α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
BACKGROUND Early control of low-density lipoprotein cholesterol(LDL-C)is crucial for reducing the progress of cardiovascular disease.However,its additional role to the risk of primary osteoporosis in men with coronary...BACKGROUND Early control of low-density lipoprotein cholesterol(LDL-C)is crucial for reducing the progress of cardiovascular disease.However,its additional role to the risk of primary osteoporosis in men with coronary heart disease was inconclusive.Our study aims to determine the association of LDL-C and its trajectories for osteoporosis risk in the middle-aged and aged men of China.METHODS The retrospective cohort study of 1546 men aged 69.74±11.30 years conducted in Beijing,China from 2015 to 2022.And the incidence of primary osteoporosis was annually recorded.LDL-C trajectories were further identified by latent class growth model using repeated measurements of LDL-C.The association of baseline LDL-C for osteoporosis was estimated using hazard ratio(HR)with 95%CI in Cox proportional hazard model,while mean level and trajectories of LDL-C for osteoporosis were evaluated using odds ratio(OR)with 95%CI in logistic regression model.RESULTS During the median 6.2-year follow-up period,70 men developed primary osteoporosis.The higher level of baseline LDLC(HR=1.539,95%CI:1.012–2.342)and mean LDL-C(OR=2.190,95%CI:1.443–3.324)were associated with higher risk of osteoporosis in men with coronary heart disease after adjusted for covariates.Compared with those in the LDL-C trajectory of low-stable decrease,participants with medium-fluctuant trajectory,whose longitudinal LDL-C started with a medium LDL-C level and appeared an increase and then decrease,were negatively associated with osteoporosis risk(OR=2.451,95%CI:1.152–5.216).And participants with initially high LDL-C level and then a rapid decrease demonstrated a tendency towards reduced risk(OR=0.718,95%CI:0.212–2.437).CONCLUSIONS Elevated LDL-C level and its long-term fluctuation may increase the risk of primary osteoporosis in men.Early controlling a stable level of LDL-C is also essential for bone health.展开更多
Loss-of-function variants of low-density lipoprotein receptor-related protein 5(LRP5)can lead to reduced bone formation,culminating in diminished bone mass.Our previous study reported transcription factor osterix(SP7)...Loss-of-function variants of low-density lipoprotein receptor-related protein 5(LRP5)can lead to reduced bone formation,culminating in diminished bone mass.Our previous study reported transcription factor osterix(SP7)-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration.However,the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown.In this study,we used mice with a conditional knockout(c KO)of LRP5 in mature osteoblasts,which presented decreased osteogenesis.The in vitro experimental results showed that SP7 could promote LRP5 expression,thereby upregulating the osteogenic markers such as alkaline phosphatase(ALP),Runt-related transcription factor 2(Runx2),andβ-catenin(P<0.05).For the in vivo experiment,the SP7 overexpression virus was injected into a bone defect model of LRP5 c KO mice,resulting in increased bone mineral density(BMD)(P<0.001)and volumetric density(bone volume(BV)/total volume(TV))(P<0.001),and decreased trabecular separation(Tb.Sp)(P<0.05).These data suggested that SP7 could ameliorate bone defect healing in LRP5 c KO mice.Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.展开更多
Nuclear magnetic resonance(NMR)spectroscopy is an excellent tool for simultaneous identification and quantification of metabolites(metabolomics).NMR quantification of human lipoprotein subfractions and their component...Nuclear magnetic resonance(NMR)spectroscopy is an excellent tool for simultaneous identification and quantification of metabolites(metabolomics).NMR quantification of human lipoprotein subfractions and their components has proven to be a powerful approach to reveal pathophysiological insights in numerous diseases[1,2].This method has now been standardized with excellent inter-laboratory reproducibility within 10 days for simultaneous quantification of 105 lipoprotein components and 24 low-molecular weight(LMW)metabolites[3];close clustering was also shown for 12 quality-control(QC)samples measured in 3 months although without statistical details[2].However,these reports[[1],[2],[3]]did not cover many vital parameters for lipoprotein components(e.g.,cholesterol-esters and total-lipids),fatty acids,and N-acetyl-glycoproteins(NAGs).展开更多
