ResearchPad - cholesterol https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Association between attending exercise-based cardiac rehabilitation and cardiovascular risk factors at one-year post myocardial infarction]]> https://www.researchpad.co/article/elastic_article_7688 Randomized trials confirm the benefits of exercise-based cardiac rehabilitation on cardiovascular risk factors. Whether exercise-based cardiac rehabilitation provides the same favourable effects in real-life cardiac rehabilitation settings, in the modern era of myocardial infarction treatment, is less well known. We examined the association between attending exercise-based cardiac rehabilitation and improvements in cardiovascular risk factors at one-year post myocardial infarction in patients included in the Swedish heart disease registry, SWEDEHEART.MethodsIn this retrospective registry-based cohort study, we included 19 136 patients post myocardial infarction (75% men, 62.8±8.7 years) who were registered in SWEDEHEART between 2011 and 2013. The association between attending exercise-based cardiac rehabilitation (43% participation rate) and changes in cardiovascular risk profile between baseline and one-year follow-up was assessed using multivariable regression analysis adjusting for age, comorbidities and medication.ResultsAttenders more often reported to have stopped smoking (men 64% vs 50%; women 64% vs 53%, p<0.001 for both, only smokers at baseline considered), be more physically active (men 3.9±2.5 vs 3.4±2.7 days/week; women 3.8±2.6 vs 3.0±2.8 days/week, p<0.001 for both) and achieved a slightly larger reduction in triglycerides (men -0.2±0.8 vs -0.1±0.9 mmol/L, p = 0.001; women -0.1±0.6 vs 0.0±0.8 mmol/L, p = 0.01) at one-year compared to non-attenders. Male attenders gained less weight (+0.0±5.7 vs +0.3±5.7 kg, p = 0.01) while female attenders achieved better lipid control (total cholesterol -1.2±1.4 vs -0.9±1.4 mmol/L, p<0.001; low-density lipoprotein -1.2±1.2 vs -0.9 ±1.2 mmol/L, p<0.001) compared to non-attenders.ConclusionsIn an unselected registry cohort of patients post myocardial infarction, compared to non-attenders those attending exercise-based cardiac rehabilitation achieved significantly larger improvements in cardiovascular risk factors at one-year after the acute event. ]]> <![CDATA[Opposing effects of HNP1 (α-defensin-1) on plasma cholesterol and atherogenesis]]> https://www.researchpad.co/article/Ndf7081dd-c312-4392-aa9c-ddf6cf67dfa0

Atherosclerosis, the predominant cause of death in well-resourced countries, may develop in the presence of plasma lipid levels within the normal range. Inflammation may contribute to lesion development in these individuals, but the underlying mechanisms are not well understood. Transgenic mice expressing α-def-1 released from activated neutrophils develop larger lipid and macrophage-rich lesions in the proximal aortae notwithstanding hypocholesterolemia caused by accelerated clearance of α-def-1/low-density lipoprotein (LDL) complexes from the plasma. The phenotype does not develop when the release of α-def-1 is prevented with colchicine. However, ApoE-/- mice crossed with α-def-1 mice or given exogenous α-def-1 develop smaller aortic lesions associated with reduced plasma cholesterol, suggesting a protective effect of accelerated LDL clearance. Experiments were performed to address this seeming paradox and to determine if α-def-1 might provide a means to lower cholesterol and thereby attenuate atherogenesis. We confirmed that exposing ApoE-/- mice to α-def-1 lowers total plasma cholesterol and decreases lesion size. However, lesion size was larger than in mice with total plasma cholesterol lowered to the same extent by inhibiting its adsorption or by ingesting a low-fat diet. Furthermore, α-def-1 levels correlated independently with lesion size in ApoE-/- mice. These studies show that α-def-1 has competing effects on atherogenesis. Although α-def-1 accelerates LDL clearance from plasma, it also stimulates deposition and retention of LDL in the vasculature, which may contribute to development of atherosclerosis in individuals with normal or even low plasma levels of cholesterol. Inhibiting α-def-1 may attenuate the impact of chronic inflammation on atherosclerotic vascular disease.

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<![CDATA[Reporting quality and spin in abstracts of randomized clinical trials of periodontal therapy and cardiovascular disease outcomes]]> https://www.researchpad.co/article/N5a52c97b-59d0-4564-8bd9-d8b1530b3570

Objective

Poor reporting in randomized clinical trial (RCT) abstracts reduces quality and misinforms readers. Spin, a biased presentation of findings, could frequently mislead clinicians to accept a clinical intervention despite non-significant primary outcome. Therefore, good reporting practices and absence of spin enhances research quality. We aim to assess the reporting quality and spin in abstracts of RCTs evaluating the effect of periodontal therapy on cardiovascular (CVD) outcomes.

