Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance ...Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.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
Regulation of neurosteroid biosynthesis is primarily mediated by the steroidogenic acute regulatory(StAR,commonly known as STARD1)protein.The StAR protein,by mobilizing the transport of intra-mitochondrial cholesterol...Regulation of neurosteroid biosynthesis is primarily mediated by the steroidogenic acute regulatory(StAR,commonly known as STARD1)protein.The StAR protein,by mobilizing the transport of intra-mitochondrial cholesterol,mediates the rate-limiting step in neurosteroid biosynthesis.The first steroid produced by the action of cytochrome P450 cholesterol side-chain cleavage enzyme(CYP11A1),at the mitochondrial inner membrane,is pregnenolone(the precursor of all neurosteroids),which is then converted to various steroids by tissue-specific enzymes.展开更多
Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol ...Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.展开更多
Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improv...Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.展开更多
The 18 kDa translocator protein(TSPO)located on the outer mitochondrial membrane regulates several key cellular processes including mitochondrial homeostasis,cholesterol transport,apoptosis,cell proliferation,and main...The 18 kDa translocator protein(TSPO)located on the outer mitochondrial membrane regulates several key cellular processes including mitochondrial homeostasis,cholesterol transport,apoptosis,cell proliferation,and maintenance of mitochondrial health(Rupprecht et al.,2022,2023).TSPO is expressed in both peripheral organs and the central nervous system,with a more pronounced expression in tissues that produce steroids.The main reason why TSPO has garnered so much attention is because it plays a key role in neurosteroidogenesis by transferring cholesterol from the outer to the inner mitochondrial membrane,which is the rate-limiting step in neurosteroid synthesis.A cholesterol-recognizing amino acid consensus domain has been identified in the cytosolic C terminus of the TSPO protein by both in vitro and site-directed mutagenesis experiments(Li et al.,2001).However,the role of TSPO in the process of neurosteroid synthesis has been challenged by several studies,particularly TSPO knockout models,which suggest that TSPO removal does not affect the phenotype or the system’s viability(Tu et al.,2014).However,ligands targeting TSPO have been shown to enhance levels of neurosteroids which suggests that neurosteroidogenesis is one of the major functional roles mediated by the TSPO protein.展开更多
Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primar...Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.展开更多
Surgical intervention is currently the primary treatment for hepatolithiasis;how-ever,some patients still experience residual stones and high recurrence rates after surgery.Cholesterol metabolism seems to play an impo...Surgical intervention is currently the primary treatment for hepatolithiasis;how-ever,some patients still experience residual stones and high recurrence rates after surgery.Cholesterol metabolism seems to play an important role in hepatoli-thiasis pathogenesis.A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis.Therefore,regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery.Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepato-lithiasis.This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis,as well as food intake and targeted therapeutic drugs.展开更多
BACKGROUND Phytosterolemia,also known as sitosterolemia,is a rare autosomal recessive disease characterized by elevated plasma plant sterol levels and xanthomata,which is easily misdiagnosed as familial hypercholester...BACKGROUND Phytosterolemia,also known as sitosterolemia,is a rare autosomal recessive disease characterized by elevated plasma plant sterol levels and xanthomata,which is easily misdiagnosed as familial hypercholesterolemia.Patients with homozygous phytosterolemia often have severe clinical manifestations,with xanthomata in childhood and premature atherosclerosis.Our patient had a milder clinical phenotype.CASE SUMMARY This report describes a patient with homozygous phytosterolemia who presented with only elevated cholesterol and low-density lipoprotein cholesterol(LDL-C)without xanthomata,arteriosclerosis,or hematological abnormalities.Homozygous mutation of ABCG5 which encodes an ATP-binding cassette transporter,was detected by whole exome sequencing and diagnosed as phytosterolemia.Measurement of the patient’s plasma plant sterol levels detected significant elevations in stigmasterol,rapeseed oil-derived plant sterol,andβ-glutaminol levels.Ezetimibe was started and a low plant sterol diet was recommended.The patient’s blood lipid profile was reexamined one month later and showed significant decreases in total cholesterol and LDL-C levels.Phytosterolemia has similar clinical features as familial hypercholesterolemia,is highly susceptible to misdiagnosis,and has a very low incidence,and therefore clinicians need to consider a genetic diagnosis of a definitively hyperlipidemic disorder when statin drugs fail to lower lipid levels.CONCLUSION Phytosterolemia is easily misdiagnosed as familial hypercholesterolaemia and can be treated by dietary modification and cholesterol absorption inhibitors to lower blood lipids.展开更多
BACKGROUND The association between the uric acid-to-high-density lipoprotein cholesterol ratio(UHR)and mental health among individuals with type 2 diabetes mellitus(T2DM)has not been thoroughly investigated.AIM To exa...BACKGROUND The association between the uric acid-to-high-density lipoprotein cholesterol ratio(UHR)and mental health among individuals with type 2 diabetes mellitus(T2DM)has not been thoroughly investigated.AIM To examine the link between UHR and symptoms of depression and anxiety in patients with T2DM.METHODS A cross-sectional analysis was carried out from March 2023 to April 2024,involving participants diagnosed with T2DM.Data on sociodemographic characteristics,clinical parameters,and UHR values were systematically gathered.The Self-Rating Depression Scale(SDS)and Self-Rating Anxiety Scale(SAS)were utilized to evaluate depressive and anxiety symptoms,respectively.To assess the relationships between UHR and SDS/SAS scores,linear regression models were employed,incorporating adjustments for potential confounding variables.Additionally,smooth curve fitting and threshold effect