Two new ceramides,(2S,3S,4R)-2-N-[(2 R)-2 -hydroxypentacosanoylamino]-nonacosane-1,3,4-triol(1) and(2S,3S,4R,8E)-2- N-[(2 R)-2 -hydroxytetracosanoylamino]-8-eicosylene-1,3,4-triol(2) have been isolated from the stems ...Two new ceramides,(2S,3S,4R)-2-N-[(2 R)-2 -hydroxypentacosanoylamino]-nonacosane-1,3,4-triol(1) and(2S,3S,4R,8E)-2- N-[(2 R)-2 -hydroxytetracosanoylamino]-8-eicosylene-1,3,4-triol(2) have been isolated from the stems of Piper betle L.collected from Baoshan city of Yunnan Province in China.Their structures were determined by spectroscopic and chemical methods.展开更多
A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as (25,35,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-l,3,4-triol(I)and 1-O-β-...A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as (25,35,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-l,3,4-triol(I)and 1-O-β-D-glucopyranosy1-(2S,3S,4R,8E)-2-[(2'R)-hydroxy-hexade-canoylamino]-8-tetracosene-1,3,4-triol (II) on the basis of chemical and spectroscopic studies.展开更多
In the present study, a new ceramide, namely 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diol(1), along with four known steroids, including 24-methylcholesta-5, 24(28)-diene-3β-ol(2), 24-methylchol...In the present study, a new ceramide, namely 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diol(1), along with four known steroids, including 24-methylcholesta-5, 24(28)-diene-3β-ol(2), 24-methylcholesta-5, 24(28)-diene-3β-acetate(3), 4-methyl-24-methylcholesta- 22-ene-3-ol(4), and cholesterol, was isolated and characterized from CH2Cl2/Me OH extract of Cespitularia stolonifera. A new acetate derivative of compound 1, termed 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diacetate(1a), was also prepared in the present study. All the structures were established on the basis of modern spectroscopic techniques, including FT-IR, 1D, 2D-NMR, HRESI-MS, and GC-MS, in addition of chemical methods.(-)-Alloaromadendren, ledane,(1)-alloaromadendren oxide, isoaromadendrene epoxide and(-)-caryophellen oxide were identified from the n-hexane fraction using GC-MS. The extract and the two ceramides(1) and(1a) exhibited significant cytotoxic activity against lung cancer A549 cells, while the extract and the two steroids(2) and(3) exhibited significant cytotoxic activity against breast cancer MCF-7 cells. The CH_2Cl_2/MeOH extract exhibited significant antiulcer activity in both ethanol and acetic acid induced ulcer models in rats, as evidenced by histopathological, histochemical, and biochemical examinations.展开更多
BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile...BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile acids in the peripheral circulation reflect the amount of bile acids in the gut.Therefore,a further investigation of luminal bile acids following DJB is of great significance.AIM To investigate changes of luminal bile acids following DJB.METHODS Salicylhydroxamic acid(SHAM),DJB,and DJB with oral chenodeoxycholic acid(CDCA)supplementation were performed in a high-fat-diet/streptozotocininduced diabetic rat model.Body weight,energy intake,oral glucose tolerance test,luminal bile acids,serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTS Compared to SHAM,DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor(FXR)-inhibitory bile acids within the common limb.Intestinal ceramide synthesis was repressed with decreased serum ceramides,and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSION DJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels.There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.展开更多
Ceramides,formed by the dehydration of long-chain fatty acids with phytosphingosine and its derivatives,are widely used in skincare,cosmetics,and pharmaceuticals.Due to the exceedingly low concentration of phytos-phin...Ceramides,formed by the dehydration of long-chain fatty acids with phytosphingosine and its derivatives,are widely used in skincare,cosmetics,and pharmaceuticals.Due to the exceedingly low concentration of phytos-phingosine in plant seeds,relying on the extraction method is highly challenging.Currently,the primary method for obtaining phytosphingosine is the deacetylation of tetraacetyl phytosphingosine(TAPS)derived from fermentation.Wickerhamomyces ciferrii,an unconventional yeast from the pods of Dipteryx odorata,is the only known microorganism capable of naturally secreting TAPS,which is of great industrial value.In recent years,research and applications focused on modifying W.ciferrii for TAPS overproduction have increased rapidly.This review first describes the discovery history,applications,microbial synthesis pathway of TAPS.Research progress in using haploid breeding,mutagenesis breeding,and metabolic engineering to improve TAPS pro-duction is then summarized.In addition,the future prospects of TAPS production using the W.ciferrii platform are discussed in light of the current progress,challenges,and trends in this field.Finally,guidelines for future researches are also emphasized.展开更多
Background:Previously,dihydroceramide(d18:0/24:0)(dhCer(d18:0/24:0))was reported to be a potential biomarker for acute-onchronic liver failure(ACLF)prognosis.In this study,we further explored the role of dhCer(d18:0/2...Background:Previously,dihydroceramide(d18:0/24:0)(dhCer(d18:0/24:0))was reported to be a potential biomarker for acute-onchronic liver failure(ACLF)prognosis.In this study,we further explored the role of dhCer(d18:0/24:0)in the progression of ACLF to validate the biomarker using ACLF rat model.Methods:ACLF rats were sacrificed at 4 and 8 h post-D-galactosamine(D-gal)/lipopolysaccharide(LPS)administration to investigate the liver biochemical markers,prothrombin time and liver histopathology.Change in dhCer and other sphingolipids levels were investigated by high-performance liquid chromatography coupled to tandem mass spectrometry(HPLC-MS/MS).Rats were treated with N-(4-hydroxyphenyl)retinamide(4-HPR)to examine the mortality rate and its role in improving ACLF.Results:LPS/D-gal administration resulted in significant elevation in alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.Prothrombin time was prolonged and histopathological examination showed abnormality.HPLC-MS/MS results showed total dhCer levels in ACLF group(64.10±8.90 pmol/100 mL,64.22±6.78 pmol/100 mL for 4 and 8 h,respectively)were decreased significantly compared with control group(121.61±23.09 pmol/100 mL)(P<0.05).In particular,dhCer(d18:0/24:0),dhCer(d18:0/20:0),and dhCer(d18:0/22:0)levels