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Common genetic variation detected by genome-wide association studies (GWAS) partially explains variability in the spectrum of cardiac phenotypes. In this work, we explore genetic correlations among 58 cardiac-related traits/diseases, detecting novel ones. We subsequently employ multi-trait analysis of GWAS (MTAG), which meta-analyzes genetically correlated traits, to improve genomic loci discovery and prediction in atrial fibrillation (AF), coronary artery disease (CAD), and heart failure (HF). We identify 19 novel loci specific for AF, 131 for CAD, and 141 for HF. Polygenic scores (PGS) in 15,177 Canadian individuals show similar results when PGS are derived from conventional GWAS versus MTAG summary statistics, although MTAG-PGS improve prediction and discrimination of CAD in females [∆R Show less

Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Show less

Numerous studies have established lipoprotein(a) [Lp(a)] as an independent and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). As such Lp(a) has become the focus of targeted drug therapy development with the goal of reducing Lp(a) serum concentrations and improving outcomes. This review aims to inform readers on the investigational agents currently in clinical trials and highlight key differences including dosing intervals and routes of administration that may facilitate uptake and retention of a particular potential medication in certain patient populations. Five investigational agents are currently undergoing various stages of clinical trials for the treatment of elevated Lp(a). Three potential therapies are small interfering RNA (siRNA) molecules and a fourth is an antisense oligonucleotide (ASO) all of which are subcutaneously injected. A fifth agent is a small molecule inhibitor that is orally administered. A sixth agent, a cholesteryl ester transfer protein (CETP) inhibitor that is primarily being studied for LDL-C reduction has shown promise for reducing Lp(a). A seventh agent based on gene-editing is currently in the developmental stage. Results have revealed notable reductions in Lp(a) with favorable tolerability and safety. Phase 3 trials will be crucial in determining the viability of lowering Lp(a) with such therapies and improving cardiovascular outcomes. Promising results indicate the potential in the near future to have medications primarily for lowering Lp(a) which has thus far eluded targeted drug therapy. As such advances stand to benefit large segments of the population living with and at risk for ASCVD, future research is vital to validate safety and efficacy in the long-term as well to understand how to optimize uptake and retention among patients with diverse circumstances. Show less

Acute coronary syndrome (ACS) survivors have heightened risk for subsequent cardiovascular events. All baseline characteristics collected in both the Dal-Outcomes and Dal-GenE trials were considered as potential risk markers. A prediction index for subsequent fatal and non-fatal myocardial infarction (MI) following ACS was developed using Cox proportional hazards modeling on data from Dal-Outcomes placebo patients (n=7086). This prediction index was then applied in all Dal-GenE participants (n=5989) to determine whether the reduction in MI observed with dalcetrapib (versus placebo) in patients with the AA genotype at rs1967309 in the ADCY9 gene remained significant, independent of the other markers integrated into the prediction index. Of the 36 baseline variables considered as potential risk markers, 18 contributed to the prediction index with a Harrell's C-index of 0.72 (95% CI, 0.69-0.75) in Dal-Outcomes placebo patients. Prior history of coronary events, LDL-C, blood pressure, A1c, hs-CRP, smoking and age were contributors. The prediction index was strongly predictive when applied to the 5989 AA genotype patients from Dal-GenE, with a HR for MI of 1.92 (95%CI: 1.78-2.08) for each SD increase in score. When adjusting for the prediction index, the HR for dalcetrapib versus placebo was 0.77 (95% CI, 0.63-0.94) in Dal-GenE. Despite guideline directed therapy following ACS, history of prior coronary events and on-treatment LDL-C, A1c, hs-CRP and blood pressure remain determinants of future MI. In the Dal-GenE AA genotype patients, dalcetrapib reduced the rate of MI, independently of those variables. The Dal-GenE 2 trial is designed to confirm this pharmacogenetic hypothesis. Show less