BACKGROUND Psoriasis is a chronic inflammatory condition related to an increased athero-sclerotic cardiovascular disease(ASCVD)risk.AIM To investigate whether lipoprotein(a)[Lp(a)]levels are increased in patients with...BACKGROUND Psoriasis is a chronic inflammatory condition related to an increased athero-sclerotic cardiovascular disease(ASCVD)risk.AIM To investigate whether lipoprotein(a)[Lp(a)]levels are increased in patients with psoriasis.METHODS A comprehensive literature search up to January 30,2025 was conducted utilizing PubMed and Cochrane Library databases.A qualitative synthesis and a meta-analysis on Lp(a)mean differences(MD)between psoriasis cases and healthy controls(HC)was performed.The protocol of this meta-analysis has been re-gistered to PROSPERO(No.CRD420250652465).RESULTS Eighteen studies with 1650 psoriasis patients and 1621 HC were eligible for qua-litative synthesis.Pooled analysis from 16 studies(1401 psoriasis patients and 1320 HC)demonstrated that psoriasis patients had significantly higher Lp(a)levels compared with the HC group(MD:6.72 mg/dL,95%CI:4.32-9.12,P<0.00001,I2=71%).Sensitivity analyses according to the region of origin was also performed.The pooled analysis of the European sub-population showed a pronounced increase in Lp(a)levels in 189 patients with psoriasis vs 178 HC(MD:15.86 mg/dL,95%CI:5.79-25.92,P<0.002,I2=79%),while the pooled analysis on the Asian sub-population demonstrated a smaller but still significant difference in Lp(a)levels between 1177 psoriasis patients and 1127 HC(MD:4.95 mg/dL,95%CI:2.99-6.92,P<0.00001,I2=58%).CONCLUSION Our findings suggest that Lp(a)levels are significantly elevated in psoriasis patients,further adding to their ASCVD risk.展开更多
Background Lipoprotein(a)[Lp(a)]has been demonstrated to be closely associated with the development of cardiovascular disease(CVD),but its prognostic value in maintenance hemodialysis(MHD)patients remains controversia...Background Lipoprotein(a)[Lp(a)]has been demonstrated to be closely associated with the development of cardiovascular disease(CVD),but its prognostic value in maintenance hemodialysis(MHD)patients remains controversial.This study aimed to evaluate the association between Lp(a)levels and adverse outcomes in this highrisk population,with a focus on both mortality and new-onset cardiovascular events(CV events).Methods In this retrospective observational study,we enrolled181 MHD patients who were stratified into normal Lp(a)level group[Lp(a)≤300 mg/L,n=112]and elevated Lp(a)level group[Lp(a)>300 mg/L,n=69].Survival analysis was performed using Kaplan-Meier curves,and Cox regression models were employed to evaluate the impact on all-cause mortalityand new-onset CV events.Results Over a median follow-up of 79.0 months(IQR:45.0-109.0),the elevated Lp(a)group exhibited significantly increased CV events incidence(79.7%vs.29.5%,P<0.001).Elevated Lp(a)was independently associated with higher risks of all-cause mortality(multivariable-adjusted HR:2.220,95%CI:1.039-4.740)and new-0nset CV events(HR:3.614,95%CI:2.164-6.035).Each 10 mg/L Lp(a)increment conferred a 1.1%increased cardiovascular risk(P<0.001).ConclusionssElevated Lp(a)is a strong,independent predictor of all-cause mortality and new-onset CV events in MHD patients.These findings highlighted the potential utility of Lp(a)in routine CVD risk assessment and underscored the need for targeted therapies to mitigate residual risk in this population.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 Esophageal cancer(EC)is one of the most common malignancies worldwide,and lymph node(LN)metastasis remains one of the leading causes of EC recurrence.Metabolic disorders critically affect cancer progression...BACKGROUND Esophageal cancer(EC)is one of the most common malignancies worldwide,and lymph node(LN)metastasis remains one of the leading causes of EC recurrence.Metabolic disorders critically affect cancer progression,and lipid levels are closely associated with the occurrence of EC and several other tumor types.This study analyzed pretreatment lipid levels to determine their association with LN metastasis.AIM To dissect the possible mechanisms underlying LN metastasis and clarify the prognostic role of lipid profiles in EC.METHODS Serum lipid levels and clinicopathological information were retrospectively collected from 294 patients,and risk factors for LN metastasis were confirmed using a logistic regression model.Latent factors were explored using information from publicly accessible databases and immunofluorescence and immunohistochemical staining techniques.RESULTS High serum levels of low-density lipoprotein(LDL)cholesterol promote LN metastasis in EC,while high-density lipoprotein cholesterol has the opposite role.Information of a public database revealed that LDL receptors LRP5 and LRP6 are highly expressed in ECs,and LRP6 overexpression positively correlated with the infiltration of B lymphocytes and a poor prognosis.Immunofluorescence and immunohistochemical staining revealed that the expression of LRP6 and infiltrated B lymphocytes in patients with≥1 regional LN metastasis,containing N1-3(N+group)were significantly higher than those in the N0 group.LRP6 was also highly expressed in the B lymphocytes of the N+group.There was no difference in CXCL13 expression between the N+and N0 groups.However,CXCR5 expression was significantly higher in the N0 group than in the N+group.CONCLUSION High serum LDL levels can promote LN metastasis in EC,and the mechanisms may be related to LRP6 expression and the infiltration of B lymphocytes.展开更多