were decreased.Treatment with 4-HPR significantly increased the levels of dhCers,including dhCer(d18:0/24:0)compared with ACLF group,for the level of dhCer(d18:0/24:0)in 4-HPR group was 20.10±8.60 pmol/100 mL and the level of dhCer(d18:0/24:0)in ACLF group was 9.74±2.99 pmol/100 mL(P<0.05).This was associated with reduced mortality rate and prolonged survival time.The ALT and AST in 4-HPR group were significantly decreased compared with ACLF group.The prothrombin time of 4-HPR group(41.49 s)was significantly lower than the prothrombin time of ACLF group(57.96 s)(P<0.05).4-HPR also decreased plasma ammonia levels slightly,as the plasma ammonia levels in 4-HPR group and ACLF group were 207.37±60.43,209.15±60.43 mmol/L,respectively.Further,4-HPR treatment improved histopathological parameters.Conclusions:DhCer,especially dhCer(d18:0/24:0),is involved in the progression of ACLF.Increasing the levels of dhCer can reduce the mortality rate of ACLF rats and alleviate liver injury.展开更多
This study used non-invasive evaluation methods measured six skin physiological parameters of the lower lip in 180 subjects,including moisture content,transepidermal water loss(TEWL),smoothness(SESM),scaliness of the ...This study used non-invasive evaluation methods measured six skin physiological parameters of the lower lip in 180 subjects,including moisture content,transepidermal water loss(TEWL),smoothness(SESM),scaliness of the skin(SESC),wrinkles(SEW),and red area of the lip skin,and compared the effects of 6 groups of lip balms(no-additive group,marine oligosaccharides group,ceramides group,glycyrrhizinic acid group,allantoin group,and mixed group;30 each)on the skin physiological parameters of dry,flaking,and cracked lip subjects.The results showed that the lip mositure content of the subjects in the marine oligosaccharide group,glycyrrhetinic acid group,and allantoin group increased significantly by 44.40%,42.84%and 58.08%after 7 days of lip balm(P<0.05).The TEWL in the ceramide group and the allantoin group was significantly reduced by 21.83%and 24.72%,respectively,after 7 days of lip paste use(P<0.05).The lip skin smoothness values of subjects in the glycyrrhizic acid group and the allantoin group were significantly reduced by 18.76%and 14.97%,respectively,after 28 days of lip balm application(P<0.05).The lip skin scaling indices of subjects in the marine oligosaccharide group,the ceramides group,and the allantoin group were significantly reduced by 33.77%,42.69%,and 38.07%,respectively,after 28 days of lip balm application(P<0.05).The wrinkle parameters of the lip skin of the subjects in the marine oligosaccharide,glycyrrhizinic acid and allantoin groups were significantly reduced by 23.06%,23.29%and 25.98%,respectively,after 28 days of lip balm application(P<0.05).And the area of the red zone of the lip skin of the subjects in the allantoin group was significantly reduced by 4.27%,after 28 days of lip balm application(P<0.05).Combining the effects of the four active ingredients on the secretion of hyaluronic acid(moisturizing effect)and inflammatory factor(IL-6)in HSF cells,it suggests that marine oligosaccharides and allantoin have a perfect impact on enhancing the water content of the skin on the lips of the subjects,and further improve the symptoms of flaking and wrinkles on the lips of the subjects.The ceramide and allantoin can repair the skin barrier well and have a good effect on the chapped and flaky lips of the subjects.After 28 days of using lip balm,the water content of lips in the mixed group increased,the skin barrier was repaired and became smoother,and the wrinkles,scale index,and red zone value were reduced,which could well relieve chronic lip inflammation and lay a foundation for developing lip products for the treatment of chronic cheilitis.展开更多
Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and t...Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.展开更多
Two new ceramides were isolated from the 95% EtOH extract of traditional Chinese medicinal plant Isatis indigotica. Their structures were elucidated as 1-O-β-D-glucopyranosyl-(2S, 3R)-N-(2'-hydroxypentacosanoyl)-...Two new ceramides were isolated from the 95% EtOH extract of traditional Chinese medicinal plant Isatis indigotica. Their structures were elucidated as 1-O-β-D-glucopyranosyl-(2S, 3R)-N-(2'-hydroxypentacosanoyl)-octadeca-11E-sphingenine (1) and 1-O-β-D-glucopyranosyl-(2S,3R)-N-(2'-hydroxyhe xacosanoyl)-octadeca-11E-sphingenine (2) on the basis of spectroscopic data. Their cytotoxic effects were evaluated by using MTT method.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
Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases,posing a significant global public health challenge.Al-though the association between ceramides(Cers)and metabolic disease...Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases,posing a significant global public health challenge.Al-though the association between ceramides(Cers)and metabolic diseases is well-established,the role of the acid sphingomyelinase(ASMase)/Cer pathway in these diseases remains underexplored.This review synthesizes recent research on the biological functions,regulatory mechanisms,and targeted therapies related to the ASMase/Cer pathway in metabolic conditions,including obesity,diabetes,non-alcoholic fatty liver disease,and cardiovascular disease.The effects of the ASMase/Cer pathway on metabolic disease-related indicators,such as glycolipid metabolism,insulin resistance,inflammation,and mitochondrial homeostasis are elucidated.Moreover,this article discusses the therapeutic strategies using ASMase/Cer inhibitors for inverse prevention and treatment of these metabolic diseases in light of the possible efficacy of blockade of the ASMase/Cer pathway in arresting the progression of metabolic diseases.These insights offered herein should provide insight into the contribution of the ASMase/Cer pathway to metabolic diseases and offer tools to develop therapeutic interventions for such pathologies and their severe complications.展开更多
Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biog...Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin.We report,for the first time,that human tau expression elevates brain ceramides and nSMase2 activity.Methods To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model.Additionally,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus.The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored.We examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse plasma.Results Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC treatment.The PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human AD.PDDC treatment reduced these changes.The plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated mice.In the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slowing of tau spread in AD mice.展开更多
