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
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
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
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
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
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
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
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
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
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
Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects,decreasing therapeutical effects.To improve the transdermal delivery efficiency of eutomer,this work ...Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects,decreasing therapeutical effects.To improve the transdermal delivery efficiency of eutomer,this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers.Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers.The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer,in which the enhancement effect(ER)of Lmenthol on S-enantiomer(ER=3.23)was higher than that on R-enantiomer(ER=1.49).According to the pharmacokinetics results,L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer(2.56 fold),and showed excellent in vitro/in vivo correlations.The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention,but the D-isomer by improving partition for better permeation.Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation.Additionally,stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects.In conclusion,enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery,rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects,increasing transdermal therapeutical efficiency.展开更多
Non-alcoholic fatty liver disease(NAFLD),the most common chronic liver disorder in Western countries,comprises steatosis to nonalcoholic steatohepatitis(NASH),with the latter having the potential to progress to cirrho...Non-alcoholic fatty liver disease(NAFLD),the most common chronic liver disorder in Western countries,comprises steatosis to nonalcoholic steatohepatitis(NASH),with the latter having the potential to progress to cirrhosis.The transition from isolated steatosis to NASH is still poorly understood,but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression.Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD.Changes in glycerophospholipid,sphingolipid,and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD,implicating that specific lipid species are involved in oxidative stress,inflammation,and cell death.In this article,we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.展开更多
The nucleus-initiated augmentation of ER membrane is reflected in a coordinated synthesis and intercalation of the explicit proteins and lipids required for the replacement, repair and function of the cell and its org...The nucleus-initiated augmentation of ER membrane is reflected in a coordinated synthesis and intercalation of the explicit proteins and lipids required for the replacement, repair and function of the cell and its organelles. The direct connection between nucleus and the membranes containing labeled sphingosine (SphN) and ceramide (Cer) was affirmed by determining synthetic activity of serine palmitoyltransferase (SPT). The SPT and the newly synthesized serine-labeled lipid products were identified in the Outer- and Inner-Nuclear Membrane (ONM, INM) and ER. The pulse-chase experiments disclosed that the incorporation of radiolabeled lipids into both nuclear membranes declined upon their simultaneous increase in Endoplasmic Reticulum (ER). These results, and prior findings regarding metabolic transfer of nuclear membrane phosphoinositides to the outer leaflet of ER [Slomiany and Slomiany, Health, 2011, 3, 187-199], allowed us to reason that INM and ONM are not distinct entities, but uninterrupted continuum facing nucleosol and then cytosol when protracted into segment known as ER. Consequently, the identification of SPT and its products in the inner leaflet of nuclear and ER microsomes lent credence to the luminal presence of Cer in Golgi, luminal synthesis of glycosphingolipids (GSphLs), sphingomyelin (SM), and their delivery to the outer leaflet of apical and basolateral cell membrane, respectively. The findings presented in this communication provide further support to our concept that the factual intercalation of proteins and lipids into the cell membranes can only take place during their simultaneous synthesis that is guided by the nuclear and cytosolic processes enacted in nuclear-ER membrane continuum. At the nuclear stage, the signal-specific genes expression promotes active synthesis and intercalation of lipids into the organelles’ customized membrane that is protracted and articulated in ER in form of transport vesicles.展开更多
Ceramides are a class of lipid molecules widely distributed in eukaryotic cells in small amount. To investigate the possibility of ceramide production by yeast, a yeast strain Yarrowia lipolitica was grown under diffe...Ceramides are a class of lipid molecules widely distributed in eukaryotic cells in small amount. To investigate the possibility of ceramide production by yeast, a yeast strain Yarrowia lipolitica was grown under different conditions including changing carbon/nitrogen ratio, and serine concentration, dissolved oxygen and presence of ethanol. It was found that increased dissolved oxygen supply increased the ceramide content in the yeast 2.5 fold of its normal control level. Ethanol treatment could also enhance ceramide accumulation by 3.3 fold compared with the control although the cell growth was negatively affected. Cellular redox potential was shown to affect ceramide accumulation by the yeast. This was possibly related to the cellular reactive oxygen species presented in the yeast.展开更多