BACKGROUND Patients with type 2 diabetes mellitus(T2DM)face a heightened risk of future cardiovascular events.It is therefore important to stratify these patients according to their future cardiovascular event risk to...BACKGROUND Patients with type 2 diabetes mellitus(T2DM)face a heightened risk of future cardiovascular events.It is therefore important to stratify these patients according to their future cardiovascular event risk to allow early intervention and improve prognosis.Recent proposals have indicated that nontraditional lipoprotein ratios may be superior predictors of cardiovascular events compared to traditional lipid parameters.However,further evidence is required for widespread clinical ap-plication.AIM To elucidate the associations of nontraditional lipoprotein ratios with future cardiovascular events in patients with T2DM.METHODS This study performed post-hoc analysis of data obtained during a clinical trial involving 10182 participants.To ascertain the correlations between nontraditional lipoprotein ratios and future cardiovascular events,including major adverse cardiovascular events(MACEs)and congestive heart failure(CHF).We employed univariable and multivariable-adjusted Cox proportional hazards regression models.Potential dose-response relationships and threshold values were explored by conducting restricted cubic spline analyses and two-piecewise linear regression models.Possible relevant interactions influencing independent relationships were tested using subgroup and interaction analyses.RESULTS After adjustment for confounding factors,all nontraditional lipoprotein ratios studied were strongly associated with MACE risk in patients with T2DM.In comparison with patients in the lowest quartile,the hazard ratios(95%confidence intervals)of those in the highest quartile were 1.50(1.29-1.73),1.51(1.30-1.74),1.50(1.29-1.73),and 1.30(1.12-1.50)for total cholesterol/high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol/HDL-C,non-HDL-C/HDL-C,and remnant cholesterol/HDL-C,respectively.Similar findings were noted for CHF.Dose-response relationships between nontraditional lipoprotein ratios and MACE were observed,with threshold values of 7.29,6.29,and 2.15 for total cholesterol/HDL-C,non-HDL-C/HDL-C,and remnant cholesterol/HDL-C,respectively.However,no notable dose-response relationships were detected between nontraditional lipoprotein ratios and CHF.CONCLUSION Elevated nontraditional lipoprotein ratios may independently predict the risk of MACE and CHF in patients with T2DM.展开更多
BACKGROUND The association between the serum uric acid-to-high-density lipoprotein cholesterol ratio(UHR)and cardiovascular disease(CVD)risk in Asian populations with metabolic dysfunction-associated steatotic liver d...BACKGROUND The association between the serum uric acid-to-high-density lipoprotein cholesterol ratio(UHR)and cardiovascular disease(CVD)risk in Asian populations with metabolic dysfunction-associated steatotic liver disease(MASLD)remains insufficiently elucidated.AIM To investigate the relevance and dose-responsive relationship between UHR and 10-year CVD risk among Asian MASLD patients.METHODS In this retrospective analysis,3901 MASLD patients were enrolled based on established screening criteria.As measured by the Framingham risk score,participants were stratified according to their 10-year CVD risk.The association between UHR and CVD risk was evaluated using binary logistic regression,while dose-response patterns were explored through restricted cubic spline(RCS)modeling.The discriminatory capability of UHR,in comparison with conventional biomarkers,was further examined by receiver operating characteristic curve analysis.RESULTS Multivariable-adjusted analyses revealed that elevated UHR levels were significantly associated with an increased likelihood of intermediate-to-high CVD risk.RCS modeling demonstrated a linear dose-response relationship between UHR and the Framingham risk score(P for nonlinearity=0.114).Sex-stratified RCS analyses further indicated that this linear association persisted among males(P for nonlinearity=0.167)but was