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
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
Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the ...Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the aqueous extract of I.batatas leaves in a rat model of diet-induced hypercholesterolemia.Methods:Hypercholesterolemia was induced in male Wistar rats by exclusive feeding with a cholesterolenriched(1%)standard diet for four weeks.Then,rats were treated once daily(per os)with I.batatas extract at doses of 400,500 and 600 mg/kg or with atorvastatin(2 mg/kg),for four weeks.Following treatment,animals were observed for another four weeks and then sacrificed.Aortas were excised and processed for histopathological studies,and blood glucose level and lipid profile were measured.Results:Hypercholesterolemic animals experienced a 21.5%faster increase in body weight,significant increases in blood glucose and blood lipids(148.94%triglycerides,196.97%high-density lipoprotein cholesterol,773.04%low-density lipoprotein cholesterol,148.93%very low-density lipoprotein cholesterol and 210.42%total cholesterol),and increases in aorta thickness and atherosclerotic plaque sizes compared to rats fed standard diet.Treatment of hypercholesterolemic rats with the extract mitigated these alterations and restored blood glucose and blood lipid levels to normocholesterolemic values.Conclusion:Our findings suggest that I.batatas leaves have hypolipidemic and anti-atherosclerogenic properties and justify their use in traditional medicine.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
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
Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross t...Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain barrier.The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.Methods The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron microscopy.Results High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and striatum.Electron microscopy revealed that the enzyme was localized in the axon terminals.One the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and brainstem.Conclusion The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.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
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
Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to...Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.展开更多
The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism.Therefore,targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer.In this s...The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism.Therefore,targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer.In this study,a nanosystem(AVA-COD@Fe)exhibiting dual enzymatic activity was developed through a biomimetic mineralization approach.Cholesterol oxidase(COD)facilitated the consumption of cholesterol,thereby impairing the migratory capacity of tumor cells and diminishing resilience on oxidative stress.Concurrently,COD catalyzed the production of hydrogen peroxide(H2O2),which compensated for inadequate levels of tumor cells,thereby enhancing ferroptosis and ultimately inhibiting tumor growth and metastasis.Meanwhile,as an immune sensitizer,avasimibe altered cholesterol distribution,and promoted the infiltration and vitality of cytotoxic T lymphocytes into tumors jointly with immunogenic cell death(ICD)induced by ferroptosis,and enhanced anti-tumor immunity.To elicit significant immune memory effects,this nanosystem was further combined with the anti-programmed cell death protein ligand-1 antibody,which effectively inhibited the growth of both primary and metastatic tumors,and demonstrated a robust systemic anti-tumor immune response.This study addressed modulation of tumor cell cholesterol metabolism as a strategic entry point for tumor suppression,significantly curtailing tumor progression,and activating systemic immune responses,thereby offering a new perspective for future cancer therapies.展开更多
Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dieta...Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.展开更多
This prospective study aimed to investigate the associations of untreated cholesterol levels and their longitudinal changes,especially low levels,with all-cause and cause-specific mortality in different populations.Pa...This prospective study aimed to investigate the associations of untreated cholesterol levels and their longitudinal changes,especially low levels,with all-cause and cause-specific mortality in different populations.Participants were drawn from two Chinese cohorts and the UK Biobank,excluding those with lipid-lowering medications,coronary heart disease(CHD),stroke,cancer,clinically diagnosed chronic obstructive pulmonary disease,low body mass index(<18.5 kg·m^(-2))at baseline,and deaths within the first two years to minimize reverse causality.Individual cholesterol changes were assessed in a subset who attended the resurvey after over four years.Mortality data were linked to registries,and risks were estimated using Cox proportional hazards models.A total of 163115 Chinese and 317305 UK adults were included(mean age,49-61 years),with 43%,81%,and 44%males in Dongfeng-Tongji,Kailuan,and UK Biobank cohorts,respectively.During a median follow-up of 9.7-12.9 years,9553 and 15760 deaths were documented