More than four decades ago it was established that an elevated low-density lipoprotein-cholesterol level was a risk for developing coronary artery disease. For the last two decades, statins have been the cornerstone o...More than four decades ago it was established that an elevated low-density lipoprotein-cholesterol level was a risk for developing coronary artery disease. For the last two decades, statins have been the cornerstone of reducing low-density lipoprotein-cholesterol, but despite significant clinical efficacy in the majority of patients, a large number of patients suffer from side effects and cannot tolerate the required statin dose to reach their recommended low-density lipoprotein-cholesterol goals. Preliminary clinical studies indicate that monoclonal antibodies to PCSK9 appear to be highly efficacious in lowering low-density lipoprotein-cholesterol with a favourable adverse event profile. However, further longer-term clinical studies are required to determine their safety. From the early-proposed concept for high-density lipoprotein-mediated cholesterol efflux for the treatment of coronary artery disease, the concentration of the cholesterol content in high-density lipoprotein particles has been considered a surrogate measurement for the efficacy of the reverse cholesterol transport process. However, unlike the beneficial effects of the statins and monoclonal antibodies to PCSK9 in reducing low-density lipoprotein-cholesterol, no significant advances have been made to increase the levels of high-density lipoprotein-cholesterol. Here it is shown that by a non-pharmacological plasma delipidation means, the atherogenic low-density lipoproteins can be converted to anti-atherogenic particles and that the high-density lipoproteins are converted to particles with extreme high affinity to cause rapid regression of atherosclerosis.展开更多
Antimicrobial peptides(AMPs)are potentially powerful alternatives to conven-tional antibiotics in combating multidrug resistance,given their broad spectrum of activity.They mainly interact with cell membranes through ...Antimicrobial peptides(AMPs)are potentially powerful alternatives to conven-tional antibiotics in combating multidrug resistance,given their broad spectrum of activity.They mainly interact with cell membranes through surface electrostatic potentials and the formation of secondary structures,resulting in permeability and destruction of target microorganism membranes.Our earlier work showed that two leading AMPs,MSI-78(4–20)and pardaxin(1–22),had potent antimicrobial activ-ity against a range of bacteria.It is known that the attachment of moderate-length lipid carbon chains to cationic peptides can further improve the functionality of these peptides through enhanced interactions with the membrane lipid bilayer,inducing membrane curvature,destabilization,and potential leakage.Thus,in this work,we aimed to investigate the antimicrobial activity,oligomerization propensity,and lipid-membrane binding interactions of a range of N-terminal lipidated analogs of MSI-78(4–20)and pardaxin(1–22).Molecular modeling results suggest that aggregation of the N-lipidated AMPs may impart greater structural stability to the peptides in solu-tion and a greater depth of lipid bilayer insertion for the N-lipidated AMPs over the parental peptide.Our experimental and computationalfindings provide insights into how N-terminal lipidation of AMPs may alter their conformations,with subsequent effects on their functional properties in regard to their self-aggregation behavior,membrane interactions,and antimicrobial activity.展开更多
Traumatic spinal cord injury often leads to the disintegration of nerve cells and axons,resulting in a substantial accumulation of myelin debris that can persist for years.The abnormal buildup of myelin debris at site...Traumatic spinal cord injury often leads to the disintegration of nerve cells and axons,resulting in a substantial accumulation of myelin debris that can persist for years.The abnormal buildup of myelin debris at sites of injury greatly impedes nerve regeneration,making the clearance of debris within these microenvironments crucial for effective post-spinal cord injury repair.In this review,we comprehensively outline the mechanisms that promote the clearance of myelin debris and myelin metabolism and summarize their roles in spinal cord injury.First,we describe the composition and characteristics of myelin debris and explain its effects on the injury site.Next,we introduce the phagocytic cells involved in myelin debris clearance,including professional phagocytes(macrophages and microglia)and non-professional phagocytes(astrocytes and microvascular endothelial cells),as well as other cells that are also proposed to participate in phagocytosis.Finally,we focus on the pathways and associated targets that enhance myelin debris clearance by phagocytes and promote lipid metabolism following spinal cord injury.Our analysis indicates that myelin debris phagocytosis is not limited to monocyte-derived macrophages,but also involves microglia,astrocytes,and microvascular endothelial cells.By modulating the expression of genes related to phagocytosis and lipid metabolism,it is possible to modulate lipid metabolism disorders and influence inflammatory phenotypes,ultimately affecting the recovery of motor function following spinal cord injury.Additionally,therapies such as targeted mitochondrial transplantation in phagocytic cells,exosome therapy,and repeated trans-spinal magnetic stimulation can effectively enhance the removal of myelin debris,presenting promising potential for future applications.展开更多
Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,includi...Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).展开更多
Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter rel...Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.展开更多
Recent studies have shown that lipid metabolism is a key factor affecting anther development and male fertility.However,how plants regulating the metabolic balance of multiple lipids to ensure proper anther developmen...Recent studies have shown that lipid metabolism is a key factor affecting anther development and male fertility.However,how plants regulating the metabolic balance of multiple lipids to ensure proper anther development and male fertility remains unclear.Analyzing lipid molecules related to anther fertility and genes responsible for their biosynthesis is crucial for understanding the physiological significance of lipid metabolism in crop fertility.In this study,we compared the transcriptome and the composition and content of lipids in anthers of two upland cotton(Gossypium hirsutum) materials,Shida 98(WT) and its nearly-isogenic male sterile line Shida 98A(MS).Transcriptomics analysis identified many differentially expressed genes(DEGs) between the two materials,with the genes of the alpha-linolenic acid metabolism pathway being the most significantly associated with the male sterility phenotype.Investigations on lipids revealed that the MS anthers over-accumulated free fatty acids(FFAs),phosphatidic acid(PA),mono-and di-galactosyldiacylglycerol(MGDG and DGDG),and had a decreased content of triacylglycerol(TAG),which was closely related to the abnormal metabolism of alpha-linolenic acid(C18:3);therefore,the major lipids containing C18:3-acyl chains,such as PA,MGDG,DGDG,and TAG,are proposed to play a major role in cotton anther development.We also showed that an excessive level of MGDG and DGDG caused jasmonic acid(JA) overaccumulation in MS anthers,which in turn inhibited the expression of GhFAD3 and consequently reduced the C18:3 content,presumably via a feedback regulation mechanism,ultimately affecting plant fertility.Together,our results revealed the importance of a balanced lipid metabolism in regulating the development of cotton anther and pollen and consequently male fertility.展开更多
