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JACC. Advances Feb 2024The initiation of coronary artery calcium (CAC) is an important physiologic milestone associated with increased cardiovascular disease risk. However, traditional risk...
BACKGROUND
The initiation of coronary artery calcium (CAC) is an important physiologic milestone associated with increased cardiovascular disease risk. However, traditional risk factors (RF) do not perform well for predicting incident CAC among the 54 million older U.S. adults.
OBJECTIVES
The authors sought to assess the association between nontraditional cardiovascular disease RF and incident CAC in older persons.
METHODS
There were 815 MESA (Multi-Ethnic Study of Atherosclerosis) participants ≥65 years of age who had CAC = 0 at Visit 1 and a follow-up CAC scan. Multivariable adjusted Cox hazards ratios (aHR) and C-statistics were calculated to examine the association of nontraditional RF with incident CAC.
RESULTS
The mean age was 70.2 years and 67% were women. The median follow-up time to repeat CAC scan was 3.6 years (IQR: 2.6-9.2 years) and 45% of participants developed incident CAC. Albuminuria (aHR: 1.50, 95% CI: 1.07-2.09), carotid plaque (aHR: 1.32, 95% CI: 1.04-1.66), and thoracic aortic calcification (TAC) (aHR: 1.38, 95% CI: 1.10-1.75) were significantly associated with incident CAC, while higher levels of nontraditional RF including apolipoprotein-B, lipoprotein(a), high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide were not. When added to demographics, albuminuria, carotid plaque, and TAC provided a greater C-statistic improvement (+0.047, = 0.004) vs all traditional RF combined (+0.033, = 0.05).
CONCLUSIONS
Among nontraditional RF and measures of subclinical atherosclerosis, only albuminuria, carotid plaque, and TAC were significantly associated with incident CAC in persons ≥65 years of age. Identification of albuminuria or extracoronary atherosclerosis may help guide the timing of repeat CAC scoring in older persons with baseline CAC = 0.
PubMed: 38939371
DOI: 10.1016/j.jacadv.2023.100755 -
Frontiers in Aging Neuroscience 2024At least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer's disease (AD) are involved in lipid metabolism, lipid...
INTRODUCTION
At least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer's disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. In fact, a common genetic variant (ε4) in a cholesterol and phospholipid transporter, Apolipoprotein E (), is the primary genetic risk factor for late-onset AD. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, cerebrospinal fluid, blood, and multiple mouse models of AD.
METHODS
We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of lipidomics and transcriptomics from the Religious Order Study and Rush Memory Aging Project (ROSMAP) using differential analysis and network correlation analysis.
RESULTS
Coordinated differences in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and carriers. Interestingly, these correlations were weakened when adjusting for education. Indeed, the cognitively non-impaired carriers have higher education levels in the ROSMAP cohort, suggesting that this lipid signature may be associated with a resilience phenotype. Network correlation analysis identified multiple differential lipids within a single module that are substrates and products in the Lands Cycle for acyl chain remodeling. In addition, our analyses identified multiple genes in the Lands Cycle acyl chain remodeling pathway, which were associated with cognitive decline independent of amyloid-β (Aβ) load and tau tangle pathologies.
DISCUSSION
Our studies highlight the critical differences in acyl chain remodeling in brain tissue from carriers and individual non-carriers with MCI. A coordinated lipid profile shift in dorsolateral prefrontal cortex from both carriers and MCI suggests differences in lipid metabolism occur early in disease stage and highlights lipid homeostasis as a tractable target for early disease modifying intervention.
PubMed: 38938596
DOI: 10.3389/fnagi.2024.1419253 -
Frontiers in Endocrinology 2024The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish...
The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish between organic and psychogenic causes when diagnosing ED. It is difficult to believe that Apos play a role in psychogenic ED. To address these issues, our study explored the causal relationship between lipoproteins and ED using Mendelian randomization (MR) analysis and differentiate between organic and psychogenic ED through the use of nocturnal penile tumescence and rigidity (NPTR) monitoring. Multivariate MR analysis revealed significant causal associations between high-density lipoprotein (HDL), Apo A1, and Apo B/A1 with ED (OR and 95% CI were 0.33 (0.14-0.78), 3.58 (1.52-8.43), and 0.30 (0.13-0.66)). we conducted statistical and analytical analyses on the data of 212 patients using multivariate analyses and receiver operating characteristic (ROC) curves. Patients with organic ED had significantly lower levels of HDL, Apo A1 and Apo A1/B, whereas patients with organic ED had considerably higher levels of Apo B and low-density lipoprotein (LDL). The diagnostic value of Apos in predicting the risk of organic ED was evaluated using ROC curves. The results indicated that Apo A1 and Apo A1/B demonstrated good predictive value. HDL, Apo A1, and Apo A1/B have been identified as risk factors for ED in our study. Furthermore, our research highlights the significance of Apo A1 and Apo A1/Apo B in the development of organic ED and suggests their potential use as indicators to assess the risks associated with organic ED.