analyses were conducted to explore potential nonlinear relationships.RESULTS A total of 285 patients with T2DM were included.Initial univariate analysis demonstrated a significant positive correlation between elevated UHR levels and higher SDS and SAS scores.Multivariate regression analysis revealed that a one-unit rise in UHR was associated with a 1.13-point increase in SDS scores(95%CI:0.69-1.58)and a 0.57-point increase in SAS scores(95%CI:0.20-0.93).After controlling for confounders,UHR remained positively correlated with SDS(β=1.55,95%CI:0.57-2.53)and SAS(β=0.72,95%CI:0.35-1.09).Nonlinear analysis identified critical thresholds at UHR values of 5.02 for SDS and 4.00 for SAS,beyond which the relationships between UHR and psychological symptom scores became markedly stronger(P<0.05).CONCLUSION Higher UHR levels are significantly linked to exacerbated depressive and anxiety symptoms in patients with T2DM.These results indicate that UHR may function as a promising biomarker to identify individuals at greater risk of mental health complications within this population.展开更多
Background Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics betw...Background Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics between MDD and dyslipidaemia remain elusive.Aims To comprehensively disentangle the genetic causality between MDD and various phenotypes of blood lipids, thereby facilitating the advancement of management strategies for these conditions.Methods We conducted a two-sample univariable Mendelian randomisation (MR) analysis using different models, including the inverse variance weighted (IVW) method and causal analysis using the summary effect (CAUSE) estimates, as well as a multivariable MR analysis. This analysis used summary statistics from genome-wide association studies (GWAS) of MDD and five lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol and triglycerides (TG), encompassing 5 237 893 individuals of European and East Asian ancestries. For MDD, a total of 598 701 individuals were included, with 500 199 individuals of European ancestry (Ncase=170 756, Ncontrol=329 443) and 98 502 of East Asian ancestry (Ncase=12 588, Ncontrol=85 914). Lipid data were collected from 4 639 192 individuals through the Global Lipids Genetics Consortium (European, N=4 096 085;East Asian, N=543 107). Next, we used the two-step MR to explore the mediating factors between MDD and TG, and the risk factors affecting TG through MDD. Finally, we conducted a GWAS meta-analysis and enrichment analysis.Results In univariable MR, we observed a negative causal effect of low-density lipoprotein on MDD in both European populations (IVW: odds ratio (OR): 0.972, 95% confidence interval (CI) 0.947 to 0.998, p=0.037) and East Asian populations (IVW: OR: 0.928, 95% CI 0.864 to 0.997, p=0.042). Additionally, we identified a bidirectional causal relationship between TG and MDD, with TG having a causal effect on MDD (IVW: OR: 1.052, 95% CI 1.020 to 1.085, p=0.001) and MDD having a causal effect on TG (IVW: OR: 1.075, 95% CI 1.047 to 1.104, p<0.001). Multivariable MR analysis further supported the role of TG in MDD (OR: 1.205, 95% CI 1.034 to 1.405, p=0.017). CAUSE estimates indicated that the causal model of MDD on TG provided a better fit than the sharing model (p=0.003), while the association of TG on MDD was more likely due to horizontal correlated pleiotropy than causality. Mediation analyses revealed that waist-hip ratio (WHR) mediated 69% of the total causal effect of MDD on TG, while other identified risk factors exhibited lower mediating proportions either mediated through MDD (≤17%) or originating from MDD (≤29%). The GWAS meta-analysis highlighted potential pathways related to lipid processes and nucleosome assembling, with significant cell types identified in brain regions and liver tissues.Conclusions The findings indicate that genetic proxies of MDD are associated with elevated levels of TG, with WHR serving as a clinical indicator of the association. This suggests that interventions targeting WHR may be effective in reducing TG levels in patients with MDD.展开更多
BACKGROUND The global rise in overweight and obesity has reached alarming levels,substantially increasing the risk of metabolic disorders such as dyslipidemia.We outlined the evolving trends in baseline blood lipid le...BACKGROUND The global rise in overweight and obesity has reached alarming levels,substantially increasing the risk of metabolic disorders such as dyslipidemia.We outlined the evolving trends in baseline blood lipid levels among patients experiencing overweight or obesity,as observed in placebo-controlled randomized trials,to address the unmet clinical requirements.AIM To assess long-term trends in lipid profiles in overweight or obese populations and their association with clinical and treatment factors.METHODS EMBASE,PubMed,Cochrane Library,and Web of Science databases were searched up to October 9,2024.Randomized placebo-controlled trials of participants with overweight or obesity,with reports of baseline lipid levels,were included.The main outcome was a correlation between pooled baseline levels of triglycerides(TG),total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C)with study year.Subgroup analysis was conducted based on characteristics of the populations and intervention types.RESULTS A comprehensive meta-analysis encompassing 866 studies across nearly 60 countries and regions worldwide,involving 3300 participants,revealed significant temporal trends in baseline lipid profiles.The analysis revealed a significant decline in TG(Rs=-0.704,P<0.001,I^(2)=98.6%),TC(Rs=-0.884,P<0.001,I^(2)=99.6%),and LDL-C(Rs=-0.808,P<0.001,I^(2)=96.8%)levels.In contrast,HDL-C(Rs=0.336,P=0.041,I^(2)=99.2%)levels exhibited a progressive increase over the study period.Subgroup analyses revealed that sex,body mass index,blood pressure,diabetes status,and type of intervention influenced the observed trends,especially with patients receiving pharmacological therapies demonstrating more pronounced improvements(TG:Rs=-0.449,P_(adj)=0.011;I^(2)=98.9%;TC:Rs=-0.650,P_(adj)=0.001;I^(2)=99.4%;HDL-C:Rs=0.650,P_(adj)=0.002;I^(2)=98.6%;LDL-C:Rs=-0.417,P_(adj)=0.031;I²=98.0%).CONCLUSION Despite rising obesity rates,lipid control has improved over three decades among individuals with overweight or obesity,reflecting the positive impact of public health efforts and effective dyslipidemia treatment strategies.展开更多