The goal of this study was examination of the association between the expression levels of the genes involved in high-density lipoprotein metabolism and atherogenesis and underlying metabolic pathways and the number of stenotic coronary arteries. Expression of 65 preselected genes in the peripheral blood mononuclear cells of the control patients ( Show less

The evaluation of the effect of dulaglutide on glycated hemoglobin (HbA1c) and non-invasive indices of hepatic steatosis among different genotypes of the PNPLA3 I148M (rs738409) and CETP Taq1B (rs708272) polymorphisms in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Relevant data from patients with inadequately controlled T2DM, also displaying NAFLD, administered 1.5 mg dulaglutide weekly for 6 months were retrospectively retrieved. The non-invasive indices, fatty liver index (FLI) and hepatic steatosis index (HSI), were calculated. Genotyping for rs738409 and rs708272 were performed with polymerase chain reaction. Data from 80 patients (39 females), aged 64.4 ± 9.5 years and displaying a baseline BMI of 34.5 ± 5.8 kg/m rs738409, but not rs708272, was associated with the effect of dulaglutide on HbA1c, but not on presumed hepatic steatosis or other relevant parameters. Sex-specific effects were also noticed. Show less

Cholesteryl ester transfer protein (CETP) deficiency is a representative molecular abnormality in familial hyperalphalipoproteinemia, a hereditary disorder of lipid metabolism characterized by markedly elevated plasma high-density lipoprotein cholesterol (HDL-C) levels. In this condition, dysfunction of CETP, which mediates the transfer of cholesteryl esters from HDL particles to apolipoprotein (Apo)B-containing lipoproteins, leads to the abnormal accumulation of HDL-C. These HDL particles are unusually large and enriched in cholesteryl esters, ApoCIII, and ApoE, whereas low-density lipoprotein (LDL) particles are small, depleted of cholesteryl esters, and enriched in triglycerides. Both HDL and LDL particles in CETP deficiency are functionally abnormal. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, has consistently been demonstrated in clinical trials to increase HDL-C levels by 16% to 22% in patients with dyslipidemia and low baseline HDL-C. Herein, we describe the unexpected finding of a marked reduction in HDL-C levels in a patient with CETP deficiency following pemafibrate treatment. To better understand this paradoxical response, we analyzed the patient's clinical data and investigated potential mechanisms underlying pemafibrate's effects on HDL metabolism. Show less

Breast cancer (BC) is one of the most prevalent malignant diseases affecting women. Cytochrome c (Cyt c) plays a critical role in various pathological processes, however, its precise mechanism in BC remains unclear. This study aimed to identify prognostic genes linked to Cyt c in BC and explore their underlying mechanisms. Transcriptome data related to BC were initially obtained from TCGA and GEO database. Prognostic genes were identified through differential expression analysis, univariate Cox regression, and LASSO analysis. A risk model was subsequently developed and validated. Additionally, enrichment analysis, immune microenvironment analysis, and the construction of a TFs-mRNA network were conducted. Finally, the expression levels of prognostic genes were examined in both tumor and normal tissue samples, with confirmation through RT-qPCR. Eight prognostic genes ( Show less

