Search Results (1,159)

Background: Studying patients carrying identical-by-descent (IBD) pathogenic gene variants allows us to control for the disease-causing genetic background and to more accurately document the impact of modifiers. Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and premature atherosclerosis and is often caused by defects in the LDLR gene. There is a high prevalence of FH in French Canada as a result of a founder effect from France in the 17th century. Several FH patients currently living in French Canada (founder population) and in France (colonizing population) carry IBD FH-causing variants. The expression of FH is affected by environmental and genetic modifiers, and patients with IBD variants may present different characteristics. Methods: In this study, we compared FH clinical expression patients carrying IBD LDLR pathogenic variants living in France or Canada. Four IBD variants, namely c.259T>G p.(Trp87Gly), c.2000G>A p.(Cys667Tyr), c.682G>A p.(Glu228Lys), and c.1048C>T p.(Arg350*), were selected. Untreated plasma lipid profiles, the apolipoprotein E (APOE) genotype, cardiovascular risk factors, and the occurrence of symptomatic ASCVD were compared in 105 adult carriers (30 from France and 75 from French Canada). Results: All parameters were similar between the two populations, except for untreated total cholesterol (10.14 ± 1.89 mmol/L vs. 8.65 ± 1.84 mmol/L, p = 0.0006) and LDL-c concentrations (7.94 ± 1.86 mmol/L vs. 6.93 ± 1.78 mmol/L, p = 0.016), which were significantly higher in FH patients living in France, an observation that was revealed across all studied LDLR variants. Conclusions: This study illustrates that FH patients sharing IBD pathogenic LDLR variants that have evolved in different geographic, cultural, and socio-economic environments for hundreds of years differ in terms of cholesterol levels, highlighting the importance of better understanding the interplay between genetic and environmental modulators of FH expression. Full article

Epidemiological evidence suggests that fruit and vegetable intake significantly positively affects cardiovascular health. Since vegetable juice is more accessible than raw vegetables, it attracts attention as a health functional food for circulatory diseases. Therefore, this study measured blood lipids, antioxidants, blood circulation indicators, and changes in the microbiome to confirm the effect of organic vegetable mixed juice (OVJ) on improving blood circulation. This 4-week, randomized, double-blinded, placebo-controlled study involved adult men and women with borderline total cholesterol (TC) and low-density lipoprotein (LDL) levels. As a result, blood lipid profile indicators, such as TC, triglycerides, LDL cholesterol, and apolipoprotein B, decreased (p < 0.05) in the OVJ group compared with those in the placebo group. Additionally, the antioxidant biomarker superoxide dismutase increased (p < 0.05). In contrast, systolic and diastolic blood viscosities, as blood circulation-related biomarkers, decreased (p < 0.05) in the OVJ group compared with those in the placebo group. After the intervention, a fecal microbiome analysis confirmed differences due to changes in the intestinal microbiome composition between the OVJ and placebo groups. In conclusion, our research results confirmed that consuming OVJ improves blood circulation by affecting the blood lipid profile, antioxidant enzymes, and microbiome changes. Full article

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by significantly elevated levels of low-density lipoprotein (LDL) cholesterol, which plays a major role in the progression of atherosclerosis and leads to a heightened risk of premature atherosclerotic cardiovascular disease. Methods: We have carried out an observational study on a group of 17 patients treated at the Outpatient Lipid Clinic from 2019 to 2024. Result: The most frequent mutation observed was found in the LDL receptor (LDLR) gene, which was identified in ten patients (58.8%). Five patients were identified to have a mutation in the apolipoprotein B (APOB) gene, whereas two patients had two points mutations, one in the LDLR, and the other in the APOB gene. The average age of patients with LDLR mutation was 54.8 (12.3); for APOB mutation it was 61.4 (9.3) and for patients with two points mutation it was 61.5 (14.8). The study results showed that at Week 12, individuals with LDLR-defective heterozygotes who were given alirocumab 150 mg every two weeks experienced a 63.0% reduction in LDL cholesterol levels. On the other hand, individuals with APOB heterozygotes experienced a 59% reduction in LDL cholesterol levels. However, in patients with double heterozygous for mutations in LDLR and APOB genes, there was a hyporesponsiveness to alirocumab, and the reduction in LDL-C was only by 23% in two individuals. Conclusions: In patients with a single mutation, there was a greater response to treatment with alirocumab in contrast to patients with double heterozygous mutation, who did not respond to treatment with PCSK9 inhibitors. Full article

