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Keywords = apolipoprotein AI

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19 pages, 2301 KB  
Article
Lactase Persistence-Associated rs4988235 Polymorphism: A Novel Genetic Link to Cardiovascular Risk via Modulation of ApoB100 and ApoAI
by Nihad Kharrat Helu, Habib Al Ashkar, Nora Kovacs, Roza Adany and Peter Piko
Nutrients 2025, 17(17), 2741; https://doi.org/10.3390/nu17172741 - 24 Aug 2025
Viewed by 1430
Abstract
Background/Objectives: As part of the human adaptation to dairy consumption, the presence of the rs4988235-T variant in the MCM6 gene primarily determines lactase persistence in adult European populations, increasing the expression of the lactase-encoding LCT gene. Carriers of the C/C variant are [...] Read more.
Background/Objectives: As part of the human adaptation to dairy consumption, the presence of the rs4988235-T variant in the MCM6 gene primarily determines lactase persistence in adult European populations, increasing the expression of the lactase-encoding LCT gene. Carriers of the C/C variant are lactose intolerant, while carriers of the T/T or T/C variant have persistent lactase enzyme activity and are able to digest lactose in adulthood. While the association between lactose intolerance and increased cardiovascular risk (CVR) is well-known, the underlying causes have only been partly explored. The present study aimed to investigate the association of rs4988235 polymorphism with significant lipids affecting cardiovascular health and estimated CVR. Methods: The rs4988235 polymorphism was genotyped in 397 subjects from the general Hungarian population and 368 individuals from the Roma population. To characterize the overall lipid profile, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), apolipoprotein AI (ApoAI), and apolipoprotein B100 (ApoB100) levels were measured, and their ratios (TG/HDL-C, LDL-C/HDL-C, and ApoB100/ApoAI) were calculated. Cardiovascular risk was estimated using the Framingham Risk Score (FRS), Pooled Cohort Equations (PCE), Revised Pooled Cohort Equations (RPCE), and the Systematic Coronary Risk Evaluations (SCORE and SCORE2) algorithms. Adjusted linear and logistic regression analyses were performed, with p < 0.05 considered significant. Results: The Roma population had a significantly higher prevalence of the C/C genotype than the general population (65.5% vs. 40.3%, respectively). The results of the adjusted linear regression analysis showed a significant association between the C/C genotype and higher LDL-C level (B = 0.126, p = 0.047) and ApoB100 level (B = 0.046, p = 0.013), as well as a higher LDL-C/HDL-C ratio (B = 0.174, p = 0.021) and a higher ApoB100/ApoAI ratio (B = 0.045, p = 0.002), as well as a lower HDL-C level (B = −0.041, p = 0.049). The C/C genotype was also significantly associated with an increased cardiovascular risk (CVR) as estimated by the SCORE (B = 0.235, p = 0.034), SCORE2 (B = 0.414, p = 0.009), PCE (B = 0.536, p = 0.008), and RPCE (B = 0.289, p = 0.045) but not the FRS. After adjusting the statistical model further for ApoAI and ApoB100 levels, the significant correlation with the risk estimation algorithms disappeared (SCORE: p = 0.099; SCORE2: p = 0.283; PCE: p = 0.255; and RPCE: p = 0.370). Conclusions: Our results suggest that the C/C genotype of rs4988235 is associated with significantly higher ApoB100 and lower ApoAI levels and consequently higher ApoB100/ApoAI ratios, potentially contributing to an increased risk of cardiovascular disease. The results of the statistical analyses suggest that the association between lactose intolerant genotype and cardiovascular risk may be mediated indirectly via modification of the apolipoprotein profile. Full article
(This article belongs to the Special Issue Lipids and Lipoproteins in Cardiovascular Diseases)
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17 pages, 1080 KB  
Article
Combined Effects of Exercise and Broccoli Supplementation on Metabolic and Lipoprotein Biomarkers in Adults with Type 2 Diabetes: A Randomized Controlled Trial
by Maryam Delfan, Masoumeh Gharedaghi, Farzaneh Zeynali, Rawad El Hage, Anthony C. Hackney, Halil İbrahim Ceylan, Ayoub Saeidi, Ismail Laher, Nicola Luigi Bragazzi and Hassane Zouhal
Nutrients 2025, 17(17), 2735; https://doi.org/10.3390/nu17172735 - 23 Aug 2025
Viewed by 1532
Abstract
Aim: To investigate the synergistic effects of exercise training and Brassica oleracea var. italica (broccoli sprout) supplementation on Apolipoprotein A-I, B-100, and J levels in men with Type 2 diabetes mellitus (T2DM). Methods: Forty-four males with T2DM were randomly assigned to four groups: [...] Read more.
