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Backgroundː Numerous in vivo human cohort studies have suggested that the apolipoprotein B100/apolipoprotein AI (ApoB100/ApoAI) ratio might be a risk factor in coronary heart disease. The aim of this study was to measure ApoB100/ApoAI ratio changes in cell secretions by incubating HepG2 cells with various amounts of glucose in vitro. Methods ː HepG2 cells were cultured in low-, normal- or high-glucose Dulbecco's Modified Eagle Medium (DMEM) (1, 4.5 and 10g/L, respectively). Levels of ApoAI and ApoB100 were measured with commercial sandwich enzyme-linked immunosorbent assay kits (cat#: H0123 and H0124) from ShangHai MEIXUAN Biological Science and Technology Ltd (Shanghai, China). Experiments were repeated six times for each assay. Resultsː The results showed that ApoB100/ApoAI ratio have positive correlations with the glucose concentration increase. Conclusionsː A higher concentration of glucose induced an undesirable ApoB100/ApoAI ratio change, which suggests a new regulatory pathway in lipoprotein catabolism and provides a cell model for further mechanism study. This finding may lead to novel therapeutic ways for diagnosis and treatment for coronary artery disease.

In this study, we report the development of a recombinant human G-CSF fused with apolipoprotein A-I. The chimeric protein was expressed in Pichia pastoris. Using human bone marrow cells, the fusion protein was shown to retain the granulocyte activity of authentic G-CSF, more effectively inducing the differentiation and maturation of segmented neutrophils and maintaining the viability of progenitor cells. Using human mononuclear cells and THP cells, the resulting protein demonstrated monocytic activity, manifested by an increase in both total and CD14+ cell counts. By maintaining cell viability, the chimeric protein reduced the number of cells expressing caspase 3/7. G-CSF-ApoAI demonstrated accelerated cytokine regulation, promoting a more rapid transition of inflammation phases, accompanied by increased phagocytosis of latex particles, compared with G-CSF, increasing phagocytosis by 1.4-fold in the LPS-induced inflammation model. This suggests that this new pleotropic factor may be useful for pathogen clearance in infected wounds.

Background/Aim To investigate the prognostic value of circulating apolipoprotein AI (apoAI) levels and develop a new prognostic model in individuals with acute-on-chronic liver failure (ACLF) and acute decompensation (AD) of liver cirrhosis caused by hepatitis B virus (HBV) infection. Methods Baseline levels of serum lipids were measured, and data concerning the presence of complications were collected from 561 HBV-ACLF and AD patients. Survival analysis was conducted by log-rank test. Proportional hazards model was used to perform multivariate analysis. The dynamics of serum apoAI levels were also explored in 37 HBV-ACLF patients. Results In the cohort, the negatively correlation was found between the Model for End-Stage Liver Disease (MELD) score and serum apoAI levels ( r = -0.7946, P  < 0.001). Circulating apoAI concentration was an independent risk factor for 90-day survival according to Cox multivariate analysis. A new prognostic score-integrated serum lipid profile for ACLF patients (Lip-ACLF score = 0.86×International Normalized Ratio (INR) + 0.0034×total bilirubin (TBIL) (µmol/L) + 0.99× hepatorenal syndrome (HRS) (HRS: no/1; with/2) + 0.50×hepatic encephalopathy (HE) (grade/ponint: no/1; 1–2/2; 3–4/3) − 2.97×apoAI (g/L) + 5.2) was subsequently designed for the derivation cohort. Compared to MELD score, Child-Turcotte-Pugh (CTP) score or apoAI, Lip-ACLFs was superior for the prediction of 90-day outcomes (receiver operating characteristic curve (ROC): 0.930 vs. 0.885, 0.833 or 0.856, all P  < 0.01), as was the validation cohort (ROC 0.906 vs. 0.839, 0.857 or 0.837, all P  < 0.05). In Kaplan‒Meier survival analysis, low apoAI levels (< 0.42 g/L) at baseline indicated poor prognosis in ACLF and AD patients. Among the 37 patients, the deceased individuals were characterised with significantly decreased serum apoAI levels during the follow-up test compared with those at baseline ( P  < 0.05), whereas in patients with a good prognosis, the serum apoAI levels remained stable during the follow-up. Conclusion In HBV-ACLF and AD patients, lower serum apoAI levels suggest greater disease severity and 90-day mortality risk. For predicting the short-term prognosis of these patients, the new Lip-ACLF score might serve as a potential model.