A new triterpenoid saponin, namely pomatoside A (3) 13beta, 28-epoxy-16-oleananone-3-O-[alpha-L-rhamnopyranosyl-(1 -->6)-O-beta-D-glucopyranosyl-(1 -->4)-O-beta-D-glucopyranosyl-(1 -->6)-O-beta-D-glucopyranos...A new triterpenoid saponin, namely pomatoside A (3) 13beta, 28-epoxy-16-oleananone-3-O-[alpha-L-rhamnopyranosyl-(1 -->6)-O-beta-D-glucopyranosyl-(1 -->4)-O-beta-D-glucopyranosyl-(1 -->6)-O-beta-D-glucopyranosyl-(1 -->2)]-beta-D-glucopyranoside, together with twelve known compounds, was isolated for the first time from Pomatosace filicula Maxim., a monotypic endemic plant, grown in the Qinghai-Xizang Plateau of China. Their structures were elucidated by spectroscopic analyses and chemical methods, especially 2D-NMR.展开更多
A new ceramide, (2S,3S,4R, 10E)-2-[(2'R)-2'-hydroxytetracosanoyl amino]-10-octadecene-1, 3,4-triol (1), together with twelve known compounds, cerebroside A, cerebroside B, cerebroside D, cytochalasin D, epoxyc...A new ceramide, (2S,3S,4R, 10E)-2-[(2'R)-2'-hydroxytetracosanoyl amino]-10-octadecene-1, 3,4-triol (1), together with twelve known compounds, cerebroside A, cerebroside B, cerebroside D, cytochalasin D, epoxycytochalasin D, cytochalasin C, loganin, cerevisterol, ergosta-7,22-dien-3beta, 5alpha, 6alpha-triol, ergosta-4,6,8(14),22-tetraen-3-one, ergosterol peroxide and ergosta-5,7,22-trien-3-ol, was isolated from ethyl acetate fraction of Engleromyces goetzei P. Henn. The structure of new ceramide (1) was elucidated by spectral data and chemical method, especially by 2D-NMR techniques. All of the compounds except cytochalasin D were first obtained from this fungus.展开更多
A mixture of new ceramides (1, 2, 3, 4 and 5) together with a binary mixture of ceramides with long chain alkyl (6 and 7), triterpenoid (10) and steroids (11 and 12) have been isolated from bark of the fruits and of t...A mixture of new ceramides (1, 2, 3, 4 and 5) together with a binary mixture of ceramides with long chain alkyl (6 and 7), triterpenoid (10) and steroids (11 and 12) have been isolated from bark of the fruits and of the stems of Luffa operculata (Cucurbitaceae). The structures were elucidated by comprehensive spectro- scopic analysis including 1H and 13C NMR, DEPT (distortionless enhancement by polarization transfer), COSY (correlated spectroscopy), HMQC (heteronuclear multiple quantum coherence), HMBC (heteronu- clear multiple bond connectivity), IR (infrared), HR-ESI-MS (electrospray ionization-high resolution mass spectra) and LR-MS (low resolution electron ionization mass spectra) experiments. All the ceramides are reported for the first time in Cucurbitaceae and this is the first report of the rare triterpene 10 isolated from Luffa operculata. The ceramides 6 and 7 showed a high acetylcholine esterase inhibitory effect.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.
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 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.
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.
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.
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. .
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supported by the National Natural Science Foundation of China(Grant No.82273879)
文摘Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects,decreasing therapeutical effects.To improve the transdermal delivery efficiency of eutomer,this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers.Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers.The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer,in which the enhancement effect(ER)of Lmenthol on S-enantiomer(ER=3.23)was higher than that on R-enantiomer(ER=1.49).According to the pharmacokinetics results,L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer(2.56 fold),and showed excellent in vitro/in vivo correlations.The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention,but the D-isomer by improving partition for better permeation.Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation.Additionally,stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects.In conclusion,enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery,rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects,increasing transdermal therapeutical efficiency.
文摘Non-alcoholic fatty liver disease(NAFLD),the most common chronic liver disorder in Western countries,comprises steatosis to nonalcoholic steatohepatitis(NASH),with the latter having the potential to progress to cirrhosis.The transition from isolated steatosis to NASH is still poorly understood,but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression.Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD.Changes in glycerophospholipid,sphingolipid,and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD,implicating that specific lipid species are involved in oxidative stress,inflammation,and cell death.In this article,we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.