Aim: To investigate the synergistic effects of exercise training and Brassica oleracea var. italica (broccoli sprout) supplementation on Apolipoprotein A-I, B-100, and J levels in men with Type 2 diabetes mellitus (T2DM). Methods: Forty-four males with T2DM were randomly assigned to four groups: Control (CG), Supplement (SG), Training (TG), and Training + Supplement (TSG) groups. Participants in the supplement groups (SG and TSG) received 10 g of broccoli supplement after meals for 12 weeks, while those in the training groups (TG and TSG) participated in a structured exercise program (resistance and aerobic), performed three times per week for 12 weeks, at intensities of 60–70% one-repetition maximum (1RM) for resistance training and 60–70% peak oxygen uptake (VO2peak) for aerobic training. Results: Circulating levels of apolipoproteins improved after 12 weeks in the TSG, TG, and SG groups. However, the TSG group exhibited the most pronounced improvements across metabolic and lipoprotein markers, reflecting an additive effect of both interventions. Specifically, the TSG group demonstrated absolute reductions in ApoB-100 (−48.30 ± 7.20 mg/dL) and ApoJ (−44.05 ± 5.76 mg/dL), along with an increase in ApoA-I (+44.92 ± 6.05 mg/dL). Main effect analysis revealed that exercise training elicited the most substantial improvements across metabolic and lipoprotein markers, with large effect sizes for glucose (η2p = 0.787), insulin (η2p = 0.640), HOMA-IR (η2p = 0.856), ApoA-I (η2p = 0.685), ApoB-100 (η2p = 0.774), ApoJ (η2p = 0.848), and HDL-C (η2p = 0.535). Supplementation showed moderate effects, particularly on HOMA-IR (η2p = 0.370), ApoA-I (η2p = 0.383), and ApoB-100 (η2p = 0.334), supporting an additive but exercise-dominant benefit. The combined intervention group (TSG) showed the most pronounced improvements across all measured outcomes, with large effect sizes for ApoA-I (η2p = 0.883), glucose (η2p = 0.946), insulin (η2p = 0.881), HOMA-IR (η2p = 0.904), and ApoJ (η2p = 0.852). Conclusions: The effects of combining training and broccoli sprout supplementation on apolipoprotein levels are likely to result from the activation of two separate pathways, one from training and the other from supplementation. This dual-modality intervention could serve as an effective complementary strategy in managing metabolic and cardiovascular risk factors for individuals with T2DM. However, the magnitude of change induced by the combination of exercise training and broccoli supplementation was largely driven by the training component, with supplementation providing complementary but less consistent benefits. Full article
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17 pages, 360 KB  
Review
Nanocarrier-Assisted Delivery of Drug(s) for the Targeted Treatment of Neurodegenerative Disease
by Joseph S. D’Arrigo
Int. J. Transl. Med. 2025, 5(3), 37; https://doi.org/10.3390/ijtm5030037 - 19 Aug 2025
Viewed by 694
Abstract
Apolipoprotein A-I (apoA-I)-coated nanoemulsion particles target scavenger receptors. Adsorbed apoA-I (from the bloodstream) mediates/facilitates this targeted molecular contact, which is followed by receptor-mediated endocytosis and subsequent transcytosis of these same nanoemulsion (nanocarrier) particles across the blood–brain barrier (BBB). When the right drugs are [...] Read more.
Apolipoprotein A-I (apoA-I)-coated nanoemulsion particles target scavenger receptors. Adsorbed apoA-I (from the bloodstream) mediates/facilitates this targeted molecular contact, which is followed by receptor-mediated endocytosis and subsequent transcytosis of these same nanoemulsion (nanocarrier) particles across the blood–brain barrier (BBB). When the right drugs are added in advance to these high-density lipoprotein (HDL)-like nanocarriers, multifunctional combination treatment is achieved. This medication penetrates the BBB and targets particular cell-surface scavenger receptors, mainly class B type I (SR-BI). As a result, these (drug-carrying) nanoemulsions may find application in the biomedical therapy of complex medical disorders, such as dementia, as well as some aspects of aging. According to recent research, sustained inflammatory stimulation in the gut, such as via serum amyloid A (SAA), may cause the release of proinflammatory cytokines. Thus, using this “HDL-like” nanoemulsion vehicle to target drugs early (or even proactively) toward a major SAA receptor (like SR-BI), which is implicated in SAA-mediated cell-signaling processes that lead to aging and/or cognitive decline (and eventually Alzheimer’s disease or dementia), may be a useful preventive and therapeutic strategy. Full article
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19 pages, 1856 KB  
Article
Combination Therapy with Trehalose and Hyaluronic Acid Restores Tear Lipid Layer Functionality by Ameliorating Inflammatory Response Protein Markers on the Ocular Surface of Dry Eye Patients
by Natarajan Perumal, Caroline Manicam, Eunjin Jeong, Sarah Runde, Norbert Pfeiffer and Franz H. Grus
J. Clin. Med. 2025, 14(15), 5525; https://doi.org/10.3390/jcm14155525 - 5 Aug 2025
Viewed by 1455
Abstract
Objectives: Topical lubricants are the fundamental treatment for dry eye disease (DED). However, the molecular mechanisms underlying their efficacy remain unknown. Here, the protective effects of Thealoz® Duo with 3% trehalose and 0.15% hyaluronic acid are investigated in DED patients by a [...] Read more.