Background Fatty liver syndrome is a prevalent metabolic disorder in transition dairy cows,characterized by excessive hepatic lipid accumulation that impairs liver function and leads to systemic metabolic disturbances...Background Fatty liver syndrome is a prevalent metabolic disorder in transition dairy cows,characterized by excessive hepatic lipid accumulation that impairs liver function and leads to systemic metabolic disturbances.Docosahexaenoic acid(DHA),a prominent n-3 polyunsaturated fatty acid(PUFA),not only exhibits anti-inflammatory and anti-oxidative properties,but also holds potential in ameliorating lipid metabolism.This study integrated in vitro bovine primary hepatocyte models and in vivo dairy cow trials to investigate the regulatory effects of DHA on hepatic lipid deposition.Results In vitro,40μmol/L DHA significantly reduced triglyceride(TAG)accumulation in steatotic hepatocytes by downregulating genes involved in fatty acid transport(FABP-1,CD36)and lipogenesis(DGAT2,FAS,SREBP-1C),while upregulating markers of lipolysis(CGI-58,ATGL)and fatty acid oxidation(ACADL,CPT1A,CPT2).Transmission electron microscopy(TEM)confirmed DHA-mediated restoration of mitochondrial ultrastructure and enhanced lipid droplet(LD)-mitochondria interactions.In vivo,dietary rumen-protected DHA(180 g/d)supplementation reduced hepatic lipid deposition,improved liver function(evidenced by decreased total bilirubin and alanine aminotransferase),reduced oxidative stress and inflammation(suppressed malondialdehyde,glutathione peroxidase,and lipopolysaccharide),coincided with relieving insulin resistance(reduced insulin and glucose,as well increased adiponectin)in dairy cows with fatty liver.These improvements may be attributed to increased expression of TOMM20 and MtCo-1,promoting mitochondrial biogenesis andβ-oxidation,along with an elevated plasma n-3/n-6 ratio.Conclusions Collectively,these findings suggest that DHA supplementation represents a promising nutritional strategy for preventing spontaneous fatty liver in transition dairy cows by enhancing hepatic lipid clearance and restoring metabolic homeostasis.展开更多
Background The decline in reproductive performance of aged hens is mainly attributed to oxidative damage in reproductive organs,hepatic lipid metabolism disorders,and intestinal microbiota dysbiosis.Glycyrrhizin(GL)ha...Background The decline in reproductive performance of aged hens is mainly attributed to oxidative damage in reproductive organs,hepatic lipid metabolism disorders,and intestinal microbiota dysbiosis.Glycyrrhizin(GL)has been proven to enhance antioxidant capacity,regulate lipid metabolism and gut microbiota in mammals,but its efficacy in hens remains unclear.Hence,this study aimed to investigate whether dietary GL supplementation improves reproductive performance in hens during the late laying stage by modulating intestinal microbiota composition,hepatic lipid metabolism and ovarian antioxidant status.Results Dietary supplementation with 100 mg/kg GL significantly improved the egg production rate,egg quality,and hatching rate in aged breeder hens(P<0.05).GL supplementation also increased the serum levels of HDLC,TP and ALB,and enhanced the antioxidant capacity in both serum and ovary(P<0.05).In addition,dietary GL elevated the serum progesterone(P4)levels by enhancing the transcription level of steroid synthesis key enzymes(CYP11A1 and 3β-HSD)in the ovary(P<0.05).Dietary GL also promoted the synthesis and transport of vitellogenin(VTG)by upregulating the VTG-II(P<0.05)and APOV1(P=0.077)expression levels in the liver,thereby increasing the number of grade follicles and small yellow follicles.Moreover,dietary GL enhanced hepatic fatty acidβ-oxidation by upregulating PPARαand CPT-I(P<0.05),and downregulating ACC expression levels(P<0.05).In agreement,liver metabolomics analysis revealed that dietary GL supplementation significantly altered hepatic metabolism,with 389 differentially identified metabolites(P<0.05).The key metabolites(e.g.,taurocholic acid,tauroursodeoxycholic acid,nicotinuric acid,glycodeoxycholic acid(hydrate))were identified,and they were mainly functionally enriched in betaalanine metabolism nicotinate,taurine and hypotaurine metabolism(P<0.05).Finally,16S rRNA gene sequencing revealed that dietary GL reversed age-induced changes in gut microbiota composition,characterized by a significant increase in Lactobacillus abundance and a decrease in Bacteroides(P<0.05).Conclusions These results collectively demonstrate that dietary supplementation with 100 mg/kg GL improved reproductive performance by reversing age-induced changes in gut microbiota,enhancing hepatic vitellogenin synthesis,and ameliorating ovarian function in aged breeder hens.This study suggests that dietary GL is a potential strategy to improve reproductive performance in broiler breeder hens during the late laying period.展开更多
A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative...A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.展开更多
Alzheimer’s disease(AD)is the most common form of dementia,affecting over 50 million people worldwide.This figure is projected to nearly double every 20 years,reaching 82 million by 2030 and 152 million by 2050(Alzhe...Alzheimer’s disease(AD)is the most common form of dementia,affecting over 50 million people worldwide.This figure is projected to nearly double every 20 years,reaching 82 million by 2030 and 152 million by 2050(Alzheimer’s Disease International).The apolipoproteinε4(APOE4)allele is the strongest genetic risk factor for late-onset AD(after age 65 years).Apolipoprotein E,a lipid transporter,exists in three variants:ε2,ε3,andε4.APOEε2(APOE2)is protective against AD,APOEε3(APOE3)is neutral,while APOE4 significantly increases the risk.Individuals with one copy of APOE4 have a 4-fold greater risk of developing AD,and those with two copies face an 8-fold risk compared to non-carriers.Even in cognitively normal individuals,APOE4 carriers exhibit brain metabolic and vascular deficits decades before amyloid-beta(Aβ)plaques and neurofibrillary tau tangles emerge-the hallmark pathologies of AD(Reiman et al.,2001,2005;Thambisetty et al.,2010).Notably,studies have demonstrated reduced glucose uptake,or hypometabolism,in brain regions vulnerable to AD in asymptomatic middle-aged APOE4 carriers,long before clinical symptoms arise(Reiman et al.,2001,2005).展开更多
