Search Results (523)

Thrombosis is a cardiovascular disease characterized by the pathological formation of a fibrin clot in blood vessels. Currently available fibrinolytic enzymes have some limitations, including severe side effects, high cost, short half-life, and low fibrin specificity. Proteins from microalgae and cyanobacteria have various biological effects and are emerging as promising sources for fibrinolytic enzymes. In this study, bioinformatics tools were used to evaluate the intrinsic disorder predisposition of microalgal fibrinolytic proteins, their capability to undergo liquid–liquid phase separation (LLPS), and the presence of disorder-based functional regions, and short linear motifs (SLiMs). Analysis revealed that these proteins are predominantly hydrophilic and exhibit acidic (pI 3.96–6.49) or basic (pI 8.05–11.0) isoelectric points. Most of them are expected to be moderately (61.4%) or highly disordered proteins (6.8%) and associated with LLPS, with nine proteins being predicted to behave as droplet drivers (i.e., being capable of spontaneous LLPS), and twenty-five proteins being expected to be droplet clients. These observations suggest that LLPS may be related to the regulation of the functionality of microalgal fibrinolytic proteins. The majority of these proteins belong to the blood coagulation inhibitor (disintegrin) 1 hit superfamily, which can inhibit fibrinogen binding to integrin receptors, preventing platelet aggregation. Furthermore, the SLiM-centered analysis indicated that the main motifs found in these proteins are MOD_GlcNHglycan and CLV_PCSK_SKI1_1, which can also play different roles in thrombolytic activity. Finally, Fisher and conservation analysis indicated that CLV_NRD_NRD_1, CLV_PCSK_FUR_1, CLV_PCSK_PC7_1, and MOD_Cter_Amidation motifs are enriched in intrinsically disordered regions (IDRs) of these proteins, showing significant conservation and suggesting compatibility with proteolytic activation and post-translational processing. These data provide important information regarding microalgal proteins with potential thrombolytic effects, which can be realized through protein–protein interactions mediated by SLiMs present in intrinsically disordered regions (IDRs). Additional analyses should be conducted to confirm these observations using experimental in vitro and in vivo approaches. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) significantly elevates the risk of coronary artery disease (CAD), particularly in Asian populations where both conditions are epidemic. While shared genetic factors contribute to this comorbidity, evidence from Asian cohorts remains fragmented, with limited focus on population-specific variants. This meta-analysis synthesizes evidence on genetic variants associated with CAD risk in Asian patients with T2DM. Methods: We systematically searched several databases according to the PRISMA statement and checklist. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using random-effects models, with heterogeneity assessed via I² and Cochran’s Q, and publication bias via funnel plots and Egger’s test. Results: In total, data on 11,268 subjects were reviewed, including 4668 cases and 6600 controls. Among 950 identified studies, 18 met eligibility criteria, and 14 studies provided sufficient data for the meta-analysis. The random-effects pooled estimate across all studied variants was not statistically significant (OR = 1.16 [95% CI: 0.68–2.00]; z = 0.56, p = 0.58). However, analysis of individual loci revealed gene-specific associations with CAD among this population: PCSK1 gene (OR = 2.12 [95% CI: 1.26–3.52]; p < 0.05; weight = 8.77%), GLP1R gene (OR = 2.25 [95% CI: 1.27–3.97]; p < 0.01; weight = 8.62%). ADIPOQ gene (OR = 8.00 [95% CI: 2.34–27.14]; p < 0.01; weight = 6.35%). Several genes were associated with an elevated risk of CAD: PCSK1 gene (OR = 2.12 [95% CI: 1.26–3.52]; p < 0.05; weight = 8.77%), GLP1R gene (OR = 2.25 [95% CI: 1.27–3.97]; p < 0.01; weight = 8.62%) and ADIPOQ gene (OR = 8.00 [95% CI: 2.34–27.14]; p < 0.01; weight = 6.35%). Several genes were associated with possible protective effects: ACE gene (OR = 0.41 [95% CI: 0.23–0.73]; p < 0.01; weight = 8.57%), Q192R gene (OR = 0.20 [95% CI: 0.08–0.52]; p < 0.001; weight = 7.41%). Heterogeneity was substantial (τ² = 0.78; I² = 81.95%; Q (13) = 64.67, p < 0.001). Conclusions: This first meta-analysis of genetic variants associated with CAD in Asian populations with T2DM identified specific locus-level associations implicating lipid metabolism, incretin signaling, and oxidative stress pathways. The lack of a significant pooled effect, alongside high heterogeneity, underscores the complexity and population-specific nature of this genetic architecture. These findings suggest that effective precision risk stratification may depend more on specific variants than on a broad polygenic signal, highlighting the need for further research in a larger, distinct sample size. Full article

