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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 -
Pharmaceutical Research Jun 2024Individuals with Alzheimer's disease (AD) often require many medications; however, these medications are dosed using regimens recommended for individuals without AD....
BACKGROUND
Individuals with Alzheimer's disease (AD) often require many medications; however, these medications are dosed using regimens recommended for individuals without AD. This is despite reduced abundance and function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in AD, which can impact brain exposure of drugs. The fundamental mechanisms leading to reduced P-gp abundance in sporadic AD remain unknown; however, it is known that the apolipoprotein E (apoE) gene has the strongest genetic link to sporadic AD development, and apoE isoforms can differentially alter BBB function. The aim of this study was to assess if apoE affects P-gp abundance and function in an isoform-dependent manner using a human cerebral microvascular endothelial cell (hCMEC/D3) model.
METHODS
This study assessed the impact of apoE isoforms on P-gp abundance (by western blot) and function (by rhodamine 123 (R123) uptake) in hCMEC/D3 cells. Cells were exposed to recombinant apoE3 and apoE4 at 2 - 10 µg/mL over 24 - 72 hours. hCMEC/D3 cells were also exposed for 72 hours to astrocyte-conditioned media (ACM) from astrocytes expressing humanised apoE isoforms.
RESULTS
P-gp abundance in hCMEC/D3 cells was not altered by recombinant apoE4 relative to recombinant apoE3, nor did ACM containing human apoE isoforms alter P-gp abundance. R123 accumulation in hCMEC/D3 cells was also unchanged with recombinant apoE isoform treatments, suggesting no change to P-gp function, despite both abundance and function being altered by positive controls SR12813 (5 µM) and PSC 833 (5 µM), respectively.
CONCLUSIONS
Different apoE isoforms have no direct influence on P-gp abundance or function within this model, and further in vivo studies would be required to address whether P-gp abundance or function are reduced in sporadic AD in an apoE isoform-specific manner.
PubMed: 38937373
DOI: 10.1007/s11095-024-03731-0 -
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 -
The Canadian Journal of Cardiology Apr 2024Plant-based meat alternatives (PBMAs) are highly processed food products that typically replace meat in the diet. In Canada, the growing demand for PBMAs coincides with... (Review)
Review
Plant-based meat alternatives (PBMAs) are highly processed food products that typically replace meat in the diet. In Canada, the growing demand for PBMAs coincides with public health recommendations to reduce ultra-processed food consumption, which prompts the need to investigate the long-term health implications of PBMAs. This review assesses the available literature on PBMAs and cardiovascular disease (CVD), including an evaluation of their nutritional profile and impact on CVD risk factors. Overall, the nutritional profiles of PBMAs vary considerably but generally align with recommendations for improving cardiovascular health; compared with meat, PBMAs are usually lower in saturated fat and higher in polyunsaturated fat and dietary fibre. Some dietary trials that have replaced meat with PBMAs have reported improvements in CVD risk factors, including total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B-100, and body weight. No currently available evidence suggests that the concerning aspects of PMBAs (eg, food processing and high sodium content) negate the potential cardiovascular benefits. We conclude that replacing meat with PBMAs may be cardioprotective; however, long-term randomised controlled trials and prospective cohort studies that evaluate CVD events (eg, myocardial infarction, stroke) are essential to draw more definitive conclusions.
PubMed: 38934982
DOI: 10.1016/j.cjca.2023.11.005 -
Journal of the American Heart... Jul 2024Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins... (Comparative Study)
Comparative Study
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.
Topics: Animals; Insulin Resistance; Atherosclerosis; Rats; Antibodies, Monoclonal; Male; Lipoproteins; Disease Models, Animal; Vaccines; Time Factors
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 -
British Journal of Haematology Jun 2024Glomerular hyperfiltration and albuminuria are frequent kidney abnormalities in children with sickle cell anaemia (SCA). However, little is known about their persistence...
Glomerular hyperfiltration and albuminuria are frequent kidney abnormalities in children with sickle cell anaemia (SCA). However, little is known about their persistence in African SCA children. This prospective study included 600 steady-state SCA children aged 2-18 years from the Democratic Republic of Congo. Participants were genotyped for apolipoprotein L1 (APOL1) risk variants (RVs) and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. Kidney abnormalities were defined as albuminuria, hyperfiltration or decreased estimated creatinine-based glomerular filtration rate (eGFRcr). At baseline, 247/600 (41.2%) participants presented with kidney abnormalities: 82/592 (13.8%) with albuminuria, 184/587 (31.3%) with hyperfiltration and 15/587 (2.6%) with decreased eGFRcr. After a median follow-up of 5 months, repeated testing was performed in 180/247 (72.9%) available participants. Persistent hyperfiltration and persistent albuminuria (PA) were present in 29.2% (38/130) and 39.7% (23/58) respectively. eGFR normalized in all participants with a baseline decreased eGFRcr. Haemoglobinuria (p = 0.017) and male gender (p = 0.047) were significantly associated with PA and persistent hyperfiltration respectively. APOL1 RVs (G1G1/G2G2/G1G2) were borderline associated with PA (p = 0.075), while HMOX1 long repeat was not associated with any persistent kidney abnormality. This study reveals that a single screening can overestimate the rate of kidney abnormalities in children with SCA and could lead to overtreatment.
PubMed: 38934404
DOI: 10.1111/bjh.19603 -
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