadband sum frequency generation vibrational spectr...This report investigated the ordering of the alky chain of sphingomyelin （SMs） monolayers induced by cholesterol at the air/water interface using high-resolution broadband sum frequency generation vibrational spectroscopy （HR-BB-SFG-VS）. The SFG spectra of the three nature sphingomyelin/cholesterol mixture monolayers with two concentrations of the cholesterol at the air/water interface are performed under different polarization combination. A new resolved CH2 symmetric stretching （d＋, ~2834 cm-1） and the CH3 symmetric stretching （r＋, ~2874 cm-1） mode are applied to characterize the conformational order in the sphingomyelin/cholesterol mixture monolayers. It was found that the cholesterol make the sphingosine backbones more conformational order. During this process, the conformational order of the N-linked acyl chain remains unaltered. Moreover, the sphingosine backbones of SMs have much larger contributions to gauche defects of SMs than one in the N-linked acyl chain. These results presented here not only shed lights on understanding of the interactions of sphingomyelin molecules with cholesterol molecules at interface but also demonstrates the ability of HR-BB-SFG to probe such complicated molecular systems.展开更多
Gastric cancer(GC)is a global health problem and a leading cause of cancerrelated deaths,with its mortality rate ranking third among all cancers.The etiology and progression of GC are characterized by a complex interp...Gastric cancer(GC)is a global health problem and a leading cause of cancerrelated deaths,with its mortality rate ranking third among all cancers.The etiology and progression of GC are characterized by a complex interplay of genetic and epigenetic changes,which present challenges for its early diagnosis and effective treatment.Elucidating the mechanisms underlying the occurrence and development of GC and identifying novel biomarkers for early detection and prognosis are crucial to improving patient outcomes.This editorial examines the role of methyltransferase-like 5(METTL5)in the progression of GC through sphingomyelin metabolism by considering an article published by Zhang et al in the World Journal of Gastrointestinal Oncology in 2024,which is entitled“METTL5 promotes GC progression via sphingomyelin metabolism”.These authors investigated the biological behavior of METTL5 in GC by examining its expression patterns,clinical relevance,functional effect,and potential mechanisms,as well as its response to chemotherapy.This editorial provides valuable insights into the role of METTL5 in the progression of GC and its potential as a therapeutic target.展开更多
Dry eye disease(DED)is a prevalent and intractable ocular disease induced by a variety of causes.Elevated sphingomyelin(SM)levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients,part...Dry eye disease(DED)is a prevalent and intractable ocular disease induced by a variety of causes.Elevated sphingomyelin(SM)levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients,particularly in the meibomian glands.Sphingomyelin synthase 2(SMS2),one of the proteins involved in SM synthesis,would light a novel way of developing a DED therapy strategy.Herein,we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis(IC50,SMS2 Z 28 nmol/L).Moreover,14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells(HCEC)under TNF-a-hyperosmotic stress conditions in vitro,with an acceptable ocular specific distribution(corneas and meibomian glands)and pharmacokinetics(PK)profiles(t_(1/2,cornea)= 1.11 h;t_(1/2,meibomian glands) = 4.32 h)in rats.Furthermore,14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice.Mechanically,14l reduced the mRNA expression of Tnf-a,Il-1b and Mmp-9 in corneas,as well as the proportion of very long chain SM in meibomian glands.Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.展开更多
Nearly 30%of patients with schizophrenia respond inadequately to current antipsychotics,with unclear markers and mechanisms of antipsychotic efficacy.A total of 208 patients with schizophrenia treated for 6 weeks with...Nearly 30%of patients with schizophrenia respond inadequately to current antipsychotics,with unclear markers and mechanisms of antipsychotic efficacy.A total of 208 patients with schizophrenia treated for 6 weeks with oral paliperidone were analyzed through genotyping,mass spectrometry proteomic,and metabolomic profiling to explore underlying markers and mechanisms of antipsychotic efficacy.Machine learning analysis identified 20 proteins and 20 metabolites at baseline predictive of treatment response.Proteomic and metabolomic models achieved a cross-site mean AUC of 0.923 and 0.816,respectively.A multi-omics ensemble model achieved 0.941.GWAS and differential analyses