As the aging population continues to grow,age-related health issues are becoming increasingly prominent,attracting widespread attention and concern from society.While research on the mechanisms of aging is relatively ...As the aging population continues to grow,age-related health issues are becoming increasingly prominent,attracting widespread attention and concern from society.While research on the mechanisms of aging is relatively extensive,studies on the association between aging and related diseases remain limited.G.lucidum,a traditional medicinal fungus,has garnered significant attention due to its diverse bioactive properties.Recent studies have revealed that G.lucidum and its active components exhibit significant potential in anti-aging and regulating dysregulation of glucose and lipid metabolism.However,a comprehensive and detailed review of recent research findings has yet to be thoroughly explored.This paper summarizes and elucidates the latest advances in the pathological mechanisms of aging-related glucose and lipid metabolism disorders by retrieving data from databases such as X-mol and PubMed,provides a detailed account of the regulatory effects of G.lucidum’s primary active components on aging and lipid metabolism,and explores their potential mechanisms.Additionally,it discusses the application prospects of G.lucidum in the fields of anti-aging and metabolic regulation,aiming to provide a reference for research on aging-mediated lipid metabolism disorders and to lay a theoretical foundation for the further development and application of G.lucidum.展开更多
Alzheimer’s disease is the most common cause of dementia.Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease,the overall profile of lipid and sterol chan...Alzheimer’s disease is the most common cause of dementia.Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease,the overall profile of lipid and sterol changes that occur in the brain during Alzheimer’s disease remains unclear.In this study,we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer’s disease model mice,which carry mutations in the amyloid precursor protein(APP)and presenilin 1(PS1)genes.Using untargeted lipidomics and sterolomics techniques,we investigated the metabolic profiles of lipids,with a focus on sterols specifically,in three brain regions:cerebellum,hippocampus,and olfactory bulb.Our results revealed significant alterations in various lipids,particularly in the hippocampus and olfactory bulb,suggesting changes in energy levels in these regions.Further pathway analysis indicated notable disruptions in key metabolic processes,particularly those related to fatty acids and cell membrane components.Additionally,we observed decreased expression of 15 genes involved in lipid and sterol regulation.Collectively,these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer’s disease,highlighting potential metabolic pathways involved in the development of this debilitating disease.展开更多
Alternate wetting and drying irrigation(AWD)significantly influences the cooking and eating quality of rice(Oryza sativa L.).However,the mechanisms by which AWD affects rice cooking and eating quality remain unclear.L...Alternate wetting and drying irrigation(AWD)significantly influences the cooking and eating quality of rice(Oryza sativa L.).However,the mechanisms by which AWD affects rice cooking and eating quality remain unclear.Lipid and free fatty acid contents in grains correlate positively with cooking and eating quality of rice.This study examined Yangdao 6(YD6,a conventional taste indica inbred)and Nanjing 9108(NJ9108,a superior taste japonica inbred)cultivated under conventional irrigation(CI),alternate wetting and moderate drying irrigation(AWMD),and alternate wetting and severe drying irrigation(AWSD)from 10 days after transplanting to maturity.The research investigated the relationship between lipid and free fatty acid biosynthesis in grains and the cooking and eating quality of rice.Compared to CI treatment,AWMD significantly enhanced the contents of lipid,total free fatty acids(TFFAs),free unsaturated fatty acids(FUFAs),linoleic acid,and oleic acid in milled rice by increasing activities of enzymes associated with lipid synthesis,while AWSD produced opposite effects.Correlation analysis revealed that elevated levels of lipid,TFFAs,FUFAs,linoleic acid,and oleic acid contribute to improved rice cooking and eating quality.The findings demonstrate that AWMD enhances cooking and eating quality of milled rice through optimization of lipid and fatty acid synthesis in rice grains.展开更多
Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes.Among these,protein lipidations which refer to lipid attachment...Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes.Among these,protein lipidations which refer to lipid attachment to proteins are prominent,which primarily encompassing five types including S-palmitoylation,N-myristoylation,S-prenylation,glycosylphosphatidylinositol(GPl)anchor and cholesterylation.Lipid attachment to proteins plays an essential role in the regulation of protein trafficking,localisation,stability,conformation,interactions and signal transduction by enhancing hydrophobicity.Accumulating evidence from genetic,structural,and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases.Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation,and several agents have been developed and tested in preclinical and clinical studies,some of which,such as asciminib and lonafarnib are FDA-approved for therapeutic use,indicating that targeting protein lipidations represents a promising therapeutic strategy.Here,we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types,outline the impact of protein lipidations on physiology and disease,and highlight potential therapeutic targets and clinical research progress,aiming to provide a comprehensive reference for future protein lipidation research.展开更多
Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxid...Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.展开更多
