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
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
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
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
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
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
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
Cholesterol is a sterol with a four-membered ring structure and a single hydroxyl group attached to one of the rings. It is the active, raw form of cholesterol. Cholesteryl Ester is the inactive form in which choleste...Cholesterol is a sterol with a four-membered ring structure and a single hydroxyl group attached to one of the rings. It is the active, raw form of cholesterol. Cholesteryl Ester is the inactive form in which cholesterol is esterified to be transported to target organs. The newly developed process of making bulky esters from unprecedented tertiary alcohols is applied to synthesize cholesterol esters successfully. Although cholesterol is a secondary alcohol, it is a very bulky and interesting compound due to its immense application. Usually, specific enzymes catalyze cholesterol to cholesterol ester. This project aims to develop a cross-coupling chemistry process to synthesize cholesterol esters and see the broader application of those new cholesterol esters in chemical biology. The mixture of cholesterol, sodium tert-butoxide, aroyl chloride, the catalyst PdCl2 (dtbpf) complex, and the solvent 1,4-dioxane, when microwaved at 100˚C for 2 hours, works well for the formation of cross-coupling cholesterol ester products in good to high yields.展开更多
Free cholesterol has been considered to be a critical risk factor of nonalcoholic fatty liver disease(NAFLD).It remains unknown whether dietary intake of condensed tannins(CTs)have distinguishable effects to alleviate...Free cholesterol has been considered to be a critical risk factor of nonalcoholic fatty liver disease(NAFLD).It remains unknown whether dietary intake of condensed tannins(CTs)have distinguishable effects to alleviate liver damage caused by a high cholesterol diet.Male C57BL/6 mice were fed a high cholesterol diet for 6 weeks,and given CTs treatment at a dosage of 200 mg/(kg·day)at the same time.The results indicated that compared with mice fed a normal diet,a high cholesterol diet group resulted in significant weight loss,dysregulation of lipid metabolism in blood and liver,and oxidative stress in the liver,but CTs treatment dramatically reversed these negative effects.Hematoxylin and eosin(H&E)staining and frozen section observation manifested that CTs treatment could effectively reduce the deposition of liver cholesterol and tissue necrosis caused by high cholesterol intake.CTs alleviated liver injury mainly by regulating the expression of related genes in cholesterol metabolism pathway and AMPK phosphorylation.Our results confirmed that CTs have remarkable cholesterol lowering and anti-liver injury effects in vivo.展开更多
This study was aimed to analyze the effect of procyanidin B2(PC)and tannin acid(TA)on the activities of cholesterol esterase(CEase)and the inhibitory mechanisms of enzymatic activity.The interaction mechanisms were in...This study was aimed to analyze the effect of procyanidin B2(PC)and tannin acid(TA)on the activities of cholesterol esterase(CEase)and the inhibitory mechanisms of enzymatic activity.The interaction mechanisms were investigated by enzymatic kinetics,multi-spectroscopy methods,thermodynamics analysis,molecular docking,and dynamic simulations.PC and TA could bind with CEase and inhibit the activity of enzyme in a mixed-competitive manner and non-competitive manner,which was verified by molecular docking simulations and dynamics simulations.Also,PC and TA showed the synergistic inhibition with orlistat.Fluorescence,UVvis and the thermodynamic analysis revealed that the complexes were formed from CEase and inhibitors by noncovalent interaction.As revealed by the circular dichroism results,both PC and TA decreased enzymatic activities by altering the conformations of CEase.The inhibition of PC and TA on CEase might be one mechanism for its cholesterol-lowering effect.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
Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed...Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.Methods Ninety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.Results The rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins(DEPs) interacted with differentially acetylated proteins(DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group(P < 0.05). Lipidomics detected a variety of sphingolipids(SPs) and glycerophospholipids(GPs) were negatively correlated with hepatic steatosis(r ≤-0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.Conclusions In addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.展开更多