Background: Alzheimer’s disease (AD) is a leading cause of dementia, and it is significantly influenced by the apolipoprotein E4 (APOE4) gene and gender. This study aimed to use machine learning (ML) algorithms to predict brain age and assess AD risk by considering the effects of the APOE4 genotype and gender. Methods: We collected brain volumetric MRI data and medical records from 1100 cognitively unimpaired individuals and 602 patients with AD. We applied three ML regression models—XGBoost, random forest (RF), and linear regression (LR)—to predict brain age. Additionally, we introduced two novel metrics, brain age difference (BAD) and integrated difference (ID), to evaluate the models’ performances and analyze the influences of the APOE4 genotype and gender on brain aging. Results: Patients with AD displayed significantly older brain ages compared to their chronological ages, with BADs ranging from 6.5 to 10 years. The RF model outperformed both XGBoost and LR in terms of accuracy, delivering higher ID values and more precise predictions. Comparing the APOE4 carriers with noncarriers, the models showed enhanced ID values and consistent brain age predictions, improving the overall performance. Gender-specific analyses indicated slight enhancements, with the models performing equally well for both genders. Conclusions: This study demonstrates that robust ML models for brain age prediction can play a crucial role in the early detection of AD risk through MRI brain structural imaging. The significant impact of the APOE4 genotype on brain aging and AD risk is also emphasized. These findings highlight the potential of ML models in assessing AD risk and suggest that utilizing AI for AD identification could enable earlier preventative interventions. Full article

High-density lipoprotein (HDL) cholesterol is traditionally viewed as protective against cardiovascular disease (CVD). However, emerging evidence reveals that dysfunctional HDL, characterized by impaired reverse cholesterol transport (RCT), reduced anti-inflammatory and antioxidant activities and increased endothelial dysfunction, which can contribute to coronary artery disease (CAD). Dysfunctional HDL, resulting from oxidative modifications of Apolipoprotein A-1 (Apo A-1) and enzyme inactivation, fails to effectively remove cholesterol from peripheral tissues and may promote inflammation and atherosclerosis. Genetic mutations affecting HDL metabolism further complicate its role in cardiovascular health. Studies have shown that conventional therapies aimed at raising HDL-C levels do not necessarily reduce cardiovascular events, highlighting the need for new approaches that improve HDL functionality. Therapeutic strategies such as Apo A-1 mimetic peptides, reconstituted HDL infusions, and drugs targeting specific HDL metabolic pathways are being explored. Additionally, weight loss, statin therapy, and niacin have shown potential in enhancing HDL function. The pathophysiology of dysfunctional HDL involves complex mechanisms, including oxidative stress, inflammation, and genetic mutations, which alter its structure and function, diminishing its cardioprotective effects. New functional assays, such as the cholesterol efflux capacity (CEC) and HDL inflammatory index, provide more accurate predictions of cardiovascular risk by assessing HDL quality rather than quantity. As research progresses, the focus is shifting towards therapeutic strategies that enhance HDL function and address the root causes of its dysfunction, offering a more effective approach to reducing cardiovascular risk and preventing CAD. Full article

Background: Capsaicin, a bioactive compound found in peppers, is recognized for its anti-inflammatory, antioxidant, and anti-lipidemic properties. This study aimed to evaluate the effects of capsaicin on atherosclerosis progression. Methods: Apolipoprotein E knockout mice and their C57BL/6 controls were utilized to assess blood lipid profile, inflammatory status, and atherosclerotic lesions. We also examined the influence of capsaicin on cholesterol influx and efflux, and the role of TRPV1 and PPARγ signaling pathways in bone marrow-derived macrophages. Results: Capsaicin treatment reduced weight gain, visceral adiposity, blood triglycerides, and total and non-HDL cholesterol. These improvements were associated with a reduction in atherosclerotic lesions in the aorta and carotid. Capsaicin also improved hepatic oxidative and inflammatory status. Systemic inflammation was also reduced, as indicated by reduced leukocyte rolling and adhesion on the mesenteric plexus. Capsaicin decreased foam cell formation by reducing cholesterol influx through scavenger receptor A and increasing cholesterol efflux via ATP-binding cassette transporter A1, an effect primarily linked to TRPV1 activation. Conclusions: These findings underscore the potential of capsaicin as a promising agent for atherosclerosis prevention, highlighting its comprehensive role in modulating lipid metabolism, foam cell formation, and inflammatory responses. Full article

