We have investigated the morphology of dimyristoyl phosphatidyl choline (DMPC)—cholesterol mixed monolayer formed on the water surface by dropping method using surface tension measurement (STm), Brewster angle micros...We have investigated the morphology of dimyristoyl phosphatidyl choline (DMPC)—cholesterol mixed monolayer formed on the water surface by dropping method using surface tension measurement (STm), Brewster angle microscopy (BAM), and infrared external reflection spectroscopy (IERS). STm results showed negative deviation of the limiting molecular area (A0) of cholesterol occurred when cholesterol was added to the DMPC monolayer. BAM images showed the expandable DMPC monolayer changed to the condensed rigid monolayer at more than cholesterol mole fraction (xChol) 0.4. IERS recordings showed that the addition of cholesterol at xChol = 0.4 occurred structural change from gauche- to trans- conformation of two DMPC molecule alkyl chains. From these results, it is found that cholesterol molecule has specific properties that cause structural transition of DMPC molecule alkyl chains.展开更多
AIM:To study whether patients with excess deoxycholic acid (DCA) differ from those with normal percentage of DCA with respect to biliary lipid composition and cholesterol saturation of gallbladder bile. METHODS:Bile w...AIM:To study whether patients with excess deoxycholic acid (DCA) differ from those with normal percentage of DCA with respect to biliary lipid composition and cholesterol saturation of gallbladder bile. METHODS:Bile was collected during operation through puncturing into the gallbladder from 122 cholesterol gallstone patients and 46 gallstone-free subjects undergoing cholecystectomy.Clinical data,biliary lipids,bile add composition, presence of crystals and nucleation time were analyzed. RESULTS:A subgroup of gallstone patients displayed a higher proportion of DCA in bile than gallstone free subjects. By choosing a cut-off level of the 90th percentile,a group of 13 gallstone patients with high DCA levels (mean 50 percent of total bile acids) and a large group of 109 patients with normal DCA levels (mean 21 percent of total bile acids) were obtained.The mean age of the patients with high DCA levels was higher than that of the group with normal levels (mean age:62 years vs45 years) and so was the mean BMI (28.3 vs.24.7).Plasma levels of cholesterol and triglycerides were slightly higher in the DCA excess groups compared with those in the normal DCA group.There was no difference in biliary lipid composition,cholesterol saturation,nucleation time or occurrence of cholesterol crystals in bile between patients with high and normal levels of DCA. CONCLUSION:Gallstone patients with excess DCA were of older age and had higher BMI than patients with normal DCA.The two groups of patients did not differ with respect to biliary lipid composition,cholesterol saturation,nucleation time or occurrence of cholesterol crystals.It is concluded that DCA in bile does not seem to contribute to gallstone formation in cholesterol gallstone patients.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
The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considere...The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considered in adults with short duration of diabetes, long life expectancy, and no significant cardiovascular disease if this can be achieved without significant hypoglycemia or other adverse effects of treatment. A hemoglobin A1c level less than 8.0% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced macrovascular and microvascular complications, extensive comorbidities, and long-standing diabetes in whom the hemoglobin A1c goal is difficult to attain despite multiple glucoselowering drugs including insulin. The ADA 2013 guidelines recommend that the systolic blood pressure in most diabetics with hypertension should be reduced to less than 140 mmHg. These guidelines also recommend use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the treatment of hypertension in diabetics unless they are pregnant. Diabetics at high risk for cardiovascular events should have theirserum low-density lipoprotein (LDL) cholesterol lowered to less than 70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dL. Combination therapy of a statin with either a fibrate or niacin has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not recommended. Hypertriglyceridemia should be treated with dietary and lifestyle changes. Severe hypertriglyceridemia should be treated with drug therapy to reduce the risk of acute pancreatitis.展开更多
BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modif...BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.展开更多
Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-ric...Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumu- lation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocho-lesterolemic strategies will also be introduced.展开更多
The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipopro...The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipoprotien (LDL) in subendothelial cells of arterial wall, is an absolute requirement for lesion development. This allows us to consider intracellular cholesterol retention as a novel target for anti-atherosclerotic therapy. In this case, the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review summarizes the results of our basic studies shedding light on the mechanisms of intracellular cholesterol retention. We describe our cellular models to search for anti-atherosclerotic agents and demonstrate the use of these models for the development of anti-atherosclerotic drugs. We use natural products as the basis of anti-atherosclerotic drugs because anti-atherosclerotic therapy should be long-term or even lifelong. Using cellular models and natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured subendothelial aortic cells. We have developed drugs that reduce intracellular cholesterol retention, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with Allicor or Inflaminat caused regression of carotid atherosclerosis in asymptomatic men. Karinat prevented the development of new atherosclerotic plaques in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinics. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.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
Aims: Small dense LDL (sdLDL) cholesterol is considered a cardiovascular risk. Our purpose in this study was to evaluate the efficacy of rosuvastatin in reducing sdLDL and large buoyant LDL (lbLDL-C) in hypercholester...Aims: Small dense LDL (sdLDL) cholesterol is considered a cardiovascular risk. Our purpose in this study was to evaluate the efficacy of rosuvastatin in reducing sdLDL and large buoyant LDL (lbLDL-C) in hypercholesterolemia. Methods: Fifty-six patients with a mean baseline LDL-cholesterol (LDL-C) concentration of 173.9 ± 40.5 mg/dL were treated with rosuvastatin 2.5 mg/day for 12 weeks. LDL-C, sdLDL-C, and apolipoprotein (apo) B were assessed and l lbLDL-C was calculated (LDL-C minus sdLDL-C). Results: After 12-week treatment with rosuvastatin 2.5mg, sdLDL-C and lbLDL-C were significantly reduced from 62.1 ± 23.8 mg/dL to 34.0 ± 13.4 mg/dL, p <0.001 and 112.7 ± 34.9 mg/dL to 77.2± 29.2 mg/dL, p < 0.001 respectively, and sdLDL-C/lbLDL-C ratio and apo B also decreased significantly, from 0.36 ± 0.02 to 0.32 ± 0.02, p < 0.005 and 134.2 ± 4.3 to 93.6 ± 3.5 mg/dl, p < 0.001, respectively. In diabetic subjects there was significant correlation between percent reductions in the plasma triglyceride and sdLDL-C/ lbLDL-C ratio (r = 0.58, p < 0.005), but not between the percentage decrease in plasma triglyceride and sdLDL-C. Conclusions: Treatment with rosuvastatin is associated with significant reduction in sdLDL, lbLDL and sdLDL/lbLDL ratio.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
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
AIM: To assess potential contributions of biliary IgA for crystal agglomeration into gallstones, we visualized cholesterol crystal binding of biliary IgA. METHODS: Crystal binding biliary proteins were extracted from ...AIM: To assess potential contributions of biliary IgA for crystal agglomeration into gallstones, we visualized cholesterol crystal binding of biliary IgA. METHODS: Crystal binding biliary proteins were extracted from human gallbladder bile using lectin affinity chromatography.Biliary IgA was isolated from the bound protein fraction by immunoaffinity chromatography. Pure cholesterol monohydrate crystals were incubated with biliary IgA and fluoresceine isothiocyanate (FITC)conjugated anti IgA at 37 degree. Samples were examined under polarizing and fluorescence light microscopy with digital image processing. RESULTS: Binding of biliary IgA to cholesterol monohydrate crystals could be visualized with FITC conjugated anti IgA antibodies.Peak fluorescence occurred at crystal edges and dislocations. Controls without biliary IgA or with biliary IgG showed no significant fluorescence. CONCLUSION: Fluorescence light microscopy provided evidence for cholesterol crystal binding of biliary IgA. Cholesterol crystal binding proteins like IgA might be important mediators of crystal agglomeration and growth of cholesterol gallstones by modifying the evolving crystal structures in vivo.展开更多
Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacyl...Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacylglycerols tributyrin(Tb)and tripropionin(Tp)are odorless and can be directly used as healthy supplements.In view that no study has investigated the relative biological potency of Tb and Tp,the present study was designed to compare the effects of Tp and Tb on plasma cholesterol and gut microbiota using hypercholesterolemic hamsters as a model.Male golden hamsters were randomly allocated to 6 groups fed one of the following 6 diets,namely,low-cholesterol diet(LCD),high-cholesterol diet(HCD),HCD+0.5%Tp(LTp),HCD+1%Tp(HTp),HCD+0.5%Tb(LTb),and HCD+1%Tb(HTb).Results showed that Tb administration at 1%could significantly reduce plasma total cholesterol(TC),non-high-density lipoprotein cholesterol(non-HDLC),and the ratio of non-HDLC to HDLC,whereas Tp supplementation had no effect.Mechanistically,Tb but not Tp could decrease plasma cholesterol by increasing the excretion of fecal bile acids via upregulating gene expression of cholesterol 7α-hydroxylase(CYP7A1)and liver X receptor alpha(LXRα).In addition,Tb supplementation at 1%could increase the gut microbiota diversity,reduce the ratio of Firmicutes/Bacteroidetes and favorably increase the abundance of beneficial microbial genera Bifidobacterium.In conclusion,dietary Tb supplementation was more effective than Tp in mitigating hypercholesterolemia by increasing the excretion of fecal bile acids and favorably modulating gut microbiota.展开更多
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
AIM: To investigate the mechanisms and effects of sphincter of Oddi(SO) motility on cholesterol gallbladder stone formation in guinea pigs.METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into...AIM: To investigate the mechanisms and effects of sphincter of Oddi(SO) motility on cholesterol gallbladder stone formation in guinea pigs.METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into two groups, the control group(n = 10) and the cholesterol gallstone group(n = 24), which was sequentially divided into four subgroups with six guinea pigs each according to time of sacrifice. The guinea pigs in the cholesterol gallstone group were fed a cholesterol lithogenic diet and sacrificed after 3, 6, 9, and 12 wk. SO manometry and recording of myoelectric activity were obtained by a multifunctional physiograph at each stage. Cholecystokinin-A receptor(CCKAR) expression levels in SO smooth muscle were detected by quantitative real-time PCR(q RT-PCR) and serum vasoactive intestinal peptide(VIP), gastrin, and cholecystokinin octapeptide(CCK-8) were detected by enzyme-linked immunosorbent assay at each stage in the process of cholesterol gallstone formation.RESULTS: The gallstone formation rate was 0%, 0%, 16.7%, and 83.3% in the 3, 6, 9, and 12 wk groups, respectively. The frequency of myoelectric activity in the 9 wk group, the amplitude of myoelectric activity in the 9 and 12 wk groups, and the amplitude and the frequency of SO in the 9 wk group were all significantly decreased compared to the control group. The SO basal pressure and common bile duct pressure increased markedly in the 12 wk group, and the CCKAR expression levels increased in the 6 and 12 wk groups compared to the control group. Serum VIP was elevated significantly in the 9 and 12 wk groups and gastrin decreased significantly in the 3 and 9 wk groups. There was no difference in serum CCK-8 between the groups.CONCLUSION: A cholesterol gallstone-causing diet can induce SO dysfunction. The increasing tension of the SO along with its decreasing activity may play an important role in cholesterol gallstone formation. Expression changes of CCKAR in SO smooth muscle and serum VIP and CCK-8 may be important causes of SO dysfunction.展开更多
BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the p...BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the progression of NASH. METHODS A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAOtreated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influxrelated Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.展开更多
Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investiga...Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investigate the rate of optimal low-density lipoprotein (LDL) cholesterol level in a multicenter registry of patients at high risk for cardiovascular events. Methods A multicenter registry of EAD and MRF patients was conducted. Demographic data,medical history,cardiovascular risk factors,anthropometric data,laboratory data,and medications were recorded and analyzed. We classified patients according to target LDL levels based on recommendation by the European Society of Cardiology (ESC) 2011 into Group 1 which is EAD and diabetes or chronic kidney disease (CKD)–target LDL below 70 mg/dL,and Group 2 which is MRF without diabetes or CKD–target LDL below 100 mg/dL. The rate of optimal LDL level in patients with Group 1 and Group 2 was analyzed and stratified according to the treatment pattern of lipid-lowering medications. Results A total of 3100 patients were included. Of those,51.7% were male. Average age was 65.8 ± 9.7 years. Average LDL level was 96.3 ± 32.6 mg/dL. A vast majority (92.7%) received statin and 9.3% received ezetimibe. Optimal LDL level was achieved in 20.3% of patients in Group 1 (LDL < 70 mg/dL),and in 46.6% in Group 2 (LDL < 100 mg/dL). The overall rate of optimal LDL control was 23% since 89.6% of study population belongs to Group 1. The rate of optimal LDL was not different between high and low potency statin. Factors that were associated with optimal LDL control were older age,the presence of coronary artery disease or peripheral artery disease. Conclusions The rates of optimal LDL level were unacceptably low in this study population. As such,a strategy to improve LDL control in high-risk population should be implemented.展开更多
The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membra...The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. For this reason, defects in the biosynthesis of cholesterol can variably affect the development of central nervous system. Moreover, defective synthesis of cholesterol and its intermediates may reflect both on structural cell anomalies and on the response to inflammatory stimuli. Examples of such disorders include mevalonate kinase deficiency, and Smith-Lemli-Opitz syndrome, due to deficiency in biosynthetic enzymes, and type C Niemann-Pick syndrome, due to altered cholesterol trafficking across cell compartments. Autophagy, as a crucial pathway dedicated to the degradation of cytosolic proteins and organelles, plays an essential role in the maintenance of homeostasis and in the turnover of the cytoplasmic material especially in the presence of imbalances such as those resulting from alteration of cholesterol metabolism. Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders.展开更多
In the present study, 20 selected Lactobacillus strains already characterized in a previous research for their capability to grow in conditions simulating the intestinal environment, their resistance to antibiotics, t...In the present study, 20 selected Lactobacillus strains already characterized in a previous research for their capability to grow in conditions simulating the intestinal environment, their resistance to antibiotics, their antibacterial activity and their adhesion capability to intestinal human Caco-2 TC7 and HT-29 MTX cell lines, were further investigated to explore more their probiotic properties. Growth behaviour in the presence of prebiotic (fructooligosac-charides (FOS) and lactulose) at a concentration of 2%, cholesterol removal by measuring the residual cholesterol in medium supplemented with cholesterol, ability to deconjugate bile salts using BSH enzyme and antioxidant activity of culture supernatant of Lactobacillus strains by ABTS·+ and DPPH methods were analyzed. All probiotic strains demonstrated important prebiotic assimilation (P > 0.05) even with OD600 > 3 after 30 h of contact, cholesterol removal ability with maximum percentage of 57% after 24 h of contact and they were found to liberate significantly (P < 0.05) more cholic acid with maximum of 0.40 mM of sodium glycocholate, 0.33 mM of sodium taurocholate and 0.41 mM of their mixte and scavenge both radicals with 52% and 2.19% of ABTS·+ and DPPH respectively. This study confirmed the suitability of these probiotic strains for application in functional food formulations especially where cholesterol reduction and antioxidant activity in food are needed to assess possible in vivo human health benefits.展开更多
Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly co...Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly controlled at multiple levels. It has been clearly shown that cholesterol redistribution and depletion from the sperm membrane is a key part of the spermatozoon＇s preparation for fertilization. Some factors that regulate these events are described （e.g., bicarbonate, calcium） but the mechanisms underlying cholesterol export are poorly understood. How does a hydrophobic cholesterol molecule inserted in the sperm plasma membrane enter the energetically unfavorable aqueous surroundings？ This review will provide an overview of knowledge in this area and highlight our gaps in understanding. The overall aim is to better understand cholesterol redistribution in the sperm plasma membrane, its relation to the possible activation of a cholesterol transporter and the role of cholesterol acceptors. Armed with such knowledlze, sl）erm handlin~ techniques can be adapted to better prepare spermatozoa for in vitro and in vivo fertilization.展开更多
文摘We have investigated the morphology of dimyristoyl phosphatidyl choline (DMPC)—cholesterol mixed monolayer formed on the water surface by dropping method using surface tension measurement (STm), Brewster angle microscopy (BAM), and infrared external reflection spectroscopy (IERS). STm results showed negative deviation of the limiting molecular area (A0) of cholesterol occurred when cholesterol was added to the DMPC monolayer. BAM images showed the expandable DMPC monolayer changed to the condensed rigid monolayer at more than cholesterol mole fraction (xChol) 0.4. IERS recordings showed that the addition of cholesterol at xChol = 0.4 occurred structural change from gauche- to trans- conformation of two DMPC molecule alkyl chains. From these results, it is found that cholesterol molecule has specific properties that cause structural transition of DMPC molecule alkyl chains.
文摘AIM:To study whether patients with excess deoxycholic acid (DCA) differ from those with normal percentage of DCA with respect to biliary lipid composition and cholesterol saturation of gallbladder bile. METHODS:Bile was collected during operation through puncturing into the gallbladder from 122 cholesterol gallstone patients and 46 gallstone-free subjects undergoing cholecystectomy.Clinical data,biliary lipids,bile add composition, presence of crystals and nucleation time were analyzed. RESULTS:A subgroup of gallstone patients displayed a higher proportion of DCA in bile than gallstone free subjects. By choosing a cut-off level of the 90th percentile,a group of 13 gallstone patients with high DCA levels (mean 50 percent of total bile acids) and a large group of 109 patients with normal DCA levels (mean 21 percent of total bile acids) were obtained.The mean age of the patients with high DCA levels was higher than that of the group with normal levels (mean age:62 years vs45 years) and so was the mean BMI (28.3 vs.24.7).Plasma levels of cholesterol and triglycerides were slightly higher in the DCA excess groups compared with those in the normal DCA group.There was no difference in biliary lipid composition,cholesterol saturation,nucleation time or occurrence of cholesterol crystals in bile between patients with high and normal levels of DCA. CONCLUSION:Gallstone patients with excess DCA were of older age and had higher BMI than patients with normal DCA.The two groups of patients did not differ with respect to biliary lipid composition,cholesterol saturation,nucleation time or occurrence of cholesterol crystals.It is concluded that DCA in bile does not seem to contribute to gallstone formation in cholesterol gallstone patients.
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.
文摘The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considered in adults with short duration of diabetes, long life expectancy, and no significant cardiovascular disease if this can be achieved without significant hypoglycemia or other adverse effects of treatment. A hemoglobin A1c level less than 8.0% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced macrovascular and microvascular complications, extensive comorbidities, and long-standing diabetes in whom the hemoglobin A1c goal is difficult to attain despite multiple glucoselowering drugs including insulin. The ADA 2013 guidelines recommend that the systolic blood pressure in most diabetics with hypertension should be reduced to less than 140 mmHg. These guidelines also recommend use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the treatment of hypertension in diabetics unless they are pregnant. Diabetics at high risk for cardiovascular events should have theirserum low-density lipoprotein (LDL) cholesterol lowered to less than 70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dL. Combination therapy of a statin with either a fibrate or niacin has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not recommended. Hypertriglyceridemia should be treated with dietary and lifestyle changes. Severe hypertriglyceridemia should be treated with drug therapy to reduce the risk of acute pancreatitis.
