Search Results (449)

Background/Objectives: Hyperlipidemia is a major risk factor for cardiovascular disease and atherosclerosis. Polyphenols found in polyphenol-rich extra virgin olive oil (EVOO) have been shown to possess strong antioxidant, anti-inflammatory, and cardioprotective properties. The present study aimed to assess the effects of two types of EVOO with different polyphenol content and dosages on the lipid profile of hyperlipidemic patients. Methods: In this single-blind, randomized clinical trial, 50 hyperlipidemic patients were randomized to receive either a higher-dose, lower-phenolic EVOO (414 mg/kg phenols, 20 g/day) or a lower-dose, higher-phenolic EVOO (1021 mg/kg phenols, 8 g/day), for a period of 4 weeks. These doses were selected to ensure equivalent daily polyphenol intake in both groups (~8.3 mg of total phenols/day), based on chemical analysis performed using NMR spectroscopy. The volumes used (8–20 g/day) reflect typical daily EVOO intake and were well tolerated by participants. A group of 20 healthy individuals, separated into two groups, also received the two types of EVOO, respectively, for the same duration. Primary endpoints included blood levels of total blood cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, lipoprotein-a (Lpa), and apolipoproteins A1 and B. Measurements were performed at baseline and at the end of the 4-week intervention. Linear mixed models were performed for the data analysis. Results: The higher-phenolic, lower-dose EVOO group showed a more favorable change in total blood cholesterol (p = 0.045) compared to the lower-phenolic, higher-dose group. EVOO intake was associated with a significant increase in HDL (p < 0.001) and reduction in Lp(a) (p = 0.040) among hyperlipidemic patients in comparison to healthy individuals. Conclusions: EVOO consumption significantly improved the lipid profile of hyperlipidemic patients. Higher-phenolic EVOO at lower dosages appears to be more effective in improving the lipid profile than lower-phenolic EVOO in higher dosages. 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

Background: High-density lipoprotein cholesterol (HDL-C) is known for its cardiovascular and neuroprotective effects, but its association with cognitive function remains unclear, particularly in relation to genetic factors such as apolipoprotein E ε4 (APOE4). We aimed to investigate the association between serum HDL-C levels and cognition and to examine the moderating effect of APOE4 on this relationship. Methods: This cross-sectional study included 196 dementia-free older adults (aged 65–90) recruited from a memory clinic and the community. Cognitive function was assessed across multiple domains using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery. Serum HDL-C levels were measured, and APOE4 genotyping was performed. Multiple linear regression analyses were conducted, adjusting for age, sex, APOE4 status, education, diagnosis, vascular risk, nutritional status, physical activity, and blood biomarkers. Results: Higher HDL-C levels were significantly associated with better episodic memory (B = 0.109, 95% confidence interval [CI]: 0.029–0.189, p = 0.008) and global cognition (B = 0.130, 95% CI: 0.001–0.261, p = 0.049). These associations were significantly moderated by APOE4 status. In APOE4-positive individuals, HDL-C was strongly associated with both episodic memory (B = 0.357, 95% CI: 0.138–0.575, p = 0.003) and global cognition (B = 0.519, 95% CI: 0.220–0.818, p = 0.002), but no such associations were observed in APOE4-negative participants. Conclusions: This study indicates a significant association between serum HDL-C levels and cognitive function, particularly in episodic memory and global cognition, with APOE4 status potentially moderating this relationship. While these findings may suggest a protective role of HDL-C in individuals at increased genetic risk due to APOE4, they should be interpreted with caution given the cross-sectional design. Future longitudinal and mechanistic studies are warranted to clarify causality and potential clinical implications. Full article