Methods

PubMed, Scopus, the Cochrane Central Register of Controlled Trials (CENTRAL), and 17 trial registration platforms were searched. Cohort, non-randomized, non-English studies, and pediatric studies were excluded. RCT abstracts were reviewed by 2 authors using the CONSORT for abstracts and spin checklists for data extraction. Cohen’s Kappa statistic was used to assess inter-rater agreement. Data on the selected RCT publication metrics were collected. Descriptive analysis was performed with non-parametric methods. Correlation analysis between quality, spin and bibliometric parameters was conducted.

Results

24 RCTs were selected for CONSORT analysis and 14 fulfilled the criteria for spin analysis. Several important RCT elements per CONSORT were neglected in the abstract including description of the study population (100%), explicitly stated primary outcome (87%), methods of randomization and blinding (100%), trial registration (87%). No RCT examined true outcomes (CVD events). A significant fraction of the abstracts appeared with at least one form of spin in the results and conclusions (86%) and claimed some treatment benefit in spite of non-significant primary outcome (64%). High-quality reporting had a significant positive correlation with reporting of trial registration (p = 0.04) and funding (p = 0.009). Spinning showed marginal negative correlation with reporting quality (p = 0.059).

Conclusion

Poor adherence to the CONSORT guidelines and high levels of data spin were found in abstracts of RCTs exploring the effects of periodontal therapy on CVD outcomes. Our findings indicate that journal editors and reviewers should consider strict adherence to proper reporting guidelines to improve reporting quality and reduce waste.

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<![CDATA[Agreement between cardiovascular disease risk assessment tools: An application to the United Arab Emirates population]]> https://www.researchpad.co/article/N9ca1ffb4-d1e9-4710-8aa8-6eec943148b3

Introduction

Evidence regarding the performance of cardiovascular disease (CVD) risk assessment tools is limited in the United Arab Emirates (UAE). Therefore, we assessed the agreement between various externally validated CVD risk assessment tools in the UAE.

Methods

A secondary analysis of the Abu Dhabi Screening Program for Cardiovascular Risk Markers (AD-SALAMA) data, a large population-based cross-sectional survey conducted in Abu Dhabi, UAE during the period 2009 until 2015, was performed in July 2019. The analysis included 2,621 participants without type 2 Diabetes and without history of cardiovascular diseases. The CVD risk assessment tools included in the analysis were the World Health Organization for Middle East and North Africa Region (WHO-MENA), the systematic coronary risk evaluation for high risk countries (SCORE-H), the pooled cohort risk equations for white (PCRE-W) and African Americans (PCRE-AA), the national cholesterol education program Framingham risk score (FRAM-ATP), and the laboratory Framingham risk score (FRAM-LAB).

Results

The overall concordance coefficient was 0.50. The agreement between SCORE-H and PCRE-W, PCRE-AA, FRAM-LAB, FRAM-ATP and WHO-MENA, were 0.47, 0.39, 0.0.25, 0.42 and 0.18, respectively. PCRE-AA classified the highest proportion of participants into high-risk category of CVD (16.4%), followed by PCRE-W (13.6%), FRAM-LAB (6.9%), SCORE-H (4.5%), FRAM-ATP (2.7%), and WHO-MENA (0.4%).

Conclusions

We found a poor agreement between various externally validated CVD risk assessment tools when applied to a large data collected in the UAE. This poses a challenge to choose any of these tools for clinical decision-making regarding the primary prevention of CVD in the country.

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<![CDATA[The association of serum 25-hydroxyvitamin D concentrations with elevated serum ferritin levels in normal weight, overweight and obese Canadians]]> https://www.researchpad.co/article/5c8acc82d5eed0c48498f8c4