Ceramides are important signaling molecules involved in a variety of cellular processes, including cell growth, differentiation, and apoptosis. Currently, different methods are used for ceramide analysis, some of whic...Ceramides are important signaling molecules involved in a variety of cellular processes, including cell growth, differentiation, and apoptosis. Currently, different methods are used for ceramide analysis, some of which are insensitive or cumbersome. This paper described methods utilizing thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) followed by evaporative light scattering detection (ELSD) to detect ceramide directly in cell extracts without derivatization, which was proved to be efficient and reproducible. Five kinds of ceramides were used as standards. Both TLC and normal-phase HPLC/ELSD results indicate that yeast contains several kinds of ceramides.展开更多
OBJECTIVE:To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription(慈菇消脂方,CGXZ)in the treatment of the non-alcoholic fatty liver disease(NAFLD)by detoxification and phlegm-reducing,the effect of ...OBJECTIVE:To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription(慈菇消脂方,CGXZ)in the treatment of the non-alcoholic fatty liver disease(NAFLD)by detoxification and phlegm-reducing,the effect of CGXZ prescription on ceramide-mediated lipid apoptosis in Hep G2 cells with NAFLD.METHODS:The experiment was randomly divided into 6groups:normal control group,model group,CGXZ prescription medicated serum high,medium,and low dose groups,and pioglitazone positive control group.Using 500μmol/L free fatty acid(FFA)mixture to induce Hep G2 cells to establish NAFLD cell model,respectively,with 2%,4%,and 6%concentration of CGXZ prescription medicated serum intervention for 24 h.The changes in organelles and lipid droplet accumulation were observed under the electron microscope.Furthermore,Td T-mediated d UTP Nick-End Labeling method was used to assay hepatocyte apoptosis;Biochemical determination of glutamic-pyruvic transaminase,glutamic oxalacetic transaminase,triglycerides,and FFA levels in Hep G2cells;the content of ceramide was determined by highperformance thin-layer chromatography.Finally,Western Blot and quantitative real-time polymerase chain reaction(q RT-PCR)were used to determine the protein and gene expression levels,such as inducible nitric oxide synthase(i NOS),nuclear factorκB(NF-κB),B cell lymphoma 2(Bcl-2)and Bcl-2-associated X(Bax).RESULTS:Under the electron microscope,the cells in the model group showed moderate-to-severe steatosis,and apoptotic bodies could be seen.The model group had greater improvements in the apoptosis rate(P<0.01),and the levels of ceramide C2 and FFA in the cytoplasm(P<0.01)than the normal control group.The protein expressions of NF-κB,i NOS,and Bax were significantly up-regulated(P<0.05),while the Bcl-2 had no significant change(P>0.05).Compared with the model group,the levels of ceramide C2 and FFA(P<0.01),the protein expressions of NF-κB,i NOS,and Bax(P<0.05)in the CGXZ prescription treatment group and pioglitazone positive control group were significantly decreased;Only the Bcl-2 protein was significantly up-regulated in the high-dose Chinese medicine group(P<0.05).The downregulation of Bax m RNA expression in each Chinese medicine treatment group was significantly better than in the pioglitazone positive control group(P<0.01).CONCLUSIONS:The CGXZ prescription,formulated with the method of detoxification and phlegm,can inhibit lipoapoptosis in the NAFLD cell model by downregulating the levels of ceramide C2 and FFA,which may be achieved by regulating ceramide/i NOS/NF-κB signaling pathway.展开更多
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
Cyanidin-3-glucoside(C3G)is the most common anthocyanin in dark grains and berries and is a food functional factor to improve visual health.However,the mechanisms of C3G on blue light-induced retinal pigment epithelia...Cyanidin-3-glucoside(C3G)is the most common anthocyanin in dark grains and berries and is a food functional factor to improve visual health.However,the mechanisms of C3G on blue light-induced retinal pigment epithelial(RPE)cell photooxidative damage needs further exploration.We investigated the effects of C3G on blue light-irradiated A2E-containing RPE cells and explored whether sphingolipid,mitogen-activated protein kinase(MAPK),and mitochondria-mediated pathways are involved in this mechanism.Blue light irradiation led to mitochondria and lysosome damage in RPE cells,whereas C3G preserved mitochondrial morphology and function and maintained the lysosomal integrity.C3G suppressed the phosphorylation of JNK and p38 MAPK and mitochondria-mediated pathways to inhibit RPE cell apoptosis.Lipidomics data showed that C3G protected RPE cells against blue light-induced lipid peroxidation and apoptosis by maintaining sphingolipids balance.C3G significantly inhibited ceramide(Cer d18:0/15:0,Cer d18:0/16:0 and Cer d18:0/18:0)accumulation and elevated galactosylceramide(GalCer d18:1/15:0 and GalCer d18:1/16:0)levels in the irradiated A2E-containing RPE cells.Furthermore,C3G attenuated cell membrane damage by increasing phosphatidylcholine and phosphatidylserine levels.C3G inhibited apoptosis and preserved the structure of mitochondria and lysosome by regulating sphingolipid signaling and suppression of MAPK activation in RPE cells.Thus,dietary supplementation of C3G prevents retinal photooxidative damage.展开更多