Obesity is closely linked to dyslipidemia, hepatic injury, and chronic inflammation through disturbances in the gut–liver axis. Here, we evaluated the anti-obesity effects of L. rhamnosus (Lacticaseibacillus rhamnosus) CU262 in a high-fat diet (HFD) mouse model and elucidated mechanisms using an integrated multi-omics strategy. Male C57BL/6 mice received CU262 during 12 weeks of HFD feeding. Phenotypes, serum/liver biochemistry, gut microbiota (16S rRNA sequencing), fecal short-chain fatty acids (SCFAs), and hepatic transcriptomes (RNA-seq) were assessed. CU262 significantly attenuated weight gain and adiposity; improved serum TC, TG, LDL-C and HDL-C; lowered ALT/AST and FFA; and mitigated oxidative stress and inflammatory imbalance (↓ IL-6/TNF-α, ↑ IL-10). CU262 restored alpha diversity, reduced the Firmicutes/Bacteroidetes ratio, enriched beneficial taxa (e.g., Akkermansia), and increased acetate and butyrate. Liver transcriptomics showed CU262 reversed HFD-induced activation of cholesterol/steroid biosynthesis and endoplasmic reticulum stress, with downregulation of key genes (Mvk, Mvd, Fdps, Nsdhl, and Dhcr7) and Pcsk9, yielding negative enrichment of steroid and terpenoid backbone pathways and enhancement of oxidative phosphorylation and glutathione metabolism. Correlation analyses linked Akkermansia and SCFAs with improved lipid/inflammatory indices and repression of cholesterol-synthetic and stress-response genes. These findings demonstrate that CU262 alleviates HFD-induced metabolic derangements via microbiota-SCFA-hepatic gene network reprogramming along the gut–liver axis, supporting its potential as a functional probiotic for obesity management. Full article

This study introduces a novel hybrid model for an electromembrane stack, unifying an equivalent electrical circuit model incorporating specific resistance ($R_M,R_s$) and capacitance ($C_{gs},C_{dl}$) parameters with an empirical fouling model in a single framework. The model simplifies the traditional approach by serially connecting N ($N=10$) ion exchange membranes (anionic PC-SA and cationic PC-SK) and is validated using $NaCl$ and $N{a}_{2}S{O}_4$ solutions in comparison with laboratory tests using various voltage signals, including direct current and electrically pulsed reversal operations at frequencies of 2000 and 4000 Hz. The model specifically accounts for the chemical stratification of the cell unit into bulk solution, diffusion, and Stern layers. We also included a calibration method using correction factors (${\alpha }_i$) to fine-tune the electrical current signals induced by voltage stimulation. The empirical component of the model uses experimental data to simulate membrane fouling, ensuring consistency with laboratory-scale desalination processes performed under pulsed reversal operations and achieving a prediction error of less than 10%. In addition, a comparative analysis was used to assess the increase in electrical resistance due to fouling. By integrating electronic and empirical electrochemical data, this hybrid model opens the way to the construction of simple, practical, and reliable models that complement theoretical approaches, signifying an advance for a variety of electromembrane-based technologies. Full article

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools—including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors—and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as PCSK9, ANGPTL3, CETP, APOC3, ASGR1, LPA, and IDOL, supported by findings from human genetics, preclinical models, and recent first-in-human trials. Emerging delivery vehicles (AAVs, LNPs, lentivirus, virus-like particles) and their translational implications are discussed. The review highlights ongoing clinical trials employing liver-targeted in vivo editing modalities (LivGETx-CVD) and provides insights into challenges in delivery, off-target effects, genotoxicity, and immunogenicity. Collectively, this review captures the rapid progress of LivGETx-CVD from conceptual innovation to clinical application, and positions gene editing as a transformative, single-dose strategy with the potential to redefine prevention and long-term management of dyslipidemia and atherosclerotic cardiovascular disease. Full article

