Search Results (589)

Background: Nowadays, there is a lack of reliable and minimally invasive diagnosis methods for the early detection of Alzheimer’s disease. The development and validation of such tools could significantly reduce the dependence on more invasive and costly confirmatory procedures, such as cerebrospinal fluid biomarkers analysis and neuroimaging techniques. Objectives: The main objective of this study is to validate the clinical performance of a previously developed diagnosis model based on plasma biomarkers from patients in a cognitive disorder unit. Methods: A new cohort of patients was recruited from the same cognitive disorder unit (n = 93). Specifically, demographic data (gender, age, and educational level), plasma biomarkers levels, and genotype (glial fibrillary acidic protein, phosphorylated Tau 181, amyloid-beta42/amyloid-beta40, apolipoprotein E) were collected to evaluate both approaches of the previous diagnosis model (one-cut-off, two-cut-off). Results: The one-cut-off approach showed a sensitivity of 74.3%, a specificity of 89.5%, and an area under the curve of 0.888, while the values for the two-cut-off approach were sensitivity of 66.7%, specificity of 99.9%, and area under the curve of 0.867. Conclusions: A multivariate diagnostic tool was temporally validated for implementation in a clinical unit. In fact, satisfactory results were obtained from both approaches (one-cut-off, two-cut-offs), but the two cut-offs approach was more consistent in correctly identifying non-Alzheimer’s disease cases, allowing us to identify a large number of cases with high specificity. Full article

The growth plate is a specialized cartilage structure near the ends of long bones that orchestrates longitudinal bone growth during fetal and postnatal stages. Within this region reside a dynamic population of growth plate skeletal stem cells (gpSSCs), primarily located in the resting zone, which possess self-renewal and multilineage differentiation capacity. Recent advances in cell-lineage tracing, single-cell transcriptomics, and in vivo functional studies have revealed distinct subpopulations of gpSSCs, which are defined by markers such as parathyroid hormone-related protein (PTHrP), CD73, axis inhibition protein 2 (Axin2), forkhead box protein A2 (FoxA2), and apolipoprotein E (ApoE). These stem cells interact intricately with their niche, particularly after the formation of the secondary ossification center, through stage-specific regulatory mechanisms involving several key signaling pathways. This review summarizes the current understanding of gpSSC identity, behavior, and regulation, focusing on how these cells sustain growth plate function through adapting to biomechanical and molecular cues. Full article

Alzheimer’s disease (AD) instantly requires affordable diagnostic tools for targeting the responsible molecular biomarkers. In this review, we briefly discussed the overview of the AD population, performance of different analytical techniques and nanoparticles/composites, molecular biomarkers, and the interest of countries towards the detection of AD biomarkers during 2012–2025. The desired result was attained by lateral flow assay, surface-enhanced Raman scattering, and colorimetric sensor techniques with nanoparticles of magnetic, gold, and carbon-containing silver, and iridium oxide nanoparticles, upon biomarkers of dopamine, amyloid beta41, and Apolipoprotein E, individually. Additionally, the outstanding performance of nanoparticles including gold nanoparticles, carbon-containing nanoparticles, and manganese dioxide with their particle size of 5.7 nm, 35 nm, 37.3 nm, 120 nm, and 220 nm, respectively, has been discussed. Moreover, the percentages of AD-related biomarkers including amyloid beta42 having research articles of 21.2%, amyloid beta1-42 12.1%, amyloid beta oligomer 12.1%, phosphorylated Tau detection 12.1%, amyloid beta1-40 9.09%, Dopamine 9.09%, amyloid beta40 9.17%, apolipoprotein 6.06%, etc., have also been included. Additionally, LOD comparison with respect to applied analytical techniques, investigated through a timeline and electrochemical sensor, was found most suitable. Finally, a portable molecular diagnostic device to combine amyloid beta1-42, amyloid beta1-40, and phosphorylated Tau detection in non-invasive bodily fluid was proposed for the future and clinical diagnosis. Full article