Objective To analyze the interactions between different structural types of volatile oil compo-nents(VOCs)and skin lipid molecules;and investigate the mechanism of volatile oil in Chi-nese materia medica(VOCMM)as pene...Objective To analyze the interactions between different structural types of volatile oil compo-nents(VOCs)and skin lipid molecules;and investigate the mechanism of volatile oil in Chi-nese materia medica(VOCMM)as penetration enhancers.Methods In this study;210 different structural types of VOCs were selected from the VOCMM penetration enhancer database;and the molecular docking experiments were conducted with three main lipid molecules of skin:ceramide 2(CER2);cholesterol(CHL);and free fatty acid(FFA).Each VOC was docked individually with each lipid molecule.Cluster analysis was used to explore the relationship between the binding energy of VOCs and their molecular struc-tures.Nine specific pathogen-free(SPF)Sprague Dawley(SD)rats were randomly divided in-to Control;Nootkatone;and 3-Butylidenephthalide groups for in vitro percutaneous experi-ments;with three rats in each group.The donor pool solutions were 3%gastrodin;3%gas-trodin+3%nootkatone;and 3%gastrodin+3%3-butylidenephthalide;respectively.The pen-etration enhancing effects of VOCs with higher binding energy were evaluated by comparing the 12-hour cumulative percutaneous absorption of gastrodin(Q12;µg/cm²).Results(i)Most of the VOCs were non-hydrogen bonded to the hydrophobic parts of CHL and FFA;and hydrogen bonded to the head group of CER2.Among them;sesquiterpene ox-ides showed the most pronounced binding affinity to CER2.The VOCs with 2-4 rings(in-cluding carbon rings;benzene rings;and heterocycles)demonstrated stronger binding affini-ty for three skin lipid molecules compared with the VOCs without intramolecular rings(P<0.01).(ii)According to the cluster analysis;most of the VOCs that bond well to CER2 had 2-3 intramolecular rings.The non-oxygenated VOCs were bonded to CER2 in a hydrophobic manner.The oxygenated VOCs were mostly bonded to CER2 by hydrogen bonding.(iii)The results of Franz diffusion cell experiment showed that the Q12 of Control group was 260.60±25.09µg/cm2;and the transdermal absorption of gastrodin was significantly increased in Nootkatone group(Q12=5503.00±1080.00µg/cm²;P<0.01).The transdermal absorption of gastrodin was also increased in 3-Butylidenephthalide group(Q12=495.40±56.98µg/cm²;P>0.05).(iv)The type of oxygen-containing functional groups in VOCs was also an influencing factor of binding affinity to CER2.Conclusion The interactions between different types of VOCs with different structures in the VOCMM and three skin lipid molecules in the stratum corneum were investigated at the molecular level in this paper.This research provided theoretical guidance and data support for the screening of volatile oil-based penetration enhancers;and a simple and rapid method for studying the penetration-enhancing mechanism of volatile oils.展开更多
Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and ...Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.展开更多
The skin’s primary function is to protect the body against a spectrum of environmental stressors, including mechanical insults, microorganisms, chemicals, and allergens. Located in the outermost layers, the primary s...The skin’s primary function is to protect the body against a spectrum of environmental stressors, including mechanical insults, microorganisms, chemicals, and allergens. Located in the outermost layers, the primary structures and components responsible for the skin’s barrier function are susceptible to environmental variables, dermatological conditions, and the aging process. The ensuing alterations to structure, composition, and organizational attributes of the epidermal barrier can impact its integrity and functionality. The aim of this study was to assess the effect of a novel complex composed of a ceramide, energizing peptide, and Camu Camu extract (SUPCERAT<sup>TM</sup> complex) on specific markers of epidermal barrier integrity, as well as epidermal and dermal function. All the experiments were conducted on fresh human abdominal skin explants. Intradermal production of hyaluronic acid, epidermal claudin-1, and ceramide synthase 3 expressions, as well as epidermal lipids content were assessed using specific fluorescent stainings on ex vivo skin after the application of the complex or placebo. Additionally, dermal elastase and collagenase activities were assessed using in tubo enzymatic assays. Lastly, the effect of a cosmetic cream containing SUPCERAT<sup>TM</sup> complex was assessed using subjective Global Aesthetic Improvement Scale (GAIS) in a small cohort of patients after 60 days of use. The application of the SUPCERAT<sup>TM</sup> complex on ex vivo skin led to significant increase in dermal hyaluronic acid content and epidermal activity of claudin-1, ceramide synthase 3 and epidermal ceramide content. Furthermore, in tubo enzymatic assays demonstrated inhibition of both dermal elastase and collagenase activities. In addition, the patient-reported results indicated significant improvements in skin quality and appearance. .展开更多
Lipids in stratum corneum are largely responsible for skin barrier function.There have been numerous studies on skin barrier repairing and moisturizing effects of products containing occlusives,emollients and humectan...Lipids in stratum corneum are largely responsible for skin barrier function.There have been numerous studies on skin barrier repairing and moisturizing effects of products containing occlusives,emollients and humectants.However,currently there are few studies systematically evaluating effect of moisturizers containing endogenous lipids on skin barrier properties.The objective of this study was to study the effect of products containing endogenous lipids on various barrier-related indicators.A total 89 subjects with dry skin were enrolled.To evaluate the effect of the test products on skin barrier function and hydration after 28 days of use on the face,this study combined clinical assessments of skin condition(skin redness,global appearance of dry line,skin roughness and radiance),instrumental assessments(transepidermal water loss,skin hydration and scaliness)and photo tracking(VISIA-CR,VC20 and 3D in-vivo Reflectance Confocal Microscope).Adverse reactions were also assessed.All test products showed significant improvement in all the attributes assessed by both clinical assessments and instrumental assessments after 28 days of treatment.In addition,the products containing skinidentical ceramides and niacinamide show improvement on TEWL and skin hydration.Two products containing exogenous lipids can improve skin hydration and barrier function which have demonstrated efficacy in improving dry skin condition.展开更多
基金supported by the Key Project of Chinese Ministry of Education(No.209116)
文摘Two new ceramides,(2S,3S,4R)-2-N-[(2 R)-2 -hydroxypentacosanoylamino]-nonacosane-1,3,4-triol(1) and(2S,3S,4R,8E)-2- N-[(2 R)-2 -hydroxytetracosanoylamino]-8-eicosylene-1,3,4-triol(2) have been isolated from the stems of Piper betle L.collected from Baoshan city of Yunnan Province in China.Their structures were determined by spectroscopic and chemical methods.