Background: High residual platelet reactivity (HRPR) and persistent dyslipidemia remain important unmet needs in cardiovascular risk management, particularly in patients undergoing coronary revascularization. Despite intensive lipid-lowering and antiplatelet therapy, a substantial proportion of patients fail to reach recommended low-density lipoprotein cholesterol (LDL-C) targets or exhibit inadequate platelet inhibition. Inclisiran, a PCSK9-targeting small interfering RNA, represents an emerging approach for long-term LDL-C reduction. Methods: A narrative review of the literature published between 2009 and 2025 was performed using PubMed, Scopus, Web of Science, and MEDLINE. Studies evaluating the addition of inclisiran to standard lipid-lowering therapy in patients with dyslipidemia and HRPR, assessed using the VerifyNow assay, were included. Illustrative clinical cases from Kazakhstan were analyzed to demonstrate real-world changes in LDL-C levels and platelet reactivity following insufficient response to conventional treatment. The review had a descriptive design. Results: Available evidence indicates that a significant proportion of high- and very-high-risk patients do not achieve LDL-C targets or are unable to tolerate high-intensity statin therapy. Inclisiran consistently induces sustained reductions in LDL-C and circulating PCSK9 levels. Emerging data suggest a potential indirect modulation of platelet reactivity associated with intensive lipid lowering. In patients at extreme cardiovascular risk—including those after coronary artery bypass grafting (CABG) and with long-standing multivessel coronary artery disease—inclisiran therapy was associated with marked LDL-C reduction and a trend toward normalization of platelet reactivity. Conclusions: Assessment of platelet function using the VerifyNow assay may improve identification of residual thrombotic risk in patients with advanced atherosclerotic disease. Inclisiran appears to be a promising adjunctive therapy for dyslipidemic patients with persistently elevated cardiovascular risk and HRPR despite standard treatment. Further prospective studies are warranted to clarify the relationship between intensive LDL-C lowering, platelet reactivity, and clinical outcomes, and to optimize integrated lipid-lowering and antiplatelet strategies. Full article

Atherosclerosis is a chronic, multifactorial vascular disease and the leading global cause of cardiovascular morbidity. Its development reflects interconnected disturbances in lipid metabolism, endothelial function, inflammation, smooth muscle cell (SMC) phenotypic switching, and extracellular matrix remodeling. Genetic predisposition, including monogenic disorders such as familial hypercholesterolemia and polygenic risk variants, modulates disease susceptibility by altering lipid homeostasis as well as inflammatory and thrombotic pathways. Epigenetic regulators and noncoding RNAs, such as histone modifications, microRNAs, and long noncoding RNAs, further shape gene expression and link environmental cues to vascular pathology. Endothelial injury promotes lipoprotein retention and oxidation, triggering monocyte recruitment and macrophage-driven foam cell formation, cytokine secretion, and necrotic core development. Persistent inflammation, macrophage heterogeneity, and SMC plasticity collectively drive plaque growth and destabilization. Emerging insights into immune cell metabolism, intracellular signaling networks, and novel regulatory RNAs are expanding therapeutic possibilities beyond lipid-lowering. Current and evolving treatments include statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, anti-inflammatory agents targeting interleukin-1 beta (IL-1β) or NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and advanced approaches such as gene editing, siRNA, and nanoparticle-based delivery. Integrating multi-omics, biomarker-guided therapy, and precision medicine promises improved risk stratification and next-generation targeted interventions. This review summarizes recent molecular advances and highlights translational opportunities for enhancing atherosclerosis prevention and treatment. Full article

Cancer remains a major global health challenge, largely due to its biological heterogeneity and the capacity of tumor cells to adapt under metabolic and environmental stress. Lipid metabolism has increasingly been recognized as a contributor to tumor progression and treatment response. Proprotein convertase subtilisin/kexin type 9 (PCSK9), widely known for regulating low-density lipoprotein (LDL) receptor turnover and systemic cholesterol levels, has recently been implicated in cancer biology. Emerging evidence shows that PCSK9 influences processes such as cell survival, MHC-I-mediated immune recognition, membrane receptor trafficking, and cellular stress responses, indicating roles that extend beyond its canonical metabolic function. These mechanisms also raise the potential relevance of PCSK9 to affect treatment tolerance and drug responsiveness. This review summarizes current knowledge on the biological functions of PCSK9 in cancer and examines how these pathways may have implications for therapeutic resistance. Full article

Aortic valve stenosis (AVS) is the most common valvular disease in developed countries, and no pharmacological therapy is currently available. Increasing evidence identifies lipoprotein(a) [Lp(a)] as a causal factor linking lipid metabolism, inflammation, and valve calcification. Lp(a) levels are largely genetically determined and remain stable throughout life, making them a potential therapeutic target. This review summarizes the current evidence on Lp(a) and AVS pathophysiology, the diagnostic and prognostic role of Lp(a), and the therapeutic potential of Lp(a)-lowering agents. Emerging Lp(a)-targeted therapies, including antisense oligonucleotides and siRNA-based agents, could reshape AVS management by providing the first pharmacological option to slow disease progression in selected high-risk patients. Full article