Atherosclerotic cardiovascular disease (ASCVD) remains the leading global cause of morbidity and mortality, even in the era of aggressive low-density lipoprotein cholesterol (LDL-C) lowering. This persistent residual risk has prompted a reevaluation of atherogenic lipid markers, with non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (Apo B) emerging as superior indicators of the total atherogenic particle burden. Unlike LDL-C, non-HDL-C includes cholesterol from all atherogenic lipoproteins, while Apo B reflects the total number of atherogenic particles regardless of cholesterol content. Their clinical relevance is underscored in populations with diabetes, obesity, and hypertriglyceridemia, where LDL-C may not adequately reflect cardiovascular risk. This review explores the biological, clinical, and genetic foundations of non-HDL-C and Apo B as critical tools for risk stratification and therapeutic targeting. It highlights discordance analysis, inflammatory mechanisms in atherogenesis, the influence of metabolic syndromes, and their utility in specific populations, including those with chronic kidney disease and children with familial hypercholesterolemia. Additionally, the role of lipoprotein (a), glycation in diabetes, and hypertriglyceridemia are examined as contributors to residual risk. Clinical trials and genetic studies support Apo B and non-HDL-C as more robust predictors of cardiovascular events than LDL-C. Current guidelines increasingly endorse these markers as secondary or even preferred targets in complex lipid disorders. The incorporation of Apo B and non-HDL-C into routine clinical practice, especially for patients with residual risk, represents a paradigm shift toward personalized cardiovascular prevention. The review concludes with recommendations for guideline integration, emerging therapies, and future directions in biomarker-driven cardiovascular risk management. Full article

The Apolipoprotein L1 (APOL1) innate immunity gene product represents the sole member of the APOL gene family in humans capable of secretion into circulation, thereby mediating the trypanolysis of T. brucei brucei. Gain-of-function variants of the APOL1 gene originated and spread among human population groups to extend APOL1’s protective capacity to include also serum-resistant subspecies, such as T. brucei gambiense (S342G known as APOL1-G1) and T. brucei rhodesiense (N388_Y389del known as APOL1-G2). The biochemical pathways underlying the lytic activity of these evolutionary favored mutations against bloodstream trypanosomes have been elucidated with remarkable precision. However, the intricate molecular mechanisms by which such variants confer an increased susceptibility to renal cellular injury and consequent kidney disease remain incompletely defined. In the absence of a consistent mechanistic explanation for differential kidney injury, we propose pursuing three interrelated avenues of investigation informed by prior epidemiological and mechanistic evidence linking them to APOL1’s cytotoxicity: (1) Molecular evolution of APOL1 haplotypes in human populations, (2) APOL1 splicing and consequent splice isoforms, (3) Interaction of APOL1 with other APOL gene family members, prioritizing APOL3. In the current study, we use reanalysis of population genetics datasets to resolve the haplotype contexts of all protein-altering APOL1 variants, uncovering previously unrecognized variant–haplotype couplings. We further characterize distinct cellular physiological properties among APOL1 splice isoforms, stressing the importance of isoform vB and what can be learned from isoform vC. Finally, a native interaction, and its interface, between APOL1 and APOL3 is reported, and shown to be differentially modulated by G1 and G2. We contend that continuing studies integrating these three interrelated domains will substantially advance mechanistic insights into APOL1 variant-driven renal injury, and leverage the findings to provide a more cohesive framework to guide future research. Full article

Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer’s disease (AD), with APOEε4 being the strongest genetic risk factor for late-onset AD, while APOEε2 appears protective. Despite extensive research, the precise mechanisms by which APOE alleles contribute to AD pathology remain incompletely understood. Recent advances in multi-omics technologies and single-cell analyses have revealed that APOE alleles shape microglial phenotypes, thereby affecting amyloid clearance, inflammatory responses, tau pathology, and lipid metabolism. In this review, we provide a detailed overview of how APOE alleles differentially regulate microglial activation, inflammatory signaling, phagocytic activity, and lipid metabolism in the context of AD, with a particular focus on the APOEε4-mediated disruption of microglial homeostasis via pathways such as TREM2 signaling, NF-κB/NLRP3 activation, ACSL1 upregulation, and HIF-1α induction. These insights not only advance our understanding of APOE allele-specific contributions to AD pathology, but also highlight novel therapeutic strategies targeting the APOE–microglia axis. Full article

Peritoneal fluid (PF) is intimately associated with the gastrointestinal tract, and changes in the PF may directly reflect abdominal pathology. We aimed to quantify differences in the PF proteome between intestinal lesion type (ischemic vs. non-ischemic) and location (small vs. large intestine). PF samples were collected at hospital admission from horses presenting for abdominal pain (colic). Cases were clinically categorized by lesion type and location after resolution (10 per group). PF proteins were extracted and quantified by label-free liquid chromatography-tandem mass spectroscopy. Data were analyzed in Perseus and R, with functional annotation by UniProtKB and interaction visualization in STRING. Sixteen proteins unique to ischemic lesions and twelve unique to small intestinal lesions had significant network enrichment with functions related to inflammatory and immune responses. Identified proteins related to ischemic and small intestinal lesions included calprotectin, lactotransferrin, alpha 2 macroglobulin, and serine proteases/protease inhibitors, as well as apolipoprotein B and lipid metabolism pathways not previously described in relation to ischemic intestinal disease. While no single biomarker is expected to adequately diagnose or predict the outcome of equine colic, the proteins identified here should be considered as candidates for further study in a larger population. Full article