文摘A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as (25,35,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-l,3,4-triol(I)and 1-O-β-D-glucopyranosy1-(2S,3S,4R,8E)-2-[(2'R)-hydroxy-hexade-canoylamino]-8-tetracosene-1,3,4-triol (II) on the basis of chemical and spectroscopic studies.
基金supported by the Science and Technology Development Fund(STDF)(No.6554)
文摘In the present study, a new ceramide, namely 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diol(1), along with four known steroids, including 24-methylcholesta-5, 24(28)-diene-3β-ol(2), 24-methylcholesta-5, 24(28)-diene-3β-acetate(3), 4-methyl-24-methylcholesta- 22-ene-3-ol(4), and cholesterol, was isolated and characterized from CH2Cl2/Me OH extract of Cespitularia stolonifera. A new acetate derivative of compound 1, termed 2S, 3R-4E, 8E-2-(heptadecanoylamino)-heptadeca-4, 8-diene-1, 3-diacetate(1a), was also prepared in the present study. All the structures were established on the basis of modern spectroscopic techniques, including FT-IR, 1D, 2D-NMR, HRESI-MS, and GC-MS, in addition of chemical methods.(-)-Alloaromadendren, ledane,(1)-alloaromadendren oxide, isoaromadendrene epoxide and(-)-caryophellen oxide were identified from the n-hexane fraction using GC-MS. The extract and the two ceramides(1) and(1a) exhibited significant cytotoxic activity against lung cancer A549 cells, while the extract and the two steroids(2) and(3) exhibited significant cytotoxic activity against breast cancer MCF-7 cells. The CH_2Cl_2/MeOH extract exhibited significant antiulcer activity in both ethanol and acetic acid induced ulcer models in rats, as evidenced by histopathological, histochemical, and biochemical examinations.
文摘BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile acids in the peripheral circulation reflect the amount of bile acids in the gut.Therefore,a further investigation of luminal bile acids following DJB is of great significance.AIM To investigate changes of luminal bile acids following DJB.METHODS Salicylhydroxamic acid(SHAM),DJB,and DJB with oral chenodeoxycholic acid(CDCA)supplementation were performed in a high-fat-diet/streptozotocininduced diabetic rat model.Body weight,energy intake,oral glucose tolerance test,luminal bile acids,serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTS Compared to SHAM,DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor(FXR)-inhibitory bile acids within the common limb.Intestinal ceramide synthesis was repressed with decreased serum ceramides,and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSION DJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels.There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.
基金supported by the National Natural Science Foundation of China(22178173)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20231119)+3 种基金the China Postdoctoral Science Foundation(2024M751420)the Jiangsu Agricultural Science and Technology Independent Innovation Fund Project(CX(22)3015)the Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture(XTC2204)the Newton Advanced Fellowships(NAF\R1\201187).
文摘Ceramides,formed by the dehydration of long-chain fatty acids with phytosphingosine and its derivatives,are widely used in skincare,cosmetics,and pharmaceuticals.Due to the exceedingly low concentration of phytos-phingosine in plant seeds,relying on the extraction method is highly challenging.Currently,the primary method for obtaining phytosphingosine is the deacetylation of tetraacetyl phytosphingosine(TAPS)derived from fermentation.Wickerhamomyces ciferrii,an unconventional yeast from the pods of Dipteryx odorata,is the only known microorganism capable of naturally secreting TAPS,which is of great industrial value.In recent years,research and applications focused on modifying W.ciferrii for TAPS overproduction have increased rapidly.This review first describes the discovery history,applications,microbial synthesis pathway of TAPS.Research progress in using haploid breeding,mutagenesis breeding,and metabolic engineering to improve TAPS pro-duction is then summarized.In addition,the future prospects of TAPS production using the W.ciferrii platform are discussed in light of the current progress,challenges,and trends in this field.Finally,guidelines for future researches are also emphasized.
基金This work was supported by the National Natural Science Foundation of China(No.81573487)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2017-12M-1-013)the Drug Innovation Major Project(No.2018ZX09711001-003-011).
文摘Background:Previously,dihydroceramide(d18:0/24:0)(dhCer(d18:0/24:0))was reported to be a potential biomarker for acute-onchronic liver failure(ACLF)prognosis.In this study,we further explored the role of dhCer(d18:0/24:0)in the progression of ACLF to validate the biomarker using ACLF rat model.Methods:ACLF rats were sacrificed at 4 and 8 h post-D-galactosamine(D-gal)/lipopolysaccharide(LPS)administration to investigate the liver biochemical markers,prothrombin time and liver histopathology.Change in dhCer and other sphingolipids levels were investigated by high-performance liquid chromatography coupled to tandem mass spectrometry(HPLC-MS/MS).Rats were treated with N-(4-hydroxyphenyl)retinamide(4-HPR)to examine the mortality rate and its role in improving ACLF.Results:LPS/D-gal administration resulted in significant elevation in alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.Prothrombin time was prolonged and histopathological examination showed abnormality.HPLC-MS/MS results showed total dhCer levels in ACLF group(64.10±8.90 pmol/100 mL,64.22±6.78 pmol/100 mL for 4 and 8 h,respectively)were decreased significantly compared with control group(121.61±23.09 pmol/100 mL)(P<0.05).In particular,dhCer(d18:0/24:0),dhCer(d18:0/20:0),and dhCer(d18:0/22:0)levels were decreased.Treatment with 4-HPR significantly increased the levels of dhCers,including dhCer(d18:0/24:0)compared with ACLF group,for the level of dhCer(d18:0/24:0)in 4-HPR group was 20.10±8.60 pmol/100 mL and the level of dhCer(d18:0/24:0)in ACLF group was 9.74±2.99 pmol/100 mL(P<0.05).This was associated with reduced mortality rate and prolonged survival time.The ALT and AST in 4-HPR group were significantly decreased compared with ACLF group.The prothrombin time of 4-HPR group(41.49 s)was significantly lower than the prothrombin time of ACLF group(57.96 s)(P<0.05).4-HPR also decreased plasma ammonia levels slightly,as the plasma ammonia levels in 4-HPR group and ACLF group were 207.37±60.43,209.15±60.43 mmol/L,respectively.Further,4-HPR treatment improved histopathological parameters.Conclusions:DhCer,especially dhCer(d18:0/24:0),is involved in the progression of ACLF.Increasing the levels of dhCer can reduce the mortality rate of ACLF rats and alleviate liver injury.