Objectives: Topical lubricants are the fundamental treatment for dry eye disease (DED). However, the molecular mechanisms underlying their efficacy remain unknown. Here, the protective effects of Thealoz® Duo with 3% trehalose and 0.15% hyaluronic acid are investigated in DED patients by a longitudinal clinical study and subsequent elucidation of the tear proteome and cell signaling changes. Methods: Participants were classified as moderate to severe DED (DRY, n = 35) and healthy (CTRL, n = 23) groups. Specific DED subgroups comprising evaporative (DRYlip) and aqueous-deficient with DRYlip (DRYaqlip) were also classified. Only DED patients received Thealoz® Duo. All participants were clinically examined before (day 0, T1) and after the application of Thealoz® Duo at day 28 (T2) and day 56 (T3). Next, 174 individual tear samples from all groups at three time-points were subjected to proteomics analysis. Results: Clinically, Thealoz® Duo significantly improved the ocular surface disease index at T2 vs. T1 (DRY, p = 1.4 × 10−2; DRYlip, p = 9.2 × 10−3) and T3 vs. T1 (DRY, p = 2.1 × 10−5; DRYlip, p = 1.2 × 10−4), and the tear break-up time at T3 vs. T1 (DRY, p = 3.8 × 10−2; DRYlip, p = 1.4 × 10−2). Thealoz® Duo significantly ameliorated expression of inflammatory response proteins (p < 0.05) at T3, which was observed at T1 (DRY, p = 3.4 × 10−4; DRYlip, p = 7.1 × 10−3; DRYaqlip, p = 2.7 × 10−8). Protein S100-A8 (S100A8), Alpha-1-antitrypsin (SERPINA1), Annexin A1 (ANXA1), and Apolipoprotein A-I (APOA1) were found to be significantly reduced in all the DED subgroups. The application of Thealoz® Duo showed the therapeutic characteristic of the anti-inflammatory mechanism by promoting the expression of (Metalloproteinase inhibitor 1) TIMP1 in all the DED subgroups. Conclusions: Thealoz® Duo substantially improved the DED symptoms and restored the functionality of the tear lipid layer to near normal in DRYlip and DRY patients by ameliorating inflammation. Notably, this study unravels the novel mechanistic alterations underpinning the healing effects of Thealoz® Duo in DED subgroups in a time-dependent manner, which supports the improvement in corresponding clinical attributes. Full article
(This article belongs to the Section Ophthalmology)
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24 pages, 4271 KB  
Article
Proteomic Profiling Reveals Novel Molecular Insights into Dysregulated Proteins in Established Cases of Rheumatoid Arthritis
by Afshan Masood, Hicham Benabdelkamel, Assim A. Alfadda, Abdurhman S. Alarfaj, Amina Fallata, Salini Scaria Joy, Maha Al Mogren, Anas M. Abdel Rahman and Mohamed Siaj
Proteomes 2025, 13(3), 32; https://doi.org/10.3390/proteomes13030032 - 4 Jul 2025
Cited by 1 | Viewed by 1099
Abstract
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that predominantly affects synovial joints, leading to inflammation, pain, and progressive joint damage. Despite therapeutic advancements, the molecular basis of established RA remains poorly defined. Methods: In this study, we conducted an untargeted [...] Read more.
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that predominantly affects synovial joints, leading to inflammation, pain, and progressive joint damage. Despite therapeutic advancements, the molecular basis of established RA remains poorly defined. Methods: In this study, we conducted an untargeted plasma proteomic analysis using two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in samples from RA patients and healthy controls in the discovery phase. Results: Significantly (ANOVA, p ≤ 0.05, fold change > 1.5) differentially abundant proteins (DAPs) were identified. Notably, upregulated proteins included mitochondrial dicarboxylate carrier, hemopexin, and 28S ribosomal protein S18c, while CCDC124, osteocalcin, apolipoproteins A-I and A-IV, and haptoglobin were downregulated. Receiver operating characteristic (ROC) analysis identified CCDC124, osteocalcin, and metallothionein-2 with high diagnostic potential (AUC = 0.98). Proteins with the highest selected frequency were quantitatively verified by multiple reaction monitoring (MRM) analysis in the validation cohort. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) revealed the underlying molecular pathways and key interaction networks involved STAT1, TNF, and CD40. These central nodes were associated with immune regulation, cell-to-cell signaling, and hematological system development. Conclusions: Our combined proteomic and bioinformatic approaches underscore the involvement of dysregulated immune pathways in RA pathogenesis and highlight potential diagnostic biomarkers. The utility of these markers needs to be evaluated in further studies and in a larger cohort of patients. Full article
(This article belongs to the Special Issue Proteomics in Chronic Diseases: Issues and Challenges)
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18 pages, 3937 KB  
Article
Preliminary Evaluation of 3D-Printed Alginate/Gelatin Scaffolds for Protein Fast Release as Suitable Devices for Personalized Medicine
by Benedetta Ghezzi, Ruben Foresti, Luisa Pia Scialoia, Maddalena Botti, Arianna Mersanne, Fulvio Ratto, Francesca Rossi, Chiara Martini, Paolo Perini, Elda Favari and Antonio Freyrie
Biomedicines 2025, 13(6), 1365; https://doi.org/10.3390/biomedicines13061365 - 2 Jun 2025
Cited by 1 | Viewed by 1026
Abstract
Background/Objectives: Drug-coated balloons (DCBs) are emerging as a promising treatment for peripheral artery disease; however, current technologies lack flexibility in customizing drug release profiles and composition, limiting their therapeutic potential. This study aims to develop a Gelatin (Gel) and Sodium Alginate (Alg) bioink [...] Read more.