The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.Obesity-related conditions like type 2 d...The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship.Peripheral lipid accumulation,particularly in the liver,initiates a cascade of inflammatory processes that extend to the brain,influencing critical metabolic regulatory regions.Ceramide and palmitate,key lipid components,along with lipid transporters lipocalin-2 and apolipoprotein E,contribute to neuroinflammation by disrupting blood–brain barrier integrity and promoting gliosis.Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation.Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models.However,translating these findings to clinical practice requires further investigation into human subjects.In conclusion,metabolic dysfunction,peripheral inflammation,and insulin resistance are integral to neuroinflammation and neurodegeneration.Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.展开更多
Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic...Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.展开更多
Lipids serve as fundamental constituents of cell membranes and organelles.Recent studies have highlighted the significance of lipids as biomarkers in the diagnosis of breast cancer.Although liquid chromatography coupl...Lipids serve as fundamental constituents of cell membranes and organelles.Recent studies have highlighted the significance of lipids as biomarkers in the diagnosis of breast cancer.Although liquid chromatography coupled with tandem mass spectrometry(LC-MS/MS)is widely employed for lipid analysis in complex samples,it suffers from limitations such as complexity and time-consuming procedures.In this study,we have developed dopamine-modified TiO_(2)nanoparticles(TiO_(2)-DA)and applied the materials to assist the analysis of lipids by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS).The TiO_(2)-DA can provide large specific surface area and acidic environment,well suited for lipid analysis.The method was initially validated using standard lipid molecules.Good sensitivity,reproducibility and quantification performance was observed.Then,the method was applied to the analysis of 90 serum samples from 30 patients with breast cancer,30 patients with benign breast disease and 30 healthy controls.Five lipid molecules were identified as potential biomarkers for breast cancer.We constructed a classification model based on the MALDI-TOF MS signal of the 5 lipid molecules,and achieved high sensitivity,specificity and accuracy for the differentiation of breast cancer from benign breast disease and healthy control.We further collected another 60 serum samples from 20 healthy controls,20 patients with benign breast disease and 20 patients with breast cancer for MALDITOF MS analysis to verify the accuracy of the classification model.This advancement holds great promise for the development of diagnostic models for other lipid metabolism-related diseases.展开更多
Gastric Carcinoma(GC)is a highly fatal malignant tumor with a poor prognosis.Its elevated mortality rates are primarily due to its proclivity for late-stage metastasis.Exploring the metabolic interactions between tumo...Gastric Carcinoma(GC)is a highly fatal malignant tumor with a poor prognosis.Its elevated mortality rates are primarily due to its proclivity for late-stage metastasis.Exploring the metabolic interactions between tumor microenvironment and the systemic bloodstream could help to clearly understand the mechanisms and identify precise biomarkers of tumor growth,proliferation,and metastasis.In this study,an integrative approach that combines plasma metabolomics with mass spectrometry imaging of tumor tissue was developed to investigate the global metabolic landscape of GC tumorigenesis and metastasis.The results showed that the oxidized glutathione to glutathione ratio(GSSH/GSH)became increased in non-distal metastatic GC(M0),which means an accumulation of oxidative stress in tumor tissues.Furthermore,it was found that the peroxidation of polyunsaturated fatty acids,such as 9,10-EpOMe,9-HOTrE,etc.,were accelerated in both plasma and tumor tissues of distal metastatic GC(M1).These changes were further confirmed the potential effect of CYP2E1 and GGT1 in metastatic potential of GC by mass spectrometry imaging(MSI)and immunohistochemistry(IHC).Collectively,our findings reveal the integrated multidimensional metabolomics approach is a clinical useful method to unravel the bloodtumor metabolic crosstalk,illuminate reprogrammed metabolic networks,and provide reliable circulating biomarkers.展开更多
Ferroptosis,a type of programmed cell death,represents a distinct paradigm in cell biology.It is characterized by the iron-dependent accumulation of reactive oxygen species,which induce lipid peroxidation(LPO),and is ...Ferroptosis,a type of programmed cell death,represents a distinct paradigm in cell biology.It is characterized by the iron-dependent accumulation of reactive oxygen species,which induce lipid peroxidation(LPO),and is orchestrated by the interplay between iron,lipid peroxides,and glutathione.In this review,we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis,including iron intake and export as well as ferritinophagy,and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases,especially P450 oxidoreductases,in modulating LPO.We summarize how various types of fatty acids(FAs),including saturated,monounsaturated,and polyunsaturated FAs,differentially influence ferroptosis when incorporated into phospholipids.Furthermore,we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis,shedding light on therapeutic avenues for ferroptosis-associated diseases.展开更多
文摘More than four decades ago it was established that an elevated low-density lipoprotein-cholesterol level was a risk for developing coronary artery disease. For the last two decades, statins have been the cornerstone of reducing low-density lipoprotein-cholesterol, but despite significant clinical efficacy in the majority of patients, a large number of patients suffer from side effects and cannot tolerate the required statin dose to reach their recommended low-density lipoprotein-cholesterol goals. Preliminary clinical studies indicate that monoclonal antibodies to PCSK9 appear to be highly efficacious in lowering low-density lipoprotein-cholesterol with a favourable adverse event profile. However, further longer-term clinical studies are required to determine their safety. From the early-proposed concept for high-density lipoprotein-mediated cholesterol efflux for the treatment of coronary artery disease, the concentration of the cholesterol content in high-density lipoprotein particles has been considered a surrogate measurement for the efficacy of the reverse cholesterol transport process. However, unlike the beneficial effects of the statins and monoclonal antibodies to PCSK9 in reducing low-density lipoprotein-cholesterol, no significant advances have been made to increase the levels of high-density lipoprotein-cholesterol. Here it is shown that by a non-pharmacological plasma delipidation means, the atherogenic low-density lipoproteins can be converted to anti-atherogenic particles and that the high-density lipoproteins are converted to particles with extreme high affinity to cause rapid regression of atherosclerosis.