In light of the growing body of literature suggesting a beneficial effect of vitamin D on inflammatory response, we hypothesized that vitamin D affects serum ferritin (SF), a biomarker of inflammation. The objective of the present study is to examine the association of serum 25-hydroxyvitamin D [25(OH)D] with elevated SF concentrations indicative of inflammation as no earlier study has done so. Data from 5550 Canadian adults who participated in the 2012/2013 and the 2014/2015 Canadian Health Measures Surveys were analysed. We observed that 9.4% of Canadian adults have elevated SF concentrations and that 35.6% were vitamin D insufficient. Among Canadians with under/normal body weights, those with serum 25(OH)D ≥ 75 nmol/L relative to those with serum 25(OH)D < 50 nmol/L, were substantially less at risk for elevated SF concentrations (OR = 0.24; 95% CI = 0.06, 0.89; p = 0.034). We did not observe this association for overweight and obese Canadians. Canadians of older age, non-white ethnicity, males, those with income above $100,000, those who consumed alcohol, and those with high total cholesterol concentrations and elevated blood pressures were more likely to have elevated SF concentrations. Serum 25(OH)D ≥ 75 nmol/L is likely to provoke anti-inflammatory benefits, but intervention studies that achieve high 25(OH)D concentrations and with long follow up are needed to establish the role of vitamin D on SF.

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<![CDATA[The serum level of a novel lipogenic protein Spot 14 was reduced in metabolic syndrome]]> https://www.researchpad.co/article/5c6f14f9d5eed0c48467abe8

Spot 14 (S14) protein is primarily expressed in adipogenic tissues. Compared to wild type, S14 knockout mice had better resistance to diet-induced obesity and glucose tolerance. However, the association between serum S14 level and metabolic variables in humans has never been investigated. The objectives of this study were to evaluate the associations between serum S14 concentrations with components of metabolic syndrome (MetS). A total of 327 subjects were recruited in this cross-sectional study and categorized by presence of MetS. The mean serum levels of S14 were significantly lower in subjects with MetS than those without (87.1±26.3 μg/L vs. 107.3±40.2 μg/L, p<0.001). In addition, the subjects with central obesity, low high density lipoprotein-C (HDL-C) or hypertriglyceridemia also had significantly lower S14 levels in comparison to those without. Adjusted with age and sex, diagnosis of MetS (β = -0.227, p<0.001), central obesity (β = -0.176, p = 0.001), low HDL-C (β = -0.149, p = 0.005), and high triglyceride (TG) (β = -0.198, p<0.001) were negatively associated with log transformation of serum S14 levels (logS14). With 25% logS14 increased, the risk of MetS (OR 0.65, 95% CI, 0.51–0.82, p<0.001), central obesity (OR 0.72, 95% CI, 0.58–0.89, p = 0.002), low HDL-C (OR 0.76, 95% CI, 0.61–0.95, p = 0.015) or high TG (OR 0.65, 95% CI, 0.51–0.83, p = 0.001) was reduced with a dose response trend. Our analysis revealed that patients with MetS had lower serum S14 levels than those without. Negative associations existed between MetS, central obesity, high TG, low HDL-C and logS14.

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<![CDATA[Baseline high-sensitivity C-reactive protein predicts the risk of incident ankylosing spondylitis: Results of a community-based prospective study]]> https://www.researchpad.co/article/5c706756d5eed0c4847c6e7f

Background

A hospitalized-based cohort study suggested that elevated C-reactive protein (CRP) levels are associated with radiographic sacroiliitis progression in ankylosing spondylitis (AS) patients. However, data from community-based populations are limited.

Objective

We sought to determine the association between elevated CRP levels and AS diagnosis in a prospective community-based study of 129,681 Chinese adults over a follow-up period of 8 years.

Methods

We measured the plasma CRP concentration at baseline and every 2 years thereafter with the high-sensitivity (hs)-CRP test. Incident AS cases were confirmed on the basis of modified New York diagnostic criteria after review of medical records. We used Cox proportional-hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for AS on the basis of hs-CRP concentrations, adjusting for age, sex, education, income, cigarette smoking, alcohol intake, physical activity, body mass index, blood-pressure status, blood glucose status, total cholesterol, history of cardiovascular disease, and use of antihypertensives, lipid-lowering agents, and aspirin.

Results

During 1,033,609 person-years (average 7.97 ± 1.36 years per person) of follow-up, we identified 55 incident AS cases. Baseline hs-CRP was positively associated with the risk of future AS. Compared with hs-CRP <1 mg/L, the HR was 1.28 (95% CI 0.54–3.08) for hs-CRP of 1.00–2.99 mg/L, 4.71 (95% CI 2.26–9.81) for hs-CRP of 3.00–9.99 mg/L, and 19.8 (95% CI 9.6–40.9) for hs-CRP ≥10.00 mg/L (P-trend <0.001) after adjustment for potential confounders. We found similar results after excluding AS cases that occurred in the first 2 years of follow-up, and using the cumulative average hs-CRP concentration as a predictor.