Background/Objectives: Drug-coated balloons (DCBs) are emerging as a promising treatment for peripheral artery disease; however, current technologies lack flexibility in customizing drug release profiles and composition, limiting their therapeutic potential. This study aims to develop a Gelatin (Gel) and Sodium Alginate (Alg) bioink loaded with apolipoprotein A-I (apoA-I) for controlled drug delivery by using additive manufacturing technologies. Methods: We developed and printed via rapid freeze prototyping (RFP) a Gel and Alg bioink loaded with different concentrations of apoA-I. Mechanical properties related to compressional and tensile forces have been studied, as well as the structural stability and active release from the 3D structure of apoA-I (cholesterol efflux assays). The biological behavior of HUVEC cells with and without ApoA-I was assessed by proliferation assay, metabolic activity analysis, and fluorescence imaging. Results: The 3D structures presented breakpoint stress values consistent with the mechanical requirements for integration within a DCB, and the ability to effectively promote cholesterol transport in J774 cells. Moreover, in vitro studies on HUVECs revealed that the scaffolds exhibited no cytotoxic effects, leading to increased ATP levels and enhanced metabolic activity over time, confirming the possibility to obtain RFP-printed Alg/Gel scaffolds able to provide a stable structure capable of controlled apoA-I release. Conclusions: These findings support the potential of Alg/Gel+apoA-I scaffolds as biocompatible drug delivery systems for vascular applications. Their ability to maintain structural integrity while enabling controlled biomolecular release positions them as promising candidates for personalized cardiovascular therapy, facilitating the rapid customization of bioprinted therapeutic platforms. Full article
(This article belongs to the Section Biomedical Engineering and Materials)
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17 pages, 788 KB  
Review
Amyloid β-Induced Inflammarafts in Alzheimer’s Disease
by Shihui Ding, Soo-Ho Choi and Yury I. Miller
Int. J. Mol. Sci. 2025, 26(10), 4592; https://doi.org/10.3390/ijms26104592 - 10 May 2025
Cited by 2 | Viewed by 1477
Abstract
The formation of amyloid beta (Aβ) plaques is a central process in the development of Alzheimer’s disease (AD). Although its causative role or the effectiveness of therapeutic targeting is still debated, the key involvement of Aβ in the pathogenesis of neuroinflammation and neurodegeneration [...] Read more.
The formation of amyloid beta (Aβ) plaques is a central process in the development of Alzheimer’s disease (AD). Although its causative role or the effectiveness of therapeutic targeting is still debated, the key involvement of Aβ in the pathogenesis of neuroinflammation and neurodegeneration in AD is broadly accepted. In this review, we emphasize the role of lipid rafts, both in APP cleavage producing Aβ in neurons and in mediating Aβ inflammatory signaling in microglia. We introduce the term inflammarafts to characterize the Aβ-driven formation of enlarged, cholesterol-rich lipid rafts in activated microglia, which support protein–protein and lipid–protein interactions of inflammatory receptors. Examples reviewed include toll-like receptors (TLR2, TLR4), scavenger receptors (CD36, RAGE), and TREM2. The downstream pathways lead to the production of cytokines and reactive oxygen species, intensifying neuroinflammation and resulting in neuronal injury and cognitive decline. We further summarize emerging therapeutic strategies and emphasize the utility of apolipoprotein A-I binding protein (AIBP) in selective targeting of inflammarafts and attenuation of microglia-driven inflammation. Unlike the targeting of a single inflammatory receptor or a secretase, selective disruption of inflammarafts and preservation of physiological lipid rafts offer a novel approach to targeting multiple components and processes that contribute to neuroinflammation in AD. Full article
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16 pages, 4233 KB  
Article
Exploring the Histopathological Features of Thrombus-Associated Localized Amyloid Deposition: Comprehensive Analysis Employing Immunohistochemistry and Proteomics
by Shojiro Ichimata, Tsuneaki Yoshinaga, Mitsuto Sato, Nagaaki Katoh, Fuyuki Kametani, Masahide Yazaki, Yoshiki Sekijim, Yukiko Hata and Naoki Nishida
Int. J. Mol. Sci. 2025, 26(10), 4505; https://doi.org/10.3390/ijms26104505 - 8 May 2025
Viewed by 3065
Abstract
Amyloid deposition has been reported to localize within thrombi; however, its pathological characteristics, particularly its precursor proteins, remain poorly understood. This study aimed to elucidate the pathological features of thrombus-associated amyloid deposition by immunohistochemistry combined with proteomic analyses using liquid chromatography–tandem mass spectrometry [...] Read more.