The timing of anti-inflammatory therapy in acute myocardial infarction (AMI) may be critical, yet has not been systematically assessed. While several agents have shown benefit in secondary prevention, their efficacy during the early inflammatory phase of AMI remains uncertain. This study evaluated the effectiveness of anti-inflammatory therapies in AMI and whether early initiation within 24 h of symptom onset modifies clinical outcomes. We conducted a network meta-analysis of 23 randomized controlled trials including 28,220 patients with AMI. Interventions included colchicine, anakinra (IL-1β inhibitor), tocilizumab (IL-6 inhibitor), varespladib (PLA2 inhibitor), losmapimod (p38 MAPK inhibitor), cyclosporine (mitochondrial pore inhibitor), and pexelizumab (complement C5 inhibitor). Primary outcomes were major adverse cardiovascular events (MACE), heart failure (HF), and ischemic events. Treatment effects were summarized as incidence rate ratios (IRRs), defined as the ratio of incidence rates between intervention and control groups. Subgroup analyses stratified trials by treatment initiation ≤24 h vs > 24 h from symptom onset. Colchicine significantly reduced MACE ([IRR] 0.71; 95 % confidence interval [CI] 0.53-0.97) and ischemic events (IRR 0.65; 95 % CI 0.43-0.98). Anakinra reduced HF events (IRR 0.38; 95 % CI 0.16-0.89). These effects were observed exclusively when treatment was initiated within 24 h. No benefit was seen with delayed therapy, and no other intervention showed clinical efficacy. Safety outcomes, including infection risk, were neutral across treatments. This network meta-analysis demonstrates that anti-inflammatory therapy improves outcomes in AMI only when initiated early. Colchicine and anakinra were the only effective agents, highlighting a narrow therapeutic window and supporting a time-sensitive approach to inflammation-targeted treatment in AMI. Show less

Hydrogen (H₂) will play a crucial role in Europe's green energy transition, necessitating efficient storage solutions such as underground storage in salt caverns or porous media. However, the potential microbial H₂ consumption in these subsurface environments poses risks to storage stability and safety, and its magnitude remains relatively unexplored. Within the HyLife-CETP project, we developed a brine sampling protocol for the field operators and tested a standardized laboratory procedure for estimating microbial hydrogen consumption rates in these original brine samples, combining precise gas, chemical, and genetic analyses. Four labs tested and compared the developed enrichment protocol in a round-robin-like test using artificial brine and the hydrogen-consuming, sulfate-reducer Oleidesulfovibrio alaskensis as a reference strain. This test revealed consistent trends in microbial hydrogen consumption and corresponding pH increase across labs, indicating that the developed protocol effectively captures the overall microbial activity. However, inter-laboratory variability in the reported H Show less

Hyperlipidemia, a key risk factor for cardiovascular disease, is characterized by elevated low-density lipoprotein cholesterol (LDL-C), triglycerides, and reduced high-density lipoprotein cholesterol (HDL-C). Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, obicetrapib, evacetrapib, dalcetrapib, and torcetrapib, aim to improve lipid profiles by increasing HDL-C and reducing LDL-C, but their comparative efficacy remains unclear. This systematic review and frequentist network meta-analysis, conducted per PRISMA-NMA guidelines, included 33 randomized controlled trials (RCTs) involving 120,292 adults with hyperlipidemia. We compared CETP inhibitors, alone or with statins, against placebo or other lipid-lowering therapies. Primary outcome was LDL-C reduction; secondary outcomes included HDL-C, triglycerides, and total cholesterol changes. Random-effects models calculated mean differences (MD) with 95% confidence intervals (CI), and P-scores ranked interventions. Atorvastatin + obicetrapib showed the largest reduction in LDL-C levels (MD: -69.00, 95% CI: -95.96 to -42.04, p < 0.0001), followed by rosuvastatin + obicetrapib (MD: -60.70, 95% CI: -99.28 to -22.12, p = 0.0020). Atorvastatin + obicetrapib yielded highly significant increase in HDL-C levels (MD: 149.90, 95% CI: 121.70 to 178.10, p < 0.0001), but rosuvastatin + obicetrapib showed the greatest increase (MD: 158.90, 95% CI: 118.59 to 199.21, p < 0.0001) and obicetrapib monotherapy (MD: 139.00, 95% CI: 129.05 to 148.96, p < 0.0001), while rosuvastatin + evacetrapib led triglyceride reductions (MD: -31.70 mg/dL). Rosuvastatin was most effective for total cholesterol (MD: -31.60 mg/dL). CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction. The study was registered with PROSPERO to ensure transparency and adherence to methodological rigor (Registration ID: CRD420250652666). Show less