基金The National Health and Medical Research Council,Grant/Award Numbers:APP2018256,APP1142472,APP1158841,APP1185426Australian Research Council,Grant/Award Numbers:FT210100271,DP210102781,DP160101312,LE200100163+5 种基金Cancer Council Victoria funding,Grant/Award Number:APP1163284Australia-China Science and Research Fund-Joint Research Centre on Personal Health Technologies,Grant/Award Number:ACSRF65777Australian Dental Research Foundation GrantPawsey Supercomputing CentreNational Computational InfrastructureAustralian National Fabrication Facility,Grant/Award Number:VictorianNode。
文摘Antimicrobial peptides(AMPs)are potentially powerful alternatives to conven-tional antibiotics in combating multidrug resistance,given their broad spectrum of activity.They mainly interact with cell membranes through surface electrostatic potentials and the formation of secondary structures,resulting in permeability and destruction of target microorganism membranes.Our earlier work showed that two leading AMPs,MSI-78(4–20)and pardaxin(1–22),had potent antimicrobial activ-ity against a range of bacteria.It is known that the attachment of moderate-length lipid carbon chains to cationic peptides can further improve the functionality of these peptides through enhanced interactions with the membrane lipid bilayer,inducing membrane curvature,destabilization,and potential leakage.Thus,in this work,we aimed to investigate the antimicrobial activity,oligomerization propensity,and lipid-membrane binding interactions of a range of N-terminal lipidated analogs of MSI-78(4–20)and pardaxin(1–22).Molecular modeling results suggest that aggregation of the N-lipidated AMPs may impart greater structural stability to the peptides in solu-tion and a greater depth of lipid bilayer insertion for the N-lipidated AMPs over the parental peptide.Our experimental and computationalfindings provide insights into how N-terminal lipidation of AMPs may alter their conformations,with subsequent effects on their functional properties in regard to their self-aggregation behavior,membrane interactions,and antimicrobial activity.
基金supported by the National Natural Science Foundation of China,Nos.82271411(to RG),51803072(to WL)the International Cooperative Project of Talent Cultivation“Xinghai Project”at the China-Japan Union Hospital of Jilin University,No.XHLH202404(to WL)+1 种基金the Science and Technology Development Plan of Jilin Province,No.YDZJ202201ZYTS038(to WL)Jilin Provincial Finance Program,No.2022SCZ10(to WL)。
文摘Traumatic spinal cord injury often leads to the disintegration of nerve cells and axons,resulting in a substantial accumulation of myelin debris that can persist for years.The abnormal buildup of myelin debris at sites of injury greatly impedes nerve regeneration,making the clearance of debris within these microenvironments crucial for effective post-spinal cord injury repair.In this review,we comprehensively outline the mechanisms that promote the clearance of myelin debris and myelin metabolism and summarize their roles in spinal cord injury.First,we describe the composition and characteristics of myelin debris and explain its effects on the injury site.Next,we introduce the phagocytic cells involved in myelin debris clearance,including professional phagocytes(macrophages and microglia)and non-professional phagocytes(astrocytes and microvascular endothelial cells),as well as other cells that are also proposed to participate in phagocytosis.Finally,we focus on the pathways and associated targets that enhance myelin debris clearance by phagocytes and promote lipid metabolism following spinal cord injury.Our analysis indicates that myelin debris phagocytosis is not limited to monocyte-derived macrophages,but also involves microglia,astrocytes,and microvascular endothelial cells.By modulating the expression of genes related to phagocytosis and lipid metabolism,it is possible to modulate lipid metabolism disorders and influence inflammatory phenotypes,ultimately affecting the recovery of motor function following spinal cord injury.Additionally,therapies such as targeted mitochondrial transplantation in phagocytic cells,exosome therapy,and repeated trans-spinal magnetic stimulation can effectively enhance the removal of myelin debris,presenting promising potential for future applications.
基金supported by the Hellenic Foundation for Research and Innovation,HFRI,“2nd Call for HFRI Research Projects to support Faculty Members&Researchers”Project 02667 to GL.
文摘Lysophosphatidic acid(LPA)is a pleiotropic lipid agonist essential for functions of the central nervous system(CNS).It is abundant in the developing and adult brain while its concentration in biological fluids,including cerebrospinal fluid,varies significantly(Figure 1Α;Yung et al.,2014).LPA actually corresponds to a variety of lipid species that include different stereoisomers with either saturated or unsaturated fatty acids bearing likely differentiated biological activities(Figure 1Α;Yung et al.,2014;Hernández-Araiza et al.,2018).
基金supported by the National Natural Science Foundation of China,No.82201568(to QQ)Capital’s Funds for Health Improvement and Research,No.2024-2-1031(to QQ)Beijing Nova Program,No.20240484566(to QQ).
文摘Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.