In this study, we aimed to characterize intramuscular fat (IMF) tissue in fattening steers through a comparison with subcutaneous fat (SCF) tissue. The IMF of the longissimus thoracis et lumborum and the SCF of the back fat from three fattening steers (mean body weight of 703.50 ± 11.45 kg) were collected, and the muscle tissue, connective tissue, and fascia were carefully removed. Gene and protein expressions and the lipid contents were assessed via transcriptomic, proteomic, and lipidomic analyses, respectively. Subsequently, tissue-specific factors were identified using integrated analysis. The results revealed that the expressions of sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 2 (ATP2A2), enolase 3 (ENO3), fructose-bisphosphatase 2 (FBP2), myosin heavy chain 7 (MYH7), myosin light chain 3 (MYL3), myosin light chain kinase (MYLK), glycogen phosphorylase (PYGM), troponin C1 (TNNC1), and tropomyosin 2 (TPM2) significantly increased in IMF at both the mRNA and protein levels, whereas those of fatty acid-binding protein 4 (FABP4), stearoyl-CoA desaturase (SCD), and apolipoprotein E (APOE) were reduced. The abundances of both phosphatidylinositol (PI) (18:1/20:4) and phosphatidylcholine (PC) (15:0/18:2) were positively correlated with APOE. Conversely, that of PI (18:1/20:4) was negatively correlated with ENO3 and PYGM, whereas PC (15:0/18:2) was negatively correlated with TNNC1 and MYLK. In conclusion, we identified calcium signaling and glycolysis as key IMF-regulating pathways. ATP2A2, ENO3, FBP2, MYH7, MYL3, MYLK, PYGM, TNNC1, TPM2, and LPE 18:0 were negatively associated with IMF deposition, whereas FABP4, SCD, APOE, PI (18:1/20:4), and PC (15:0/18:2) were positively associated with it. These findings offer underlying IMF-related targets to promote IMF deposition in cattle. Full article

Atherosclerosis (AS), the leading cause of cardiovascular disease (CVD), is the thickening and stiffening of arterial walls, mainly of coronary arteries, the aorta, and the internal carotid artery. Blood flow is restricted by the deposit of lipid-rich macrophages (foam cells), calcium, fibrin, and cellular debris into plaques on the inner lining (tunica intima) of arterial walls. Damaged endothelia become inflamed and accumulate macrophages, monocytes, granulocytes, and dendritic cells, which intensifies plaque formation and increases the risk of myocardial infarction (MI) and thrombosis. Many of the anatomical and physiological abnormalities in arterial walls can be linked to colonic bacteria that produce inflammation-inducing metabolites, e.g., succinate, fumarate, fatty acids (FAs), reactive oxygen species (ROS), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO). TMAO triggers platelet formation, inhibits the synthesis of bile acids (BAs), accelerates the formation of aortic lesions, and upregulates the expression of membrane glycoprotein CD36 (also known as platelet glycoprotein 4) on the surface of platelets and epithelial cells. The ability of internal mammary arteries (IMAs) to produce higher levels of apolipoprotein C-III (apo-CIII) and paraoxonase (PON), compared to coronary arteries, prevents plaque buildup. The tunica intima of IMAs is rich in heparin sulfate and endothelial nitric oxide synthase (eNOS). Increased production of NO relaxes VSMCs and suppresses GTP cyclohydrolase (GTPCH), which lowers blood pressure. Higher levels of prostacyclin (PG12) produced by IMAs inhibit platelet aggregation. IMAs are structurally different from coronary arteries by having a thinner, non-fenestrated, tunica intima without a prominent internal elastic lamina. These characteristics render IMAs ideal conduits in coronary artery bypass graft (CABG) surgery. This review provides information that may explain why IMAs are less affected by inflammatory reactions and more resilient to plaque formation. Full article

We investigated associations between apolipoprotein E (APOE) alleles and motor manifestations in Alzheimer’s dementia (AD) capitalizing on National Alzheimer’s Coordinating Center data: the baseline evaluations of older adults (≥60 years) with a diagnosis of AD were analyzed. Those with a concomitant diagnosis Parkinson’s disease or other parkinsonian syndrome, and those treated with anti-parkinsonian agents were excluded. Three APOE groups were formed: APOE2 (APOE2 carriers), APOE3 (APOE3/APOE3) and APOE4 (APOE4/APOE4, APOE4/APOE3). UPDRS-III was used to assess the presence or absence of motor signs in 9 domains. Adjusted binary logistic models featuring the three APOE groups as exposures and motor domains as outcomes were estimated. There were 389 individuals in the APOE2, 1799 in the APOE3 and 2791 in the APOE4 groups. Compared to the APOE2 group, individuals in the APOE4 group had lower odds of having at least one motor sign [0.64 (0.50–0.82)]. Among motor signs, rigidity [0.53 (0.34–0.81)], bradykinesia [0.56 (0.40–0.77)], impaired chair rise [0.54 (0.37–0.78)] and impaired posture-gait [0.54 (0.36, 0.81)] exhibited significant associations. Exploratory analyses featuring APOE genotypes suggested dose–response relationships for both APOE2 and APOE4. In conclusion, APOE2 confers a risk towards motor (mainly parkinsonian) signs in AD. APOE4 may have a protective effect. Full article