not statistically significant in females(P for nonlinearity=0.476).Further stratified analyses revealed that the association was particularly pronounced among younger individuals(<50 years),males,and those with central obesity,whereas it was attenuated in older adults(≥50 years)and females.Receiver operating characteristic analysis demonstrated that UHR outperformed individual biomarkers in predicting 10-year CVD risk,showing an area under the curve of 0.655(95%confidence interval:0.635-0.674).CONCLUSION UHR functioned as an independent predictor of 10-year CVD risk in Asian patients with MASLD,demonstrating a linear dose-response association and superior discriminative performance relative to conventional biomarkers,especially among younger individuals,males,and those with central obesity.展开更多
Objective： To investigate the association between the mutations in lipoprotein lipase gene and hypertriglyceridemia （HTG）. Methods： The lipoprotein lipase （LPL） gene was screened for mutations in 386 Chinese sub...Objective： To investigate the association between the mutations in lipoprotein lipase gene and hypertriglyceridemia （HTG）. Methods： The lipoprotein lipase （LPL） gene was screened for mutations in 386 Chinese subjects with （108 cases in the HTG group） or without HTG （278 cases in the control group）, by single-strand conformation polymorphism （SSCP） analysis and DNA sequencing. Results： One novel silent mutation L103L, one missense mutation P207L, three splicing mutations Int3/3＇ -ass/C（-6）→T, and the common S447X polymorphism has been identified in the whole coding region and exon-intron junctions of the LPL gene were examined. Heterozygous P207L found in the HTG group was the first case reported in Asia and subsequently another P207L heterozygote was found in the proband＇s family, all of which suggested that P207L was one of the causes of familial combined hyperlipidemia, but was not so prevalent as that in French Canadian. Int3/3＇-ass/C（-6）→T was found in both groups in the present study although it was regarded as a pathogenic variant to HTG earlier on. Moreover about the beneficial polymorphism S447X, there was also some supportive evidence that the levels of triglycerides （TG） in S447X carriers were significantly lower than noncarders in the subjects without HTG. Conclusions： The association between the LPL variants and HTG is quite complicated and versatile, genotyping of LPL in a larger-scale screening should be necessary and justifiable.展开更多
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金supported by the Multi-center RCT Clinical Project of the National Clinical Research Center for Geriatric Diseases,Chinese PLA General Hospital(NCRCGPLAGH-2023001)the Beijing Nova Program(No.20220484020)+1 种基金the Beijing Natural Science Foundation(No.7252181)the Capital’s Funds for Health Improvement and Research(No.2024-2G-5033).
文摘BACKGROUND Early control of low-density lipoprotein cholesterol(LDL-C)is crucial for reducing the progress of cardiovascular disease.However,its additional role to the risk of primary osteoporosis in men with coronary heart disease was inconclusive.Our study aims to determine the association of LDL-C and its trajectories for osteoporosis risk in the middle-aged and aged men of China.METHODS The retrospective cohort study of 1546 men aged 69.74±11.30 years conducted in Beijing,China from 2015 to 2022.And the incidence of primary osteoporosis was annually recorded.LDL-C trajectories were further identified by latent class growth model using repeated measurements of LDL-C.The association of baseline LDL-C for osteoporosis was estimated using hazard ratio(HR)with 95%CI in Cox proportional hazard model,while mean level and trajectories of LDL-C for osteoporosis were evaluated using odds ratio(OR)with 95%CI in logistic regression model.RESULTS During the median 6.2-year follow-up period,70 men developed primary osteoporosis.The higher level of baseline LDLC(HR=1.539,95%CI:1.012–2.342)and mean LDL-C(OR=2.190,95%CI:1.443–3.324)were associated with higher risk of osteoporosis in men with coronary heart disease after adjusted for covariates.Compared with those in the LDL-C trajectory of low-stable decrease,participants with medium-fluctuant trajectory,whose longitudinal LDL-C started with a medium LDL-C level and appeared an increase and then decrease,were negatively associated with osteoporosis risk(OR=2.451,95%CI:1.152–5.216).And participants with initially high LDL-C level and then a rapid decrease demonstrated a tendency towards reduced risk(OR=0.718,95%CI:0.212–2.437).CONCLUSIONS Elevated LDL-C level and its long-term fluctuation may increase the risk of primary osteoporosis in men.Early controlling a stable level of LDL-C is also essential for bone health.