Atherosclerosis(AS)is a major cause of cardiovascular diseases(CVDs)and a strong link with hepatic steatosis.Silver carp muscle hydrolysate(SCH)possess various beneficial activities but its effect on AS and hepatic st...Atherosclerosis(AS)is a major cause of cardiovascular diseases(CVDs)and a strong link with hepatic steatosis.Silver carp muscle hydrolysate(SCH)possess various beneficial activities but its effect on AS and hepatic steatosis is yet unknown.This study aimed to investigate the effects of SCH on AS lesions and hepatic steatosis using apoE-/-mice.Results showed that SCH significantly reduced the vascular AS plaques and alleviated hepatic steatosis lesions in apoE-/-mice.Consistent with this,the lipid levels both in circulation and liver were lowered by SCH.The mechanism analysis showed SCH down-regulated the expression of genes involved in lipoproteins production while up-regulated the expression of genes related to reverse cholesterol transport(RCT)in liver.Meanwhile,SCH remarkably promoted transintestinal cholesterol excretion(TICE)process in intestine,partly contributing to the reduction of blood lipids.The peptide profile data indicated LYF,HWPW,FPK,and YPR are the main peptides in SCH that play a vital role in alleviating AS lesions and hepatic steatosis.Our findings provided new knowledge for the application of SCH in ameliorating CVDs and liver diseases.展开更多
Cardiovascular diseases(CVDs)are the leading global cause of mortality and disease burden.Statins are the most prescribed lipid-lowering drugs to treat hypercholesterolemia and prevent CVDs.The biochemical mechanism o...Cardiovascular diseases(CVDs)are the leading global cause of mortality and disease burden.Statins are the most prescribed lipid-lowering drugs to treat hypercholesterolemia and prevent CVDs.The biochemical mechanism of statins consists of competitive inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme(HMG-CoAR),the limiting enzyme in cholesterol biosynthesis.Due to statin intolerance in some patient groups,the search for new inhibitors is a field of great interest.This review focusses on the studies reporting the inhibitory effect of protein hydrolysates and biopeptides on the HMG-CoAR enzyme activity.The analysis of the action mechanism and physicochemical characteristics of the HMG-CoAR inhibitory peptides revealed that the molecular weight,amino acid composition,charge,and polarity are key aspects of the interaction with the HMG-CoAR enzyme.In conclusion,this review reveals the potential of using food peptides as new cholesterol-lowering agents and opens a new interesting field of research.However,clinical approaches are mandatory to confirm their therapeutic hypercholesterolemic effect.展开更多
Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer.Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells.Inhibiting tumor cell cholesterol uptake ...Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer.Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells.Inhibiting tumor cell cholesterol uptake or biosynthesis pathways,through the modulation of receptors and enzymes such as liver X receptor and sterolregulatory element binding protein 2,effectively restrains lung tumor growth.Similarly,promoting cholesterol excretion yields comparable effects.Cholesterol metabolites,including oxysterols and isoprenoids,play a crucial role in regulating cholesterol metabolism within tumor cells,consequently impacting cancer progression.In lung cancer patients,both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth,proliferation,and metastasis.The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells,B cells,macrophages,myeloid-derived suppressor cells,among others.Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments.Statins,targeting the cholesterol biosynthesis pathway,are widely employed in lung cancer treatment,either as standalone agents or in combination with other drugs.Additionally,drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer.In this review,we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.展开更多
AIM:To evaluate the relationship between monocyte to high-density lipoprotein cholesterol ratio(MHR)and the disease activity of thyroid-associated ophthalmopathy(TAO).METHODS:A total of 87 patients were classified int...AIM:To evaluate the relationship between monocyte to high-density lipoprotein cholesterol ratio(MHR)and the disease activity of thyroid-associated ophthalmopathy(TAO).METHODS:A total of 87 patients were classified into two groups based on clinical activity score(CAS)scoring criteria:high CAS group(n=62,the CAS score was≥3);low CAS group(n=25,the CAS score was<3).In addition,a group of healthy people(n=114)were included to compared the MHR.Proptosis,MHR,average signal intensity ratio(SIR),average lacrimal gland(LG)-SIR,average extraocular muscles(EOM)area from 87 patients with TAO were calculated in magnetic resonance imaging(MRI),and compared between these two groups.Correlation testing was utilized to evaluate the association of parameters among the clinical variables.RESULTS:Patients in high CAS group had a higher proptosis(P=0.041)and MHR(P=0.048).Compared to the healthy group,the MHR in the TAO group was higher(P=0.001).Correlation testing declared that CAS score was strongly associated with proptosis and average SIR,and MHR was positively associated with CAS score,average SIR,and average LG-SIR.The area under the receiver operating characteristic curve(AUC)of MHR was 0.6755.CONCLUSION:MHR,a novel inflammatory biomarker,has a significant association with CAS score and MRI imaging(average SIR and LG-SIR)and it can be a new promising predictor during the active phase of TAO.展开更多