BackgroundCardiovascular diseases (CVDs) are highly prevalent in obstructive sleep apnea (OSA), and dyslipidemia is an important factor. Atherogenic index of plasma (AIP, log[TG/HDL-C]) and apolipoproteinB to apolipoproteinAI ratio (apoB/apoAI ratio) are considered high quality predictors of cardiovascular risk. However, the associations between OSA severity and AIP and apoB/apoAI ratio remained unclear.MethodsA retrospective study was performed in 284 patients. Subjects were assessed with polysomnography (PSG) test, and OSA severity was defined by AHI. Data collected included anthropometric measurements, medical history, sleep parameters, fasting plasma lipids, fasting blood glucose, and insulin.ResultsParticipants were classified based on AHI into the following groups: control group (n = 28), mild group (n = 52), moderate group (n = 53), and severe group (n = 151). Triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apoAI, AIP, apoB/apoAI ratio (low-density lipoprotein cholesterol), LDL-C/HDL-C ratio, and HDL-C/apoAI ratio showed statistical significance among AHI subgroups (P < 0.05). The Pearson correlation analysis revealed that AIP (r = 0.32, P < 0.001) and apoB/apoAI ratio (r = 0.24, P < 0.001) were positively related to AHI. By multivariate linear regression analysis, we found that AHI was independently related to AIP (β = 0.24, P = 0.001), apoB/apoAI ratio (β = 0.24, P<0.001).ConclusionAHI was independently correlated with AIP and apoB/apoAI ratio in OSA. Our findings suggested that AIP and apoB/apoAI ratio increased with OSA severity, which might be partly responsible for the high risk of CVDs in OSA.

Trypanosoma brucei causes African trypanosomiasis in humans. Infection with T. brucei elicits a potent pro-inflammatory immune response within infected human hosts, and this response is thought to at least be partially due to Toll-like receptor (TLR) activation. In response to stimulation by lipopolysaccharide and other pathogen antigens, TLR4 translocates to lipid rafts, which induces the expression of pro-inflammatory genes. However, cholesterol efflux is acknowledged as anti-inflammatory due to promoting lipid raft disruption. In this study, we wanted to assess the impact of T. brucei “ghosts”, which are non-viable T. brucei essentially devoid of intracellular contents, in stimulating macrophage TLR4 translocation to lipid rafts, and whether promoting cholesterol efflux in macrophages incubated with T. brucei ghosts attenuates TLR4-target gene expression. When cultured macrophages were exposed to T. brucei ghosts, we observed an increase in lipid raft TLR4 protein content, which suggests certain surface molecules of T. brucei serve as ligands for TLR4. However, pretreating macrophages with cholesterol acceptors before T. brucei ghost exposure decreased lipid raft TLR4 protein content and the expression of pro-inflammatory TLR4-target genes. Taken together, these results imply that macrophage cholesterol efflux weakens pro-inflammatory responses which occur from T. brucei infection via increasing macrophage lipid raft disruption.