Unlike most plants, members of the genus Solanum produce cholesterol and use this as a precursor for steroidal glycoalkaloids. The production of the compounds begins as a branch from brassinosteroid biosynthesis, whic...Unlike most plants, members of the genus Solanum produce cholesterol and use this as a precursor for steroidal glycoalkaloids. The production of the compounds begins as a branch from brassinosteroid biosynthesis, which produces cholesterol that is further modified to produce steroidal glycoalkaloids. During the cholesterol biosynthesis pathway, genetic engineering could alter the formation of cholesterol from provitamin D3(7-dehydrocholesterol) and produce vitamin D3. Cholesterol is a precursor for many steroidal glycoalkaloids, including a-tomatine and esculeoside A. Alpha-tomatine is consumed by mammals and it can reduce cholesterol content and improve LDL:HDL ratio. When there is a high a-tomatine content, the fruit will have a bitter flavor, which together with other steroidal glycoalkaloids serving as protective and defensive compounds for tomato against insect, fungal, and bacterial pests. These compounds also affect the rhizosphere bacteria by recruiting beneficial bacteria. One of the steroidal glycoalkaloids, esculeoside A increases while fruit ripening. This review focuses on recent studies that uncovered key reactions of the production of cholesterol and steroidal glycoalkaloids in tomato connecting to human health, fruit flavor, and plant defense and the potential application for tomato crop improvement.展开更多
Cholesterol(CH)plays a crucial role in enhancing the membrane stability of drug delivery systems(DDS).However,its association with conditions such as hyperlipidemia often leads to criticism,overshadowing its influence...Cholesterol(CH)plays a crucial role in enhancing the membrane stability of drug delivery systems(DDS).However,its association with conditions such as hyperlipidemia often leads to criticism,overshadowing its influence on the biological effects of formulations.In this study,we reevaluated the delivery effect of CH using widely applied lipid microspheres(LM)as a model DDS.We conducted comprehensive investigations into the impact of CH on the distribution,cell uptake,and protein corona(PC)of LM at sites of cardiovascular inflammatory injury.The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage.Then,the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy.Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma(PPAR-γ)expression in vascular endothelial cells and estrogen receptor alpha(ERα)protein levels in myocardial cells,thereby enhancing LM uptake at cardiovascular inflammation sites.Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V(Apoa5);this may be a major contributing factor to their prolonged circulation in vivo and explains why CH enhances the distribution of LM at cardiovascular inflammatory injury sites.It should be noted that changes in cell types and physiological environments can also influence the biological behavior of formulations.The findings enhance the conceptualization of CH and LM delivery,providing novel strategies for investigating prescription factors'bioactivity.展开更多
Atherosclerotic cardiovascular disease remains the leading cause of global mortality,with low-density lipoprotein cholesterol established as a primary causal risk factor.Despite widespread implementation of statin the...Atherosclerotic cardiovascular disease remains the leading cause of global mortality,with low-density lipoprotein cholesterol established as a primary causal risk factor.Despite widespread implementation of statin therapy,substantial interindividual variability in treatment response persists,necessitating precision medicine approaches to optimize therapeutic outcomes.This comprehensive narrative review synthesizes current understanding of pharmacogenomic determinants influencing lipid-lowering therapy efficacy,examines mechanisms underlying residual cardiovascular risk,and evaluates emerging therapeutic modalities targeting previously unexploited pathways in lipid metabolism.Genetic variants in key genes including 3-hydroxy-3-methylglutaryl-CoA reductase,apolipoprotein E,low-density lipoprotein receptor,and proprotein convertase subtilisin/kexin type 9 demonstrate significant associations with differential treatment responses,with specific polymorphisms conferring enhanced efficacy or increased intolerance risk.Beyond traditional statin therapy,novel therapeutic approaches targeting proprotein convertase subtilisin/kexin type 9,angiopoietin-like protein 3,apolipoprotein C-Ⅲ,and ATP citrate lyase offer substantial low-density lipoprotein cholesterol reductions of 50-80%,while RNA-based therapies including antisense oligonucleotides and small interfering RNA provide precise molecular targeting capabilities.Despite intensive lipid-lowering interventions,residual cardiovascular risk persists through four principal mechanisms:triglyceride-rich lipoproteins,lipoprotein(a),inflammatory processes,and suboptimal treatment adherence.Integration of pharmacogenomic insights with emerging therapeutic modalities enables personalized risk stratification and treatment selection,representing a paradigm shift toward precision medicine in cardiovascular disease prevention and management.展开更多
Immune evasion is a hallmark of cancer.Recent advancements suggest that targeting cholesterol metabolism to regulate stimulator of interferon genes(STING)signaling offers a promising approach to overcome this challeng...Immune evasion is a hallmark of cancer.Recent advancements suggest that targeting cholesterol metabolism to regulate stimulator of interferon genes(STING)signaling offers a promising approach to overcome this challenge.While STING pathway activation is critical for enhancing anti-tumor immunity,its excessive or prolonged activation can lead to chronic inflammation and immune suppression.This review examines how cholesterol-lowering nanomedicines can balance STING activation to promote effective immune responses.Nanoparticles(NPs)enable precise delivery of cholesterol-lowering agents,reducing chronic STING activation and transforming the tumor microenvironment(TME)into an immunostimulatory state.Furthermore,NPs can co-deliver STING agonists to synergize innate immune activation,providing enhanced anti-tumor responses while mitigating the risks of inflammation.By integrating cholesterol metabolism modulation with advanced nanotechnologies,this approach holds significant translational potential for developing next-generation immunotherapies.Future research should focus on optimizing NP design and exploring combination strategies with existing cancer immunotherapies to improve clinical outcomes and address immune resistance.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.展开更多