BACKGROUND Dyslipidemia is frequently present in patients with diabetes.The associations of remnant cholesterol and mortality remains unclear in patients with diabetes.AIM To explore the associations of remnant choles...BACKGROUND Dyslipidemia is frequently present in patients with diabetes.The associations of remnant cholesterol and mortality remains unclear in patients with diabetes.AIM To explore the associations of remnant cholesterol with all-cause and cardiovas-cular mortality in patients with diabetes.METHODS This prospective cohort study included 4740 patients with diabetes who par-ticipated in the National Health and Nutrition Examination Survey from 1999 through 2018.Remnant cholesterol was used as the exposure variable,and all-cause and cardiovascular mortality were considered outcome events.Outcome data were obtained from the National Death Index,and all participants were followed from the interview date until death or December 31,2019.Multivariate proportional Cox regression models were used to explore the associations between exposure and outcomes,in which remnant cholesterol was modeled as both a categorical and a continuous variable.Restricted cubic splines(RCSs)were calculated to assess the nonlinearity of associations.Subgroup(stratified by sex,age,body mass index,and duration of diabetes)and a series of sensitivity analyses were performed to evaluate the robustness of the associations.RESULTS During a median follow-up duration of 83 months,1370 all-cause deaths and 389 cardiovascular deaths were documented.Patients with remnant cholesterol levels in the third quartile had a reduced risk of all-cause mortality[hazard ratio(HR)95%confidence interval(CI):0.66(0.52-0.85)];however,when remnant cholesterol was modeled as a continuous variable,it was associated with increased risks of all-cause[HR(95%CI):1.12(1.02-1.21)per SD]and cardiovascular[HR(95%CI):1.16(1.01-1.32),per SD]mortality.The RCS demonstrated nonlinear associations of remnant cholesterol with all-cause and cardiovascular mortality.Subgroup and sensitivity analyses did not reveal significant differences from the above results.CONCLUSION In patients with diabetes,higher remnant cholesterol was associated with increased risks of all-cause and cardiovascular mortality,and diabetes patients with slightly higher remnant cholesterol(0.68-1.04 mmol/L)had a lower risk of all-cause mortality.展开更多
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 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.
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.
基金supported by the National Natural Science Foundation of China funded project(32172627)Chongqing Modern Tea Technology System for Efficient Agriculture in Mountainous Areas 2022[8]the Germplasm Creation Research Program of Southwest University。
文摘Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
文摘Cholesterol is a sterol with a four-membered ring structure and a single hydroxyl group attached to one of the rings. It is the active, raw form of cholesterol. Cholesteryl Ester is the inactive form in which cholesterol is esterified to be transported to target organs. The newly developed process of making bulky esters from unprecedented tertiary alcohols is applied to synthesize cholesterol esters successfully. Although cholesterol is a secondary alcohol, it is a very bulky and interesting compound due to its immense application. Usually, specific enzymes catalyze cholesterol to cholesterol ester. This project aims to develop a cross-coupling chemistry process to synthesize cholesterol esters and see the broader application of those new cholesterol esters in chemical biology. The mixture of cholesterol, sodium tert-butoxide, aroyl chloride, the catalyst PdCl2 (dtbpf) complex, and the solvent 1,4-dioxane, when microwaved at 100˚C for 2 hours, works well for the formation of cross-coupling cholesterol ester products in good to high yields.
基金supported by the National Basic Research Program of China(2013CB127106)。
文摘Free cholesterol has been considered to be a critical risk factor of nonalcoholic fatty liver disease(NAFLD).It remains unknown whether dietary intake of condensed tannins(CTs)have distinguishable effects to alleviate liver damage caused by a high cholesterol diet.Male C57BL/6 mice were fed a high cholesterol diet for 6 weeks,and given CTs treatment at a dosage of 200 mg/(kg·day)at the same time.The results indicated that compared with mice fed a normal diet,a high cholesterol diet group resulted in significant weight loss,dysregulation of lipid metabolism in blood and liver,and oxidative stress in the liver,but CTs treatment dramatically reversed these negative effects.Hematoxylin and eosin(H&E)staining and frozen section observation manifested that CTs treatment could effectively reduce the deposition of liver cholesterol and tissue necrosis caused by high cholesterol intake.CTs alleviated liver injury mainly by regulating the expression of related genes in cholesterol metabolism pathway and AMPK phosphorylation.Our results confirmed that CTs have remarkable cholesterol lowering and anti-liver injury effects in vivo.