in the Chinese cohorts and UK Biobank,respectively.After multivariate adjustments,nonlinear relationships were observed between total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),and non-high-density lipoprotein cholesterol(non-HDL-C)levels and mortality.In both populations,high cholesterol was primarily associated with CHD mortality,while low cholesterol associated with all-cause and cancer mortality(Pnonlinear≤0.0161).The optimal levels for all-cause mortality risk in Chinese adults(TC:200 mg·dL^(-1);LDL-C:130 mg·dL^(-1);non-HDL-C:155 mg·dL^(-1))were lower than those in the UK Biobank but consistent with guideline recommendation.Additionally,decreasing cholesterol levels over four years were associated with higher all-cause and cancer mortality in the Chinese cohorts(P_(nonlinear)≤0.0100).Participants with low TC,LDL-C,or non-HDL-C levels at both baseline and resurvey experienced elevated all-cause mortality risks in both populations,as did those with low/medium baseline levels and>20%reductions over time in Chinese adults.In conclusion,higher TC,LDL-C,and non-HDL-C levels are associated with elevated CHD mortality.Importantly,low and/or longitudinally decreasing cholesterol levels are robustly associated with increased all-cause and cancer mortality,potentially serving as markers of premature death.Regular cholesterol monitoring,with attention to both high and low levels,is recommended to inform guideline updates and clinical strategies.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
Correction to:Cellular&Molecular Immunology https://doi.org/10.1038/s41423-025-01319-1,published online 10 July 2025 The article“Cholesterol promotes autoimmune pathology through T follicular helper cells”,writt...Correction to:Cellular&Molecular Immunology https://doi.org/10.1038/s41423-025-01319-1,published online 10 July 2025 The article“Cholesterol promotes autoimmune pathology through T follicular helper cells”,written by Wei Li&George C.Tsokos,was originally published open access under a Creative Commons Attribution 4.0 International License.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
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
The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remn...The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.展开更多
Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by...Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.展开更多
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partly funded by the Faculty of Science,University of Ngaoundere。
文摘Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the aqueous extract of I.batatas leaves in a rat model of diet-induced hypercholesterolemia.Methods:Hypercholesterolemia was induced in male Wistar rats by exclusive feeding with a cholesterolenriched(1%)standard diet for four weeks.Then,rats were treated once daily(per os)with I.batatas extract at doses of 400,500 and 600 mg/kg or with atorvastatin(2 mg/kg),for four weeks.Following treatment,animals were observed for another four weeks and then sacrificed.Aortas were excised and processed for histopathological studies,and blood glucose level and lipid profile were measured.Results:Hypercholesterolemic animals experienced a 21.5%faster increase in body weight,significant increases in blood glucose and blood lipids(148.94%triglycerides,196.97%high-density lipoprotein cholesterol,773.04%low-density lipoprotein cholesterol,148.93%very low-density lipoprotein cholesterol and 210.42%total cholesterol),and increases in aorta thickness and atherosclerotic plaque sizes compared to rats fed standard diet.Treatment of hypercholesterolemic rats with the extract mitigated these alterations and restored blood glucose and blood lipid levels to normocholesterolemic values.Conclusion:Our findings suggest that I.batatas leaves have hypolipidemic and anti-atherosclerogenic properties and justify their use in traditional medicine.
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.
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(No.30901940)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Education Ministry of China
文摘Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain barrier.The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.Methods The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron microscopy.Results High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and striatum.Electron microscopy revealed that the enzyme was localized in the axon terminals.One the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and brainstem.Conclusion The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.
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.
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National Key Research and Development Program of China(Grant No.2022YFC3501700)the Beijing Municipal Natural Science Foundation(Grant No.7144219).
文摘Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.
基金supported by the National Natural Science Foundation of China(No.32571629)the Natural Science Foundation of Liaoning Province(Nos.2024011874-JH4/4800,2023-MS-198,and 2023011989-JH3/4600)+1 种基金Scientific Research Projects of Liaoning Provincial Department of Education(Nos.LJ212410163004 and LJKMZ20221786)Career Development Support Program for Young and Middle-aged Teachers(No:ZQN202208)of Shenyang Pharmaceutical University.