文摘This study used non-invasive evaluation methods measured six skin physiological parameters of the lower lip in 180 subjects,including moisture content,transepidermal water loss(TEWL),smoothness(SESM),scaliness of the skin(SESC),wrinkles(SEW),and red area of the lip skin,and compared the effects of 6 groups of lip balms(no-additive group,marine oligosaccharides group,ceramides group,glycyrrhizinic acid group,allantoin group,and mixed group;30 each)on the skin physiological parameters of dry,flaking,and cracked lip subjects.The results showed that the lip mositure content of the subjects in the marine oligosaccharide group,glycyrrhetinic acid group,and allantoin group increased significantly by 44.40%,42.84%and 58.08%after 7 days of lip balm(P<0.05).The TEWL in the ceramide group and the allantoin group was significantly reduced by 21.83%and 24.72%,respectively,after 7 days of lip paste use(P<0.05).The lip skin smoothness values of subjects in the glycyrrhizic acid group and the allantoin group were significantly reduced by 18.76%and 14.97%,respectively,after 28 days of lip balm application(P<0.05).The lip skin scaling indices of subjects in the marine oligosaccharide group,the ceramides group,and the allantoin group were significantly reduced by 33.77%,42.69%,and 38.07%,respectively,after 28 days of lip balm application(P<0.05).The wrinkle parameters of the lip skin of the subjects in the marine oligosaccharide,glycyrrhizinic acid and allantoin groups were significantly reduced by 23.06%,23.29%and 25.98%,respectively,after 28 days of lip balm application(P<0.05).And the area of the red zone of the lip skin of the subjects in the allantoin group was significantly reduced by 4.27%,after 28 days of lip balm application(P<0.05).Combining the effects of the four active ingredients on the secretion of hyaluronic acid(moisturizing effect)and inflammatory factor(IL-6)in HSF cells,it suggests that marine oligosaccharides and allantoin have a perfect impact on enhancing the water content of the skin on the lips of the subjects,and further improve the symptoms of flaking and wrinkles on the lips of the subjects.The ceramide and allantoin can repair the skin barrier well and have a good effect on the chapped and flaky lips of the subjects.After 28 days of using lip balm,the water content of lips in the mixed group increased,the skin barrier was repaired and became smoother,and the wrinkles,scale index,and red zone value were reduced,which could well relieve chronic lip inflammation and lay a foundation for developing lip products for the treatment of chronic cheilitis.
基金supported by the National Natural Science Foundation of China(Grant No.:82374552)Hunan Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.:2024JJ2086)+1 种基金the Science and Technology Innovation Program of Hunan Province,China(Grant No.:2022RC1220)Support Plan for High-level Health and Medical Talents in Hunan Province,China.
文摘Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
文摘Two new ceramides were isolated from the 95% EtOH extract of traditional Chinese medicinal plant Isatis indigotica. Their structures were elucidated as 1-O-β-D-glucopyranosyl-(2S, 3R)-N-(2'-hydroxypentacosanoyl)-octadeca-11E-sphingenine (1) and 1-O-β-D-glucopyranosyl-(2S,3R)-N-(2'-hydroxyhe xacosanoyl)-octadeca-11E-sphingenine (2) on the basis of spectroscopic data. Their cytotoxic effects were evaluated by using MTT method.
基金supported by grants from the National Key Research and Development Program of China,No.2017YFA0105400(to LR)the Key Research and Development Program of Guangdong Province,No.2019B020236002(to LR)the National Natural Science Foundation of China,Nos.81972111(to LZ),81772349(to BL).
文摘Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord injury.However,the precise mechanism remains unclear.To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury,we performed single-cell RNA sequencing dataset analysis,focusing on changes in microglial subpopulations.We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis,sphingomyelin metabolism,and neuroinflammation at high levels.Subsequently,we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury.Finally,we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells.Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis.Furthermore,ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway.Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function.Pla2g7 formed a“bridge”between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway.Collectively,these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3,thereby exerting neuroprotective effects.
基金Supported by Ganzhou City’s“Light of the Soviet Area”Talent Project,No.GZSQZG202301009。
文摘Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases,posing a significant global public health challenge.Al-though the association between ceramides(Cers)and metabolic diseases is well-established,the role of the acid sphingomyelinase(ASMase)/Cer pathway in these diseases remains underexplored.This review synthesizes recent research on the biological functions,regulatory mechanisms,and targeted therapies related to the ASMase/Cer pathway in metabolic conditions,including obesity,diabetes,non-alcoholic fatty liver disease,and cardiovascular disease.The effects of the ASMase/Cer pathway on metabolic disease-related indicators,such as glycolipid metabolism,insulin resistance,inflammation,and mitochondrial homeostasis are elucidated.Moreover,this article discusses the therapeutic strategies using ASMase/Cer inhibitors for inverse prevention and treatment of these metabolic diseases in light of the possible efficacy of blockade of the ASMase/Cer pathway in arresting the progression of metabolic diseases.These insights offered herein should provide insight into the contribution of the ASMase/Cer pathway to metabolic diseases and offer tools to develop therapeutic interventions for such pathologies and their severe complications.