基金supported by the Science and Technology Major Program of Bingtuan,China (2023AA008)the National Natural Science Foundation of China (31960369)+1 种基金the Bingtuan Science and Technology Program,China (2025DA001)the Henan Provincial Science and Technology Research Project,China (222102110200)。
文摘Recent studies have shown that lipid metabolism is a key factor affecting anther development and male fertility.However,how plants regulating the metabolic balance of multiple lipids to ensure proper anther development and male fertility remains unclear.Analyzing lipid molecules related to anther fertility and genes responsible for their biosynthesis is crucial for understanding the physiological significance of lipid metabolism in crop fertility.In this study,we compared the transcriptome and the composition and content of lipids in anthers of two upland cotton(Gossypium hirsutum) materials,Shida 98(WT) and its nearly-isogenic male sterile line Shida 98A(MS).Transcriptomics analysis identified many differentially expressed genes(DEGs) between the two materials,with the genes of the alpha-linolenic acid metabolism pathway being the most significantly associated with the male sterility phenotype.Investigations on lipids revealed that the MS anthers over-accumulated free fatty acids(FFAs),phosphatidic acid(PA),mono-and di-galactosyldiacylglycerol(MGDG and DGDG),and had a decreased content of triacylglycerol(TAG),which was closely related to the abnormal metabolism of alpha-linolenic acid(C18:3);therefore,the major lipids containing C18:3-acyl chains,such as PA,MGDG,DGDG,and TAG,are proposed to play a major role in cotton anther development.We also showed that an excessive level of MGDG and DGDG caused jasmonic acid(JA) overaccumulation in MS anthers,which in turn inhibited the expression of GhFAD3 and consequently reduced the C18:3 content,presumably via a feedback regulation mechanism,ultimately affecting plant fertility.Together,our results revealed the importance of a balanced lipid metabolism in regulating the development of cotton anther and pollen and consequently male fertility.
基金supported by the National Key R&D Program of China(No.2022YFD1301001)。
文摘Background Fatty liver syndrome is a prevalent metabolic disorder in transition dairy cows,characterized by excessive hepatic lipid accumulation that impairs liver function and leads to systemic metabolic disturbances.Docosahexaenoic acid(DHA),a prominent n-3 polyunsaturated fatty acid(PUFA),not only exhibits anti-inflammatory and anti-oxidative properties,but also holds potential in ameliorating lipid metabolism.This study integrated in vitro bovine primary hepatocyte models and in vivo dairy cow trials to investigate the regulatory effects of DHA on hepatic lipid deposition.Results In vitro,40μmol/L DHA significantly reduced triglyceride(TAG)accumulation in steatotic hepatocytes by downregulating genes involved in fatty acid transport(FABP-1,CD36)and lipogenesis(DGAT2,FAS,SREBP-1C),while upregulating markers of lipolysis(CGI-58,ATGL)and fatty acid oxidation(ACADL,CPT1A,CPT2).Transmission electron microscopy(TEM)confirmed DHA-mediated restoration of mitochondrial ultrastructure and enhanced lipid droplet(LD)-mitochondria interactions.In vivo,dietary rumen-protected DHA(180 g/d)supplementation reduced hepatic lipid deposition,improved liver function(evidenced by decreased total bilirubin and alanine aminotransferase),reduced oxidative stress and inflammation(suppressed malondialdehyde,glutathione peroxidase,and lipopolysaccharide),coincided with relieving insulin resistance(reduced insulin and glucose,as well increased adiponectin)in dairy cows with fatty liver.These improvements may be attributed to increased expression of TOMM20 and MtCo-1,promoting mitochondrial biogenesis andβ-oxidation,along with an elevated plasma n-3/n-6 ratio.Conclusions Collectively,these findings suggest that DHA supplementation represents a promising nutritional strategy for preventing spontaneous fatty liver in transition dairy cows by enhancing hepatic lipid clearance and restoring metabolic homeostasis.
基金supported and funded by the National Key Research and Development Program of China(2023YFD1300801)the Agricultural Science and Technology Innovation Program in Chinese Academy of Agricultural Sciences(ASTIP-IAS-08)。
文摘Background The decline in reproductive performance of aged hens is mainly attributed to oxidative damage in reproductive organs,hepatic lipid metabolism disorders,and intestinal microbiota dysbiosis.Glycyrrhizin(GL)has been proven to enhance antioxidant capacity,regulate lipid metabolism and gut microbiota in mammals,but its efficacy in hens remains unclear.Hence,this study aimed to investigate whether dietary GL supplementation improves reproductive performance in hens during the late laying stage by modulating intestinal microbiota composition,hepatic lipid metabolism and ovarian antioxidant status.Results Dietary supplementation with 100 mg/kg GL significantly improved the egg production rate,egg quality,and hatching rate in aged breeder hens(P<0.05).GL supplementation also increased the serum levels of HDLC,TP and ALB,and enhanced the antioxidant capacity in both serum and ovary(P<0.05).In addition,dietary GL elevated the serum progesterone(P4)levels by enhancing the transcription level of steroid synthesis key enzymes(CYP11A1 and 3β-HSD)in the ovary(P<0.05).Dietary GL also promoted the synthesis and transport of vitellogenin(VTG)by upregulating the VTG-II(P<0.05)and APOV1(P=0.077)expression levels in the liver,thereby increasing the number of grade follicles and small yellow follicles.Moreover,dietary GL enhanced hepatic fatty acidβ-oxidation by upregulating PPARαand CPT-I(P<0.05),and downregulating ACC expression levels(P<0.05).In agreement,liver metabolomics analysis revealed that dietary GL supplementation significantly altered hepatic metabolism,with 389 differentially identified metabolites(P<0.05).The key metabolites(e.g.,taurocholic acid,tauroursodeoxycholic acid,nicotinuric acid,glycodeoxycholic acid(hydrate))were identified,and they were mainly functionally enriched in betaalanine metabolism nicotinate,taurine and hypotaurine metabolism(P<0.05).Finally,16S rRNA gene sequencing revealed that dietary GL reversed age-induced changes in gut microbiota composition,characterized by a significant increase in Lactobacillus abundance and a decrease in Bacteroides(P<0.05).Conclusions These results collectively demonstrate that dietary supplementation with 100 mg/kg GL improved reproductive performance by reversing age-induced changes in gut microbiota,enhancing hepatic vitellogenin synthesis,and ameliorating ovarian function in aged breeder hens.This study suggests that dietary GL is a potential strategy to improve reproductive performance in broiler breeder hens during the late laying period.