Conclusion

This is the first study in a community-based cohort to demonstrate that CRP plasma concentrations predict the risk of future AS, thus providing a test that is easy to routinely perform in the clinic to assess for AS risk.

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<![CDATA[Apolipoprotein B correlates with intra-plaque necrotic core volume in stable coronary artery disease]]> https://www.researchpad.co/article/5c75ac91d5eed0c484d08a4e

Objective

To determine the relationship between plaque composition and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo-B), and Apo-A1 using virtual-histology intravascular ultrasound (VH-IVUS).

Methods

We assessed plaque composition in patients with stable coronary artery disease (SCD) admitted to our hospital for percutaneous coronary intervention (PCI) between November 1, 2012, and March 10, 2015. Before PCI, fibrous (FI), fibrofatty (FF), necrotic core (NC), and dense calcium (DC) regions were evaluated using VH-IVUS, and the contributions of each to the culprit lesion volume were recorded. Plasma LDL-C, HDL-C, Apo-B, and Apo-A1 levels were assessed before PCI. The relationship between the regions on VH-IVUS and plasma lipid levels was assessed. Patients were categorized into low Apo-B (LAB) and high Apo-B (HAB) groups, based on the overall cohort median Apo-B level.

Results

We enrolled 115 patients (median Apo-B, 91 mg/dL, male n = 88) with 57 and 58 patients in the LAB (Apo-B ≤ 90 mg/dL) and HAB (Apo-B ≥ 91 mg/dL) groups, respectively. Vessel, plaque, and %NC volumes were significantly greater in the HAB group than in the LAB group. The %FI, %FF, and %DC volumes were similar in both groups. In all 115 patients, the %NC volume correlated with LDL-C (r = 0.2353, P = 0.0114) and Apo-B (r = 0.2487, P = 0.0074) but not with HDL-C and Apo A-1. The high-sensitivity C-reactive protein level tended to be higher in the HAB group than in the LAB group. Multiple regression analysis showed that being male, Apo-A1, and Apo-B were significant predictors of %NC volume extent.

Conclusions

Elevated Apo-B level was related to the %NC in target coronary artery lesions in SCD patients, suggesting a role of Apo-B as a biomarker of unstable plaque in this population.

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<![CDATA[Association between social jetlag food consumption and meal times in patients with obesity-related chronic diseases]]> https://www.researchpad.co/article/5c6c75d4d5eed0c4843d0285

Chronic disruption of the synchronous relationship between endogenous and exogenous circadian timing is associated with the development of obesity and metabolic disease. Social jetlag is a measure of circadian misalignment and has been identified as a risk factor for overweight and related diseases. However, the mechanisms involved in this relationship remain underexplored. The objective of this study was to investigate the association between social jetlag and food consumption at late meal timing in patients with obesity-related chronic diseases. This study included 792 individuals (73% female; age 55.9 ± 12.4 years) in which the prevalence of social jetlag (>1h) was 24.4% (n = 194). Participants with social jetlag reported late meal timing for breakfast, early afternoon snack and dinner. Individuals with social jetlag also reported a higher intake of total calories (kcal), protein, total fat, saturated fat, cholesterol, and servings of meat and eggs and sweets in relation to those without social jetlag. Regarding the consumption during each meal of the day, participants with social jetlag had consumed more calories, saturated fat and cholesterol during dinner; more protein, total fat, saturated fat, and cholesterol during lunch; and more total fat and saturated fat during morning snack. In addition, individuals with social jetlag had a higher risk of inadequate consumption of total fat, saturated fat and cholesterol intake when compared with those without social jetlag. We conclude that social jetlag is associated with a poor diet and later meal times, which should be avoided in individuals with obesity-related chronic diseases. More studies are needed to confirm these findings.