基金supported by the National Institute of Health Grants R01 AG059799(to BSS),R01AG057420 and R01MH131219(to NJH),P30 MH075673(to NJH and BSS)a grant from the Tau Consortium and Alzheimer’s Association(T-PEP-18-579974C,to BSS)a grant from the Richman Family Precision Medicine Center of Excellence in Alzheimer’s disease(to BSS and DK).KC and TRJ were Funded by NIH R25GM109441(Hopkins PREP).
文摘Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin.We report,for the first time,that human tau expression elevates brain ceramides and nSMase2 activity.Methods To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model.Additionally,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus.The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored.We examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse plasma.Results Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC treatment.The PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human AD.PDDC treatment reduced these changes.The plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated mice.In the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slowing of tau spread in AD mice.
文摘Ceramides are important signaling molecules involved in a variety of cellular processes, including cell growth, differentiation, and apoptosis. Currently, different methods are used for ceramide analysis, some of which are insensitive or cumbersome. This paper described methods utilizing thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) followed by evaporative light scattering detection (ELSD) to detect ceramide directly in cell extracts without derivatization, which was proved to be efficient and reproducible. Five kinds of ceramides were used as standards. Both TLC and normal-phase HPLC/ELSD results indicate that yeast contains several kinds of ceramides.
基金Natural Science Foundation-funded Project:the Interaction of mi RNAs and Hh Signaling Pathway in NASH Related Liver Fibrosis and the Intervention of Sagittaria Xiaozhi Pill(No.81860821)Toxin and Eliminating Phlegm Intervention Ceramide and Induced iNOS Nonalcoholic Fatty Liver Disease Fat Research of Apoptosis Signaling(No.81460710)。
文摘OBJECTIVE:To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription(慈菇消脂方,CGXZ)in the treatment of the non-alcoholic fatty liver disease(NAFLD)by detoxification and phlegm-reducing,the effect of CGXZ prescription on ceramide-mediated lipid apoptosis in Hep G2 cells with NAFLD.METHODS:The experiment was randomly divided into 6groups:normal control group,model group,CGXZ prescription medicated serum high,medium,and low dose groups,and pioglitazone positive control group.Using 500μmol/L free fatty acid(FFA)mixture to induce Hep G2 cells to establish NAFLD cell model,respectively,with 2%,4%,and 6%concentration of CGXZ prescription medicated serum intervention for 24 h.The changes in organelles and lipid droplet accumulation were observed under the electron microscope.Furthermore,Td T-mediated d UTP Nick-End Labeling method was used to assay hepatocyte apoptosis;Biochemical determination of glutamic-pyruvic transaminase,glutamic oxalacetic transaminase,triglycerides,and FFA levels in Hep G2cells;the content of ceramide was determined by highperformance thin-layer chromatography.Finally,Western Blot and quantitative real-time polymerase chain reaction(q RT-PCR)were used to determine the protein and gene expression levels,such as inducible nitric oxide synthase(i NOS),nuclear factorκB(NF-κB),B cell lymphoma 2(Bcl-2)and Bcl-2-associated X(Bax).RESULTS:Under the electron microscope,the cells in the model group showed moderate-to-severe steatosis,and apoptotic bodies could be seen.The model group had greater improvements in the apoptosis rate(P<0.01),and the levels of ceramide C2 and FFA in the cytoplasm(P<0.01)than the normal control group.The protein expressions of NF-κB,i NOS,and Bax were significantly up-regulated(P<0.05),while the Bcl-2 had no significant change(P>0.05).Compared with the model group,the levels of ceramide C2 and FFA(P<0.01),the protein expressions of NF-κB,i NOS,and Bax(P<0.05)in the CGXZ prescription treatment group and pioglitazone positive control group were significantly decreased;Only the Bcl-2 protein was significantly up-regulated in the high-dose Chinese medicine group(P<0.05).The downregulation of Bax m RNA expression in each Chinese medicine treatment group was significantly better than in the pioglitazone positive control group(P<0.01).CONCLUSIONS:The CGXZ prescription,formulated with the method of detoxification and phlegm,can inhibit lipoapoptosis in the NAFLD cell model by downregulating the levels of ceramide C2 and FFA,which may be achieved by regulating ceramide/i NOS/NF-κB signaling pathway.
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funded by the National Natural Science Foundation of China(31901698)Young Elite Scientists Sponsorship Program by the China Association for Science and Technology(2019QNRC001)。
文摘Cyanidin-3-glucoside(C3G)is the most common anthocyanin in dark grains and berries and is a food functional factor to improve visual health.However,the mechanisms of C3G on blue light-induced retinal pigment epithelial(RPE)cell photooxidative damage needs further exploration.We investigated the effects of C3G on blue light-irradiated A2E-containing RPE cells and explored whether sphingolipid,mitogen-activated protein kinase(MAPK),and mitochondria-mediated pathways are involved in this mechanism.Blue light irradiation led to mitochondria and lysosome damage in RPE cells,whereas C3G preserved mitochondrial morphology and function and maintained the lysosomal integrity.C3G suppressed the phosphorylation of JNK and p38 MAPK and mitochondria-mediated pathways to inhibit RPE cell apoptosis.Lipidomics data showed that C3G protected RPE cells against blue light-induced lipid peroxidation and apoptosis by maintaining sphingolipids balance.C3G significantly inhibited ceramide(Cer d18:0/15:0,Cer d18:0/16:0 and Cer d18:0/18:0)accumulation and elevated galactosylceramide(GalCer d18:1/15:0 and GalCer d18:1/16:0)levels in the irradiated A2E-containing RPE cells.Furthermore,C3G attenuated cell membrane damage by increasing phosphatidylcholine and phosphatidylserine levels.C3G inhibited apoptosis and preserved the structure of mitochondria and lysosome by regulating sphingolipid signaling and suppression of MAPK activation in RPE cells.Thus,dietary supplementation of C3G prevents retinal photooxidative damage.