文摘A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.
基金supported by National Institute on Aging(NIH-NIA)R01AG054459(to ALL).
文摘Alzheimer’s disease(AD)is the most common form of dementia,affecting over 50 million people worldwide.This figure is projected to nearly double every 20 years,reaching 82 million by 2030 and 152 million by 2050(Alzheimer’s Disease International).The apolipoproteinε4(APOE4)allele is the strongest genetic risk factor for late-onset AD(after age 65 years).Apolipoprotein E,a lipid transporter,exists in three variants:ε2,ε3,andε4.APOEε2(APOE2)is protective against AD,APOEε3(APOE3)is neutral,while APOE4 significantly increases the risk.Individuals with one copy of APOE4 have a 4-fold greater risk of developing AD,and those with two copies face an 8-fold risk compared to non-carriers.Even in cognitively normal individuals,APOE4 carriers exhibit brain metabolic and vascular deficits decades before amyloid-beta(Aβ)plaques and neurofibrillary tau tangles emerge-the hallmark pathologies of AD(Reiman et al.,2001,2005;Thambisetty et al.,2010).Notably,studies have demonstrated reduced glucose uptake,or hypometabolism,in brain regions vulnerable to AD in asymptomatic middle-aged APOE4 carriers,long before clinical symptoms arise(Reiman et al.,2001,2005).
基金supported by grants from Natural Science Foundation of Jilin Province(No.23JQ08,No.YDZJ202502 CXJD077,No.JLARS-2025-0802-09 and No.YDZJ202501ZY TS706).
文摘As the aging population continues to grow,age-related health issues are becoming increasingly prominent,attracting widespread attention and concern from society.While research on the mechanisms of aging is relatively extensive,studies on the association between aging and related diseases remain limited.G.lucidum,a traditional medicinal fungus,has garnered significant attention due to its diverse bioactive properties.Recent studies have revealed that G.lucidum and its active components exhibit significant potential in anti-aging and regulating dysregulation of glucose and lipid metabolism.However,a comprehensive and detailed review of recent research findings has yet to be thoroughly explored.This paper summarizes and elucidates the latest advances in the pathological mechanisms of aging-related glucose and lipid metabolism disorders by retrieving data from databases such as X-mol and PubMed,provides a detailed account of the regulatory effects of G.lucidum’s primary active components on aging and lipid metabolism,and explores their potential mechanisms.Additionally,it discusses the application prospects of G.lucidum in the fields of anti-aging and metabolic regulation,aiming to provide a reference for research on aging-mediated lipid metabolism disorders and to lay a theoretical foundation for the further development and application of G.lucidum.
基金supported by the National Natural Science Foundation of China,Nos.82200784,32271311Qizhen Foundation,No.226‐2023‐00008(all to LH).
文摘Alzheimer’s disease is the most common cause of dementia.Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease,the overall profile of lipid and sterol changes that occur in the brain during Alzheimer’s disease remains unclear.In this study,we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer’s disease model mice,which carry mutations in the amyloid precursor protein(APP)and presenilin 1(PS1)genes.Using untargeted lipidomics and sterolomics techniques,we investigated the metabolic profiles of lipids,with a focus on sterols specifically,in three brain regions:cerebellum,hippocampus,and olfactory bulb.Our results revealed significant alterations in various lipids,particularly in the hippocampus and olfactory bulb,suggesting changes in energy levels in these regions.Further pathway analysis indicated notable disruptions in key metabolic processes,particularly those related to fatty acids and cell membrane components.Additionally,we observed decreased expression of 15 genes involved in lipid and sterol regulation.Collectively,these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer’s disease,highlighting potential metabolic pathways involved in the development of this debilitating disease.
基金supported by the Natural Science Foundation of Jiangsu Province,China(BK20241931 and BK 20221371)the National Natural Science Foundation of China(32071943,32372214,and 31901444)the National Key Research and Development Program of China(2022YFD2300304)。
文摘Alternate wetting and drying irrigation(AWD)significantly influences the cooking and eating quality of rice(Oryza sativa L.).However,the mechanisms by which AWD affects rice cooking and eating quality remain unclear.Lipid and free fatty acid contents in grains correlate positively with cooking and eating quality of rice.This study examined Yangdao 6(YD6,a conventional taste indica inbred)and Nanjing 9108(NJ9108,a superior taste japonica inbred)cultivated under conventional irrigation(CI),alternate wetting and moderate drying irrigation(AWMD),and alternate wetting and severe drying irrigation(AWSD)from 10 days after transplanting to maturity.The research investigated the relationship between lipid and free fatty acid biosynthesis in grains and the cooking and eating quality of rice.Compared to CI treatment,AWMD significantly enhanced the contents of lipid,total free fatty acids(TFFAs),free unsaturated fatty acids(FUFAs),linoleic acid,and oleic acid in milled rice by increasing activities of enzymes associated with lipid synthesis,while AWSD produced opposite effects.Correlation analysis revealed that elevated levels of lipid,TFFAs,FUFAs,linoleic acid,and oleic acid contribute to improved rice cooking and eating quality.The findings demonstrate that AWMD enhances cooking and eating quality of milled rice through optimization of lipid and fatty acid synthesis in rice grains.
基金supported by the National Natural Science Foundation of China (No.82073095)the medical Sci-Tech innovation platform Foundation of Zhongnan Hospital,Wuhan University (No.PTXM2023005).