Amyloid deposition has been reported to localize within thrombi; however, its pathological characteristics, particularly its precursor proteins, remain poorly understood. This study aimed to elucidate the pathological features of thrombus-associated amyloid deposition by immunohistochemistry combined with proteomic analyses using liquid chromatography–tandem mass spectrometry with laser microdissection. Our findings revealed that thrombus-associated amyloid deposits within the thrombus and vessel wall primarily comprised apolipoprotein A-I, with a mixture of amyloid fibrils derived from amyloidogenic proteins, including transthyretin and lactoferrin. Given that these proteins are present in the blood, our results support a previous hypothesis that proteins denatured during thrombus aging are a source of amyloid. Furthermore, phagocytes were infiltrated around the intramural and extravascular deposits rather than around the amyloid deposits within the thrombus. Therefore, amyloid deposits generated within the thrombus may be transported from regions with limited blood flow to the vessel wall and surrounding tissues, where blood flow is present, during thrombus processing. These deposits were primarily removed by phagocytic cells. Our results suggest that a facilitative effect on deposition occurs via a cross-seeding mechanism between amyloid fibrils and that phagocytes can remove amyloid deposits. These findings help elucidate the pathogenesis of localized amyloidosis. Full article
(This article belongs to the Special Issue Role of Proteomics in Human Diseases and Infections)
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12 pages, 3415 KB  
Article
Causal Relationship Between Blood Metabolites and Osteoporosis: A Two-Sample Mendelian Randomization and Genetic Correlation Analysis
by Xu Liu, Guang Yang, Yusheng Li, Wenfeng Xiao, Bangbao Lu and Yaping Wang
Bioengineering 2025, 12(5), 435; https://doi.org/10.3390/bioengineering12050435 - 22 Apr 2025
Viewed by 785
Abstract
Background: Osteoporosis (OP) is a systemic bone disease often undiagnosed until fractures occur. Metabolites may influence OP, offering potential biomarkers or therapeutic targets. This study investigates the causal relationship between circulating metabolites and OP-related phenotypes using Mendelian Randomization (MR). Methods: GWAS data on [...] Read more.
Background: Osteoporosis (OP) is a systemic bone disease often undiagnosed until fractures occur. Metabolites may influence OP, offering potential biomarkers or therapeutic targets. This study investigates the causal relationship between circulating metabolites and OP-related phenotypes using Mendelian Randomization (MR). Methods: GWAS data on 233 metabolic traits from 136,016 participants were analyzed through two-sample MR. Linkage disequilibrium score regression (LDCS) was used to estimate genetic correlations between metabolic traits and OP-related phenotypes, leveraging European ancestry linkage disequilibrium scores to account for polygenicity and stratification. MR employed the inverse-variance weighted (IVW) method, with sensitivity analyses via MR-Egger, MR-PRESSO, and weighted median methods to address pleiotropy and confounders. Results: LDCS identified significant genetic correlations between metabolites and bone mineral density (BMD) phenotypes, with total body BMD (toBMD) showing the strongest associations. Thirty-five metabolite traits, including apolipoprotein A-I, exhibited significant linkages. Among 79 metabolites influencing BMD, serum acetate levels were significantly associated with femoral neck BMD (OR: 1.28, 95% CI: 1.02–1.62), lumbar spine BMD (OR: 1.73, 95% CI: 1.32–2.27), and total body BMD (OR: 1.21, 95% CI: 1.04–1.42). Creatinine levels were consistently linked to reduced BMD, including lumbar spine BMD (OR: 0.88, 95% CI: 0.79–0.99). Triglycerides in IDL and VLDL particles also contributed to BMD variation. Conclusions: Significant genetic correlations and causal relationships were observed between specific metabolites and OP, highlighting key traits as potential biomarkers of bone health. These findings enhance the understanding of OP pathogenesis and suggest future preventive strategies. Full article
(This article belongs to the Special Issue Advanced Engineering Technologies in Orthopaedic Research)
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18 pages, 680 KB  
Article
High-Density Lipoprotein Particles, Inflammation, and Coronary Heart Disease Risk
by Eveline O. Stock, Bela F. Asztalos, John M. Miller, Lihong He, Kate Townsend Creasy, Rachel Schwemberger, Alexander Quinn, Clive R. Pullinger, Mary J. Malloy, Margaret R. Diffenderfer and John P. Kane
Nutrients 2025, 17(7), 1182; https://doi.org/10.3390/nu17071182 - 28 Mar 2025
Cited by 3 | Viewed by 1827
Abstract
Background: Coronary heart disease (CHD) remains a leading cause of death and has been associated with alterations in plasma lipoprotein particles and inflammation markers. This study aimed to evaluate and compare standard and advanced lipid parameters and inflammatory biomarkers in CHD cases and [...] Read more.