BACKGROUND Tenofovir amibufenamide(TMF)has shown antiviral efficacy comparable to tenofovir disoproxil fumarate(TDF)in chronic hepatitis B(CHB),with improved renal and bone safety profiles.While TDF is recognized for ...BACKGROUND Tenofovir amibufenamide(TMF)has shown antiviral efficacy comparable to tenofovir disoproxil fumarate(TDF)in chronic hepatitis B(CHB),with improved renal and bone safety profiles.While TDF is recognized for its lipid-lowering properties,the long-term effects of TMF on lipid metabolism remain unclear.AIM To assess lipid changes and long-term safety of TMF in CHB,including outcomes after TDF-to-TMF switch over 144 weeks.METHODS This retrospective analysis utilized data from a phase III randomized,double-blind trial involving 53 patients with CHB treated with either TMF 25 mg(n=39)or TDF 300 mg(n=14)once daily for 96 weeks.Following this blinded phase,all participants entered an open-label extension in which they received TMF until week 144.This design enabled assessment of both the comparative effects of TMF and TDF and the impact of switching from TDF to TMF,thereby reflecting real-world treatment scenarios.Virological,biochemical and imaging evaluations were performed throughout the study.RESULTS At week 96,both groups achieved comparable virological suppression and maintained stable hepatic and renal function.However,total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the TMF group compared to the TDF group(P=0.012 and P=0.040,respectively).TDF was associated with a transient increase in serum phosphate(P=0.030).After switching to TMF,lipid profiles in the former TDF group gradually aligned with those of the continuous TMF group by week 144,with no lipid abnormalities observed in either group.CONCLUSION TMF provides sustained antiviral efficacy and maintains a favourable long-term lipid and renal safety profile.These findings support TMF as a viable first-line therapy and a switch option for CHB management in clinical practice.展开更多
Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacyl...Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacylglycerols tributyrin(Tb)and tripropionin(Tp)are odorless and can be directly used as healthy supplements.In view that no study has investigated the relative biological potency of Tb and Tp,the present study was designed to compare the effects of Tp and Tb on plasma cholesterol and gut microbiota using hypercholesterolemic hamsters as a model.Male golden hamsters were randomly allocated to 6 groups fed one of the following 6 diets,namely,low-cholesterol diet(LCD),high-cholesterol diet(HCD),HCD+0.5%Tp(LTp),HCD+1%Tp(HTp),HCD+0.5%Tb(LTb),and HCD+1%Tb(HTb).Results showed that Tb administration at 1%could significantly reduce plasma total cholesterol(TC),non-high-density lipoprotein cholesterol(non-HDLC),and the ratio of non-HDLC to HDLC,whereas Tp supplementation had no effect.Mechanistically,Tb but not Tp could decrease plasma cholesterol by increasing the excretion of fecal bile acids via upregulating gene expression of cholesterol 7α-hydroxylase(CYP7A1)and liver X receptor alpha(LXRα).In addition,Tb supplementation at 1%could increase the gut microbiota diversity,reduce the ratio of Firmicutes/Bacteroidetes and favorably increase the abundance of beneficial microbial genera Bifidobacterium.In conclusion,dietary Tb supplementation was more effective than Tp in mitigating hypercholesterolemia by increasing the excretion of fecal bile acids and favorably modulating gut microbiota.展开更多
Hepatocellular carcinoma(HCC)is characterized by its highly invasive andmetastatic potential,aswell as a propensity for recurrence,contributing to treatment failure and increased mortality.Under physiological conditio...Hepatocellular carcinoma(HCC)is characterized by its highly invasive andmetastatic potential,aswell as a propensity for recurrence,contributing to treatment failure and increased mortality.Under physiological conditions,the liver maintains a balance in lipid biosynthesis,degradation,storage,and transport.HCC exhibits dysregulated lipid metabolism,driving tumor progression and therapeutic resistance.This review aims to elucidate the roles of fatty acid,sphingolipid,and cholesterol metabolism in HCC pathogenesis and explore emerging therapeutic strategies targeting these pathways.Key findings demonstrate that upregulated enzymes like fatty acid synthase(FASN),acetyl-CoA carboxylase(ACC),enhance de novo lipogenesis andβ-oxidation,and promote HCC proliferation,invasion,and apoptosis evasion.Sphingolipids exert dual functions:ceramides suppress tumors,while sphingosine-1-phosphate(S1P)drives oncogenic signaling.Aberrant cholesterolmetabolism,mediated byHMG-CoA reductase(HMGCR),liver X receptorα(LXRα),and sterol regulatory element-binding protein 1(SREBP1),contributes to immunosuppression and drug resistance.Notably,inducing ferroptosis by disrupting lipid homeostasis represents a promising approach.Pharmacological inhibition of key nodes—such as FASN(Orlistat,TVB-3664),sphingomyelin synthase(D609),or cholesterol synthesis(statins,Genkwadaphnin)—synergizes with sorafenib/lenvatinib and overcomes resistance.We conclude that targeting lipid metabolic reprogramming,alone or combined with conventional therapies,offers significant potential for novelHCC treatment strategies.Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.展开更多
基金supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)+3 种基金National Natural Science Foundation of China(82102896)China Postdoctoral Science Foundation(2024M762248)Natural Science Foundation of Sichuan Province(2024NSFSC1883)Postdoctor Research Fund of West China Hospital,Sichuan University(2024HXBH055).
文摘Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.
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 in part by funding from the Department of Internal Medicine and The CH Foundation(to PRM).
文摘Regulation of neurosteroid biosynthesis is primarily mediated by the steroidogenic acute regulatory(StAR,commonly known as STARD1)protein.The StAR protein,by mobilizing the transport of intra-mitochondrial cholesterol,mediates the rate-limiting step in neurosteroid biosynthesis.The first steroid produced by the action of cytochrome P450 cholesterol side-chain cleavage enzyme(CYP11A1),at the mitochondrial inner membrane,is pregnenolone(the precursor of all neurosteroids),which is then converted to various steroids by tissue-specific enzymes.