The main function of high-density lipoprotein (HDL) is to remove low-density lipoprotein (LDL) from blood vessels through reverse cholesterol transport. In addition, HDL has anti-inflammatory and antioxidant properties. Low HDL level is an independent risk factor for development of coronary artery disease. To manage patients with low HDL levels, general measures such as lifestyle modification, controlling acute metabolic syndrome, and participating in regular endurance exercise are essential. Smoking cessation is a must, and it will often improve HDL levels by 5% to 10%. While statin therapy is the backbone therapy for controlling LDL levels, it also results in elevation of HDL levels by at least 5%. Specific pharmacologic interventions to improve HDL level and function have been disappointing. Cholesteryl ester transfer protein (CETP) is the key metabolic pathway to transfer HDL to LDL; thus, CETP inhibitors result in elevation of HDL levels. Several products were tested in large controlled studies, such as dalcetrapib and evacetrapib; neither resulted in any clinical benefit. Anacetrapib only resulted in very limited benefit and is no longer under active development. The most recent study utilized apolipoprotein A1 infusion in high-risk patients shortly after acute myocardial infarction. There was no benefit in the primary end point of myocardial infarction, stroke, or death. In patients with low HDL, a strategy of having LDL as low as can be possibly achieved may be the most appropriate approach. Show less

(Sb,Bi)(S,Se)(Br,I) pnictogen chalcohalides constitute an emerging family of Van der Waals (VdW) semiconductors with remarkable potential for energy-related applications, including photovoltaics (PV), photocatalysis (PC), and photoelectrocatalysis (PEC). These ternary compounds exhibit a quasi-1D orthorhombic crystalline phase, and an electronic structure analogous to lead-halide perovskites, making them promising candidates for sustainable and high-performance energy devices. This study introduces a new versatile and adaptable synthesis methodology, which combines co-evaporation of binary chalcogenides with reactive annealing under high-pressure halide atmospheres, to fabricate the eight (Sb,Bi)(S,Se)(Br,I) chalcohalides. Comprehensive structural, compositional, and optoelectronic analyses reveal a wide bandgap range (1.2-2.2 eV), high absorption coefficients, and anisotropic properties driven by unique ribbon-like morphology. Theoretical and experimental results highlight their high stability, versatile chemical adaptability, and defect-tolerant characteristics. Moreover, the distinct differences in morphology and crystallization between Sb and Bi-based compounds, as well as the influence of chalcogen and halogen elements on the optical and structural properties are discussed. Demonstrations of functional devices, including photocatalytic systems, underscore the practical viability of these materials. This work establishes a foundation for the development of pnictogen chalcohalides as scalable and eco-friendly alternatives for advanced energy applications. Show less

The widespread detection of antibiotics in aquatic environments, particularly in effluent-receiving surface waters, poses significant ecological and public health concerns due to their role in promoting antimicrobial resistance. Accurate trace-level antibiotic measurement is essential for environmental risk assessment and for improving wastewater treatment strategies. This study presents the development, optimization, and validation of two complementary liquid chromatography-mass spectrometry (LC-MS) workflows for the simultaneous quantification of nine antibiotics across five therapeutic classes in creek water impacted by a Common Effluent Treatment Plant (CETP). The performance of a triple quadrupole LC-MS/MS system (LC-QqQ-MS) was compared to that of a high-resolution Orbitrap mass spectrometer (LC-Orbitrap-HRMS). Both instruments demonstrated excellent linearity ( Show less