Background: Coronary heart disease (CHD) remains a leading cause of death and has been associated with alterations in plasma lipoprotein particles and inflammation markers. This study aimed to evaluate and compare standard and advanced lipid parameters and inflammatory biomarkers in CHD cases and matched control subjects. We hypothesized that incorporating advanced lipid and inflammatory biomarkers into risk models would improve CHD risk prediction beyond the standard lipid measures. Methods: CHD cases (n = 227, mean age 61 years, 47% female) and matched controls (n = 526) underwent fasting blood collection while off lipid-lowering medications. Automated chemistry analyses were performed to measure total cholesterol (TC), triglycerides (TGs), low-density lipoprotein-C (LDL-C), small dense LDL-C (sdLDL-C), apolipoproteins (apos) A-I and B, lipoprotein(a) (Lp(a)), high-sensitivity C-reactive protein (hsCRP), serum amyloid-A (SAA), myeloperoxidase (MPO), and apoA-I in HDL particles (via 2-dimensional electrophoresis and immunoblotting). Univariate, multivariate, and machine learning analyses compared the CHD cases with the controls. Results: The most significant percent differences between male and female cases versus controls were for hsCRP (+78%, +200%), MPO (+109%, +106%), SAA (+84%, +33%), sdLDL-C (+48%; +43%), Lp(a) (+43%,+70%), apoA-I in very large α-1 HDL (−34%, −26%), HDL-C (−24%, −27%), and apoA-I in very small preβ-1 HDL (+17%; +16%). Total C, non-HDL-C, and direct and calculated LDL-C levels were only modestly higher in the cases. Multivariate models incorporating advanced parameters were statistically superior to a standard model (C statistic: men: 0.913 vs. 0.856; women: 0.903 versus 0.838). Machine learning identified apoA-I in preβ-1-HDL, α-2-HDL, α-1-HDL, α-3-HDL, MPO, and sdLDL-C as the top predictors of CHD. Conclusions: This study introduces a novel approach to CHD risk assessment by integrating advanced HDL particle analysis and machine learning. By assessing HDL subpopulations (α-1, α-2, preβ-1 HDL), inflammatory biomarkers (MPO, SAA), and small dense LDL, we provide a more refined stratification model. Notably, preβ-1 HDL, an independent risk factor reflecting impaired cholesterol efflux from the artery wall, is highlighted as a critical marker of CHD risk. Our approach allows for earlier identification of high-risk individuals, particularly those with subtle lipid or inflammatory abnormalities, supporting more personalized interventions. These findings demonstrate the potential of advanced lipid profiling and machine learning to enhance CHD risk prediction. Full article
(This article belongs to the Special Issue Impact of Lipids on Cardiovascular Health)
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19 pages, 32075 KB  
Article
Network Pharmacology-Based Elucidation of the Hypoglycemic Mechanism of Grifola frondosa GF5000 Polysaccharides via GCK modulation in Diabetic Rats
by Chun Xiao, Chunwei Jiao, Longhua Huang, Huiping Hu, Yizhen Xie and Qingping Wu
Nutrients 2025, 17(6), 964; https://doi.org/10.3390/nu17060964 - 10 Mar 2025
Viewed by 1350
Abstract
Background/Objectives: Our lab has previously reported that Grifola frondosa (maitake mushroom) GF5000 has antidiabetic potential owing to its ability to improve insulin resistance. This study aimed to gain insight into the system-level hypoglycemic mechanisms of GF5000 using transcriptomics, proteomics, and network pharmacology. This [...] Read more.