Specialized herbivores like giant pandas (Ailuropoda melanoleuca), red pandas (Ailurus fulgens), and bamboo rats, which primarily consume bamboo, are at risk of nutrient deficiencies, particularly vitamin B12 (VB12), potentially leading to cardiovascular diseases. This study explored the effects of VB12 supplementation on cardiovascular health in silver star bamboo rats (Rhizomys pruinosus). We first conducted a comprehensive genome annotation of R. pruinosus, laying the foundation for in-depth evolutionary studies. Comparative transcriptomic analysis revealed that genes related to cardiovascular disease (e.g., Sgcb, Adcy2, Itga1, Itgb8, Ifng, and Gpc1) were upregulated in the livers of R. pruinosus compared to carnivorous and omnivorous rodents, indicating a higher cardiovascular disease risk. After 60 days of VB12 supplementation, liver transcriptome analysis revealed significant improvements in cardiovascular health markers, including reduced cholesterol synthesis and enhanced fatty acid metabolism. Serum biochemical assays indicated that VB12 supplementation led to reduced homocysteine levels, decreased low-density lipoprotein (LDL)-to-high-density lipoprotein (HDL) ratios, and increased the apolipoprotein A-to-apolipoprotein B ratio. These findings suggest that VB12 may mitigate cardiovascular disease risk and could be considered in the dietary management of specialized bamboo-eating species. Our study provides valuable insights into disease prevention strategies for these species with similar dietary habits. Full article

Apolipoprotein E (APOE) remains the most robust and widely replicated genetic risk factor for late-onset Alzheimer’s disease (AD) susceptibility, with the ε4 allele (APOE4) demonstrating profound associations with accelerated symptom manifestation, enhanced disease trajectory, and modified therapeutic responsiveness. This comprehensive review synthesizes contemporary evidence regarding the clinical utility of APOE4 genotyping, emphasizing its integration into personalized therapeutic frameworks and early diagnostic paradigms. The APOE4 variant exerts pathogenic influence through impaired amyloid-β clearance, enhanced tau pathology, and compromised neuronal repair mechanisms that alter disease phenotype. We systematically examine available genotyping methodologies, encompassing polymerase chain reaction (PCR) and next-generation sequencing (NGS) platforms, and evaluate their practical implementation within clinical environments. Recent investigations demonstrate that APOE4 status profoundly influences therapeutic efficacy, particularly with anti-amyloid interventions such as lecanemab, where carriers exhibit enhanced treatment response alongside increased adverse event susceptibility. Emerging gene therapeutic approaches show promise in mitigating APOE4-associated risks through targeted molecular interventions. The integration of APOE4 genotyping with fluid biomarkers and neuroimaging techniques enables refined patient stratification and enhanced diagnostic precision, facilitating earlier intervention windows that optimize therapeutic outcomes before irreversible neuronal damage occurs. This review underscores APOE4 testing as a transformative component of precision medicine in AD management, emphasizing its contribution to diagnostic refinement, clinical decision support, and targeted therapeutic interventions. Full article

Objectives: We investigated the in vivo biodistribution of vascular cell adhesion molecule-1 (VCAM-1)-targeting polystyrene nanoparticles (PS-NPs) labeled with Rhodamine B in a murine model of atherosclerosis. Methods: Targeted PS-NPs of varying sizes were first assessed for in vitro uptake in RAW264.7 cells. In vivo evaluation with VCAM-1-targeted nanoparticles (NP T) in C57 BL/6NtaC mice was conducted, and organs were analyzed 1, 6, and 24 h post injection, ex vivo. Subsequently, both targeted (NP T) and non-targeted (NP NT) nanoparticles of 30, 60, and 120 nm were injected into Apolipoprotein E knock-out (ApoE KO) mice on a high-fat diet, with ex vivo organ analysis 24 h post injection. Results: Results showed that NP30 T and NP60 T accumulated primarily in the liver and kidney of B6 mice. In ApoE KO mice, biodistribution was largely unaffected by size and targeting, except for higher uptake of NP 120 NT and T in the lungs and spleen. All NP types, except NP60 NT, showed significantly higher signal in ApoE KO mouse aortas compared to saline controls, with no significant differences between NP groups. Conclusions: While nanoparticles accumulated significantly in ApoE KO mouse aortas compared to controls, size and targeting properties did not significantly affect biodistribution in major organs 24 h post injection. Full article

Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood–brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer’s disease (AD), stroke, Parkinson’s disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy. Full article

Alzheimer’s disease (AD) is the most common cause of cognitive decline. Among the various susceptibility genes, the gene of apolipoprotein E (APOE) is probably the most important. It may be present in three allelic forms, termed ε2, ε3 and ε4, and the most common genotype is the ε3/ε3. Recently, it has been observed that subjects with the ε4/ε4 genotype may show near-full penetrance of AD biology (pathology and biomarkers), leading to the suggestion that ε4 homozygosity may represent a distinct genetic type of AD. The aim of the present study was to investigate the role of ε4 homozygosity or heterozygosity in the presence or absence of the AD biomarker profile in patients with cognitive disorders in the Greek population. A total of 274 patients were included in the study. They underwent APOE genotyping and cerebrospinal fluid (CSF) biomarker profiling. The presence of ε4 was associated with a lower age of symptom onset and decreased amyloid biomarkers (irrespective to AD or non-AD profiles), and predicted the presence of an AD profile by a positive predictive value approaching 100%. In conclusion, the ε4 allele has a significant effect on the risk and clinical parameters of cognitive impairment and AD in the Greek population, while the ε4/ε4 genotype may be highly indicative of the (co)existence of AD in cognitively impaired patients. Full article

Background: TGF-β is an immunosuppressive cytokine. Its signaling pathway plays a role in anti-inflammatory responses. Coronary artery disease (CAD) is a clinical consequence of atherosclerosis, which manifests as chronic inflammation and involves platelet mediators, including TGF-β. The aim of this study is to validate the diagnostic utility of TGF-β levels in relation to classical and molecular risk factors for CAD. Methods: The study group included 25 women and 75 men, all aged up to 55 and 50 years, respectively, who had been diagnosed with early-onset CAD. Fasting blood samples were taken to measure plasma levels of TGF-β, sCD36, PCSK9, TNF, VEGF, IL-6, and E-selectin using the ELISA method. Furthermore, a full lipid profile, apolipoproteins (Lp(a), ApoA1, and ApoB), C-reactive protein (hsCRP), and blood morphology were analyzed at the Central Hospital Laboratory. A physical examination was also performed. Results: Positive associations were observed between TGF-β concentration and TNF, platelet count, PTC, and triglyceride levels. TNF and platelet concentration were significant independent predictors of increased plasma TGF-β levels. None of the clinical parameters showed statistically significant associations with plasma TGF-β concentration. Conclusions: Our research has demonstrated that TGF-β levels, including circulating TNF, triglycerides, and platelets, are linked to specific biochemical risk factors in early-onset CAD cases. Full article

Alzheimer’s disease (AD) and ischemic stroke (IS) are prevalent neurological disorders that frequently co-occur in the same individuals. Recent studies have demonstrated that AD and IS share several common risk factors and pathogenic elements, including an overlapping genomic architecture. However, the relationship between IS risk gene polymorphisms and AD has been less extensively studied. We aimed at determining whether IS risk gene polymorphisms were associated with the risk of AD and the severity of AD in AD patients. We utilized data of AD patients and normal controls (NCs) sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. IS risk single nucleotide polymorphisms (SNPs) were identified through the most recent and largest IS genome-wide association study (GWAS) meta-analysis. Subsequently, we conducted SNP-based association analysis of IS-risk SNPs with the risk of AD, along with amyloid, tau, and neuroimaging for AD. The generalized multifactor dimensionality reduction (GMDR) model was used to assess the interactions among IS-risk SNPs and apolipoprotein E (ApoE) ε4. Protein–protein interactions (PPIs) of the IS-risk genes product and APOE were explored using the STRING database. Seven IS-risk SNPs were involved in the study. Five SNPs were found to be associated with at least one measurement of cerebrospinal fluid (CSF) levels of amyloid-beta 1–42 (Aβ₄₂), total tau (t-tau), and phosphorylated tau 181 (p-tau₁₈₁), as well as the volumes of the hippocampus, whole brain, entorhinal cortex, and mid-temporal regions. After multiple testing corrections, we found that T allele of rs1487504 contributed to an increased risk of AD in non-ApoE ε4 carriers. The combination of rs1487504 and ApoE ε4 emerged as the optimal two-factor model, and its interaction was significantly related to the risk of AD. Additionally, C allele of rs880315 was significantly associated with elevated levels of CSF Aβ₄₂ in AD patients, and A allele of rs10774625 was significantly related to a reduction in the volume of the entorhinal cortex in AD patients. This study found that IS risk SNPs were associated with both the risk of AD and AD major indicators in the ADNI cohort. These findings elucidated the role of IS in AD from a genetic perspective and provided an innovative approach to predict AD through IS-risk SNPs. Full article