identified 32 loci(P<5×10-5),83 proteins,and 31 metabolites associated with efficacy(P<0.05).Trans-omics analysis of these efficacy-related molecules across three omic layers highlighted glycerophospholipid metabolism(P=3.25×10-5)and sphingolipid metabolism(P=0.039).Key molecules within these pathways exhibited a consistent direction of effect in regulating phosphatidylcholine(PC)and sphingomyelin(SM)metabolism,and higher PC and SM levels were found to correlate with better efficacy.These associations were further genetically validated using polygenic risk scores in two independent cohorts(2281 and 449 patients,respectively).In conclusion,multi-omics modeling is able to accurately identify antipsychotic efficacy,and higher PC and SM levels correlate with better antipsychotic efficacy,suggesting that variations in phospholipid metabolism may underlie the response to antipsychotics.展开更多
A novel series of eight SMS and sPLA2 dual inhibitors containing indole and a-amino cyanide fragments of different length and substitution position was synthesized and evaluated by three different in vitro assays. Bio...A novel series of eight SMS and sPLA2 dual inhibitors containing indole and a-amino cyanide fragments of different length and substitution position was synthesized and evaluated by three different in vitro assays. Biological evaluation showed that all compounds provided inhibitory effects against SMS （about 50% inhibition at 100 μmol/L） and sPLA2 （14-32 μmol/L）. All the compounds had the SMS activity better than the positive control compound D609 in SMS2 homogenate, with compounds 5b and fie ideal for liver homogenate and SMS2 high expression cell homogenate, respectively.展开更多
Sphingomyelin synthase （SMS） produces sphingomyelin and diacylglycerol from ceramide and phosphatidyl- choline. It plays an important role in cell survival and apoptosis, inflammation, and lipid homeostasis, and the...Sphingomyelin synthase （SMS） produces sphingomyelin and diacylglycerol from ceramide and phosphatidyl- choline. It plays an important role in cell survival and apoptosis, inflammation, and lipid homeostasis, and therefore has been noticed in recent years as a novel potential drug target. In this study, we combined homology modeling, molecular docking, molecular dynamics simulation, and normal mode analysis to derive a three-dimensional struc- ture of human sphingomyelin synthase （hSMS 1） in complex with sphingomyelin. Our model provides a reasonable explanation on the catalytic mechanism of hSMS 1. It can also explain the high selectivity of hSMS 1 towards phos- phocholine and sphingomyelin as well as some other known experimental results about hSMS1. Moreover, we also derived a complex model of D609, the only known small-molecule inhibitor of hSMS 1 so far. Our hSMS 1 model may serve as a reasonable structural basis for the discovery of more effective small-molecule inhibitors of hSMS 1.展开更多
With the wide application of rare earth in agriculture, medicament, especially theapplication of Gd-DTPA as nuclear magnetic resonance image reagent in clinical prac-tice, the studies on the toxicology in biological b...With the wide application of rare earth in agriculture, medicament, especially theapplication of Gd-DTPA as nuclear magnetic resonance image reagent in clinical prac-tice, the studies on the toxicology in biological body, as well as the study on the use asinformative probes instead of divalent calcium ion in biological and biochemical researchhave attracted intensive concern.展开更多
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
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
基金supported by the National Key Research and Development Program of China(No.2023YFC2308500)the Fundamental Research Funds for the Central Universities(project no.2042024kf0026),the Open Grant from the Pingyuan Laboratory(2023PY-OP-0101)+3 种基金the National Natural Science Foundation of China(project no.81971936,32100125 and 32300131)Hubei Province's Outstanding Medical Academic Leader Program,East Lake Hi-tech Development Zone Unveiling and Commanding Project(No.2023KJB219)Science and Technology Talent Service Enterprise Project(No.2024DJC064)Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital,Wuhan University.
文摘Dear Editor,Hepatitis B virus(HBV)is a small,enveloped DNA virus and a member of the Hepadnaviridae family(Zhao et al.,2020).It is a major human pathogen causing chronic liver disease,leading to significant morbidity and mortality worldwide(Xia and Liang,2019).According to the World Health Organization(WHO),an estimated 296 million people live with chronic HBV infection,contributing to around 820,000 deaths annually due to complications such as liver cirrhosis and hepatocellular carcinoma(HCC)(Easterbrook et al.,2021).