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<![CDATA[Expression optimization, purification, and functional characterization of cholesterol oxidase from Chromobacterium sp. DS1]]> https://www.researchpad.co/article/5c6dc9e1d5eed0c48452a3da

Cholesterol oxidase is a bifunctional bacterial flavoenzyme which catalyzes oxidation and isomerization of cholesterol. This valuable enzyme has attracted a great deal of attention because of its wide application in the clinical laboratory, synthesis of steroid derived drugs, food industries, and its potentially insecticidal activity. Therefore, development of an efficient protocol for overproduction of cholesterol oxidase could be valuable and beneficial in this regard. The present study examined the role of various parameters (host strain, culture media, induction time, isopropyl ß-D-1-thiogalactopyranoside concentration, as well as post-induction incubation time and temperature) on over-expression of cholesterol oxidase from Chromobacterium sp. DS1. Applying the optimized protocol, the yield of recombinant cholesterol oxidase significantly increased from 92 U/L to 2115 U/L. Under the optimized conditions, the enzyme was produced on a large-scale, and overexpressed cholesterol oxidase was purified from cell lysate by column nickel affinity chromatography. Km and Vmax values of the purified enzyme for cholesterol were estimated using Lineweaver-Burk plot. Further, the optimum pH and optimum temperature for the enzyme activity were determined. This study reports a straightforward protocol for cholesterol oxidase production which can be performed in any laboratory.

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<![CDATA[Epidermal growth factor receptor inhibition attenuates non-alcoholic fatty liver disease in diet-induced obese mice]]> https://www.researchpad.co/article/5c673077d5eed0c484f37b8e

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target.

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<![CDATA[Second-line glucose-lowering drugs added to metformin and the risk of hospitalization for heart failure: A nationwide cohort study]]> https://www.researchpad.co/article/5c6b26a1d5eed0c484289d9a

Aim

To compare the risks of hospitalization for heart failure (HHF) associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP-4i), and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy using the data of Korean adults with type-2 diabetes from the Korean National Health Insurance database.

Methods

We identified 98,383 people who received SU (n = 42,683), DPP-4i (n = 50,310), or TZD (n = 5,390) added to initial treatment of MET monotherapy in patients with type-2 diabetes. The main outcome was the hospitalization for HHF. Hazard ratios for HHF by type of second-line glucose-lowering medication were estimated by Cox-proportional hazard models. Sex, age, duration of MET monotherapy, Charlson Comorbidity Index and additional comorbidities, and calendar year were controlled as potential confounders.

Results

The observed numbers (rate per 100,000 person-years) of HHF events were 1,129 (658) for MET+SU users, 710 (455) for MET+DPP-4i users, and 110 (570) for MET+TZD users. Compared to that for MET+SU users (reference group), the adjusted hazard ratios for HHF events were 0.76 (95% confidence interval 0.69–0.84) for MET+DPP-4i users and 0.96 (95% confidence interval 0.79–1.17) for MET+TZD users.

Conclusion

DPP-4i as an add-on therapy to MET may lower the risks of HHF compared with SU.

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<![CDATA[The association between exposure to different aspects of shift work and metabolic risk factors in health care workers, and the role of chronotype]]> https://www.researchpad.co/article/5c5df32dd5eed0c484580e2a

Objective

Shift work has been linked to cardio-metabolic diseases, but insight into different shift work-related aspects and chronotype of shift workers and their relation with metabolic risk factors is limited. This study examined the association between current shift work status, frequency and duration of night shift work, chronotype, and metabolic risk factors in a population of health care workers.

Methods

Anthropometrics, questionnaires, and blood samples were collected from 503 shift working and 93 non-shift working health care workers employed in hospitals. Body mass index, waist circumference, cholesterol (total, HDL, LDL), triglycerides, and high-sensitivity C-reactive protein were measured. Associations of current shift work, frequency (non-night shift worker, 1–2, 3–4, ≥5 night shifts/month) and duration of night shift work (non-night shift workers, <10, 10–19, ≥20 years), and shift workers’ chronotype, with metabolic risk factors were studied using linear regression analysis.

Results

Compared to non-shift workers, shift workers’ total cholesterol level was 0.38 mmol/L lower (95%-CI = -0.73 –-0.04) and LDL cholesterol was 0.34 mmol/L lower (95%-CI = -0.60 –-0.08). For all other metabolic risk factors, no differences were found. The association between shift work and LDL cholesterol was especially found among shift workers working night shifts for ≥20 years (B = -0.49 (95%-CI = -0.78 –-0.19)). No differences were found for night shift frequency and chronotype.

Conclusion

In this population of health care workers employed in hospitals, no evidence for differences in metabolic risk factors was observed that could underlie a link between shift work and cardio-metabolic diseases. Further research using different aspects of shift work to study the association with metabolic risk factors is recommended.