Background: Childhood obesity is a growing global health concern. Metabolomics, the comprehensive study of metabolites within biological systems, offers a powerful approach to better define the phenotype and understand the complex biochemical alterations associated with obesity. The aim of this systematic review was to summarize current knowledge in the field of metabolomics in childhood obesity and to identify metabolic signatures or biomarkers associated with overweight/obesity (Ov/Ob) and Metabolically Unhealthy Obesity (MUO) in children and adolescents. Methods: We performed a systematic search of Medline and Scopus databases according to PRISMA guidelines. We included only longitudinal prospective studies or randomized controlled trials with ≥12 months of follow-up, as well as meta-analyses of the above that assessed the relation between metabolic signatures related to obesity and Body Mass Index (BMI) or other measures of adiposity in children and adolescents aged 2–19 years with overweight or obesity. Initially, 595 records were identified from PubMed and 1565 from Scopus. After removing duplicates and screening for relevance, 157 reports were assessed for eligibility. From the additional search, 75 new records were retrieved, of which none were eligible for our study. Finally, 7 reports were included in the present systematic review (4 reporting on Ov/Ob and 4 on MUO). Results: The presented studies suggest that the metabolism of amino acids and lipids is primarily affected by childhood obesity. Metabolites like glycoprotein acetyls, the Apolipoprotein B/Apolipoprotein A-1 ratio, and lactate have emerged as potential biomarkers for insulin resistance and metabolic syndrome, highlighting their potential value in clinical applications. Conclusions: There is a need for future longitudinal studies to assess metabolic changes over time, interventional studies to evaluate the efficacy of therapeutic strategies, and large-scale population studies to explore metabolic diversity across different demographics. Our findings reveal specific biomarkers in the amino acid and lipid pathway that may serve as early indicators of childhood obesity and its associated cardiometabolic complications. Full article

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are major contributors to the rise in metabolic disorders, particularly in developed countries. Despite the need for effective therapies, natural product-based interventions remain underexplored. This study investigated the therapeutic effects of Endarachne binghamiae, a type of brown algae, hot water extract (EB-WE) in ameliorating obesity and MASLD using high-fat diet (HFD)-induced ICR mice for an acute obesity model (4-week HFD feeding) and C57BL/6 mice for a long-term MASLD model (12-week HFD feeding). EB-WE administration significantly reduced body and organ weights and improved serum lipid markers, such as triglycerides (TG), total cholesterol (T-CHO), HDL (high-density lipoprotein), LDL (low-density lipoprotein), adiponectin, and apolipoprotein A1 (ApoA1). mRNA expression analysis of liver and skeletal muscle tissues revealed that EB-WE upregulated Ampkα and Cpt1 while downregulating Cebpα and Srebp1, suppressing lipogenic signaling. Additionally, EB-WE activated brown adipose tissue through Pgc1α and Ucp1, contributing to fatty liver alleviation. Western blot analysis of liver tissues demonstrated that EB-WE enhanced AMPK phosphorylation and modulated lipid metabolism by upregulating PGC-1α and UCP-1 and downregulating PPAR-γ, C/EBP-α, and FABP4 proteins. It also reduced oxidation markers, such as OxLDL (oxidized low-density lipoprotein) and ApoB (apolipoprotein B), while increasing ApoA1 levels. EB-WE suppressed lipid peroxidation by modulating oxidative stress markers, such as SOD (superoxide dismutase), CAT (catalase), GSH (glutathione), and MDA (malondialdehyde), in liver tissues. Furthermore, EB-WE regulated the glucose regulatory pathway in the liver and muscle by inhibiting the expression of Sirt1, Sirt4, Glut2, and Glut4 while increasing the expression of Nrf2 and Ho1. Tentative liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis for EB-WE identified bioactive compounds, such as pyropheophorbide A and digiprolactone, which are known to have antioxidant or metabolic regulatory activities. These findings suggest that EB-WE improves obesity and MASLD through regulation of metabolic pathways, glucose homeostasis, and antioxidant activity, making it a promising candidate for natural product-based functional foods and pharmaceuticals targeting metabolic diseases. Full article