基金Supported by Programa para el Desarrollo Profesional Docente(PRODEP)to Gonzalez-Aldaco K,No.UDG-PTC-1422Consejo Nacional de Ciencia y Tecnología(CONACYT)to Panduro A,No.2017-01-5254
文摘BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.
文摘Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumu- lation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocho-lesterolemic strategies will also be introduced.
文摘The key initiating process in atherogenesis is the subendothelial cholesterol retention, which is both necessary and sufficient to provoke lesion initiation. Retention of cholesterol transported by low density lipoprotien (LDL) in subendothelial cells of arterial wall, is an absolute requirement for lesion development. This allows us to consider intracellular cholesterol retention as a novel target for anti-atherosclerotic therapy. In this case, the target is not the level of blood cholesterol but the level of cholesterol in vascular cells. This review summarizes the results of our basic studies shedding light on the mechanisms of intracellular cholesterol retention. We describe our cellular models to search for anti-atherosclerotic agents and demonstrate the use of these models for the development of anti-atherosclerotic drugs. We use natural products as the basis of anti-atherosclerotic drugs because anti-atherosclerotic therapy should be long-term or even lifelong. Using cellular models and natural products, we have developed an approach to prevent intracellular cholesterol retention in cultured subendothelial aortic cells. We have developed drugs that reduce intracellular cholesterol retention, namely Allicor on the basis of garlic powder, anti-inflammatory drug Inflaminat (calendula, elder, and violet) possessing anti-cytokine activity and phytoestrogen-rich drug Karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid). Treatment with Allicor or Inflaminat caused regression of carotid atherosclerosis in asymptomatic men. Karinat prevented the development of new atherosclerotic plaques in postmenopausal women. Thus, the main findings of our basic research have been successfully translated into clinics. As a result, this translation, a novel approach to the development of anti-atherosclerotic therapy, has been established. Our clinical trials have confirmed the suitability of innovative approach and the efficacy of novel drugs developed on the basis our methodology.
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.
文摘Aims: Small dense LDL (sdLDL) cholesterol is considered a cardiovascular risk. Our purpose in this study was to evaluate the efficacy of rosuvastatin in reducing sdLDL and large buoyant LDL (lbLDL-C) in hypercholesterolemia. Methods: Fifty-six patients with a mean baseline LDL-cholesterol (LDL-C) concentration of 173.9 ± 40.5 mg/dL were treated with rosuvastatin 2.5 mg/day for 12 weeks. LDL-C, sdLDL-C, and apolipoprotein (apo) B were assessed and l lbLDL-C was calculated (LDL-C minus sdLDL-C). Results: After 12-week treatment with rosuvastatin 2.5mg, sdLDL-C and lbLDL-C were significantly reduced from 62.1 ± 23.8 mg/dL to 34.0 ± 13.4 mg/dL, p <0.001 and 112.7 ± 34.9 mg/dL to 77.2± 29.2 mg/dL, p < 0.001 respectively, and sdLDL-C/lbLDL-C ratio and apo B also decreased significantly, from 0.36 ± 0.02 to 0.32 ± 0.02, p < 0.005 and 134.2 ± 4.3 to 93.6 ± 3.5 mg/dl, p < 0.001, respectively. In diabetic subjects there was significant correlation between percent reductions in the plasma triglyceride and sdLDL-C/ lbLDL-C ratio (r = 0.58, p < 0.005), but not between the percentage decrease in plasma triglyceride and sdLDL-C. Conclusions: Treatment with rosuvastatin is associated with significant reduction in sdLDL, lbLDL and sdLDL/lbLDL ratio.
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.