Topics: Humans; Male; Mendelian Randomization Analysis; Erectile Dysfunction; Case-Control Studies; Middle Aged; Apolipoproteins; Adult; Apolipoprotein A-I; Lipoproteins, HDL
PubMed: 38938512
DOI: 10.3389/fendo.2024.1359015 -
Scientific Reports Jun 2024A rise in bone turnover markers (BTM) after bariatric surgery predicts poor bone health years later. This study explored factors associated with BTM and changes in BTM...
A rise in bone turnover markers (BTM) after bariatric surgery predicts poor bone health years later. This study explored factors associated with BTM and changes in BTM after bariatric surgery. Inclusion criteria were subjects 18 to 65 years of age with morbid obesity undergoing bariatric surgery. All data were measured before and 6 and 12 months after surgery. The study included 104 subjects: women/men: 83/21; mean age 43.1 (SD 8.4) years; BMI: 38.8 kg/m (SD 3.8). Surgery with Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) was performed in 84 (81%) and 20 (19%) subjects, respectively. From before to 6-12 months after surgery, procollagen type 1 N-terminal propeptid (P1NP) increased by 45.6 µg/L (95% CI 41.5-50.0, p < 0.001), and alkaline phosphatase (ALP) by 10 U/L (95% CI 7-14, p < 0.001). The increases were significantly larger after RYGB than after SG. The APOE- Ɛ3 allele was associated with low levels of BTM and high levels of leptin. There was an unfavourable increase in BTM after bariatric surgery. SG compared to RYGB and the presence of the APOE-Ɛ3 allele were associated with less unfavourable effects. The study emphasises the importance of optimal prophylactic interventions after bariatric surgery to prevent osteoporosis.
Topics: Humans; Female; Male; Adult; Middle Aged; Bone Remodeling; Biomarkers; Bariatric Surgery; Obesity, Morbid; Peptide Fragments; Procollagen; Gastrectomy; Gastric Bypass; Alkaline Phosphatase; Leptin; Aged; Adolescent
PubMed: 38937532
DOI: 10.1038/s41598-024-65952-y -
Immunobiology Jun 2024As metastatic papillary thyroid carcinoma becomes increasingly challenging to treat, immunotherapy has emerged as a new research direction. Tumor-associated macrophages...
BACKGROUND
As metastatic papillary thyroid carcinoma becomes increasingly challenging to treat, immunotherapy has emerged as a new research direction. Tumor-associated macrophages (TAMs) influence the occurrence, invasion, and metastasis of tumors. Apolipoprotein E (APOE) can regulate the polarization changes of macrophages and participate in the remodeling of the tumor microenvironment. However, the role of APOE in regulating the polarization and biological functions of TAMs in papillary thyroid carcinoma (PTC) remains unclear, as it acts as a dual biomarker.
METHODS
We probed APOE expression in PTC tissues using immunohistochemical staining. A cell co-culture model was established where different APOE-expressing K1 cells were co-cultured with THP-1-derived M0 macrophages. An in-depth analysis of macrophage polarization behavior was performed using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting. Subsequently, the impact of APOE-regulated macrophages on tumor cell behavior, especially proliferation, migration, and invasion, was evaluated utilizing IncuCyte ZOOM system, flow cytometry, colony formation, and scratch experiments. Finally, we used a xenograft model to confirm the effects of APOE on PTC tumorigenesis.
RESULTS
Tumor dimensions, stage, and lymphatic metastases were significantly associated with increased APOE expression in PTC tissues. K1 cells were markedly limited in their proliferation, migration, and invasion abilities when APOE expression was silenced, a process mediated by the PI3K/Akt/NF-κB signaling axis. Moreover, APOE is a key facilitator of the enhancement of the anti-inflammatory cytokines IL-10 and TGF-β1. In PTC cellular models, APOE contributed to the phenotypic shift of THP-1 derived macrophages towards an M2 phenotypic polarization, predominantly through the modulation of IL-10. Furthermore, in vivo studies involving athymic nude mice have demonstrated pivotal role of APOE in tumor progression and the induction of M2-like TAM polarization.