Background Lipoprotein ratios have been shown to be associated with the occurrence of coronary heart disease (CHD), but little is known about their relationships with the severity of CHD. Methods A total of 792 angiographically defined CHD patients were enrolled following their admission. Patients were stratified into three groups based on the tertile of the Gensini scores (≤33 rd percentile, 33 rd to 66 th percentile and ≥66 th percentile) or the number of stenotic coronary branches (single-branch stenosis, double-branch stenosis and multi-branch stenosis). Demographic and biochemical data were collected and lipoprotein ratios were calculated. Logistic regression and path analysis were employed to examine the relationships between the lipoprotein ratios and the severity of CHD. Results The ratios of low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B100 (apoB100)/apolipoprotein AI (apoAI) increased with the tertile of the Gensini scores ( P  < 0.05 for both). The ratios of triglyceride (TG)/HDL-C, total cholesterol (TC)/HDL-C, LDL-C/HDL-C and apoB100/apoAI increased with the number of stenotic coronary branches ( P  < 0.05 for all). The univariate logistic regression showed that the ratios of TC/HDL-C, LDL-C/HDL-C and apoB100/apoAI were positively associated with both the tertile of the Gensini scores and the number of stenotic vessels ( P  < 0.05 for all), and the ratio of TG/HDL-C was positively associated with the number of stenotic vessels ( P  < 0.05). In multivariate logistic analysis, only the ratio of apoB100/apoAI was independently and positively associated with the tertile of the Gensini scores (OR = 2.93, 95 % CI = 1.17-7.34, P  = 0.022) and the number of stenotic vessels (OR = 3.14, 95 % CI = 1.01-6.47, P  = 0.048) after adjusting for the possible confounding variables. The apoB100/apoAI ratio was also shown to be a direct mediator between the risk factors including age, BMI, HDL-C, LDL-C, apoB100 and apoAI and the severity of CHD by path analysis. Conclusion Our data indicate that the apoB100/apoAI ratio could be a useful predictor for evaluating the severity of coronary stenosis in CHD patients.

Background Hereditary amyloidosis refers to a wide spectrum of rare diseases with different causative mutations in the genes of various proteins including transthyretin, apolipoprotein AI and AII, gelsolin, lysozyme, cystatin C, fibrinogen Aα-chain, β2-microglobulin, apolipoprotein CII and CIII. Case presentation Among hereditary amyloidosis subtypes, we describe here a specific case of Apolipoprotein AI amyloidosis (AApoAI), where the diagnosis began from an almost asymptomatic hepatomegaly followed by the development of primary hypogonadism. Baseline laboratory tests showed increased liver enzymes, while imaging tests revealed a suspected infiltrative liver disease. Patient underwent into liver biopsy and histological examination detected the presence of periodic acid-Schiff (−) and Congo-red (+) amorphous eosinophilic material within normal liver tissue. In the typing of amyloid by immunoelectron microscopy, the liver appeared heavily infiltrated by anti-apoAI (+) amyloid fibrils. Gene sequencing and mutational analysis revealed a single-base mutation at position c.251 T > C resulting in an amino acid substitution from leucine to proline in the mature ApoAI protein. This amino acid change led to lower cleavage and ApoAI deposition into the involved organs. Few years later, our patient remaining without treatment, came with symptoms consistent with primary hypogonadism but testicular involvement with ApoAI deposits could not be proven since the patient refused testicular biopsy. Based on this case, we recap the diagnostic challenges, the clinical manifestations, and the potential treatment options for this indolent hereditary amyloidosis subtype. Conclusions This case-report enlarges the clinical picture of ApoAI-driven disease and its complex genetic background and in parallel suggests for a more systematic approach in any case with strong suspicion of hereditary amyloidosis.