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<![CDATA[Mortality risk in adults according to categories of impaired glucose metabolism after 18 years of follow-up in the North of Spain: The Asturias Study]]> https://www.researchpad.co/article/5c5ca2e8d5eed0c48441ed1d

People who develop type 2 diabetes (T2D) are known to have a higher mortality risk. We estimated all-cause, cardiovascular, and cancer mortality-risks in our patient cohort according to categories of impaired glucose metabolism. This 18-year retrospective analysis included a region-wide, representative sample of a population aged 30–75 years. Age- and sex-stratified hazard ratios (HRs) were calculated for 48 participants with diagnosed T2D, 83 with undiagnosed T2D (HbA1c ≥6.5%, fasting glycemia ≥126 mg/dL, or glycemia after 75 g glucose load ≥200 mg/dL); 296 with prediabetes (HbA1c 5.7%-6.4%, fasting glycemia 100–125 mg/dL, or glycemia after 75 g glucose load 140–199 mg/dL), and 607 with normoglycemia. Over 18,612 person-years, 32 individuals with undiagnosed T2D, 30 with diagnosed T2D, 62 with prediabetes, and 80 with normoglycemia died. Total sample crude mortality rate (MR) was 10.96 deaths per 1,000 person-years of follow-up. MR of the diagnosed T2D group was more than 3-times higher and that of newly diagnosed T2D was 2-times higher (34.72 and 21.42, respectively) than total sample MR. Adjusted HR for all-cause mortality was 2.02 (95% confidence interval 1.29–3.16) and 1.57 (95% CI 1.00–2.28) in the diagnosed T2D group and the newly diagnosed T2D group, respectively. Adjusted HR for cardiovascular mortality in the T2D group was 2.79 (95% CI 1.35–5.75); this risk was greatly increased in women with T2D: 6.72 (95% CI 2.50–18.07). In Asturias, age- and sex-standardized all-cause mortality is more than 2-times higher for adults with T2D than for adults without T2D. The HR for cardiovascular mortality is considerably higher in T2D women than in normoglycemic women.

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<![CDATA[Elevated cellular cholesterol in Familial Alzheimer’s presenilin 1 mutation is associated with lipid raft localization of β-amyloid precursor protein]]> https://www.researchpad.co/article/5c79afead5eed0c4841e3a1a

Familial Alzheimer’s disease (FAD)-associated presenilin 1 (PS1) serves as a catalytic subunit of γ-secretase complex, which mediates the proteolytic liberation of β-amyloid (Aβ) from β-amyloid precursor protein (APP). In addition to its proteolytic role, PS1 is involved in non-proteolytic functions such as protein trafficking and ion channel regulation. Furthermore, postmortem AD brains as well as AD patients showed dysregulation of cholesterol metabolism. Since cholesterol has been implicated in regulating Aβ production, we investigated whether the FAD PS1-associated cholesterol elevation could influence APP processing. We found that in CHO cells stably expressing FAD-associated PS1 ΔE9, total cholesterol levels are elevated compared to cells expressing wild-type PS1. We also found that localization of APP in cholesterol-enriched lipid rafts is substantially increased in the mutant cells. Reducing the cholesterol levels by either methyl-β-cyclodextrin or an inhibitor of CYP51, an enzyme mediating the elevated cholesterol in PS1 ΔE9-expressing cells, significantly reduced lipid raft-associated APP. In contrast, exogenous cholesterol increased lipid raft-associated APP. These data suggest that in the FAD PS1 ΔE9 cells, the elevated cellular cholesterol level contributes to the altered APP processing by increasing APP localized in lipid rafts.

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<![CDATA[Structural basis of human ORP1-Rab7 interaction for the late-endosome and lysosome targeting]]> https://www.researchpad.co/article/5c63397ed5eed0c484ae68d3

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a family of lipid transfer proteins conserved in eukaryotes. ORP1 transports cholesterol at the interface between the late endosomes/lysosomes (LELs) and the endoplasmic reticulum (ER). ORP1 is targeted to the endosomal membranes by forming a tripartite complex with the LE GTPase Rab7 and its effector RILP (Rab7-interacting lysosomal protein). Here, we determined the crystal structure of human ORP1 ANK domain in complex with the GTP-bound form of Rab7. ORP1 ANK binds to the helix α3 of Rab7 located away from the switching regions, which makes the interaction independent of the nucleotide-binding state of Rab7. Thus, the effector-interacting switch regions of Rab7 are accessible for RILP binding, allowing formation of the ORP1-Rab7-RILP complex. ORP1 ANK binds to Rab7 and the Rab7-RILP complex with similar micro-molar affinities, which is consistent with the independence binding of ORP1 and RILP to Rab7. The structural model of the ORP1-Rab7-RILP complex correlates with the recruitment of ORP1 at the LEL-ER interface and the role in lipid transport and regulation.