基金supported by the National Natural Science Foundation of China,No.82072110Suzhou Municipal Science and Technology Bureau,No.SKJY2021046+1 种基金Shanghai Key Lab of Forensic Medicine&Key Lab of Forensic Science,Ministry of Justice,China(Academy of Forensic Science),No.KF202201a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(all to TW).
文摘Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.
基金supported by the National Natural Science Foundation of China funded project(32172627)Chongqing Modern Tea Technology System for Efficient Agriculture in Mountainous Areas 2022[8]the Germplasm Creation Research Program of Southwest University。
文摘Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.
基金supported by the German Research Foundation(Deutsche Forschungsgemeinschaft)(DFG),project number 422179811 to RR and RA 689/12-1 to GR.
文摘The 18 kDa translocator protein(TSPO)located on the outer mitochondrial membrane regulates several key cellular processes including mitochondrial homeostasis,cholesterol transport,apoptosis,cell proliferation,and maintenance of mitochondrial health(Rupprecht et al.,2022,2023).TSPO is expressed in both peripheral organs and the central nervous system,with a more pronounced expression in tissues that produce steroids.The main reason why TSPO has garnered so much attention is because it plays a key role in neurosteroidogenesis by transferring cholesterol from the outer to the inner mitochondrial membrane,which is the rate-limiting step in neurosteroid synthesis.A cholesterol-recognizing amino acid consensus domain has been identified in the cytosolic C terminus of the TSPO protein by both in vitro and site-directed mutagenesis experiments(Li et al.,2001).However,the role of TSPO in the process of neurosteroid synthesis has been challenged by several studies,particularly TSPO knockout models,which suggest that TSPO removal does not affect the phenotype or the system’s viability(Tu et al.,2014).However,ligands targeting TSPO have been shown to enhance levels of neurosteroids which suggests that neurosteroidogenesis is one of the major functional roles mediated by the TSPO protein.
基金financially supported by the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)China Postdoctoral Science Foundation,No.2022M711733(to ZZ)+2 种基金the National Natural Science Foundation of China,No.82160920(to ZZ)Hebei Postdoctoral Scientific Research Project,No.B2022003040(to ZZ)Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine(to WP)。
文摘Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
基金Supported by Hebei Natural Science Foundation,No.H2022206539Hebei Provincial Government Funded Clinical Talents Training Project,No.ZF2023143.
文摘Surgical intervention is currently the primary treatment for hepatolithiasis;how-ever,some patients still experience residual stones and high recurrence rates after surgery.Cholesterol metabolism seems to play an important role in hepatoli-thiasis pathogenesis.A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis.Therefore,regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery.Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepato-lithiasis.This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis,as well as food intake and targeted therapeutic drugs.
基金Supported by Natural Science Foundation of Heibei Province,No.H2020209160。
文摘BACKGROUND Phytosterolemia,also known as sitosterolemia,is a rare autosomal recessive disease characterized by elevated plasma plant sterol levels and xanthomata,which is easily misdiagnosed as familial hypercholesterolemia.Patients with homozygous phytosterolemia often have severe clinical manifestations,with xanthomata in childhood and premature atherosclerosis.Our patient had a milder clinical phenotype.CASE SUMMARY This report describes a patient with homozygous phytosterolemia who presented with only elevated cholesterol and low-density lipoprotein cholesterol(LDL-C)without xanthomata,arteriosclerosis,or hematological abnormalities.Homozygous mutation of ABCG5 which encodes an ATP-binding cassette transporter,was detected by whole exome sequencing and diagnosed as phytosterolemia.Measurement of the patient’s plasma plant sterol levels detected significant elevations in stigmasterol,rapeseed oil-derived plant sterol,andβ-glutaminol levels.Ezetimibe was started and a low plant sterol diet was recommended.The patient’s blood lipid profile was reexamined one month later and showed significant decreases in total cholesterol and LDL-C levels.Phytosterolemia has similar clinical features as familial hypercholesterolemia,is highly susceptible to misdiagnosis,and has a very low incidence,and therefore clinicians need to consider a genetic diagnosis of a definitively hyperlipidemic disorder when statin drugs fail to lower lipid levels.CONCLUSION Phytosterolemia is easily misdiagnosed as familial hypercholesterolaemia and can be treated by dietary modification and cholesterol absorption inhibitors to lower blood lipids.
基金Supported by Science and Technology Program of Quzhou,China,No.2022K67Zhejiang Medical Association Clinical Research Fund Project,No.2024ZYC-A526and the Research Project of Quzhou People’s Hospital,No.KYQD2024-006.
文摘BACKGROUND The association between the uric acid-to-high-density lipoprotein cholesterol ratio(UHR)and mental health among individuals with type 2 diabetes mellitus(T2DM)has not been thoroughly investigated.AIM To examine the link between UHR and symptoms of depression and anxiety in patients with T2DM.METHODS A cross-sectional analysis was carried out from March 2023 to April 2024,involving participants diagnosed with T2DM.Data on sociodemographic characteristics,clinical parameters,and UHR values were systematically gathered.The Self-Rating Depression Scale(SDS)and Self-Rating Anxiety Scale(SAS)were utilized to evaluate depressive and anxiety symptoms,respectively.To assess the relationships between UHR and SDS/SAS scores,linear regression models were employed,incorporating adjustments for potential confounding variables.Additionally,smooth curve fitting and threshold effect analyses were conducted to explore potential nonlinear relationships.RESULTS A total of 285 patients with T2DM were included.Initial univariate analysis demonstrated a significant positive correlation between elevated UHR levels and higher SDS and SAS scores.Multivariate regression analysis revealed that a one-unit rise in UHR was associated with a 1.13-point increase in SDS scores(95%CI:0.69-1.58)and a 0.57-point increase in SAS scores(95%CI:0.20-0.93).After controlling for confounders,UHR remained positively correlated with SDS(β=1.55,95%CI:0.57-2.53)and SAS(β=0.72,95%CI:0.35-1.09).Nonlinear analysis identified critical thresholds at UHR values of 5.02 for SDS and 4.00 for SAS,beyond which the relationships between UHR and psychological symptom scores became markedly stronger(P<0.05).CONCLUSION Higher UHR levels are significantly linked to exacerbated depressive and anxiety symptoms in patients with T2DM.These results indicate that UHR may function as a promising biomarker to identify individuals at greater risk of mental health complications within this population.