文摘Loss-of-function variants of low-density lipoprotein receptor-related protein 5(LRP5)can lead to reduced bone formation,culminating in diminished bone mass.Our previous study reported transcription factor osterix(SP7)-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration.However,the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown.In this study,we used mice with a conditional knockout(c KO)of LRP5 in mature osteoblasts,which presented decreased osteogenesis.The in vitro experimental results showed that SP7 could promote LRP5 expression,thereby upregulating the osteogenic markers such as alkaline phosphatase(ALP),Runt-related transcription factor 2(Runx2),andβ-catenin(P<0.05).For the in vivo experiment,the SP7 overexpression virus was injected into a bone defect model of LRP5 c KO mice,resulting in increased bone mineral density(BMD)(P<0.001)and volumetric density(bone volume(BV)/total volume(TV))(P<0.001),and decreased trabecular separation(Tb.Sp)(P<0.05).These data suggested that SP7 could ameliorate bone defect healing in LRP5 c KO mice.Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.
基金financial supports from the National Key R&D Program of China(Grant Nos.:2022YFC3400700 and 2022YFA0806400)the Shanghai Municipal Science and Technology Major Project,China(Grant No.:2017SHZDZX01)the National Natural Science Foundation of China(Grant No.:31821002).
文摘Nuclear magnetic resonance(NMR)spectroscopy is an excellent tool for simultaneous identification and quantification of metabolites(metabolomics).NMR quantification of human lipoprotein subfractions and their components has proven to be a powerful approach to reveal pathophysiological insights in numerous diseases[1,2].This method has now been standardized with excellent inter-laboratory reproducibility within 10 days for simultaneous quantification of 105 lipoprotein components and 24 low-molecular weight(LMW)metabolites[3];close clustering was also shown for 12 quality-control(QC)samples measured in 3 months although without statistical details[2].However,these reports[[1],[2],[3]]did not cover many vital parameters for lipoprotein components(e.g.,cholesterol-esters and total-lipids),fatty acids,and N-acetyl-glycoproteins(NAGs).
文摘BACKGROUND Psoriasis is a chronic inflammatory condition related to an increased athero-sclerotic cardiovascular disease(ASCVD)risk.AIM To investigate whether lipoprotein(a)[Lp(a)]levels are increased in patients with psoriasis.METHODS A comprehensive literature search up to January 30,2025 was conducted utilizing PubMed and Cochrane Library databases.A qualitative synthesis and a meta-analysis on Lp(a)mean differences(MD)between psoriasis cases and healthy controls(HC)was performed.The protocol of this meta-analysis has been re-gistered to PROSPERO(No.CRD420250652465).RESULTS Eighteen studies with 1650 psoriasis patients and 1621 HC were eligible for qua-litative synthesis.Pooled analysis from 16 studies(1401 psoriasis patients and 1320 HC)demonstrated that psoriasis patients had significantly higher Lp(a)levels compared with the HC group(MD:6.72 mg/dL,95%CI:4.32-9.12,P<0.00001,I2=71%).Sensitivity analyses according to the region of origin was also performed.The pooled analysis of the European sub-population showed a pronounced increase in Lp(a)levels in 189 patients with psoriasis vs 178 HC(MD:15.86 mg/dL,95%CI:5.79-25.92,P<0.002,I2=79%),while the pooled analysis on the Asian sub-population demonstrated a smaller but still significant difference in Lp(a)levels between 1177 psoriasis patients and 1127 HC(MD:4.95 mg/dL,95%CI:2.99-6.92,P<0.00001,I2=58%).CONCLUSION Our findings suggest that Lp(a)levels are significantly elevated in psoriasis patients,further adding to their ASCVD risk.