基金supported by the National Key Research and Development Program of ChinaNos.2021YFC2 701800 and 2021YFC2 701805 (to QY)+2 种基金Open Research Fund of State Key Laboratory of Genetic EngineeringFudan UniversityNo.SKLGE-21 19 (to TXH and QY)
文摘In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.
基金Shanghai Natural Science Fund(Grant No.09ZR140430)partially supported by grants National Institute of Health(Grant No.HL69817),VA Merit 00090001
文摘Sphingolipids, a new class of lipid mediators, are involved in a variety of important physiological and pathological processes. Sphingomyelin synthase （SMS） is an enzyme to convert the ceramide （Cer.） and phosphatidylcholine into sphingomyelin （SM） and diacylglycerol, which plays a key role in sphingolipid biosynthesis. Two SMS isoforms, SMS1 and SMS2, have been identified with different subceUular localizations and expression level in tissues. Previous studies have shown that SMS may serve as a potential therapeutic target for the treatment of various diseases, such as cardiovascular and metabolic diseases. Thus, there is an urgent need for a rapid and sensitive method for SMS activity analysis. In our study, we developed a novel method for SMS activity by monitoring the appearance of the product, NBD-SM, in the tissue culture medium or blood and applied this method in cells and mice. In Huh7 cells, the interassay coefficient of variation of the SMS activity assay was （3.60±0.07）% . In wild type （WT） mice, we observed accumulation of NBD-SM in blood in a time dependent fashion. In SMS2 KO mice, NBD-SM in plasma collected at 5- （0%, P〈0.01）, 30- （16%, P〈0.01）, and 60 min （21%, P〈0.01） after injection of fluorescence liposome solution was significantly decreased compared with WT mice. However, in SMS1 KO mice, NBD-SM in plasma collected 5- and 30 min is similar to that in WT mice. Our results suggest that this method could be used for SMS activity measurement in vitro and in vivo.
基金supported from grants of Swedish Research CouncilSwedish Cancerfonden+2 种基金Albert P?hlsson FoundationCrafoord Foundationfoundation of Region Skane University Hospital, Lund, Sweden
文摘Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.
文摘BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells.However,its aberrant regulation in GC has not been fully elucidated.AIM To excavate the role of METTL5 in the development of GC.METHODS METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry,western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples.The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays,colony formation assays,scratch healing assays,transwell assays and flow cytometry.The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model.The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification.Next,liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism,which was confirmed by Enzyme-linked immunosorbent assay and rescue tests.In addition,we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments.RESULTS Our research revealed substantial upregulation of METTL5,which suggested a poor prognosis of GC patients.Increased METTL5 expression indicated distant lymph node metastasis,advanced cancer stage and pathological grade.An increased level of METTL5 correlated with a high degree of m6A methylation.METTL5 markedly promotes the proliferation,migration,and invasion of GC cells in vitro.METTL5 also promotes the growth of GC in animal models.METTL5 knockdown resulted in significant changes in sphingomyelin metabolism,which implies that METTL5 may impact the development of GC via sphingomyelin metabolism.In addition,high METTL5 expression led to cisplatin resistance.CONCLUSION METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.
基金Supported by the National Natural Sciences Foundation of China
文摘The interaction of trivalent lanthanide ions and divalent calcium ions with sph-'ngomyelm bilayer has been studied by FT-Raman spectroscopy.The results showed that the bonding of metal ions to the phosphate group of sphingomyelin bi-iayer,either La3+or Ca2+did not change the conformation of the choline group,that is,O-C-C-N+is still in its gauche conformation.The presence of metal ions changed the states of the interfacial region from liquid-like to amorphous state and even to crystalline.They increased the fluidity of acyl chains of sphingomyelin bilaver and made them packed disorderly.