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AIM: To assess potential contributions of biliary IgA for crystal agglomeration into gallstones, we visualized cholesterol crystal binding of biliary IgA. METHODS: Crystal binding biliary proteins were extracted from human gallbladder bile using lectin affinity chromatography.Biliary IgA was isolated from the bound protein fraction by immunoaffinity chromatography. Pure cholesterol monohydrate crystals were incubated with biliary IgA and fluoresceine isothiocyanate (FITC)conjugated anti IgA at 37 degree. Samples were examined under polarizing and fluorescence light microscopy with digital image processing. RESULTS: Binding of biliary IgA to cholesterol monohydrate crystals could be visualized with FITC conjugated anti IgA antibodies.Peak fluorescence occurred at crystal edges and dislocations. Controls without biliary IgA or with biliary IgG showed no significant fluorescence. CONCLUSION: Fluorescence light microscopy provided evidence for cholesterol crystal binding of biliary IgA. Cholesterol crystal binding proteins like IgA might be important mediators of crystal agglomeration and growth of cholesterol gallstones by modifying the evolving crystal structures in vivo.
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.
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 Natural Science Foundation of Shandong Province,China,No.ZR 2012 HM-079
文摘AIM: To investigate the mechanisms and effects of sphincter of Oddi(SO) motility on cholesterol gallbladder stone formation in guinea pigs.METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into two groups, the control group(n = 10) and the cholesterol gallstone group(n = 24), which was sequentially divided into four subgroups with six guinea pigs each according to time of sacrifice. The guinea pigs in the cholesterol gallstone group were fed a cholesterol lithogenic diet and sacrificed after 3, 6, 9, and 12 wk. SO manometry and recording of myoelectric activity were obtained by a multifunctional physiograph at each stage. Cholecystokinin-A receptor(CCKAR) expression levels in SO smooth muscle were detected by quantitative real-time PCR(q RT-PCR) and serum vasoactive intestinal peptide(VIP), gastrin, and cholecystokinin octapeptide(CCK-8) were detected by enzyme-linked immunosorbent assay at each stage in the process of cholesterol gallstone formation.RESULTS: The gallstone formation rate was 0%, 0%, 16.7%, and 83.3% in the 3, 6, 9, and 12 wk groups, respectively. The frequency of myoelectric activity in the 9 wk group, the amplitude of myoelectric activity in the 9 and 12 wk groups, and the amplitude and the frequency of SO in the 9 wk group were all significantly decreased compared to the control group. The SO basal pressure and common bile duct pressure increased markedly in the 12 wk group, and the CCKAR expression levels increased in the 6 and 12 wk groups compared to the control group. Serum VIP was elevated significantly in the 9 and 12 wk groups and gastrin decreased significantly in the 3 and 9 wk groups. There was no difference in serum CCK-8 between the groups.CONCLUSION: A cholesterol gallstone-causing diet can induce SO dysfunction. The increasing tension of the SO along with its decreasing activity may play an important role in cholesterol gallstone formation. Expression changes of CCKAR in SO smooth muscle and serum VIP and CCK-8 may be important causes of SO dysfunction.
基金Supported by National Key R and D Program of China,No.2017YFC0908903National Natural Science Foundation of China,No.81873565,No.81470840,and No.81800510Shanghai Sailing Program,No.18YF1415900
文摘BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the progression of NASH. METHODS A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAOtreated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influxrelated Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.
基金supported by the Heart Association of Thailand under the Royal Patronage of H.M. the Kingthe National Research Council of Thailand
文摘Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investigate the rate of optimal low-density lipoprotein (LDL) cholesterol level in a multicenter registry of patients at high risk for cardiovascular events. Methods A multicenter registry of EAD and MRF patients was conducted. Demographic data,medical history,cardiovascular risk factors,anthropometric data,laboratory data,and medications were recorded and analyzed. We classified patients according to target LDL levels based on recommendation by the European Society of Cardiology (ESC) 2011 into Group 1 which is EAD and diabetes or chronic kidney disease (CKD)–target LDL below 70 mg/dL,and Group 2 which is MRF without diabetes or CKD–target LDL below 100 mg/dL. The rate of optimal LDL level in patients with Group 1 and Group 2 was analyzed and stratified according to the treatment pattern of lipid-lowering medications. Results A total of 3100 patients were included. Of those,51.7% were male. Average age was 65.8 ± 9.7 years. Average LDL level was 96.3 ± 32.6 mg/dL. A vast majority (92.7%) received statin and 9.3% received ezetimibe. Optimal LDL level was achieved in 20.3% of patients in Group 1 (LDL < 70 mg/dL),and in 46.6% in Group 2 (LDL < 100 mg/dL). The overall rate of optimal LDL control was 23% since 89.6% of study population belongs to Group 1. The rate of optimal LDL was not different between high and low potency statin. Factors that were associated with optimal LDL control were older age,the presence of coronary artery disease or peripheral artery disease. Conclusions The rates of optimal LDL level were unacceptably low in this study population. As such,a strategy to improve LDL control in high-risk population should be implemented.