Differential Regulation of Lipoprotein Kinetics by Atorvastatin and Fenofibrate in Subjects With the Metabolic Syndrome Gerald F. Watts 1 , P. Hugh R. Barrett 1 , Juying Ji 1 , Adrian P. Serone 2 , Dick C. Chan 1 , Kevin D. Croft 1 , Franziska Loehrer 2 and Anthony G. Johnson 2 1 Lipoprotein Research Unit, Department of Medicine, University of Western Australia, the West Australian Institute for Medical Research, Perth, Western Australia 2 James Lance GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital, Sydney, Australia Abstract The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d 3 -leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased ( P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased ( P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL 2 cholesterol ( P < 0.001), HDL 3 cholesterol ( P < 0.01), apoAI ( P = 0.01), and apoAII ( P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased ( P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased ( P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production ( P < 0.001) and FCR ( P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered ( P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome. Footnotes Address correspondence and reprint requests to Associate Professor G.F. Watts, University Department of Medicine, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6847, Australia. E-mail: gfwatts{at}cyllene.uwa.edu.au Received for publication 28 August 2002 and accepted in revised form 2 December 2002. P.H.R.B. is a Career Development Fellow of the National Heart Foundation, and A.P.S., F.L., and A.G.J. are employees of GlaxoSmithKline. apoAI, apolipoprotein AI; apoB, apolipoprotein B-100; CETP, cholesteryl ester transfer protein; FCR, fractional catabolic rate; GCMS, gas chromatography; HOMA, homeostasis model assessment; HMG, hydroxymethylglutaryl; IDL, intermediate-density lipoprotein; LCAT, lecithin cholesterol acyltransferase; PPAR, peroxisome proliferator–activated receptor; PR, production rate. DIABETES

Obesity is a strong cardiometabolic (CM) risk factor in children. We tested potential CM risk in obese/overweight children and the effect of an intensive lifestyle intervention using newer CM markers: atherogenic index of plasma AIP [Log(TG/HDL-C)], apoB/apoAI ratio and a marker of insulin resistance HOMA-IR. The participants (194 girls, 115 boys, average age 13) were enrolled in an intensive, one-month, inpatient weight reduction program. The program consisted of individualised dietary changes and the exercise program comprised aerobic and resistance training. Anthropometrical and biochemical parameters in plasma and CM risk biomarkers – (AIP, apoB/apoAI ratio and HOMA-IR) were examined before and after the intervention. AIP and HOMA-IR significantly correlated with BMI while apoB/apoAI ratio did not. Only AIP and HOMA-IR showed systematic increases according to the level of obesity by BMI quartiles. Lifestyle intervention significantly improved anthropometrical and biochemical values and the biomarkers too. The response of lipid parameters to the intervention was considerably higher in boys than in girls. The children were stratified into three risk categories according to AIP, where 13.8 % of boys and 5.3 % of girls fell into high risk category. The monitored biomarkers may complement each other in the prognosis of CM risk. AIP was strongly related to obesity and to lipid and glycid metabolism, while the relationship of the apoB/apoAI ratio to obesity and glycid metabolism was not significant. The obese children benefited from the intensive lifestyle intervention which improved the anthropometrical and biochemical parameters and CM risk biomarkers.

Aims Fat accumulation in the liver and in the muscle results in hepatic and muscle insulin resistance and has been associated with increased cardiovascular risk. It is unclear whether the individual role of hepatic and muscle insulin resistance in the onset of dyslipidaemia is observed in nonalcoholic fatty liver disease (NAFLD) patients and whether this association is mediated through traditional risk factors. The aim of this study was to assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis. Methods We studied 132 patients with a non-invasive diagnosis of NAFLD stratified into two groups according to the severity of steatosis at ultrasound scan. In all subjects, we measured hepatic insulin resistance (H-IR) and muscle insulin sensitivity index (MISI) by oral glucose tolerance test as proposed by DeFronzo, IMT, apoB/apoAI and the components of the metabolic syndrome (MS) as defined by ATP III. Results H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group ( p  < 0.0001). By contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT ( r  = 0.35; p  < 0.0001) and the apoB/apoAI ratio ( r  = 0.43; p  < 0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independent of MS components. Conclusions In our study population, NAFLD was positively associated with carotid IMT, and this association is independent of MS components, but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio. By contrast, no significant relation was observed between MISI and carotid IMT.