Atherosclerosis (AS) is a serious threat to human health. Although glucose balance, lipid metabolism, inflammation and hypertension are closely related to AS, whether methyltransferase-like (METTL) family members are involved in the occurrence and development of AS remains elusive. Differentially expressed genes of METTLs in AS and normal blood vessels in GSE43292 and GSE100927 databases were analyzed. Random forest screening was used to screen marker genes, and the intersection genes in the two databases were selected. GSE28829/GSE41571 and clinical tissue samples were used for verification. The databases were further used to analyze marker genes' tissue and cellular localization and their correlation with lipid metabolism and efferocytosis. 7 and 17 differentially expressed METTL genes were obtained from GSE43292 and GSE100927 databases, respectively. METTL7B and METTL5 were verified as the intersection marker genes. Compared with the control group, the expression of METTL7B was significantly increased in advanced AS, AS ruptured plaque and clinical heavy-load plaque tissues. ROC curve analysis showed that the AUC of METTL7B in GSE28829 and GSE41571 was greater than 0.9. In addition, it was found that METTL7B was significantly correlated with lipid metabolism-related genes and promoted the formation of lipid droplets. METTL7B was positively correlated with atherosclerosis and macrophage-mediated efferocytosis. RNA-seq and targeted lipidomics results also confirmed that METTL7B is closely related to lipid metabolism and atherosclerosis. And further analysis also indicated that METTL7B could regulate 104 kinds of lipids, such as Lipid-n-0041, Lipid-n-0056, Lipid-n-0057, Lipid-n-0098, Lipid-n-0099 and Lipid-n-0169, mediated by AKR1C1, CETP and RORA. This study reveals a new mechanism for the occurrence and development of AS, thereby providing a potential target for the treatment of AS. In conclusion, METTL7B can be used as a predictor and therapeutic target for AS. Show less

Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse statins could be affected by cholesterol metabolism-related genetic variants in Alzheimer's disease.. This prospective observational pharmacogenetic study was conducted at the Universidade Federal de São Paulo (Unifesp), Brazil. Consecutive outpatients were prospectively followed for lipid profile variations over one year, estimated by the associations between statin therapy and the following variants: rs2695121 (NR1H2), rs3846662 (HMGCR), rs11669576 (LDLR8), rs5930 (LDLR10), rs5882 and rs708272 (CETP), rs7412 and rs429358 (APOE), and ACE insertion/deletion polymorphism. All polymorphisms in the 189 patients were in Hardy-Weinberg equilibrium. Statins resulted in lower total cholesterol and LDL cholesterol levels, whereas the effects on HDL cholesterol varied according to the statin used. Atorvastatin resulted in lower triglyceride level variations than simvastatin. APOE-ε4 carriers showed a better response to atorvastatin in elevating HDL-cholesterol than APOE-ε4 non-carriers. Carriers of the ACE insertion allele had cumulatively lower total cholesterol and LDL-cholesterol levels, regardless of statin therapy, but lower triglyceride levels when using atorvastatin. Carriers of rs11669576-G had lower total cholesterol and LDL-cholesterol levels when using simvastatin, and lower total cholesterol and triglycerides when using atorvastatin. Concerning CETP haplotypes, carriers of rs5882-A and rs708272-A benefitted the most from statins, which lowered total cholesterol and increased HDL-cholesterol levels, and from atorvastatin lowering triglycerides; however, the effects of atorvastatin lowering total cholesterol and LDL-cholesterol were more pronounced for carriers of rs5882-GG/rs708272-GG. Lipid profile variations may be pharmacogenetically mediated in Alzheimer's disease, thus, confirming their high heritability. Show less

Pancreatic adenocarcinoma (PAAD) remains highly lethal because of chemotherapy resistance and immunosuppressive microenvironments. Tertiary lymphoid structures (TLSs) were analysed in PAAD to develop personalised therapeutic strategies. Nine TLS-related genes (CCR6, CD1d, CD79B, CETP, EIF1AY, LAT, PTGDS, RBP5 and SKAP1) were selected for integrative analysis of TLS status in relation to clinical outcomes, immune cell infiltration, tumour mutational burden (TMB) and drug resistance. High TLS scores (TLS_H) were associated with improved overall survival (OS) and progression-free survival (PFS), independent of age or tumour grade. Twelve immune cell types differed across TLSs. Single-cell RNA-seq analysis revealed that the 9 TLS-related genes were enriched in distinct immune cell populations. Combining TLS and TMB improved survival prediction. Notably, the TLS_H group demonstrated enhanced sensitivity to chemotherapeutics including AZD8055, axitinib, vorinostat, nilotinib, camptothecin and paclitaxel. Real-time fluorescent quantitative PCR (RT-qPCR) validation in Mia PaCa2 and Jurkat cells indicated that LAT, RBP5 and SKAP1 may play important roles in modulating sensitivity to these chemotherapeutics. These findings establish TLS as a potential biomarker for PAAD, enabling personalised chemotherapy selection by integrating immune contexture and genomic drivers to improve clinical outcomes. Show less