Enhanced hepatic synthesis, assembly, and secretion of apolipoprotein B (ApoB)-containing lipoproteins elevate their plasma levels and—like their impaired clearance from the circulation—can increase cardiovascular risk. Both dietary fatty acids and microRNAs contribute to the nutrient-dependent regulation of hepatic gene expression. Together, these factors may modulate lipid and ApoB-containing lipoprotein synthesis in the liver, either exacerbating or mitigating dyslipidemia. Research continues to reveal the complexity of fatty acid–microRNA networks and highlights differences in regulating hepatic ApoB-containing lipoprotein synthesis between humans and rodents. Consequently, this review focuses on studies conducted in humans or human-derived hepatocytes. Full article

This review explores the mechanisms by which Human Immunodeficiency Virus type 1 (HIV-1) regulatory proteins manipulate host cellular pathways to promote viral replication and immune evasion. Key viral proteins, such as Nef, Vpu, Vif, Vpr, and Env, disrupt immune defenses by downregulating surface molecules such as CD4 (Cluster of Differentiation 4) and Major Histocompatibility Complex (MHC) class I, degrading antiviral enzymes like APOBEC3G (Apolipoprotein B mRNA editing catalytic polypeptide-3G) and SAMHD1 (Sterile Alpha Motif and Histidine Aspartate domain-containing protein 1), and counteracting restriction factors including BST-2 (Bone Marrow Stromal Antigen 2)/Tetherin and SERINC5 (Serin Incorporator 5). These interactions support viral persistence and contribute to the establishment of chronic infection. Emerging therapeutic strategies aim to disrupt these HIV-host interactions to restore innate antiviral responses and enhance immune clearance. Approaches such as stabilizing host restriction factors or blocking viral antagonists offer a promising alternative to conventional antiretroviral therapy. By targeting host-dependent pathways, these interventions may reduce drug resistance, tackle latent reservoirs, and provide a pathway toward sustained viral remission or functional cure. Full article

Background: Defective DNA repair systems result in the accumulation of mutations, loss of genomic integrity, and eventually cancer. Following initial malignant transformation due to specific DNA damage and defective DNA repair, cancer cells become reliant upon other DNA repair pathways for their survival. The co-occurrence of specific repair deficiencies brings catastrophic outcomes such as cell death for cancer cells and thus holds promise as a potential therapeutic strategy. Exploring the co-occurrence and mutual exclusivity of mutational signatures provides valuable knowledge regarding combinations of defective repair pathways that are cooperative and confer selective advantage to cancer cells and those that are detrimental and cannot be tolerated by them. Methods: Taking advantage of mutational signature profiling, we analyzed whole-genome sequences of 1014 breast cancers to reveal the underlying mutational processes and their interrelationships. Results: We found an inverse relationship between deficiencies of homologous recombination (HRd) and non-homologous end joining (NHEJd) with reactive oxygen species (ROS). Moreover, HRd and NHEJd co-occurred with APOBEC but were mutually exclusive with mismatch repair deficiency (MMRd) and ROS. Our analysis revealed that SBS8 and SBS39 signatures of currently unknown etiology correlate with NHEJd. ID1 and ID2 signatures co-occur with ROS and have mutual exclusivity with HRd, SBS8, SBS39 and NHEJd. The ID4 signature, with currently unknown etiology, has mutual exclusivity with HRd and NHEJd and co-occurred with ROS. On the other hand, the ID15 signature, with currently unknown etiology, co-occurred with SBS8, SBS39, HRd, NHEJd and DBS2, while having an inverse relationship with MMRd and ROS. Comparing the mutational signatures of HRd and non-HRd TNBC genomes reveals the unique presence of ROS signatures in non-HRd tumors and the lack of ROS signature in HRd tumors. Conclusion: Taken together, these analyses indicate the possible application of mutation signatures and their interactions in advancing patient stratification and suggest appropriate therapies targeting the make-up of individual tumors’ mutational processes. Ultimately, this information provides the opportunity to discover promising synthetic lethal candidates targeting DNA repair systems. Full article