基金supported by the National Basic Research Program of China(‘973’program,2013CB127106)。
文摘This study was aimed to analyze the effect of procyanidin B2(PC)and tannin acid(TA)on the activities of cholesterol esterase(CEase)and the inhibitory mechanisms of enzymatic activity.The interaction mechanisms were investigated by enzymatic kinetics,multi-spectroscopy methods,thermodynamics analysis,molecular docking,and dynamic simulations.PC and TA could bind with CEase and inhibit the activity of enzyme in a mixed-competitive manner and non-competitive manner,which was verified by molecular docking simulations and dynamics simulations.Also,PC and TA showed the synergistic inhibition with orlistat.Fluorescence,UVvis and the thermodynamic analysis revealed that the complexes were formed from CEase and inhibitors by noncovalent interaction.As revealed by the circular dichroism results,both PC and TA decreased enzymatic activities by altering the conformations of CEase.The inhibition of PC and TA on CEase might be one mechanism for its cholesterol-lowering effect.
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funded in part by grants from the National Natural Science Foundation of China (No.31930105)National Key Research and Development Program of China (2022YFF1000204)China Agriculture Research Systems (CARS-40)。
文摘Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.Methods Ninety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.Results The rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins(DEPs) interacted with differentially acetylated proteins(DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group(P < 0.05). Lipidomics detected a variety of sphingolipids(SPs) and glycerophospholipids(GPs) were negatively correlated with hepatic steatosis(r ≤-0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.Conclusions In addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.
基金supported by the China Agriculture Research System(CARS-45),Natural Science Foundation of Jiangsu Province(BK20240918)the“Green Yangzhou Golden Phoenix”funding of Yangzhou(137013478).
文摘Atherosclerosis(AS)is a major cause of cardiovascular diseases(CVDs)and a strong link with hepatic steatosis.Silver carp muscle hydrolysate(SCH)possess various beneficial activities but its effect on AS and hepatic steatosis is yet unknown.This study aimed to investigate the effects of SCH on AS lesions and hepatic steatosis using apoE-/-mice.Results showed that SCH significantly reduced the vascular AS plaques and alleviated hepatic steatosis lesions in apoE-/-mice.Consistent with this,the lipid levels both in circulation and liver were lowered by SCH.The mechanism analysis showed SCH down-regulated the expression of genes involved in lipoproteins production while up-regulated the expression of genes related to reverse cholesterol transport(RCT)in liver.Meanwhile,SCH remarkably promoted transintestinal cholesterol excretion(TICE)process in intestine,partly contributing to the reduction of blood lipids.The peptide profile data indicated LYF,HWPW,FPK,and YPR are the main peptides in SCH that play a vital role in alleviating AS lesions and hepatic steatosis.Our findings provided new knowledge for the application of SCH in ameliorating CVDs and liver diseases.
基金funded by Consejería de Salud,Junta de Andalucía(PC-0111-2016-0111)PEMP-0085-2020(cofinanciado con fondos FEDER,convocatoria Resolución de 7 de julio de 2021 de la Secretaría General de Investigación,Desarrollo e Innovación en Salud,que convoca subvenciones para financiar la investigación,el desarrollo y la innovación en Biomedicina y Ciencias de la Salud en Andalucía,para 2021)+5 种基金the Programa PAIDI from the Junta de Andalucía(CTS160)supported by a FPU grant from the Spanish Ministerio de Educación,Cultura y Deporte(FPU16/02339)supported by the VI Program of Inner Initiative for Research and Transfer of the University of Seville(VIPPIT2020-II.4)by a postdoctoral fellowship from the Andalusian Government Ministry of Economy,Knowledge,Business,and University(DOC_00587/2020)funded by Andalusian Government Ministry of Health(PI-0136-2019)supported by the VI Program of Inner Initiative for Research and Transfer of University of Seville
文摘Cardiovascular diseases(CVDs)are the leading global cause of mortality and disease burden.Statins are the most prescribed lipid-lowering drugs to treat hypercholesterolemia and prevent CVDs.The biochemical mechanism of statins consists of competitive inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme(HMG-CoAR),the limiting enzyme in cholesterol biosynthesis.Due to statin intolerance in some patient groups,the search for new inhibitors is a field of great interest.This review focusses on the studies reporting the inhibitory effect of protein hydrolysates and biopeptides on the HMG-CoAR enzyme activity.The analysis of the action mechanism and physicochemical characteristics of the HMG-CoAR inhibitory peptides revealed that the molecular weight,amino acid composition,charge,and polarity are key aspects of the interaction with the HMG-CoAR enzyme.In conclusion,this review reveals the potential of using food peptides as new cholesterol-lowering agents and opens a new interesting field of research.However,clinical approaches are mandatory to confirm their therapeutic hypercholesterolemic effect.