The aim of this study was to examine associations involving serum proprotein convertase subtilisin/kexin type 9 (PCSK9) in metabolic disturbances observed in women with polycystic ovary syndrome (PCOS), with particular emphasis on the potential impact of tobacco smoke exposure. The study included 88 women: 60 with PCOS (23 smokers and 37 non-smokers) and 28 without PCOS. Selected biochemical and molecular biomarkers related to lipid metabolism, oxidative stress, and inflammation were assessed. No significant differences in PCSK9 levels were observed among non-smoking women with PCOS, smoking women with PCOS, and non-smoking women without PCOS. However, in women with PCOS, excess body weight and insulin resistance were associated with increased PCSK9 concentrations. Significant correlations between PCSK9, lipid profile parameters, and the Castelli and triglycerides-glucose indices suggest a potential role of PCSK9 as a biomarker of dyslipidemia and cardiometabolic risk. Elevated PCSK9 levels may contribute not only to increased low-density lipoprotein cholesterol but also to enhanced formation of oxidized low-density lipoprotein, which is particularly detrimental to cardiovascular and metabolic health. Vitamin D levels were more strongly associated with smoking status and insulin resistance than with excess body weight. Overall, these findings indicate that PCSK9 regulation in PCOS may be driven predominantly by metabolic factors rather than PCOS status or smoking per se, and that metabolic status and vitamin D deficiency should be considered when assessing cardiometabolic risk in this population. Full article

Background/Objectives: Cardiovascular diseases continue to be the foremost global cause of morbidity and mortality, representing about 40% of all causes of death. Atherosclerotic cardiovascular disease is the most common and clinically important type of these, occurring when cholesterol accumulates over time in the artery intima, which induces an inflammatory process that leads to the production of atherosclerotic plaques. Nowadays, lipid profile alterations and high/very high cardiovascular risk can be observed in more and more patients. Combination therapy, which includes high-intensity statins, ezetimibe, bempedoic acid, and PCSK9-targeted medicines, can lower LDL-C by more than 80%, which is far more than the 50% that statin monotherapy usually achieves. Thus, novel lipid-lowering therapies are needed, as current agents—though effective in reducing cardiovascular events—leave considerable residual risk in many patients. Methods: The aim of our study was to evaluate the cost-effectiveness of Inclisiran and its association with standard of care for the prevention of cardiovascular events across multiple international settings, in articles that reported quality-adjusted life years gained and cost-effectiveness metrics. Results: Our findings suggest that the cost-effectiveness of Inclisiran is highly context-dependent, shaped by local pricing, population risk, and system-level capacity. While Inclisiran demonstrates potential economic value in high-income settings or among high-risk patients, its widespread adoption for primary prevention appears unjustified under current conditions. Conclusions: Policymakers should consider risk-based targeting, price renegotiation, and performance-based reimbursement models to improve the value proposition of such interventions. Full article

Cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) is a widely expressed enzyme involved in the hydroxylation of sterols. Generated by transposon technology in zygotes, male rats lacking Cyp7b1 expression in homozygosis showed an absence of Cyp7b1 mRNA expression in the liver, small intestine, adipose tissue, and muscle. Elevated levels of 25-hydroxycholesterol were found in the liver of mutant rats. After overnight fasting, plasma triglyceride (TG) levels were increased in the homozygous rats. In agreement with this, increased hepatic secretion of very-low-density lipoprotein-TG (VLDL) in fasting rats treated with tyloxapol and decreased low-density receptor protein (LDLr) on the hepatocyte plasma membranes were observed. The decrease in LDLr was not due to decreased mRNA expression but to increased expressions of its proteases (Psck9 and Mylip). RNA sequencing identified Fasn, Igfbp2, and Pcsk9 as targets of the Cyp7b1 absence. However, the hepatic protein contents of IGFBP2 were increased in Cyp7b1-deficient rats, accompanied by a normal glucose tolerance test. HepG2 cells lacking CYP7B1 showed increased expressions of FASN and IGFBP2. These results suggest a role of CYP7B1 in the control of hepatic IGFBP2 and VLDL-TG secretion as a prediabetes sign exerted through 25-hydroxycholesterol and transcriptional or translational mechanisms depending on the species. Full article