基金supported by the National Natural Science Foundation of China(82071500,82271540,32370724,82401759,81871055,32070679)Shanghai Clinical Research Center for Mental Health(19MC1911100)+11 种基金Shanghai Key Laboratory of Psychotic Disorders(13dz2260500)Shanghai Municipal Administrator of Traditional Chinese Medicine(ZY-(2021-2023)-0207-01)Shanghai Municipal Health Commission Collaborative Innovation Group(2024CXJQ03)Shanghai Science and Technology Innovation Action Program(24JS2840400,24ZR1439900,21Y11921100)Shanghai Municipal Science and Technology Major Project,the National Key R&D Program of China(2023YFA0913804,2024YFA0916603,2022FYC2503300)the Program of Shanghai Academic/Technology Research Leader(21XD1423300)Shanghai Pujiang Program(21PJD063)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)Shanghai Municipal Commission of Education(2024AIZD016)the National Key R&D Program of China(2019YFA0905400,2017YFC0908105,2021YFC2702100)National Program for Support of Top-Notch Young Professionals,Taishan Scholar Program of Shandong Province(tstp20240526)the Natural Science Foundation of Shandong Province(ZR2019YQ14,YDZX2021009,2021ZDSYS06).
文摘Background Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics between MDD and dyslipidaemia remain elusive.Aims To comprehensively disentangle the genetic causality between MDD and various phenotypes of blood lipids, thereby facilitating the advancement of management strategies for these conditions.Methods We conducted a two-sample univariable Mendelian randomisation (MR) analysis using different models, including the inverse variance weighted (IVW) method and causal analysis using the summary effect (CAUSE) estimates, as well as a multivariable MR analysis. This analysis used summary statistics from genome-wide association studies (GWAS) of MDD and five lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol and triglycerides (TG), encompassing 5 237 893 individuals of European and East Asian ancestries. For MDD, a total of 598 701 individuals were included, with 500 199 individuals of European ancestry (Ncase=170 756, Ncontrol=329 443) and 98 502 of East Asian ancestry (Ncase=12 588, Ncontrol=85 914). Lipid data were collected from 4 639 192 individuals through the Global Lipids Genetics Consortium (European, N=4 096 085;East Asian, N=543 107). Next, we used the two-step MR to explore the mediating factors between MDD and TG, and the risk factors affecting TG through MDD. Finally, we conducted a GWAS meta-analysis and enrichment analysis.Results In univariable MR, we observed a negative causal effect of low-density lipoprotein on MDD in both European populations (IVW: odds ratio (OR): 0.972, 95% confidence interval (CI) 0.947 to 0.998, p=0.037) and East Asian populations (IVW: OR: 0.928, 95% CI 0.864 to 0.997, p=0.042). Additionally, we identified a bidirectional causal relationship between TG and MDD, with TG having a causal effect on MDD (IVW: OR: 1.052, 95% CI 1.020 to 1.085, p=0.001) and MDD having a causal effect on TG (IVW: OR: 1.075, 95% CI 1.047 to 1.104, p<0.001). Multivariable MR analysis further supported the role of TG in MDD (OR: 1.205, 95% CI 1.034 to 1.405, p=0.017). CAUSE estimates indicated that the causal model of MDD on TG provided a better fit than the sharing model (p=0.003), while the association of TG on MDD was more likely due to horizontal correlated pleiotropy than causality. Mediation analyses revealed that waist-hip ratio (WHR) mediated 69% of the total causal effect of MDD on TG, while other identified risk factors exhibited lower mediating proportions either mediated through MDD (≤17%) or originating from MDD (≤29%). The GWAS meta-analysis highlighted potential pathways related to lipid processes and nucleosome assembling, with significant cell types identified in brain regions and liver tissues.Conclusions The findings indicate that genetic proxies of MDD are associated with elevated levels of TG, with WHR serving as a clinical indicator of the association. This suggests that interventions targeting WHR may be effective in reducing TG levels in patients with MDD.
文摘BACKGROUND The global rise in overweight and obesity has reached alarming levels,substantially increasing the risk of metabolic disorders such as dyslipidemia.We outlined the evolving trends in baseline blood lipid levels among patients experiencing overweight or obesity,as observed in placebo-controlled randomized trials,to address the unmet clinical requirements.AIM To assess long-term trends in lipid profiles in overweight or obese populations and their association with clinical and treatment factors.METHODS EMBASE,PubMed,Cochrane Library,and Web of Science databases were searched up to October 9,2024.Randomized placebo-controlled trials of participants with overweight or obesity,with reports of baseline lipid levels,were included.The main outcome was a correlation between pooled baseline levels of triglycerides(TG),total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C)with study year.Subgroup analysis was conducted based on characteristics of the populations and intervention types.RESULTS A comprehensive meta-analysis encompassing 866 studies across nearly 60 countries and regions worldwide,involving 3300 participants,revealed significant temporal trends in baseline lipid profiles.The analysis revealed a significant decline in TG(Rs=-0.704,P<0.001,I^(2)=98.6%),TC(Rs=-0.884,P<0.001,I^(2)=99.6%),and LDL-C(Rs=-0.808,P<0.001,I^(2)=96.8%)levels.In contrast,HDL-C(Rs=0.336,P=0.041,I^(2)=99.2%)levels exhibited a progressive increase over the study period.Subgroup analyses revealed that sex,body mass index,blood pressure,diabetes status,and type of intervention influenced the observed trends,especially with patients receiving pharmacological therapies demonstrating more pronounced improvements(TG:Rs=-0.449,P_(adj)=0.011;I^(2)=98.9%;TC:Rs=-0.650,P_(adj)=0.001;I^(2)=99.4%;HDL-C:Rs=0.650,P_(adj)=0.002;I^(2)=98.6%;LDL-C:Rs=-0.417,P_(adj)=0.031;I²=98.0%).CONCLUSION Despite rising obesity rates,lipid control has improved over three decades among individuals with overweight or obesity,reflecting the positive impact of public health efforts and effective dyslipidemia treatment strategies.