文摘The occurrence and development of cancer are closely related to dysregulation of cholesterol metabolism.Therefore,targeting cholesterol metabolism presents a novel diagnosis and treatment strategy for cancer.In this study,a nanosystem(AVA-COD@Fe)exhibiting dual enzymatic activity was developed through a biomimetic mineralization approach.Cholesterol oxidase(COD)facilitated the consumption of cholesterol,thereby impairing the migratory capacity of tumor cells and diminishing resilience on oxidative stress.Concurrently,COD catalyzed the production of hydrogen peroxide(H2O2),which compensated for inadequate levels of tumor cells,thereby enhancing ferroptosis and ultimately inhibiting tumor growth and metastasis.Meanwhile,as an immune sensitizer,avasimibe altered cholesterol distribution,and promoted the infiltration and vitality of cytotoxic T lymphocytes into tumors jointly with immunogenic cell death(ICD)induced by ferroptosis,and enhanced anti-tumor immunity.To elicit significant immune memory effects,this nanosystem was further combined with the anti-programmed cell death protein ligand-1 antibody,which effectively inhibited the growth of both primary and metastatic tumors,and demonstrated a robust systemic anti-tumor immune response.This study addressed modulation of tumor cell cholesterol metabolism as a strategic entry point for tumor suppression,significantly curtailing tumor progression,and activating systemic immune responses,thereby offering a new perspective for future cancer therapies.
基金supported by Hong Kong Research Grants Council General Research Fund(CUHK 14102321,14103722 and 14104923)。
文摘Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.
基金supported by the National Natural Science Foundation of China(82021005,82192903,81930092)the Chief Scientist Research Project of Hubei Shizhen Laboratory(HSL2024SX0003)+1 种基金the Fundamental Research Funds for the Central Universities(2019kfyXMBZ015)the 111 Project and the Program for Changjiang Scholars and Innovative Research Team in University.
文摘This prospective study aimed to investigate the associations of untreated cholesterol levels and their longitudinal changes,especially low levels,with all-cause and cause-specific mortality in different populations.Participants were drawn from two Chinese cohorts and the UK Biobank,excluding those with lipid-lowering medications,coronary heart disease(CHD),stroke,cancer,clinically diagnosed chronic obstructive pulmonary disease,low body mass index(<18.5 kg·m^(-2))at baseline,and deaths within the first two years to minimize reverse causality.Individual cholesterol changes were assessed in a subset who attended the resurvey after over four years.Mortality data were linked to registries,and risks were estimated using Cox proportional hazards models.A total of 163115 Chinese and 317305 UK adults were included(mean age,49-61 years),with 43%,81%,and 44%males in Dongfeng-Tongji,Kailuan,and UK Biobank cohorts,respectively.During a median follow-up of 9.7-12.9 years,9553 and 15760 deaths were documented in the Chinese cohorts and UK Biobank,respectively.After multivariate adjustments,nonlinear relationships were observed between total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),and non-high-density lipoprotein cholesterol(non-HDL-C)levels and mortality.In both populations,high cholesterol was primarily associated with CHD mortality,while low cholesterol associated with all-cause and cancer mortality(Pnonlinear≤0.0161).The optimal levels for all-cause mortality risk in Chinese adults(TC:200 mg·dL^(-1);LDL-C:130 mg·dL^(-1);non-HDL-C:155 mg·dL^(-1))were lower than those in the UK Biobank but consistent with guideline recommendation.Additionally,decreasing cholesterol levels over four years were associated with higher all-cause and cancer mortality in the Chinese cohorts(P_(nonlinear)≤0.0100).Participants with low TC,LDL-C,or non-HDL-C levels at both baseline and resurvey experienced elevated all-cause mortality risks in both populations,as did those with low/medium baseline levels and>20%reductions over time in Chinese adults.In conclusion,higher TC,LDL-C,and non-HDL-C levels are associated with elevated CHD mortality.Importantly,low and/or longitudinally decreasing cholesterol levels are robustly associated with increased all-cause and cancer mortality,potentially serving as markers of premature death.Regular cholesterol monitoring,with attention to both high and low levels,is recommended to inform guideline updates and clinical strategies.
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Correction to:Cellular&Molecular Immunology https://doi.org/10.1038/s41423-025-01319-1,published online 10 July 2025 The article“Cholesterol promotes autoimmune pathology through T follicular helper cells”,written by Wei Li&George C.Tsokos,was originally published open access under a Creative Commons Attribution 4.0 International License.
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 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Supported by grant 2001B043 from the Netherlands Heart Foundation
文摘The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.
基金supported by the National Natural Science Foundation of ChinaNo.81971826 (to AG)+5 种基金the China Postdoctoral Science FoundationNo.2020M681 689 (to YH)the Scientific Research Project of The Health Commission of Jiangsu ProvinceNo.ZDB2020003 (to AG)the Basic Scientific Research Projects of NantongNo.JC2020041 (to YH)
文摘Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.