基金the National Natural Science Foundation of China(No.21227802)the National Natural Science Foundation of China(Nos. 21503235, 21673251)the ICCAS for Start-up Funding
文摘This report investigated the ordering of the alky chain of sphingomyelin （SMs） monolayers induced by cholesterol at the air/water interface using high-resolution broadband sum frequency generation vibrational spectroscopy （HR-BB-SFG-VS）. The SFG spectra of the three nature sphingomyelin/cholesterol mixture monolayers with two concentrations of the cholesterol at the air/water interface are performed under different polarization combination. A new resolved CH2 symmetric stretching （d＋, ~2834 cm-1） and the CH3 symmetric stretching （r＋, ~2874 cm-1） mode are applied to characterize the conformational order in the sphingomyelin/cholesterol mixture monolayers. It was found that the cholesterol make the sphingosine backbones more conformational order. During this process, the conformational order of the N-linked acyl chain remains unaltered. Moreover, the sphingosine backbones of SMs have much larger contributions to gauche defects of SMs than one in the N-linked acyl chain. These results presented here not only shed lights on understanding of the interactions of sphingomyelin molecules with cholesterol molecules at interface but also demonstrates the ability of HR-BB-SFG to probe such complicated molecular systems.
基金Supported by Jiangsu Commission of Health,No.LKZ2023012Social Development Project of Zhenjiang City,No.SS2023011.
文摘Gastric cancer(GC)is a global health problem and a leading cause of cancerrelated deaths,with its mortality rate ranking third among all cancers.The etiology and progression of GC are characterized by a complex interplay of genetic and epigenetic changes,which present challenges for its early diagnosis and effective treatment.Elucidating the mechanisms underlying the occurrence and development of GC and identifying novel biomarkers for early detection and prognosis are crucial to improving patient outcomes.This editorial examines the role of methyltransferase-like 5(METTL5)in the progression of GC through sphingomyelin metabolism by considering an article published by Zhang et al in the World Journal of Gastrointestinal Oncology in 2024,which is entitled“METTL5 promotes GC progression via sphingomyelin metabolism”.These authors investigated the biological behavior of METTL5 in GC by examining its expression patterns,clinical relevance,functional effect,and potential mechanisms,as well as its response to chemotherapy.This editorial provides valuable insights into the role of METTL5 in the progression of GC and its potential as a therapeutic target.
基金supported by the National Key R&D Program of China(2023YFC3603303 and 2023YFA0915000)the National Natural Science Foundation of China(22077019 and 82171102)+3 种基金Shanghai Municipal Committee of Science and Technology(21TQ016 and 21XD1420600,China)the Shanghai Medical Innovation Research Program(22Y21900900,China)the Shanghai Key Clinical Research Program(SHDC2020CR3052B,China)the Class IV Peak Disciplines(Shanghai Institute of Precision Medicine)from the Shanghai Municipal Education Commission.The authors would like to thank Professor Weiyun Shi(Shandong Eye Hospital,Ji’nan,China).
文摘Dry eye disease(DED)is a prevalent and intractable ocular disease induced by a variety of causes.Elevated sphingomyelin(SM)levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients,particularly in the meibomian glands.Sphingomyelin synthase 2(SMS2),one of the proteins involved in SM synthesis,would light a novel way of developing a DED therapy strategy.Herein,we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis(IC50,SMS2 Z 28 nmol/L).Moreover,14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells(HCEC)under TNF-a-hyperosmotic stress conditions in vitro,with an acceptable ocular specific distribution(corneas and meibomian glands)and pharmacokinetics(PK)profiles(t_(1/2,cornea)= 1.11 h;t_(1/2,meibomian glands) = 4.32 h)in rats.Furthermore,14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice.Mechanically,14l reduced the mRNA expression of Tnf-a,Il-1b and Mmp-9 in corneas,as well as the proportion of very long chain SM in meibomian glands.Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.
基金supported by the National Natural Science Foundation of China(82330042,82441005,82501802,82301687,82571710)National Key R&D Program of China(2023YFE0119400)+6 种基金Capital’s Funds for Health Improvement and Research(2024-1-4111)STI2030-Major Projects(2021ZD0200702)Beijing Municipal Health Commission Research Ward Programme(3rd batch)Beijing Nova Program(20230484425)China Postdoctoral Science Foundation(2024M760141)National Postdoctoral Program for Innovative Talents(BX20240029)Peking University Medicine Sailing Program for Young Scholars’Scientific&Technological Innovation,the Fundamental Research Funds for the Central Universities(BMU2025YFJHPY044).