Atherosclerotic cardiovascular disease (ASCVD) persists as the foremost cause of global morbidity and mortality. Central to its pathogenesis, atherosclerosis emerges as a chronic inflammatory disorder fueled by the intricate interplay between dysregulated lipid metabolism and immune cell activation. Recent insights reveal that inflammatory cues within atherosclerotic plaques or ischemic tissues orchestrate metabolic reprogramming in immune cells, thereby modulating disease trajectories. While cholesterol-lowering agents such as statins and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have long been recognized for their lipid-modulating properties, accumulating evidence now underscores their pleiotropic anti-inflammatory effects mediated through immune cell modulation. For instance, recent clinical observations reveal that PCSK9 inhibitors not only substantially reduce low-density lipoprotein cholesterol (LDL-C) and triglycerides but also appear to reduce advanced glycoprotein signals, emerging composite biomarkers of systemic inflammation. This highlights a novel and more nuanced dimension of inflammation modulation by PCSK9 inhibitors, although current evidence remains limited and requires further confirmation. Moreover, this dual immune-metabolic influence reshapes our understanding of therapeutic mechanisms and calls for a reassessment of treatment paradigms in ASCVD management. Here, we present a synthesis of current findings that emphasize how both established and novel therapies transcend lipid-lowering to exert profound immunomodulatory actions, offering promising avenues to attenuate cardiovascular disease progression through integrated metabolic and inflammatory control. Full article

Alzheimer’s disease (AD) is increasingly associated with alterations in cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme regulating low-density lipoprotein receptor (LDLR) degradation, has been implicated in AD through mechanisms involving amyloid-β (Aβ) processing, tau phosphorylation, and synaptic dysfunction. This review aimed to evaluate clinical, genetic, and experimental evidence regarding the role of PCSK9 in AD and its potential as a biomarker or therapeutic target. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar (2020–2025) using predefined terms related to PCSK9 and Alzheimer’s disease. Eligible studies included clinical, in vivo, and in vitro investigations reporting PCSK9 expression, regulation, or inhibition in relation to AD pathology. Due to methodological heterogeneity, a narrative synthesis was performed. Forty-two studies met inclusion criteria. Preclinical findings consistently showed that elevated PCSK9 may indirectly promote Aβ accumulation, tau hyperphosphorylation, neuroinflammation, and cognitive decline, while genetic deletion or pharmacological inhibition of PCSK9 mitigates these effects. Clinical evidence was variable: several studies identified increased PCSK9 levels in cerebrospinal fluid or brain tissue of AD patients, often correlating with tau markers, but large-scale genetic and Mendelian randomization studies did not confirm a causal association. PCSK9 inhibitors, widely used in cardiovascular therapy, demonstrated potent LDL-C reduction without cognitive adverse effects. Experimental data suggest that PCSK9 contributes to AD-related pathology, whereas human evidence indicates a modulatory or biomarker role rather than a causative one. Despite strong preclinical data, human genetics lacks causal evidence for PCSK9 in Alzheimer’s. It may be a disease modifier or biomarker; its clinical relevance requires confirmation through longitudinal studies and CNS-penetrant therapies. Full article

Background: Familial hypercholesterolemia (FH) continues to be underrecognized and inadequately treated. We aimed to investigate the current status of FH diagnosis and treatment in South Korea. Methods: Patients from two tertiary hospitals in South Korea between 2010 and 2023 with either a diagnosis of FH (ICD-10 code: E7800), had LDLR, APOB, or PCSK9 mutations, or had low-density lipoprotein cholesterol (LDL-C) levels exceeding 325 mg/dL were considered for inclusion. Demographic and laboratory characteristics as well as pharmacologic treatment patterns were assessed. Results: A total of 148 patients were retrospectively identified. The mean age at diagnosis was 49.3 years, and 33 (22.3%) had a history of established atherosclerotic cardiovascular disease (ASCVD). The majority of patients were diagnosed in the cardiology or endocrinology departments. The LDL-C level at enrollment was 247 ± 98 mg/dL (conversion to treatment-naïve LDL-C: 343 ± 141 mg/dL), which decreased to 122 ± 60 mg/dL after one year, achieving guideline-recommended target levels in 11.5%. A high proportion of patients were treated with statins (80.2%) and ezetimibe (64.9%), but the use of proprotein convertase subtilisin/kexin type 9 inhibitors was low (11.7%). Patients diagnosed after 2020 achieved significantly lower LDL-C levels at one year compared to those diagnosed between 2020 and 2019 (107 ± 50 vs. 152 ± 68 mg/dL, p = 0.003). Two ischemic strokes and two myocardial infarctions occurred during a median follow-up of 25.3 months. Conclusions: FH is frequently diagnosed late after the onset of clinical ASCVD and is undertreated, although recent trends show improvement. Our results again underline the need for proper screening and identification of patients with FH. Full article