Background/Objectives: Our lab has previously reported that Grifola frondosa (maitake mushroom) GF5000 has antidiabetic potential owing to its ability to improve insulin resistance. This study aimed to gain insight into the system-level hypoglycemic mechanisms of GF5000 using transcriptomics, proteomics, and network pharmacology. This study provides new insights into the hypoglycemic mechanisms of GF5000, identifying key molecular targets involved in mitigating insulin resistance in T2DM. Methods: Liver protein and gene expression in normal control (NC), diabetic control (DC), and GF5000-treated (GF5000) rats were analyzed via iTRAQ and RNA-seq. The relationships between differentially expressed genes (DEGs), differentially expressed proteins (DEPs), and type 2 diabetes (T2DM) disease targets were studied using Metascape and the Cytoscape GeneMANIA plug-in. Results: One hundred and fifty-two DEGs and sixty-two DEPs were identified; twenty DEGs/DEPs exhibited the same trend in mRNA and protein expression levels when comparing the GF5000 vs. DC groups. The Metascape analysis revealed that the T2DM disease targets included four DEGs—Gck, Scd, Abcb4, and Cyp3a9—and two DEPs—glucokinase and acetyl-CoA carboxylase 2. A Cytoscape–GeneMANIA analysis of thirteen DEGs/DEPs related to T2DM showed that Apoa1/Apolipoprotein A-I, Gckr/glucokinase regulatory protein, and Gck/glucokinase had the highest connectivity and centrality in the topological network. The qPCR results confirmed that GF5000 increased the mRNA expression of GCK in GCK-knockdown HepG2 cells. Conclusions: These results provide theoretical evidence for the use of GF5000 as a potential active nutritional ingredient for the prevention and treatment of T2DM. Our findings suggest that GF5000 targets multiple pathways implicated in T2DM, offering a multi-faceted approach to disease management and prevention. Full article
(This article belongs to the Section Nutrition and Diabetes)
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10 pages, 487 KB  
Article
Association of Nerve Conduction Study Variables with Hematologic Tests in Patients with Type 2 Diabetes Mellitus
by Jung-Eun Han, Jun-Hwan Choi, So-Yeon Yoo, Gwan-Pyo Koh, Sang-Ah Lee, So-Young Lee and Hyun-Jung Lee
Medicina 2025, 61(3), 430; https://doi.org/10.3390/medicina61030430 - 28 Feb 2025
Viewed by 1188
Abstract
Background and Objective: Diabetic peripheral neuropathy (DPN) is a prevalent complication of type 2 diabetes mellitus (T2DM), with nerve conduction studies (NCSs) serving as the diagnostic gold standard. Early diagnosis is critical for effective management, yet many cases are detected late due [...] Read more.
Background and Objective: Diabetic peripheral neuropathy (DPN) is a prevalent complication of type 2 diabetes mellitus (T2DM), with nerve conduction studies (NCSs) serving as the diagnostic gold standard. Early diagnosis is critical for effective management, yet many cases are detected late due to the gradual onset of symptoms. This study explores the relationship between hematological tests and NCS outcomes in T2DM patients to improve the early detection of DPN. Material and Methods: This retrospective study involved T2DM patients exhibiting neuropathic symptoms, and patients were divided based on NCS findings into groups with normal and abnormal results to assess the diagnostic value of various hematological markers, clinical, and demographic data for DPN. Results: Among 400 participants, 57% (n = 228) had abnormal NCS results indicative of DPN. Significant differences were observed in the abnormal-NCS group, including older age, longer diabetes duration, higher levels of fasting plasma glucose, HbA1c, and apolipoprotein B, along with lower eGFR, HDL-C, and Apo A-I levels. Notably, negative correlations were found between HDL-C, Apo A-I, vitamin B12, and specific NCS measurements, while positive correlations existed with sural sensory nerve amplitudes. Multivariate analysis highlighted the importance of age, diabetes duration, hyperglycemia, and specific hematologic markers in predicting DPN. Conclusions: The findings confirm that NCSs, combined with hematologic testing, can effectively identify DPN in T2DM patients. Consistent with prior research, prolonged hyperglycemia and nephropathy progression are strongly linked to DPN development. Additionally, lower levels of HDL-C, Apo A-I, and vitamin B12 are associated with the condition, suggesting their potential utility in early diagnostic protocols. Full article
(This article belongs to the Special Issue Advances in Clinical Diabetes, Obesity, and Metabolic Diseases)
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28 pages, 2473 KB  
Review
High-Density Lipoprotein in Patients with Diabetic Kidney Disease: Friend or Foe?
by Ke Liu, Mark E. Cooper, Zhonglin Chai and Fang Liu
Int. J. Mol. Sci. 2025, 26(4), 1683; https://doi.org/10.3390/ijms26041683 - 16 Feb 2025
Cited by 2 | Viewed by 2136
Abstract
High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic [...] Read more.
High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD. Full article
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29 pages, 12007 KB  
Article
Molecular Simulation of the Binding of Amyloid Beta to Apolipoprotein A-I in High-Density Lipoproteins
by Chris J. Malajczuk and Ricardo L. Mancera
Int. J. Mol. Sci. 2025, 26(3), 1380; https://doi.org/10.3390/ijms26031380 - 6 Feb 2025
Cited by 1 | Viewed by 1146
Abstract
Disrupted clearance of amyloid beta (Aβ) from the brain enhances its aggregation and formation of amyloid plaques in Alzheimer’s disease. The most abundant protein constituent of circulating high-density lipoprotein (HDL) particles, apoA-I, readily crosses the blood–brain barrier from periphery circulation, exhibits low-micromolar binding [...] Read more.