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<![CDATA[Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats]]> https://www.researchpad.co/article/5c50c462d5eed0c4845e869d

We determined if HIV-1 expression in transgenic (HIV-1-Tg) rats enhanced hepatic genomic changes related to oxidative/nitrosative stress and lipogenesis during cART-treatment, and assessed effects of Mg-supplementation. A clinically used cART (atazanavir-ritonavir+Truvada) was given orally to control and HIV-1-Tg rats (18 weeks) with normal or 6-fold dietary-Mg. Oxidative/nitrosative and lipogenic genes were determined by real-time RT-PCR. cART induced a 4-fold upregulation of sterol regulatory element-binding protein-1 (SREBP-1) in HIV-1-Tg-rats, but not in controls; Tg rats displayed a 2.5-fold higher expression. Both were completely prevented by Mg-supplementation. Nrf2 (Nuclear erythroid-derived factor 2), a master transcription factor controlling redox homeostasis, was down-regulated 50% in HIV-Tg rats, and reduced further to 25% in Tg+cART-rats. Two downstream antioxidant genes, heme oxygenase-1(HmOX1) and Glutathione-S-transferase(GST), were elevated in HIV-Tg alone but were suppressed by cART treatment. Decreased Nrf2 in Tg±cART were normalized by Mg-supplementation along with the reversal of altered HmOX1 and GST expression. Concomitantly, iNOS (inducible nitric oxide synthase) was upregulated 2-fold in Tg+cART rats, which was reversed by Mg-supplementation. In parallel, cART-treatment led to substantial increases in plasma 8-isoprostane, nitrotyrosine, and RBC-GSSG (oxidized glutathione) levels in HIV-1-Tg rats; all indices of oxidative/nitrosative stress were suppressed by Mg-supplementation. Both plasma triglyceride and cholesterol levels were elevated in Tg+cART rats, but were lowered by Mg-supplementation. Thus, the synergistic effects of cART and HIV-1 expression on lipogenic and oxidative/nitrosative effects were revealed at the genomic and biochemical levels. Down-regulation of Nrf2 in the Tg+cART rats suggested their antioxidant response was severely compromised; these abnormal metabolic and oxidative stress effects were effectively attenuated by Mg-supplementation at the genomic level.

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<![CDATA[Decreased lung function is associated with risk of developing non-alcoholic fatty liver disease: A longitudinal cohort study]]> https://www.researchpad.co/article/5c521812d5eed0c484797204

Background

Decreased lung function is associated with non-alcoholic fatty liver disease (NAFLD), based on linking mechanisms such as insulin resistance and systemic inflammation However, its association with the risk of developing NAFLD is unclear. Our aim was to investigate whether baseline lung function is associated with incident NAFLD in middle-aged healthy Koreans.

Methods

A cohort study of 96,104 subjects (mean age: 35.7 years) without NAFLD were followed up from 2002 to 2015. NAFLD was diagnosed by ultrasound after the exclusion of other possible causes of liver diseases. Baseline percent predicted forced expiratory volume in one second (FEV1%) and forced vital capacity (FVC%) were categorized in quartiles. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) (using the highest quartile as reference) were calculated for incident NAFLD at follow-up, controlling for covariates and potential confounders.

Results

During 579,714.5 person-years of follow-up, 24,450 participants developed NAFLD (incidence rate, 42.2 per 1,000 person-years). The mean follow-up period was 5.9±3.4 years. Regardless of smoking history, the risk for incident NAFLD increased with decreasing quartiles of FEV1 (%) and FVC (%) in a dose-response manner (p for trend<0.001). In never smokers, the aHRs (95% CIs) for incident NAFLD were 1.15 (1.08–1.21), 1.11 (1.05–1.18), and 1.08 (1.02–1.14) in quartiles 1–3 for FEV1 (%) and 1.12 (1.06–1.18), 1.11 (1.05–1.18), and 1.09 (1.03–1.15) in quartiles 1–3 for FVC (%), compared with the highest quartile reference. Similar inverse association was present in smoke-exposed subjects (aHR for incident NAFLD were 1.14, 1.21, 1.13 and 1.17, 1.11, 1.09 across FEV1(%) and FVC(%) quartile in increasing order, respectively).