文摘Unlike most plants, members of the genus Solanum produce cholesterol and use this as a precursor for steroidal glycoalkaloids. The production of the compounds begins as a branch from brassinosteroid biosynthesis, which produces cholesterol that is further modified to produce steroidal glycoalkaloids. During the cholesterol biosynthesis pathway, genetic engineering could alter the formation of cholesterol from provitamin D3(7-dehydrocholesterol) and produce vitamin D3. Cholesterol is a precursor for many steroidal glycoalkaloids, including a-tomatine and esculeoside A. Alpha-tomatine is consumed by mammals and it can reduce cholesterol content and improve LDL:HDL ratio. When there is a high a-tomatine content, the fruit will have a bitter flavor, which together with other steroidal glycoalkaloids serving as protective and defensive compounds for tomato against insect, fungal, and bacterial pests. These compounds also affect the rhizosphere bacteria by recruiting beneficial bacteria. One of the steroidal glycoalkaloids, esculeoside A increases while fruit ripening. This review focuses on recent studies that uncovered key reactions of the production of cholesterol and steroidal glycoalkaloids in tomato connecting to human health, fruit flavor, and plant defense and the potential application for tomato crop improvement.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82260827 and U1812403-4-4)the Guizhou Provincial Science and Technology Projects,China(Grant Nos.:[2020]1Z069,ZK[2022]380,and ZK[2023]303)+3 种基金the Cultivation Project of National Natural Science Foundation of Guizhou Medical University,China(Grant No.:20NSP050)the Guizhou Provincial Scientific and Technologic Innovation Base,China(Grant No.:[2023]003)the High-level Innovation Talents of Guizhou Province,China(Grant No.:GCC[2023]048)the Startup Fund for High-Level Talent Research at Guizhou Medical University,China(Grant No.:26242020107).
文摘Cholesterol(CH)plays a crucial role in enhancing the membrane stability of drug delivery systems(DDS).However,its association with conditions such as hyperlipidemia often leads to criticism,overshadowing its influence on the biological effects of formulations.In this study,we reevaluated the delivery effect of CH using widely applied lipid microspheres(LM)as a model DDS.We conducted comprehensive investigations into the impact of CH on the distribution,cell uptake,and protein corona(PC)of LM at sites of cardiovascular inflammatory injury.The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage.Then,the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy.Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma(PPAR-γ)expression in vascular endothelial cells and estrogen receptor alpha(ERα)protein levels in myocardial cells,thereby enhancing LM uptake at cardiovascular inflammation sites.Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V(Apoa5);this may be a major contributing factor to their prolonged circulation in vivo and explains why CH enhances the distribution of LM at cardiovascular inflammatory injury sites.It should be noted that changes in cell types and physiological environments can also influence the biological behavior of formulations.The findings enhance the conceptualization of CH and LM delivery,providing novel strategies for investigating prescription factors'bioactivity.
文摘Atherosclerotic cardiovascular disease remains the leading cause of global mortality,with low-density lipoprotein cholesterol established as a primary causal risk factor.Despite widespread implementation of statin therapy,substantial interindividual variability in treatment response persists,necessitating precision medicine approaches to optimize therapeutic outcomes.This comprehensive narrative review synthesizes current understanding of pharmacogenomic determinants influencing lipid-lowering therapy efficacy,examines mechanisms underlying residual cardiovascular risk,and evaluates emerging therapeutic modalities targeting previously unexploited pathways in lipid metabolism.Genetic variants in key genes including 3-hydroxy-3-methylglutaryl-CoA reductase,apolipoprotein E,low-density lipoprotein receptor,and proprotein convertase subtilisin/kexin type 9 demonstrate significant associations with differential treatment responses,with specific polymorphisms conferring enhanced efficacy or increased intolerance risk.Beyond traditional statin therapy,novel therapeutic approaches targeting proprotein convertase subtilisin/kexin type 9,angiopoietin-like protein 3,apolipoprotein C-Ⅲ,and ATP citrate lyase offer substantial low-density lipoprotein cholesterol reductions of 50-80%,while RNA-based therapies including antisense oligonucleotides and small interfering RNA provide precise molecular targeting capabilities.Despite intensive lipid-lowering interventions,residual cardiovascular risk persists through four principal mechanisms:triglyceride-rich lipoproteins,lipoprotein(a),inflammatory processes,and suboptimal treatment adherence.Integration of pharmacogenomic insights with emerging therapeutic modalities enables personalized risk stratification and treatment selection,representing a paradigm shift toward precision medicine in cardiovascular disease prevention and management.