CONCLUSION
Our results elucidated that APOE could promote the shift of TAMs from M0-type to M2-type polarization by regulating inflammatory factors expressions in K1 cell through the PI3K/Akt/NF-κB pathway. These findings are crucial for understanding the molecular mechanisms underlying PTC pathogenesis and for developing immunological drugs to treat this disease.
PubMed: 38935988
DOI: 10.1016/j.imbio.2024.152821 -
Journal of the American Heart... Jun 2024Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins...
Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.
BACKGROUND
Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans.
METHODS AND RESULTS
Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA- rats. This competitive reduction was dose dependent (25-250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA rats.
CONCLUSIONS
Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.
PubMed: 38934863
DOI: 10.1161/JAHA.123.032419 -
MSystems Jun 2024Airway microbiota are known to contribute to lung diseases, such as cystic fibrosis (CF), but their contributions to pathogenesis are still unclear. To improve our...
Airway microbiota are known to contribute to lung diseases, such as cystic fibrosis (CF), but their contributions to pathogenesis are still unclear. To improve our understanding of host-microbe interactions, we have developed an integrated analytical and bioinformatic mass spectrometry (MS)-based metaproteomics workflow to analyze clinical bronchoalveolar lavage (BAL) samples from people with airway disease. Proteins from BAL cellular pellets were processed and pooled together in groups categorized by disease status (CF vs. non-CF) and bacterial diversity, based on previously performed small subunit rRNA sequencing data. Proteins from each pooled sample group were digested and subjected to liquid chromatography tandem mass spectrometry (MS/MS). MS/MS spectra were matched to human and bacterial peptide sequences leveraging a bioinformatic workflow using a metagenomics-guided protein sequence database and rigorous evaluation. Label-free quantification revealed differentially abundant human peptides from proteins with known roles in CF, like neutrophil elastase and collagenase, and proteins with lesser-known roles in CF, including apolipoproteins. Differentially abundant bacterial peptides were identified from known CF pathogens (e.g., ), as well as other taxa with potentially novel roles in CF. We used this host-microbe peptide panel for targeted parallel-reaction monitoring validation, demonstrating for the first time an MS-based assay effective for quantifying host-microbe protein dynamics within BAL cells from individual CF patients. Our integrated bioinformatic and analytical workflow combining discovery, verification, and validation should prove useful for diverse studies to characterize microbial contributors in airway diseases. Furthermore, we describe a promising preliminary panel of differentially abundant microbe and host peptide sequences for further study as potential markers of host-microbe relationships in CF disease pathogenesis.IMPORTANCEIdentifying microbial pathogenic contributors and dysregulated human responses in airway disease, such as CF, is critical to understanding disease progression and developing more effective treatments. To this end, characterizing the proteins expressed from bacterial microbes and human host cells during disease progression can provide valuable new insights. We describe here a new method to confidently detect and monitor abundance changes of both microbe and host proteins from challenging BAL samples commonly collected from CF patients. Our method uses both state-of-the art mass spectrometry-based instrumentation to detect proteins present in these samples and customized bioinformatic software tools to analyze the data and characterize detected proteins and their association with CF. We demonstrate the use of this method to characterize microbe and host proteins from individual BAL samples, paving the way for a new approach to understand molecular contributors to CF and other diseases of the airway.
PubMed: 38934598
DOI: 10.1128/msystems.00929-23 -
Journal of Diabetes and Metabolic... Jun 2024Metabolic syndrome (MetS) is a constellation of coexisting cardiovascular risk factors. This study aimed to assess the evidence for the association between the... (Review)
Review
OBJECTIVES
Metabolic syndrome (MetS) is a constellation of coexisting cardiovascular risk factors. This study aimed to assess the evidence for the association between the apolipoprotein B/A1 ratio, apolipoprotein B, and apolipoprotein A1, and the MetS in children and adolescents.