Background: Adequate control for confounding is key to many observational study designs. Confounders are often identified based on subject matter knowledge from empirical investigations. Negative confounders, which typically generate type 2 error, i.e., false nulls, can be elusive. Such confounders can be identified comprehensively by using Mendelian randomization (MR) to search the wealth of publicly available data systematically. Here, to demonstrate the concept, we examined whether a common positive confounder, body mass index (BMI), is also a negative confounder of any common physiological exposures on health outcomes, overall and specifically by sex. Methods: We used an MR study, based on the largest overall and sex-specific genome-wide association studies of BMI (i.e., from the Genetic Investigation of ANthropometric Traits and the UK Biobank) and of relevant exposures likely affected by BMI, to assess, overall and sex-specifically, whether BMI is a negative confounder potentially obscuring effects of harmful physiological exposures. Inverse variance weighting was the main method. We assessed sex differences using a z-test. Results: BMI was a potential negative confounder for apolipoprotein B and total testosterone in men, and for both sexes regarding low-density lipoprotein cholesterol, choline, linoleic acid, polyunsaturated fatty acids, and cholesterol. Conclusions: Using BMI as an illustrative example, we demonstrate that negative confounding is an easily overlooked bias. Given negative confounding is not always obvious or known, using MR systematically to identify potential negative confounders in relevant studies may be helpful. Full article

Background: Apolipoprotein B (ApoB), a key component of atherogenic lipoproteins, has been increasingly implicated in cardiometabolic disorders beyond dyslipidemia. However, its role in glycemic dysregulation remains unclear. This study aimed to investigate the association between ApoB levels and glycemic parameters, including fasting glucose, insulin resistance, and glycated hemoglobin (HbA1c), in individuals without diagnosed diabetes. Methods: This study was conducted at the National Research Cardiac Surgery Center (Kazakhstan) over the period between 2023 and 2024 as a cross-sectional analysis. Adults aged ≥ 20 years without diagnosed diabetes and with complete data on their ApoB and glycemic markers were included. Associations between ApoB and fasting plasma glucose (FPG), HbA1c, and HOMA-IR were assessed using multivariable linear and logistic regression models adjusted for demographic, lifestyle, and metabolic covariates. Results: Higher ApoB levels were significantly associated with increased fasting glucose (β = 2.07 mg/dL per 1-SD increase in ApoB, p < 0.001), higher HbA1c (β = 0.06%, p < 0.001), and elevated HOMA-IR (β = 0.54, p < 0.001). Participants in the highest ApoB quartile had 53% higher odds of prediabetes (adjusted OR = 1.53; 95% CI: 1.22–1.91; p < 0.001) compared to the lowest quartile. These associations remained significant after adjusting for BMI, lipid levels, and other confounders. Conclusions: Elevated ApoB is independently associated with adverse glycemic profiles in nondiabetic individuals, suggesting its potential role in early glucose metabolism disturbances. Full article

Background/Objectives: Chronic kidney disease (CKD) is associated with increased mortality, with cardiovascular disease (CVD) being the primary cause of death. Proper lipid regulation may reduce CVD risk and slow CKD progression. While there is evidence that a higher plant protein intake could ameliorate lipid levels in the general population, the effects of this dietary regimen within the CKD population remain uncertain, with studies providing conflicting results. We aim to investigate the impact of increased plant protein intake on the lipid levels of CKD patients. Methods: Two electronic databases (PubMed, Scopus) were reviewed for controlled clinical trials assessing the effect of increased plant protein intake versus the usual CKD animal-based diet in CKD patients, published until June 2024. Results: Eleven trials, encompassing 248 patients, were included in this meta-analysis. Overall, compared to the usually recommended CKD diet, increased plant protein intake was associated with statistically significant reductions in total cholesterol (−24.51 mg/dL, 95% CI −40.33, −8.69), low-density lipoprotein (LDL) (−21.71 mg/dL, 95% CI −38.32, −5.1), triglycerides (− 21.88 mg/dL, 95% CI −35.34, −8.40), and Apolipoprotein B levels (−11.21 mg/dL, 95% CI −18.18, −4.25). No significant changes were observed in high-density lipoprotein (HDL) (0.09 mg/dL, 95% CI −1.82, 1.99) and Apolipoprotein A levels (0.04 mg/dL, 95% CI −7.14, 7.21). Conclusions: Increased plant protein intake, mainly from soy, reduces total cholesterol, LDL, triglycerides, and ApoB in adult CKD patients. Further research is needed to assess these effects in dialysis patients and explore non-soy plant sources. Full article