文摘Nearly 30%of patients with schizophrenia respond inadequately to current antipsychotics,with unclear markers and mechanisms of antipsychotic efficacy.A total of 208 patients with schizophrenia treated for 6 weeks with oral paliperidone were analyzed through genotyping,mass spectrometry proteomic,and metabolomic profiling to explore underlying markers and mechanisms of antipsychotic efficacy.Machine learning analysis identified 20 proteins and 20 metabolites at baseline predictive of treatment response.Proteomic and metabolomic models achieved a cross-site mean AUC of 0.923 and 0.816,respectively.A multi-omics ensemble model achieved 0.941.GWAS and differential analyses identified 32 loci(P<5×10-5),83 proteins,and 31 metabolites associated with efficacy(P<0.05).Trans-omics analysis of these efficacy-related molecules across three omic layers highlighted glycerophospholipid metabolism(P=3.25×10-5)and sphingolipid metabolism(P=0.039).Key molecules within these pathways exhibited a consistent direction of effect in regulating phosphatidylcholine(PC)and sphingomyelin(SM)metabolism,and higher PC and SM levels were found to correlate with better efficacy.These associations were further genetically validated using polygenic risk scores in two independent cohorts(2281 and 449 patients,respectively).In conclusion,multi-omics modeling is able to accurately identify antipsychotic efficacy,and higher PC and SM levels correlate with better antipsychotic efficacy,suggesting that variations in phospholipid metabolism may underlie the response to antipsychotics.
基金The work was funded by the National Natural Science Foundation of China，Specialized Research Fund for the Doctoral Program of Higher Education，Chinese Ministry of Education,the open grant of the State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS,and open grant of Institute of Bioscience,Fudan University
文摘A novel series of eight SMS and sPLA2 dual inhibitors containing indole and a-amino cyanide fragments of different length and substitution position was synthesized and evaluated by three different in vitro assays. Biological evaluation showed that all compounds provided inhibitory effects against SMS （about 50% inhibition at 100 μmol/L） and sPLA2 （14-32 μmol/L）. All the compounds had the SMS activity better than the positive control compound D609 in SMS2 homogenate, with compounds 5b and fie ideal for liver homogenate and SMS2 high expression cell homogenate, respectively.
基金Project supported by the National Natural Science Foundation of China （Nos.30973641, 20902013）, a special research fund for the Doctoral Program of Higher Education from the Chinese Ministry of Education （No. 20090071110054） and an open grant from the State Key Laboratory of Bio-organic and Natural Products Chemistry, Chinese Academy of Sciences.
文摘Sphingomyelin synthase （SMS） produces sphingomyelin and diacylglycerol from ceramide and phosphatidyl- choline. It plays an important role in cell survival and apoptosis, inflammation, and lipid homeostasis, and therefore has been noticed in recent years as a novel potential drug target. In this study, we combined homology modeling, molecular docking, molecular dynamics simulation, and normal mode analysis to derive a three-dimensional struc- ture of human sphingomyelin synthase （hSMS 1） in complex with sphingomyelin. Our model provides a reasonable explanation on the catalytic mechanism of hSMS 1. It can also explain the high selectivity of hSMS 1 towards phos- phocholine and sphingomyelin as well as some other known experimental results about hSMS1. Moreover, we also derived a complex model of D609, the only known small-molecule inhibitor of hSMS 1 so far. Our hSMS 1 model may serve as a reasonable structural basis for the discovery of more effective small-molecule inhibitors of hSMS 1.
基金Project supported by the National Natural Science Foundation of China.
文摘With the wide application of rare earth in agriculture, medicament, especially theapplication of Gd-DTPA as nuclear magnetic resonance image reagent in clinical prac-tice, the studies on the toxicology in biological body, as well as the study on the use asinformative probes instead of divalent calcium ion in biological and biochemical researchhave attracted intensive concern.
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 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.