In vivo proton (¹H) magnetic resonance spectroscopy (MRS) is a powerful non-invasive method that can measure Alzheimer’s disease (AD)-related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by ¹H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of ¹H MRS metabolites with biofluid, PET, and postmortem AD biomarkers and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate the development of potential novel therapeutic approaches. Full article

Background: Beyond memory deterioration, spatial disorientation may occur along the continuum of normal aging—dementia of Alzheimer’s type. The present study aims at detecting behavioral disorders of spatial cognition in prodromal Alzheimer’s disease (AD) and verifying the association between Apolipoprotein E-ε4 (ApoE-ε4) genotype and gait patterns during a real-world naturalistic task. Methods: A sample of 58 elderly participants, of which 20 patients with mild cognitive impairment with CFS biomarker evidence of AD, 23 individuals with subjective cognitive decline (SCD), and 15 healthy controls (HCs), was tested by a modified version of the Detour Navigation Test (DNT-mv). Generalized linear models were run to explore the association between group belonging and wrong turns (WTs)/moments of hesitation (MsH) as behavioral disorientation scores of the DNT-mv as well as the effect of ApoE-ε4 genotype on time and walking speed registered by a smartphone app providing GPS tracking of body movement around urban environments. Results: Patients with MCI due to AD reported more WTs than individuals with SCD and HCs. Further, the ApoE-ε4 genotype determined a lower capacity in spatial information processing, influencing gait during naturalistic spatial navigation tasks. Conclusions: Behavior alterations of spatial cognition can be detected ecologically in prodromal AD. The use of technological solutions supporting gait analysis may help in corroborating the experimental observation. Full article

Background/Objectives: Survival prospects following SARS-CoV-2 infection may extend beyond the acute phase, influenced by various factors including age, health conditions, and infection severity; however, this topic has not been studied in detail. Therefore, within this study, the mortality risk post-acute COVID-19 in the CRIT-COV-U cohort was investigated. Methods: Survival data from 651 patients that survived an acute phase of COVID-19 were retrieved and the association between urinary peptides and future death was assessed. Data spanning until December 2023 were collected from six countries, comparing mortality trends with age- and sex-matched COVID-19-negative controls. A death prediction classifier was developed and validated using pre-existing urinary peptidomic datasets. Results: Notably, 13.98% of post-COVID-19 patients succumbed during the follow-up, with mortality rates significantly higher than COVID-19-negative controls, particularly evident in younger individuals (<65 years). These data for the first time demonstrate that SARS-CoV-2 infection highly significantly increases the risk of mortality not only during the acute phase of the disease but also beyond for a period of about one year. In our study, we were further able to identify 201 urinary peptides linked to mortality. These peptides are fragments of albumin, alpha-2-HS-glycoprotein, apolipoprotein A-I, beta-2-microglobulin, CD99 antigen, various collagens, fibrinogen alpha, polymeric immunoglobulin receptor, sodium/potassium-transporting ATPase, and uromodulin and were integrated these into a predictive classifier (DP201). Higher DP201 scores, alongside age and BMI, significantly predicted death. Conclusions: The peptide-based classifier demonstrated significant predictive value for mortality in post-acute COVID-19 patients, highlighting the utility of urinary peptides in prognosticating post-acute COVID-19 mortality, offering insights for targeted interventions. By utilizing these defined biomarkers in the clinic, risk stratification, monitoring, and personalized interventions can be significantly improved. Our data also suggest that mortality should be considered as one possible symptom or a consequence of post-acute sequelae of SARS-CoV-2 infection, a fact that is currently overlooked. Full article