基金funded by Open Projects Fund of Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology,Shandong University(No.2023CCG13,China)Tianjin University of Traditional Chinese Medicine Startup Funding to Yunfei Li+1 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2021I2M-1–026,China)National Key R&D Program of China(No.2019YFA090530)。
文摘Immune evasion is a hallmark of cancer.Recent advancements suggest that targeting cholesterol metabolism to regulate stimulator of interferon genes(STING)signaling offers a promising approach to overcome this challenge.While STING pathway activation is critical for enhancing anti-tumor immunity,its excessive or prolonged activation can lead to chronic inflammation and immune suppression.This review examines how cholesterol-lowering nanomedicines can balance STING activation to promote effective immune responses.Nanoparticles(NPs)enable precise delivery of cholesterol-lowering agents,reducing chronic STING activation and transforming the tumor microenvironment(TME)into an immunostimulatory state.Furthermore,NPs can co-deliver STING agonists to synergize innate immune activation,providing enhanced anti-tumor responses while mitigating the risks of inflammation.By integrating cholesterol metabolism modulation with advanced nanotechnologies,this approach holds significant translational potential for developing next-generation immunotherapies.Future research should focus on optimizing NP design and exploring combination strategies with existing cancer immunotherapies to improve clinical outcomes and address immune resistance.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
基金Supported by The Scientific Research Program of Furong Laboratory,No.2023SK2108Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009+1 种基金Hunan Provincial Natural Science Foundation,No.2023JJ60440Hunan Provincial Health Commission Research Program,No.202303088786.
文摘BACKGROUND Tenofovir amibufenamide(TMF)has shown antiviral efficacy comparable to tenofovir disoproxil fumarate(TDF)in chronic hepatitis B(CHB),with improved renal and bone safety profiles.While TDF is recognized for its lipid-lowering properties,the long-term effects of TMF on lipid metabolism remain unclear.AIM To assess lipid changes and long-term safety of TMF in CHB,including outcomes after TDF-to-TMF switch over 144 weeks.METHODS This retrospective analysis utilized data from a phase III randomized,double-blind trial involving 53 patients with CHB treated with either TMF 25 mg(n=39)or TDF 300 mg(n=14)once daily for 96 weeks.Following this blinded phase,all participants entered an open-label extension in which they received TMF until week 144.This design enabled assessment of both the comparative effects of TMF and TDF and the impact of switching from TDF to TMF,thereby reflecting real-world treatment scenarios.Virological,biochemical and imaging evaluations were performed throughout the study.RESULTS At week 96,both groups achieved comparable virological suppression and maintained stable hepatic and renal function.However,total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the TMF group compared to the TDF group(P=0.012 and P=0.040,respectively).TDF was associated with a transient increase in serum phosphate(P=0.030).After switching to TMF,lipid profiles in the former TDF group gradually aligned with those of the continuous TMF group by week 144,with no lipid abnormalities observed in either group.CONCLUSION TMF provides sustained antiviral efficacy and maintains a favourable long-term lipid and renal safety profile.These findings support TMF as a viable first-line therapy and a switch option for CHB management in clinical practice.
基金supported by Hong Kong Research Grants Council General Research Fund(14104923).
文摘Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacylglycerols tributyrin(Tb)and tripropionin(Tp)are odorless and can be directly used as healthy supplements.In view that no study has investigated the relative biological potency of Tb and Tp,the present study was designed to compare the effects of Tp and Tb on plasma cholesterol and gut microbiota using hypercholesterolemic hamsters as a model.Male golden hamsters were randomly allocated to 6 groups fed one of the following 6 diets,namely,low-cholesterol diet(LCD),high-cholesterol diet(HCD),HCD+0.5%Tp(LTp),HCD+1%Tp(HTp),HCD+0.5%Tb(LTb),and HCD+1%Tb(HTb).Results showed that Tb administration at 1%could significantly reduce plasma total cholesterol(TC),non-high-density lipoprotein cholesterol(non-HDLC),and the ratio of non-HDLC to HDLC,whereas Tp supplementation had no effect.Mechanistically,Tb but not Tp could decrease plasma cholesterol by increasing the excretion of fecal bile acids via upregulating gene expression of cholesterol 7α-hydroxylase(CYP7A1)and liver X receptor alpha(LXRα).In addition,Tb supplementation at 1%could increase the gut microbiota diversity,reduce the ratio of Firmicutes/Bacteroidetes and favorably increase the abundance of beneficial microbial genera Bifidobacterium.In conclusion,dietary Tb supplementation was more effective than Tp in mitigating hypercholesterolemia by increasing the excretion of fecal bile acids and favorably modulating gut microbiota.
基金funded by grants from Guangxi Natural Science Foundation(2022JJA140639,2022JJA140776)the National Natural Science Foundation of China(82060662,82560721)Guangxi University Student Innovation and Entrepreneurship Training Program Project(S202410601137,S202510601106).
文摘Hepatocellular carcinoma(HCC)is characterized by its highly invasive andmetastatic potential,aswell as a propensity for recurrence,contributing to treatment failure and increased mortality.Under physiological conditions,the liver maintains a balance in lipid biosynthesis,degradation,storage,and transport.HCC exhibits dysregulated lipid metabolism,driving tumor progression and therapeutic resistance.This review aims to elucidate the roles of fatty acid,sphingolipid,and cholesterol metabolism in HCC pathogenesis and explore emerging therapeutic strategies targeting these pathways.Key findings demonstrate that upregulated enzymes like fatty acid synthase(FASN),acetyl-CoA carboxylase(ACC),enhance de novo lipogenesis andβ-oxidation,and promote HCC proliferation,invasion,and apoptosis evasion.Sphingolipids exert dual functions:ceramides suppress tumors,while sphingosine-1-phosphate(S1P)drives oncogenic signaling.Aberrant cholesterolmetabolism,mediated byHMG-CoA reductase(HMGCR),liver X receptorα(LXRα),and sterol regulatory element-binding protein 1(SREBP1),contributes to immunosuppression and drug resistance.Notably,inducing ferroptosis by disrupting lipid homeostasis represents a promising approach.Pharmacological inhibition of key nodes—such as FASN(Orlistat,TVB-3664),sphingomyelin synthase(D609),or cholesterol synthesis(statins,Genkwadaphnin)—synergizes with sorafenib/lenvatinib and overcomes resistance.We conclude that targeting lipid metabolic reprogramming,alone or combined with conventional therapies,offers significant potential for novelHCC treatment strategies.Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.