Background: Inflammasomes regulate the activation of caspases resulting in inflammation; inflammasome activation is dysregulated in Alzheimer’s disease (AD) and plays a role in the pathogenesis of this condition. Glibenclamide, an anti-inflammatory drug, could be an interesting way to down-modulate neuroinflammation. Methods: In this pilot study we verified with ex vivo experiments whether a glibenclamide-loaded nanovector (GNV) could reduce the NLRP3-inflammasome cascade in cells of AD patients. Monocytes isolated from healthy controls (HC) and AD patients were cultured in medium, alone or stimulated with LPS + nigericin in presence/absence of GNV. ASC-speck positive cells and inflammasome-related genes, proteins, and miRNAs expressions were measured. The polymorphisms of ApoE (Apolipoprotein E), specifically rs7412 and rs429358, as well as those of NLRP3, namely rs35829419, rs10733113, and rs4925663, were also investigated. Results: Results showed that ASC-speck+ cells and Caspase-1, IL-1β, and IL-18 production was significantly reduced (p < 0.005 in all cases) by GNV in LPS + nigericin-stimulated cells of both AD and HC. Notably, the NLRP3 rs10733113 AG genotype was associated with excessive inflammasome-related gene and protein expression. GNV significantly down-regulates inflammasome activation in primary monocytes, at least at protein levels, and its efficacy seems to partially depend on the presence of the NLRP3 rs10733113 genotype. Conclusions: All together, these results showed that GNV is able to dampen inflammation and NLRP-3 inflammasome activation in an ex vivo monocyte model, suggesting a possible role for GNV in controlling AD-associated neuroinflammation. Full article

Apolipoprotein E (APOE) allele 4 (APOE4), one of the robust genetic risk factors for AD, has also been associated with cognitive decline in terms of memory, executive function, language, and global cognitive function. APOE genotype-stratified analysis can help to identify additional genetic loci which might be masked due to a strong effect of APOE4. We conducted a genome-wide meta-analysis in APOE2 carriers, APOE4 carriers, and APOE 3/3 homozygote groups among 2969 non-Hispanic Whites aged ≥ 65 years using slopes of decline over time across five cognitive domains (attention, language, executive function, memory, and visuospatial function) and global cognitive function. We identified novel genome-wide significant associations for decline in global cognitive function in the intergenic region between RNU7-66P/RNA5SP208 at rs116379916 (p = 1.44 × 10⁻⁹) in the APOE 3/3 group and for decline in language in the intergenic region between LINC0221/DTWD2 at rs13187183 (p = 3.79 × 10⁻⁸) in APOE4 carriers. A previously reported locus for decline in attention near RASEF at rs6559700 (p = 9.95 × 10⁻⁹) was found to be confined to the APOE 3/3 group. We also found two sub-threshold significant associations in the APOE 2 group for decline in attention (IL1RL2/rs77127114; p = 8.64 × 10⁻⁸) and decline in language (YTHDC2/KCNN2, rs116191836; p = 5.66 × 10⁻⁸). Our study points to potential biological pathways pertaining to specific domains within each APOE genotype group, and the findings suggest that immune-related pathways, plasma levels of polysaturated fatty acids, and bitter taste receptors may play roles in cognitive decline. Our findings enhance the understanding of cognitive aging and provide a framework for future studies. Full article