Atherosclerosis involves an inflammatory response due to plaque formation within the arteries, which can lead to ischemic stroke and heart disease. It is one of the leading causes of death worldwide, with various contributing factors such as hyperlipidemia, hypertension, obesity, diabetes, and smoking. Wall shear stress (WSS) is also known as a contributing factor of the formation of atherosclerotic plaques. Since the causes of atherosclerosis cannot be attributed to a single factor, clearly understanding the mechanisms and causes of its occurrence is crucial for preventing the disease and developing effective treatment strategies. To better understand atherosclerosis and define the correlation between various contributing factors, computational fluid dynamics (CFD) analysis is primarily used. CFD simulates WSS, the frictional force caused by blood flow on the vessel wall with various hemodynamic changes. Using apolipoprotein E knockout (ApoE-KO) mice subjected to partial ligation and a high-fat diet at 1-week, 2-week, and 4-week intervals as an atherosclerosis model, CFD analysis was conducted along with the reconstruction of carotid artery blood flow via magnetic resonance imaging (MRI) and compared to the inflammatory factors and pathological staining. In this experiment, a comparative analysis of the effects of high WSS and low WSS was conducted by comparing the standard deviation of time-averaged wall shear stress (TAWSS) at each point within the vessel wall. As a novel approach, the standard deviation of TAWSS within the vessel was analyzed with the staining results and pathological features. Since the onset of atherosclerosis cannot be explained by a single factor, the aim was to find the correlation between the thickness of atherosclerotic plaques and inflammatory factors through standard deviation analysis. As a result, the gap between low WSS and high WSS widened as the interval between weeks in the atherosclerosis mouse model increased. This finding not only linked the occurrence of atherosclerosis to WSS differences but also provided a connection to the causes of vulnerable plaques. Full article

Objective: This meta-analysis with a systematic review was undertaken to assess the association between APOE allelic genotypes and the risk of Alzheimer’s disease (AD) in the Italian population. Methods: The Web of Science, PubMed, and Scopus databases were searched until 15 November 2023. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using fixed and random effect models, depending on the I² statistic value. The systematic review and meta-analysis were conducted in agreement with the PRISMA guideline and registered with PROSPERO (CRD42023492580). Results: Our meta-analysis based on 15 studies revealed a higher risk of AD among Italian individuals carrying the APOE ε4 allele (OR = 3.60, 95% CI [2.90–4.47], p < 0.0001). The association of AD genotype APOE ε2ε4 (OR = 1.36, 95% CI [0.76–2.41], p = 0.29) was not statistically significant, while APOE ε3ε4 (OR = 3.43, 95% CI [2.95–3.99], p < 0.0001) has a high risk of AD development; the risk is more notably in the APOE ε4ε4 genotype (OR = 7.08, 95% CI [4.22–11.86], p < 0.0001). The APOE ε2 allele has a protective effect (APOE ε2 (OR = 0.47, 95% CI [0.29–0.74], p = 0.0013)), and similar results were achieved by APOE ε3 (OR  =  0.49, 95% CI [0.37–0.65], p < 0.0001). Subgroup analysis of three areas of Italy (southern, northern, and center) revealed that that APOE ε4 allele was a risk factor with a higher OR in northern Italy (OR 4.22; 95% CI [3.46–5.16], p < 0.0001) compared to southern and center Italy (OR 3.02; 95% CI [2.28–4.01], p < 0.0001 and OR 3.97; 95% CI [1.37–11.56], p < 0.0001, respectively). As well, APOE ε4ε4 genotype carriers had a significantly higher OR in northern Italy (OR 9.69; 95% CI [4.94–18.99], p < 0.0001) compared to in southern and center Italy (OR 4.38; 95% CI [1.54–12.47], p < 0.0001 and OR 3.59; 95% CI [0.87–14.86], p < 0.0001, respectively). Conclusions: This systematic review with a meta-analysis of the Italian population on APOE alleles, genotyping, and AD incidence, highlights that individuals harboring APOE ε4 have a higher risk of developing AD compared to those with other alleles. It also supports the protective effect of the APOE ε2 allele against the progress of AD. The qualitative analysis on the complex genetic interactions influencing Alzheimer risk emphasizes the need for further research on genetic and environmental factors for effective prevention strategies. Full article