Conclusions

Reduced lung function was a risk factor for incident NAFLD in a large middle-aged Korean cohort with over half a million person-years of follow-up.

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<![CDATA[Interaction of two antitumor peptides with membrane lipids – Influence of phosphatidylserine and cholesterol on specificity for melanoma cells]]> https://www.researchpad.co/article/5c57e69ad5eed0c484ef394a

R-DIM-P-LF11-322 and DIM-LF11-318, derived from the cationic human host defense peptide lactoferricin show antitumor activity against human melanoma. While R-DIM-P-LF11-322 interacts specifically with cancer cells, the non-specific DIM-LF11-318 exhibits as well activity against non-neoplastic cells. Recently we have shown that cancer cells expose the negatively charged lipid phosphatidylserine (PS) in the outer leaflet of the plasma membrane, while non-cancer cells just expose zwitterionic or neutral lipids, such as phosphatidylcholine (PC) or cholesterol. Calorimetric and zeta potential studies with R-DIM-P-LF11-322 and cancer-mimetic liposomes composed of PS, PC and cholesterol indicate that the cancer-specific peptide interacts specifically with PS. Cholesterol, however, reduces the effectiveness of the peptide. The non-specific DIM-LF11-318 interacts with PC and PS. Cholesterol does not affect its interaction. The dependence of activity of R-DIM-P-LF11-322 on the presence of exposed PS was also confirmed in vitro upon PS depletion of the outer leaflet of cancer cells by the enzyme PS-decarboxylase. Further corresponding to model studies, cholesterol depleted melanoma plasma membranes showed increased sensitivity to R-DIM-P-LF11-322, whereas activity of DIM-LF11-318 was unaffected. Microscopic studies using giant unilamellar vesicles and melanoma cells revealed strong changes in lateral distribution and domain formation of lipids upon addition of both peptides. Whereas R-DIM-P-LF11-322 enters the cancer cell specifically via PS and reaches an intracellular organelle, the Golgi, inducing mitochondrial swelling and apoptosis, DIM-LF11-318 kills rapidly and non-specifically by lysis of the plasma membrane. In conclusion, the specific interaction of R-DIM-P-LF11-322 with PS and sensitivity to cholesterol seem to modulate its specificity for cancer membranes.

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<![CDATA[Low, borderline and normal ankle-brachial index as a predictor of incidents outcomes in the Mediterranean based-population ARTPER cohort after 9 years follow-up]]> https://www.researchpad.co/article/5c5217f0d5eed0c484795af4

Background

Guidelines recommended adopting the same cardiovascular risk modification strategies used for coronary disease in case of low Ankle-brachial index (ABI), but here exist few studies on long-term cardiovascular outcomes in patients with borderline ABI and even fewer on the general population.

Aim

The aim of the present study was to analyze the relationship between long-term cardiovascular events and low, borderline and normal ABI after a 9-year follow up of a Mediterranean population with low cardiovascular risk.

Design and setting

A population-based prospective cohort study was performed in the province of Barcelona, Spain.

Method

A total of 3,786 subjects >49 years were recruited from 2006–2008. Baseline ABI was 1.08 ± 0.16. Subjects were followed from the time of enrollment to the end of follow-up in 2016 via phone calls every 6 months, systematic reviews of primary-care and hospital medical records and analysis of the SIDIAP (Information System for Primary Care Research) database to confirm the possible appearance of cardiovascular events.

Results

3146 individuals participated in the study. 2,420 (77%) subjects had normal ABI, 524 (17%) had borderline ABI, and 202 (6.4%) had low ABI.

In comparison with normal and borderline subjects, patients with lower ABI had more comorbidities, such as hypertension, hypercholesterolemia and diabetes.

Cumulative MACE incidence at 9 years was 20% in patients with low ABI, 6% in borderline ABI and 5% in normal ABI.

The annual MACE incidence after 9 years follow-up was significantly higher in people with low ABI (26.9/1000py) (p<0.001) than in borderline (6.6/1000py) and in normal ABI (5.6/1000py).

Subjects with borderline ABI are at significantly higher risk for coronary disease (HR: 1.58; 95% CI: 1.02–2, 43; p = 0,040) compared to subjects with normal ABI, after adjustment.

Conclusion

The results of the present study support that low ABI was independently associated with higher incidence of MACE, ICE, cardiovascular and no cardiovascular mortality; while borderline ABI had significantly moderate risk for coronary disease than normal ABI.

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