基金National Science Foundation of China(82174093)Fundamental Research Funds for the Central Universities(BUCM-2019-JYB-JS-016).
文摘Objective To analyze the interactions between different structural types of volatile oil compo-nents(VOCs)and skin lipid molecules;and investigate the mechanism of volatile oil in Chi-nese materia medica(VOCMM)as penetration enhancers.Methods In this study;210 different structural types of VOCs were selected from the VOCMM penetration enhancer database;and the molecular docking experiments were conducted with three main lipid molecules of skin:ceramide 2(CER2);cholesterol(CHL);and free fatty acid(FFA).Each VOC was docked individually with each lipid molecule.Cluster analysis was used to explore the relationship between the binding energy of VOCs and their molecular struc-tures.Nine specific pathogen-free(SPF)Sprague Dawley(SD)rats were randomly divided in-to Control;Nootkatone;and 3-Butylidenephthalide groups for in vitro percutaneous experi-ments;with three rats in each group.The donor pool solutions were 3%gastrodin;3%gas-trodin+3%nootkatone;and 3%gastrodin+3%3-butylidenephthalide;respectively.The pen-etration enhancing effects of VOCs with higher binding energy were evaluated by comparing the 12-hour cumulative percutaneous absorption of gastrodin(Q12;µg/cm²).Results(i)Most of the VOCs were non-hydrogen bonded to the hydrophobic parts of CHL and FFA;and hydrogen bonded to the head group of CER2.Among them;sesquiterpene ox-ides showed the most pronounced binding affinity to CER2.The VOCs with 2-4 rings(in-cluding carbon rings;benzene rings;and heterocycles)demonstrated stronger binding affini-ty for three skin lipid molecules compared with the VOCs without intramolecular rings(P<0.01).(ii)According to the cluster analysis;most of the VOCs that bond well to CER2 had 2-3 intramolecular rings.The non-oxygenated VOCs were bonded to CER2 in a hydrophobic manner.The oxygenated VOCs were mostly bonded to CER2 by hydrogen bonding.(iii)The results of Franz diffusion cell experiment showed that the Q12 of Control group was 260.60±25.09µg/cm2;and the transdermal absorption of gastrodin was significantly increased in Nootkatone group(Q12=5503.00±1080.00µg/cm²;P<0.01).The transdermal absorption of gastrodin was also increased in 3-Butylidenephthalide group(Q12=495.40±56.98µg/cm²;P>0.05).(iv)The type of oxygen-containing functional groups in VOCs was also an influencing factor of binding affinity to CER2.Conclusion The interactions between different types of VOCs with different structures in the VOCMM and three skin lipid molecules in the stratum corneum were investigated at the molecular level in this paper.This research provided theoretical guidance and data support for the screening of volatile oil-based penetration enhancers;and a simple and rapid method for studying the penetration-enhancing mechanism of volatile oils.
文摘Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.
文摘The skin’s primary function is to protect the body against a spectrum of environmental stressors, including mechanical insults, microorganisms, chemicals, and allergens. Located in the outermost layers, the primary structures and components responsible for the skin’s barrier function are susceptible to environmental variables, dermatological conditions, and the aging process. The ensuing alterations to structure, composition, and organizational attributes of the epidermal barrier can impact its integrity and functionality. The aim of this study was to assess the effect of a novel complex composed of a ceramide, energizing peptide, and Camu Camu extract (SUPCERAT<sup>TM</sup> complex) on specific markers of epidermal barrier integrity, as well as epidermal and dermal function. All the experiments were conducted on fresh human abdominal skin explants. Intradermal production of hyaluronic acid, epidermal claudin-1, and ceramide synthase 3 expressions, as well as epidermal lipids content were assessed using specific fluorescent stainings on ex vivo skin after the application of the complex or placebo. Additionally, dermal elastase and collagenase activities were assessed using in tubo enzymatic assays. Lastly, the effect of a cosmetic cream containing SUPCERAT<sup>TM</sup> complex was assessed using subjective Global Aesthetic Improvement Scale (GAIS) in a small cohort of patients after 60 days of use. The application of the SUPCERAT<sup>TM</sup> complex on ex vivo skin led to significant increase in dermal hyaluronic acid content and epidermal activity of claudin-1, ceramide synthase 3 and epidermal ceramide content. Furthermore, in tubo enzymatic assays demonstrated inhibition of both dermal elastase and collagenase activities. In addition, the patient-reported results indicated significant improvements in skin quality and appearance. .
文摘Lipids in stratum corneum are largely responsible for skin barrier function.There have been numerous studies on skin barrier repairing and moisturizing effects of products containing occlusives,emollients and humectants.However,currently there are few studies systematically evaluating effect of moisturizers containing endogenous lipids on skin barrier properties.The objective of this study was to study the effect of products containing endogenous lipids on various barrier-related indicators.A total 89 subjects with dry skin were enrolled.To evaluate the effect of the test products on skin barrier function and hydration after 28 days of use on the face,this study combined clinical assessments of skin condition(skin redness,global appearance of dry line,skin roughness and radiance),instrumental assessments(transepidermal water loss,skin hydration and scaliness)and photo tracking(VISIA-CR,VC20 and 3D in-vivo Reflectance Confocal Microscope).Adverse reactions were also assessed.All test products showed significant improvement in all the attributes assessed by both clinical assessments and instrumental assessments after 28 days of treatment.In addition,the products containing skinidentical ceramides and niacinamide show improvement on TEWL and skin hydration.Two products containing exogenous lipids can improve skin hydration and barrier function which have demonstrated efficacy in improving dry skin condition.