文摘The nucleus-initiated augmentation of ER membrane is reflected in a coordinated synthesis and intercalation of the explicit proteins and lipids required for the replacement, repair and function of the cell and its organelles. The direct connection between nucleus and the membranes containing labeled sphingosine (SphN) and ceramide (Cer) was affirmed by determining synthetic activity of serine palmitoyltransferase (SPT). The SPT and the newly synthesized serine-labeled lipid products were identified in the Outer- and Inner-Nuclear Membrane (ONM, INM) and ER. The pulse-chase experiments disclosed that the incorporation of radiolabeled lipids into both nuclear membranes declined upon their simultaneous increase in Endoplasmic Reticulum (ER). These results, and prior findings regarding metabolic transfer of nuclear membrane phosphoinositides to the outer leaflet of ER [Slomiany and Slomiany, Health, 2011, 3, 187-199], allowed us to reason that INM and ONM are not distinct entities, but uninterrupted continuum facing nucleosol and then cytosol when protracted into segment known as ER. Consequently, the identification of SPT and its products in the inner leaflet of nuclear and ER microsomes lent credence to the luminal presence of Cer in Golgi, luminal synthesis of glycosphingolipids (GSphLs), sphingomyelin (SM), and their delivery to the outer leaflet of apical and basolateral cell membrane, respectively. The findings presented in this communication provide further support to our concept that the factual intercalation of proteins and lipids into the cell membranes can only take place during their simultaneous synthesis that is guided by the nuclear and cytosolic processes enacted in nuclear-ER membrane continuum. At the nuclear stage, the signal-specific genes expression promotes active synthesis and intercalation of lipids into the organelles’ customized membrane that is protracted and articulated in ER in form of transport vesicles.
文摘Ceramides are a class of lipid molecules widely distributed in eukaryotic cells in small amount. To investigate the possibility of ceramide production by yeast, a yeast strain Yarrowia lipolitica was grown under different conditions including changing carbon/nitrogen ratio, and serine concentration, dissolved oxygen and presence of ethanol. It was found that increased dissolved oxygen supply increased the ceramide content in the yeast 2.5 fold of its normal control level. Ethanol treatment could also enhance ceramide accumulation by 3.3 fold compared with the control although the cell growth was negatively affected. Cellular redox potential was shown to affect ceramide accumulation by the yeast. This was possibly related to the cellular reactive oxygen species presented in the yeast.
文摘A new triterpenoid saponin, namely pomatoside A (3) 13beta, 28-epoxy-16-oleananone-3-O-[alpha-L-rhamnopyranosyl-(1 -->6)-O-beta-D-glucopyranosyl-(1 -->4)-O-beta-D-glucopyranosyl-(1 -->6)-O-beta-D-glucopyranosyl-(1 -->2)]-beta-D-glucopyranoside, together with twelve known compounds, was isolated for the first time from Pomatosace filicula Maxim., a monotypic endemic plant, grown in the Qinghai-Xizang Plateau of China. Their structures were elucidated by spectroscopic analyses and chemical methods, especially 2D-NMR.
文摘A new ceramide, (2S,3S,4R, 10E)-2-[(2'R)-2'-hydroxytetracosanoyl amino]-10-octadecene-1, 3,4-triol (1), together with twelve known compounds, cerebroside A, cerebroside B, cerebroside D, cytochalasin D, epoxycytochalasin D, cytochalasin C, loganin, cerevisterol, ergosta-7,22-dien-3beta, 5alpha, 6alpha-triol, ergosta-4,6,8(14),22-tetraen-3-one, ergosterol peroxide and ergosta-5,7,22-trien-3-ol, was isolated from ethyl acetate fraction of Engleromyces goetzei P. Henn. The structure of new ceramide (1) was elucidated by spectral data and chemical method, especially by 2D-NMR techniques. All of the compounds except cytochalasin D were first obtained from this fungus.
基金Fundacao Cearense de Amparo a Pesquisa do Estado do Ceara(FUNCAP)for grantsto Conselho Nacional do Desenvolvimento Cientifico e Tecnologico(CNPq-Brazil)for a research fellowship and grants.
文摘A mixture of new ceramides (1, 2, 3, 4 and 5) together with a binary mixture of ceramides with long chain alkyl (6 and 7), triterpenoid (10) and steroids (11 and 12) have been isolated from bark of the fruits and of the stems of Luffa operculata (Cucurbitaceae). The structures were elucidated by comprehensive spectro- scopic analysis including 1H and 13C NMR, DEPT (distortionless enhancement by polarization transfer), COSY (correlated spectroscopy), HMQC (heteronuclear multiple quantum coherence), HMBC (heteronu- clear multiple bond connectivity), IR (infrared), HR-ESI-MS (electrospray ionization-high resolution mass spectra) and LR-MS (low resolution electron ionization mass spectra) experiments. All the ceramides are reported for the first time in Cucurbitaceae and this is the first report of the rare triterpene 10 isolated from Luffa operculata. The ceramides 6 and 7 showed a high acetylcholine esterase inhibitory effect.