METHODS
The English electronic databases including PubMed, Embase, Web of Science, and Scopus were searched up to February 28, 2022. To ascertain the validity of eligible studies, modified JBI scale was used. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using the random-effects model to evaluate the association between the apolipoprotein B/A1 ratio, apolipoprotein B, and apolipoprotein A1 and the MetS. Heterogeneity amongst the studies was determined by the use of the Galbraith diagram, Cochran's Q-test, and I test. Publication bias was assessed using Egger's and Begg's tests.
RESULTS
From 7356 records, 5 studies were included in the meta-analysis, representing a total number of 232 participants with MetS and 1320 participants as control group. The results indicated that increased levels of apolipoprotein B/A1 ratio (SMD 1.26; 95% CI: 1.04, 1.47) and apolipoprotein B (SMD 0.75; 95% CI: 0.36, 1.14) and decreased levels of apolipoprotein A1 (SMD -0.53; 95% CI: -0.69, -0.37) are linked to the presence of MetS. The notable findings were, children and adolescents with MetS had elevated levels of the apolipoprotein B/A1 ratio, apolipoprotein B, and decreased levels of apolipoprotein A1.
CONCLUSIONS
Our results suggest the need to evaluate the levels of apolipoproteins for detecting the risk of MetS in children and adolescents.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40200-023-01235-z.
PubMed: 38932877
DOI: 10.1007/s40200-023-01235-z -
Medicina (Kaunas, Lithuania) Jun 2024Apolipoprotein E (APOE) gene polymorphism has been implicated in the pathogenesis of various metabolic disorders, including type 2 diabetes mellitus (T2DM). Type 2...
Apolipoprotein E (APOE) gene polymorphism has been implicated in the pathogenesis of various metabolic disorders, including type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, including in Pakistan. Cardiovascular problems linked with T2DM have a significant impact on individuals and society. The goal of this study is to investigate the relationship between Apolipoprotein E (ApoE) genotypes, dyslipidemia, and cardiovascular complications such as ischemic heart disease (IHD) and stroke. This study was carried out on 260 subjects divided into controls and diabetics. The diabetics were further divided into four subgroups such as D1: diabetics without cardiovascular issues, D2: diabetics with heart disease, D3: diabetics with stroke, and D4: diabetics with both heart disease and stroke. Anthropometric parameters (age, BMI) and risk factors (smoking, diabetes duration, hypertension) were assessed in all groups. Serum levels of TC, TG, LDL, HDL, VLDL, creatinine, BSF, and HbA1c were also measured. Apolipoprotein E gene polymorphism was determined using PCR-RFLP. Hypertension, BMI, and dyslipidemia are defined as elevated levels of total cholesterol, triglycerides, LDL, and VLDL, and decreased levels of HDL. Uncontrolled hyperglycemia (elevated fasting blood sugar and glycated hemoglobin) in T2DM was linked to vascular complications such as IHD and stroke. Hypertension was prevalent in 79.3% of the population. Stage 2 hypertension was more prevalent in all age groups. It was also noted that common genotypes in the Pakistani population are 3/3, 4/4, 2/3, and 3/4. The frequency of genotypes 3/4 and 2/3 is highest in diabetics with stroke. Genotype 3/3 is present frequently in diabetics with IHD/stroke and patients with both these complications. However, genotype 4/4 is most frequently found in diabetics with IHD. It is concluded that BMI, hypertension, hyperglycemia, atherosclerosis, and dyslipidemia are linked with cardiovascular complications of type 2 diabetes. Apolipoprotein E gene polymorphism is associated with cardiovascular disease in patients with diabetes by affecting the lipid profile.
Topics: Humans; Diabetes Mellitus, Type 2; Pakistan; Male; Female; Apolipoproteins E; Middle Aged; Cardiovascular Diseases; Adult; Polymorphism, Genetic; Aged; Risk Factors; Dyslipidemias; Genotype; Stroke
PubMed: 38929578
DOI: 10.3390/medicina60060961 -
Genes May 2024Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes...
Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the gene, rs429358 and rs7412 for the gene and rs1801157 [-3'G(801)A] for gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02-6.14, = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01-7.97, = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the Q192R is likely to play a role as a risk factor for retinal vein occlusion.
Topics: Humans; Aryldialkylphosphatase; Retinal Vein Occlusion; Male; Female; Chemokine CXCL12; Case-Control Studies; Middle Aged; Polymorphism, Single Nucleotide; Aged; Apolipoproteins E; Genetic Predisposition to Disease; Risk Factors; Greece; Haplotypes
PubMed: 38927649
DOI: 10.3390/genes15060712