文摘Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer.Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells.Inhibiting tumor cell cholesterol uptake or biosynthesis pathways,through the modulation of receptors and enzymes such as liver X receptor and sterolregulatory element binding protein 2,effectively restrains lung tumor growth.Similarly,promoting cholesterol excretion yields comparable effects.Cholesterol metabolites,including oxysterols and isoprenoids,play a crucial role in regulating cholesterol metabolism within tumor cells,consequently impacting cancer progression.In lung cancer patients,both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth,proliferation,and metastasis.The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells,B cells,macrophages,myeloid-derived suppressor cells,among others.Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments.Statins,targeting the cholesterol biosynthesis pathway,are widely employed in lung cancer treatment,either as standalone agents or in combination with other drugs.Additionally,drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer.In this review,we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.
基金Supported by the Special Fund for Clinical Research of Nanjing Drum Tower Hospital(No.2023-LCYJPY-37).
文摘AIM:To evaluate the relationship between monocyte to high-density lipoprotein cholesterol ratio(MHR)and the disease activity of thyroid-associated ophthalmopathy(TAO).METHODS:A total of 87 patients were classified into two groups based on clinical activity score(CAS)scoring criteria:high CAS group(n=62,the CAS score was≥3);low CAS group(n=25,the CAS score was<3).In addition,a group of healthy people(n=114)were included to compared the MHR.Proptosis,MHR,average signal intensity ratio(SIR),average lacrimal gland(LG)-SIR,average extraocular muscles(EOM)area from 87 patients with TAO were calculated in magnetic resonance imaging(MRI),and compared between these two groups.Correlation testing was utilized to evaluate the association of parameters among the clinical variables.RESULTS:Patients in high CAS group had a higher proptosis(P=0.041)and MHR(P=0.048).Compared to the healthy group,the MHR in the TAO group was higher(P=0.001).Correlation testing declared that CAS score was strongly associated with proptosis and average SIR,and MHR was positively associated with CAS score,average SIR,and average LG-SIR.The area under the receiver operating characteristic curve(AUC)of MHR was 0.6755.CONCLUSION:MHR,a novel inflammatory biomarker,has a significant association with CAS score and MRI imaging(average SIR and LG-SIR)and it can be a new promising predictor during the active phase of TAO.
基金Supported by Project of National Natural Science Foundation of China,No.82274345 and No.82104907Fundamental Research Funds for the Central public welfare research institutes Grant,No.ZZ13-YQ-016 and No.ZZ13-YQ-016-C1.
文摘BACKGROUND Dyslipidemia is frequently present in patients with diabetes.The associations of remnant cholesterol and mortality remains unclear in patients with diabetes.AIM To explore the associations of remnant cholesterol with all-cause and cardiovas-cular mortality in patients with diabetes.METHODS This prospective cohort study included 4740 patients with diabetes who par-ticipated in the National Health and Nutrition Examination Survey from 1999 through 2018.Remnant cholesterol was used as the exposure variable,and all-cause and cardiovascular mortality were considered outcome events.Outcome data were obtained from the National Death Index,and all participants were followed from the interview date until death or December 31,2019.Multivariate proportional Cox regression models were used to explore the associations between exposure and outcomes,in which remnant cholesterol was modeled as both a categorical and a continuous variable.Restricted cubic splines(RCSs)were calculated to assess the nonlinearity of associations.Subgroup(stratified by sex,age,body mass index,and duration of diabetes)and a series of sensitivity analyses were performed to evaluate the robustness of the associations.RESULTS During a median follow-up duration of 83 months,1370 all-cause deaths and 389 cardiovascular deaths were documented.Patients with remnant cholesterol levels in the third quartile had a reduced risk of all-cause mortality[hazard ratio(HR)95%confidence interval(CI):0.66(0.52-0.85)];however,when remnant cholesterol was modeled as a continuous variable,it was associated with increased risks of all-cause[HR(95%CI):1.12(1.02-1.21)per SD]and cardiovascular[HR(95%CI):1.16(1.01-1.32),per SD]mortality.The RCS demonstrated nonlinear associations of remnant cholesterol with all-cause and cardiovascular mortality.Subgroup and sensitivity analyses did not reveal significant differences from the above results.CONCLUSION In patients with diabetes,higher remnant cholesterol was associated with increased risks of all-cause and cardiovascular mortality,and diabetes patients with slightly higher remnant cholesterol(0.68-1.04 mmol/L)had a lower risk of all-cause mortality.