ApolipoproteinC1 (apoC1) is the main physiological inhibitor of the cholesterol ester transfer protein (CETP). Increased CETP activity is associated with macrovascular complications in patients with type 1 diabetes (T1D). ApoC1 has lost its ability to inhibit CETP in patients with T1D, and in vitro glycation of apoC1 increases CETP activity, suggesting that hyperglycemia could be a factor implicated in the loss of the inhibitory effect of apoC1 on CETP. Thus, we aimed to see whether improvement of glycemic control might restore apoC1 inhibitory effect on CETP. We studied 98 patients with T1D and HbA1c > 9% at baseline and 3 months after improvement of glycemic control by a medical intervention (insulin introduction or changes in multi-injection therapy or pump therapy introduction/therapeutic education for all patients). CETP activity was assessed by a radioactive method and plasma apoC1 levels were measured by ELISA. The different isoforms of apoC1 were determined by mass spectrometry. CETP activity was not significantly modified after improvement of glycemic control, despite a significant reduction in mean HbA1c (8.7 ± 1.7 vs. 10.8 ± 2, p < 0.0001). No association between plasma apoC1 and CETP activity was observed in patients with T1D at baseline, nor at 3 months, even in the subgroup of patients with optimal control (3-month HbA1c < 7%). We did not find any glycated form of apoC1 using mass spectrometry in people with T1D. Hyperglycemia in vivo does not seem to be a major factor implicated in the loss of apoC1 ability to inhibit CETP activity observed in T1D. Other factors, such as qualitative abnormalities of lipoproteins, could be involved. Our data emphasize the fact that hyperglycemia is not the only factor involved in lipid abnormalities and macrovascular complications in T1D. Clinical trial reg. no. NCT02816099 ClinicalTrials.gov. Full article

The absence of an early diagnosis of cardiac autonomic neuropathy might increase the risk of the disease, progressing to an irreversible stage. Therefore, this study aims to investigate the APOE gene isoforms in patients with cardiac autonomic neuropathy to identify early markers for predicting this disease in the Kazakh population. A total of 147 patients with cardiac neuropathy and 153 controls were examined in this case–control study. Patients were genotyped for two polymorphisms of the APOE gene using real-time PCR. Statistical calculations were performed using binary logistic regression. As a result of our study, we found that there was no statistically significant difference in the frequency of any APOE gene isoforms (APOE (ε2/ε2), APOE (ε2/ε3), APOE (ε2/ε4), APOE (ε3/ε3), or APOE (ε4/ε4)) between the patient group and the control group (p = 0.69, p = 0.64, p = 0.19, p = 0.22, p = 0.97, respectively). Thus, cardiac autonomic neuropathy is not associated with APOE gene isoforms in the Kazakh population. Full article

To explore the molecular mechanisms of the Litopenaeus vannamei response to infection by Photobacterium damselae, reveal its immune response and energetic metabolic effect, and provide a valuable genetic data source for the scientific prevention and control of Vibrio infection, transcriptomic analysis, RT-qPCR, and physiological and biochemical tests were conducted. The results showed that the expression of key genes involved in lipid and carbohydrate transport, such as apolipoprotein and TPS, was upregulated after pathogenic infection, which brought the accumulation of triacylglycerol and trehalose into the hemolymph. Additionally, the pathogenic infection selectively triggered an immune response in infected L. vannamei, activating certain immune pathways, such as the serpins and MAPK pathways. The pathogenic infection suppressed the activity of phenoloxidase (PO), and the prophenoloxidase (PPO) cascade responses were suppressed by the invasive bacteria. This paper will help us understand the energetic metabolism, immune response, and activation of the immune recognition response after pathogenic infection by P. damselae, and it lays a theoretical foundation for the biological prevention and control of P. damselae infection. Full article

Background: This study examined the impact of apolipoprotein ɛ4 (APOEɛ4) allele frequency and sex on the phenotype of Alzheimer’s disease (AD). Methods: This post hoc study evaluated the baseline characteristics, cerebrospinal fluid (CSF) and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50–74 years with CSF-biomarker-confirmed mild cognitive impairment or mild dementia due to AD from clinical trial NCT03186989. Results: A phenotypic spectrum was observed from a predominant amyloid and limbic–amnestic phenotype in male APOEɛ4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEɛ4 noncarriers. Amyloid pathology was inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest associations observed in male APOEɛ4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEɛ4 noncarriers. Conclusions: These data support the hypothesis that functional glial activation is influenced by apoE isoform and sex and might explain much of the biological and clinical heterogeneity in early clinical AD in those aged 50–74 years. Conclusions are limited because of the retrospective nature and small sample size. Trial Registration: Clinical Trial NCT03186989. Full article