基金supported by Tibet Autonomous Region Natural Science Foundation[No.XZ2024ZR-ZY084(Z)and No.XZ2023ZR-ZY63(Z)]Guangdong Provincial Natural Science Foundation(No.2022A1515010551)。
文摘Background Lipoprotein(a)[Lp(a)]has been demonstrated to be closely associated with the development of cardiovascular disease(CVD),but its prognostic value in maintenance hemodialysis(MHD)patients remains controversial.This study aimed to evaluate the association between Lp(a)levels and adverse outcomes in this highrisk population,with a focus on both mortality and new-onset cardiovascular events(CV events).Methods In this retrospective observational study,we enrolled181 MHD patients who were stratified into normal Lp(a)level group[Lp(a)≤300 mg/L,n=112]and elevated Lp(a)level group[Lp(a)>300 mg/L,n=69].Survival analysis was performed using Kaplan-Meier curves,and Cox regression models were employed to evaluate the impact on all-cause mortalityand new-onset CV events.Results Over a median follow-up of 79.0 months(IQR:45.0-109.0),the elevated Lp(a)group exhibited significantly increased CV events incidence(79.7%vs.29.5%,P<0.001).Elevated Lp(a)was independently associated with higher risks of all-cause mortality(multivariable-adjusted HR:2.220,95%CI:1.039-4.740)and new-0nset CV events(HR:3.614,95%CI:2.164-6.035).Each 10 mg/L Lp(a)increment conferred a 1.1%increased cardiovascular risk(P<0.001).ConclusionssElevated Lp(a)is a strong,independent predictor of all-cause mortality and new-onset CV events in MHD patients.These findings highlighted the potential utility of Lp(a)in routine CVD risk assessment and underscored the need for targeted therapies to mitigate residual risk in this population.
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.
文摘BACKGROUND Esophageal cancer(EC)is one of the most common malignancies worldwide,and lymph node(LN)metastasis remains one of the leading causes of EC recurrence.Metabolic disorders critically affect cancer progression,and lipid levels are closely associated with the occurrence of EC and several other tumor types.This study analyzed pretreatment lipid levels to determine their association with LN metastasis.AIM To dissect the possible mechanisms underlying LN metastasis and clarify the prognostic role of lipid profiles in EC.METHODS Serum lipid levels and clinicopathological information were retrospectively collected from 294 patients,and risk factors for LN metastasis were confirmed using a logistic regression model.Latent factors were explored using information from publicly accessible databases and immunofluorescence and immunohistochemical staining techniques.RESULTS High serum levels of low-density lipoprotein(LDL)cholesterol promote LN metastasis in EC,while high-density lipoprotein cholesterol has the opposite role.Information of a public database revealed that LDL receptors LRP5 and LRP6 are highly expressed in ECs,and LRP6 overexpression positively correlated with the infiltration of B lymphocytes and a poor prognosis.Immunofluorescence and immunohistochemical staining revealed that the expression of LRP6 and infiltrated B lymphocytes in patients with≥1 regional LN metastasis,containing N1-3(N+group)were significantly higher than those in the N0 group.LRP6 was also highly expressed in the B lymphocytes of the N+group.There was no difference in CXCL13 expression between the N+and N0 groups.However,CXCR5 expression was significantly higher in the N0 group than in the N+group.CONCLUSION High serum LDL levels can promote LN metastasis in EC,and the mechanisms may be related to LRP6 expression and the infiltration of B lymphocytes.
文摘BACKGROUND Patients with type 2 diabetes mellitus(T2DM)face a heightened risk of future cardiovascular events.It is therefore important to stratify these patients according to their future cardiovascular event risk to allow early intervention and improve prognosis.Recent proposals have indicated that nontraditional lipoprotein ratios may be superior predictors of cardiovascular events compared to traditional lipid parameters.However,further evidence is required for widespread clinical ap-plication.AIM To elucidate the associations of nontraditional lipoprotein ratios with future cardiovascular events in patients with T2DM.METHODS This study performed post-hoc analysis of data obtained during a clinical trial involving 10182 participants.To ascertain the correlations between nontraditional lipoprotein ratios and future cardiovascular events,including major adverse cardiovascular events(MACEs)and congestive heart failure(CHF).We employed univariable and multivariable-adjusted Cox proportional hazards regression models.Potential dose-response relationships and threshold values were explored by conducting restricted cubic spline analyses and two-piecewise linear regression models.Possible relevant interactions influencing independent relationships were tested using subgroup and interaction analyses.RESULTS After adjustment for confounding factors,all nontraditional lipoprotein ratios studied were strongly associated with MACE risk in patients with T2DM.In comparison with patients in the lowest quartile,the hazard ratios(95%confidence intervals)of those in the highest quartile were 1.50(1.29-1.73),1.51(1.30-1.74),1.50(1.29-1.73),and 1.30(1.12-1.50)for total cholesterol/high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol/HDL-C,non-HDL-C/HDL-C,and remnant cholesterol/HDL-C,respectively.Similar findings were noted for CHF.Dose-response relationships between nontraditional lipoprotein ratios and MACE were observed,with threshold values of 7.29,6.29,and 2.15 for total cholesterol/HDL-C,non-HDL-C/HDL-C,and remnant cholesterol/HDL-C,respectively.However,no notable dose-response relationships were detected between nontraditional lipoprotein ratios and CHF.CONCLUSION Elevated nontraditional lipoprotein ratios may independently predict the risk of MACE and CHF in patients with T2DM.