基金supported by a grant from the Institute for Maternal and Child Health–Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"–Trieste,Italy(RC 24/2017to AT)
文摘The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. For this reason, defects in the biosynthesis of cholesterol can variably affect the development of central nervous system. Moreover, defective synthesis of cholesterol and its intermediates may reflect both on structural cell anomalies and on the response to inflammatory stimuli. Examples of such disorders include mevalonate kinase deficiency, and Smith-Lemli-Opitz syndrome, due to deficiency in biosynthetic enzymes, and type C Niemann-Pick syndrome, due to altered cholesterol trafficking across cell compartments. Autophagy, as a crucial pathway dedicated to the degradation of cytosolic proteins and organelles, plays an essential role in the maintenance of homeostasis and in the turnover of the cytoplasmic material especially in the presence of imbalances such as those resulting from alteration of cholesterol metabolism. Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders.
文摘In the present study, 20 selected Lactobacillus strains already characterized in a previous research for their capability to grow in conditions simulating the intestinal environment, their resistance to antibiotics, their antibacterial activity and their adhesion capability to intestinal human Caco-2 TC7 and HT-29 MTX cell lines, were further investigated to explore more their probiotic properties. Growth behaviour in the presence of prebiotic (fructooligosac-charides (FOS) and lactulose) at a concentration of 2%, cholesterol removal by measuring the residual cholesterol in medium supplemented with cholesterol, ability to deconjugate bile salts using BSH enzyme and antioxidant activity of culture supernatant of Lactobacillus strains by ABTS·+ and DPPH methods were analyzed. All probiotic strains demonstrated important prebiotic assimilation (P > 0.05) even with OD600 > 3 after 30 h of contact, cholesterol removal ability with maximum percentage of 57% after 24 h of contact and they were found to liberate significantly (P < 0.05) more cholic acid with maximum of 0.40 mM of sodium glycocholate, 0.33 mM of sodium taurocholate and 0.41 mM of their mixte and scavenge both radicals with 52% and 2.19% of ABTS·+ and DPPH respectively. This study confirmed the suitability of these probiotic strains for application in functional food formulations especially where cholesterol reduction and antioxidant activity in food are needed to assess possible in vivo human health benefits.
文摘Cholesterol is an essential component of the mammalian plasma membrane because it promotes membrane stability without comprising membrane fluidity. Given this important cellular role, cholesterol levels are tightly controlled at multiple levels. It has been clearly shown that cholesterol redistribution and depletion from the sperm membrane is a key part of the spermatozoon＇s preparation for fertilization. Some factors that regulate these events are described （e.g., bicarbonate, calcium） but the mechanisms underlying cholesterol export are poorly understood. How does a hydrophobic cholesterol molecule inserted in the sperm plasma membrane enter the energetically unfavorable aqueous surroundings？ This review will provide an overview of knowledge in this area and highlight our gaps in understanding. The overall aim is to better understand cholesterol redistribution in the sperm plasma membrane, its relation to the possible activation of a cholesterol transporter and the role of cholesterol acceptors. Armed with such knowledlze, sl）erm handlin~ techniques can be adapted to better prepare spermatozoa for in vitro and in vivo fertilization.