Disrupted clearance of amyloid beta (Aβ) from the brain enhances its aggregation and formation of amyloid plaques in Alzheimer’s disease. The most abundant protein constituent of circulating high-density lipoprotein (HDL) particles, apoA-I, readily crosses the blood–brain barrier from periphery circulation, exhibits low-micromolar binding affinity for soluble, neurotoxic forms of Aβ, and modulates Aβ aggregation and toxicity in vitro. Its highly conserved N-terminal sequence, 42LNLKLLD48 (‘LN’), has been proposed as a binding region for Aβ. However, high-resolution structural characterisation of the mechanism of HDL–Aβ interaction is very difficult to attain. Molecular dynamics simulations were conducted to investigate for the first time the interaction of Aβ and the ‘LN’ segment of apoA-I. Favourable binding of Aβ by HDLs was found to be driven by hydrophobic and hydrogen-bonding interactions predominantly between the ‘LN’ segment of apoA-I and Aβ. Preferential binding of Aβ may proceed in small, protein-rich HDLs whereby solvent-exposed hydrophobic ‘LN’ segments of apoA-I interact specifically with Aβ, stabilising it on the HDL surface in a possibly non-amyloidogenic conformation, facilitating effective Aβ clearance. These findings rationalise the potentially therapeutic role of HDLs in reducing Aβ aggregation and toxicity, and of peptide mimics of the apoA-I interacting region in blocking Aβ aggregation. Full article
(This article belongs to the Special Issue Advances in Protein Dynamics)
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13 pages, 1431 KB  
Article
The Role of Paraoxonase-1 Activity, Apolipoprotein B Levels, and Apolipoprotein B/Apolipoprotein A-I Ratio as Risk Markers for Aortic Stenosis in Patients with a Bicuspid Aortic Valve
by Maria Kwiatkowska, Agnieszka Mickiewicz, Aleksandra Krzesińska, Agnieszka Kuchta, Maciej Jankowski, Marcin Gruchała and Marcin Fijałkowski
Antioxidants 2025, 14(2), 167; https://doi.org/10.3390/antiox14020167 - 30 Jan 2025
Viewed by 990
Abstract
The bicuspid aortic valve (BAV) is commonly associated with the early degeneration of the aortic valve. Up to 45% of BAV patients over the age of 50 develop aortic stenosis (AS). Although published data indicate a robust interplay between lipids and calcific AS [...] Read more.
The bicuspid aortic valve (BAV) is commonly associated with the early degeneration of the aortic valve. Up to 45% of BAV patients over the age of 50 develop aortic stenosis (AS). Although published data indicate a robust interplay between lipids and calcific AS in tricuspid aortic valve patients, the studies on the BAV population are lacking. We aimed to evaluate the association between selected lipid markers and the occurrence of AS in BAV patients. Methods: The study included 76 adults (21 female) with a BAV diagnosed by echocardiography, divided by age and AS diagnosis. Biochemical parameters concentrations in serum were measured: high density lipoprotein cholesterol (HDL-C) levels by standard enzymatic colorimetric tests, low density lipoprotein cholesterol (LDL-C) levels by the Friedewald formula, apolipoprotein A-I (Apo AI) and apolipoprotein B (Apo B) serum concentration by the nephelometric method, and paraoxonase-1 activity (PON-1 ASE) and arylesterase activity (PON-1 ARE) based on paraoxon and phenyl acetate hydrolysis. Results: A total of 54 patients (15 female) were more than 45 years old and 22 (6 female) were 45 or less years old. BAV patients with AS aged ≤45 had higher levels of Apo B, compared to those without AS [110.5 (102–132) vs. 95.6 (77–101) mg/d; p 0.044]. Similarly, Apo B/Apo AI ratio was higher in BAV patients with AS aged ≤45, compared to those without AS [(0.8 (0.7–1) vs. 0.6 (0.5–0.7); p 0.029]. In the group aged ≤45, Apo B showed a positive correlation with the aortic valve peak transvalvular velocity (AV Vmax) measurement (R Spearman 0.6, p 0.004). We found also that, among young BAV patients, those with AS had a lower level of PON-1 ARE compared to the cohort without AS [63.4 (52–80) vs. 85.3 (70–102); p 0.012]. We did not find any differences in lipid parameters in patients aged >45. Conclusions The metabolic link between Apo B level and Apo B/AI ratio with AS presence in BAV patients under 45 years of age suggests a significant impact of these parameters on the earlier development of AS in the BAV population. Molecules associated with high density lipoprotein and its antioxidant function, such as PON1, are valuable markers for AS development, compared to HDL-C and LDL-C levels. Full article
(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)
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