基金Supported by Shanghai Health and Medical Center Star Talent Program,No.2023QMX01 and No.2023QMX11.
文摘BACKGROUND The association between the serum uric acid-to-high-density lipoprotein cholesterol ratio(UHR)and cardiovascular disease(CVD)risk in Asian populations with metabolic dysfunction-associated steatotic liver disease(MASLD)remains insufficiently elucidated.AIM To investigate the relevance and dose-responsive relationship between UHR and 10-year CVD risk among Asian MASLD patients.METHODS In this retrospective analysis,3901 MASLD patients were enrolled based on established screening criteria.As measured by the Framingham risk score,participants were stratified according to their 10-year CVD risk.The association between UHR and CVD risk was evaluated using binary logistic regression,while dose-response patterns were explored through restricted cubic spline(RCS)modeling.The discriminatory capability of UHR,in comparison with conventional biomarkers,was further examined by receiver operating characteristic curve analysis.RESULTS Multivariable-adjusted analyses revealed that elevated UHR levels were significantly associated with an increased likelihood of intermediate-to-high CVD risk.RCS modeling demonstrated a linear dose-response relationship between UHR and the Framingham risk score(P for nonlinearity=0.114).Sex-stratified RCS analyses further indicated that this linear association persisted among males(P for nonlinearity=0.167)but was not statistically significant in females(P for nonlinearity=0.476).Further stratified analyses revealed that the association was particularly pronounced among younger individuals(<50 years),males,and those with central obesity,whereas it was attenuated in older adults(≥50 years)and females.Receiver operating characteristic analysis demonstrated that UHR outperformed individual biomarkers in predicting 10-year CVD risk,showing an area under the curve of 0.655(95%confidence interval:0.635-0.674).CONCLUSION UHR functioned as an independent predictor of 10-year CVD risk in Asian patients with MASLD,demonstrating a linear dose-response association and superior discriminative performance relative to conventional biomarkers,especially among younger individuals,males,and those with central obesity.
基金This work was supported by the Grant from Tianjin Municipal Natural Science Foundations (No. 033607311).
文摘Objective： To investigate the association between the mutations in lipoprotein lipase gene and hypertriglyceridemia （HTG）. Methods： The lipoprotein lipase （LPL） gene was screened for mutations in 386 Chinese subjects with （108 cases in the HTG group） or without HTG （278 cases in the control group）, by single-strand conformation polymorphism （SSCP） analysis and DNA sequencing. Results： One novel silent mutation L103L, one missense mutation P207L, three splicing mutations Int3/3＇ -ass/C（-6）→T, and the common S447X polymorphism has been identified in the whole coding region and exon-intron junctions of the LPL gene were examined. Heterozygous P207L found in the HTG group was the first case reported in Asia and subsequently another P207L heterozygote was found in the proband＇s family, all of which suggested that P207L was one of the causes of familial combined hyperlipidemia, but was not so prevalent as that in French Canadian. Int3/3＇-ass/C（-6）→T was found in both groups in the present study although it was regarded as a pathogenic variant to HTG earlier on. Moreover about the beneficial polymorphism S447X, there was also some supportive evidence that the levels of triglycerides （TG） in S447X carriers were significantly lower than noncarders in the subjects without HTG. Conclusions： The association between the LPL variants and HTG is quite complicated and versatile, genotyping of LPL in a larger-scale screening should be necessary and justifiable.