文摘Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes.Among these,protein lipidations which refer to lipid attachment to proteins are prominent,which primarily encompassing five types including S-palmitoylation,N-myristoylation,S-prenylation,glycosylphosphatidylinositol(GPl)anchor and cholesterylation.Lipid attachment to proteins plays an essential role in the regulation of protein trafficking,localisation,stability,conformation,interactions and signal transduction by enhancing hydrophobicity.Accumulating evidence from genetic,structural,and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases.Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation,and several agents have been developed and tested in preclinical and clinical studies,some of which,such as asciminib and lonafarnib are FDA-approved for therapeutic use,indicating that targeting protein lipidations represents a promising therapeutic strategy.Here,we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types,outline the impact of protein lipidations on physiology and disease,and highlight potential therapeutic targets and clinical research progress,aiming to provide a comprehensive reference for future protein lipidation research.
基金supported by the National Natural Science Foundation of China,No.82071442 (to LS)a grant from the Jilin Provincial Department of Finance,No.JLSWSRCZX2021-004 (to LS)。
文摘Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.
基金supported by a Presidential Postdoctoral Fellowship (021229-00001) from Nanyang Technological University,Singapore (to JZ)a Lee Kong Chian School of Medicine Dean’s Postdoctoral Fellowship (021207-00001) from NTU Singaporea Mistletoe Research Fellowship (022522-00001) from the Momental Foundaton,USA (to CHL)
文摘The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship.Peripheral lipid accumulation,particularly in the liver,initiates a cascade of inflammatory processes that extend to the brain,influencing critical metabolic regulatory regions.Ceramide and palmitate,key lipid components,along with lipid transporters lipocalin-2 and apolipoprotein E,contribute to neuroinflammation by disrupting blood–brain barrier integrity and promoting gliosis.Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation.Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models.However,translating these findings to clinical practice requires further investigation into human subjects.In conclusion,metabolic dysfunction,peripheral inflammation,and insulin resistance are integral to neuroinflammation and neurodegeneration.Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.
基金funded by Basic Research Program of Shanghai,No.20JC1412200(to JW)the National Key Research and Development Program of China,No.2020YFA0113000(to RCZ)。
文摘Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.
基金supported by National Natural Science Foundation of China(NSFC,Nos.22074022,22374031)the Ministry of Science and Technology of China,National Key R&D Program of China(No.2022YFC2704300).
文摘Lipids serve as fundamental constituents of cell membranes and organelles.Recent studies have highlighted the significance of lipids as biomarkers in the diagnosis of breast cancer.Although liquid chromatography coupled with tandem mass spectrometry(LC-MS/MS)is widely employed for lipid analysis in complex samples,it suffers from limitations such as complexity and time-consuming procedures.In this study,we have developed dopamine-modified TiO_(2)nanoparticles(TiO_(2)-DA)and applied the materials to assist the analysis of lipids by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS).The TiO_(2)-DA can provide large specific surface area and acidic environment,well suited for lipid analysis.The method was initially validated using standard lipid molecules.Good sensitivity,reproducibility and quantification performance was observed.Then,the method was applied to the analysis of 90 serum samples from 30 patients with breast cancer,30 patients with benign breast disease and 30 healthy controls.Five lipid molecules were identified as potential biomarkers for breast cancer.We constructed a classification model based on the MALDI-TOF MS signal of the 5 lipid molecules,and achieved high sensitivity,specificity and accuracy for the differentiation of breast cancer from benign breast disease and healthy control.We further collected another 60 serum samples from 20 healthy controls,20 patients with benign breast disease and 20 patients with breast cancer for MALDITOF MS analysis to verify the accuracy of the classification model.This advancement holds great promise for the development of diagnostic models for other lipid metabolism-related diseases.
基金financial support from the National Key R&D Program of China(No.2022YFC3401003)the National Natural Science Foundation of China(Nos.21927808,82073817,22104160)。
文摘Gastric Carcinoma(GC)is a highly fatal malignant tumor with a poor prognosis.Its elevated mortality rates are primarily due to its proclivity for late-stage metastasis.Exploring the metabolic interactions between tumor microenvironment and the systemic bloodstream could help to clearly understand the mechanisms and identify precise biomarkers of tumor growth,proliferation,and metastasis.In this study,an integrative approach that combines plasma metabolomics with mass spectrometry imaging of tumor tissue was developed to investigate the global metabolic landscape of GC tumorigenesis and metastasis.The results showed that the oxidized glutathione to glutathione ratio(GSSH/GSH)became increased in non-distal metastatic GC(M0),which means an accumulation of oxidative stress in tumor tissues.Furthermore,it was found that the peroxidation of polyunsaturated fatty acids,such as 9,10-EpOMe,9-HOTrE,etc.,were accelerated in both plasma and tumor tissues of distal metastatic GC(M1).These changes were further confirmed the potential effect of CYP2E1 and GGT1 in metastatic potential of GC by mass spectrometry imaging(MSI)and immunohistochemistry(IHC).Collectively,our findings reveal the integrated multidimensional metabolomics approach is a clinical useful method to unravel the bloodtumor metabolic crosstalk,illuminate reprogrammed metabolic networks,and provide reliable circulating biomarkers.
基金supported by grants from the National Natural Science Foundation of China(22076104)the“Taishan Scholars”Program for Young Expert of Shandong Province(tsqn202103105).
文摘Ferroptosis,a type of programmed cell death,represents a distinct paradigm in cell biology.It is characterized by the iron-dependent accumulation of reactive oxygen species,which induce lipid peroxidation(LPO),and is orchestrated by the interplay between iron,lipid peroxides,and glutathione.In this review,we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis,including iron intake and export as well as ferritinophagy,and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases,especially P450 oxidoreductases,in modulating LPO.We summarize how various types of fatty acids(FAs),including saturated,monounsaturated,and polyunsaturated FAs,differentially influence ferroptosis when incorporated into phospholipids.Furthermore,we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis,shedding light on therapeutic avenues for ferroptosis-associated diseases.