High-density lipoprotein cholesterol (HDL-C) has long been inversely associated with atherosclerotic cardiovascular disease risk, but pharmacologic efforts to raise HDL-C have consistently failed to reduce cardiovascular events. This has shifted focus from HDL quantity to quality, emphasizing functional properties such as cholesterol efflux, antioxidative capacity, and anti-inflammatory activity. Dysfunctional HDL, often modified by oxidative and inflammatory processes mediated by myeloperoxidase, loses its ability to promote reverse cholesterol transport, support endothelial function, and suppress vascular inflammation. Advanced proteomic and lipidomic studies have revealed compositional remodeling that underlies HDL's functional heterogeneity and disease-specific signatures. Functional measures like cholesterol efflux capacity and cell-free HDL assays correlate more strongly with cardiovascular outcomes than static HDL-C levels, providing a more accurate index of vascular protection. Despite the promising therapies such as cholesterol ester transfer protein (CETP) inhibitors, niacin, and apolipoprotein A-I infusions (reconstituted high-density lipoprotein (CSL112)), none have yet demonstrated definitive event reduction. Future directions include standardizing HDL functional assays, prioritizing quality over concentration, and integrating HDL-targeted and metabolic therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transport 2 (SGLT2) inhibitors, to restore HDL's protective phenotype and redefine preventive cardiology. Show less

This investigation elucidates the critical molecular determinants associated with the comorbidity of osteoporosis (OP) and periodontitis (PD) through proteomic profiling, while delineating the regulatory function of CD44 in experimental periodontitis in an OP murine model. Phase I involved collecting serum specimens from patients with OP+PD (n = 3) and healthy controls (n = 6) undergoing routine health evaluations at our institution for comparative proteomic analysis. Subsequent translational validation of differentially expressed genes (DEGs) and associated signaling cascades was conducted across clinical specimens and OP+PD murine models. To mechanistically characterize CD44's role in PD progression under osteoporotic conditions, an OP murine model was generated through bilateral ovariectomy, followed by experimental PD induction via ligature placement. Comprehensive assessments included histomorphometric alterations via hematoxylin-eosin staining, microarchitectural bone analysis at the maxillary first molar region using micro-CT, and immunoblotting evaluation of phosphoinositide-3-kinase (PI3K)/Akt pathway components. Parallel network pharmacological screening coupled with molecular docking simulations was executed to identify bioactive constituents of Angelica sinensis with therapeutic potential. Proteomic interrogation identified CST3, A2M, CD44, CDH13, CETP, and VWF as candidate pathogenic mediators in OP+PD pathogenesis. In our hands, gene set enrichment analysis revealed that PI3K/Akt signaling functions as a principal mediator of OP+PD disease progression. Quantitative reverse-transcription PCR-based validation confirmed significant CD44 upregulation in both clinical and experimental OP+PD cohorts. In vivo modulation via CD44 suppression significantly restored periodontal tissue integrity, reduced inflammatory cell infiltration, and strengthened alveolar bone microarchitecture in OP mice, concomitant with PI3K/Akt pathway inhibition. Network pharmacology revealed glycitein as the primary bioactive phytochemical in Angelica sinensis, with CD44 identified as its central molecular target. Glycitein improved alveolar bone structure in OP+PD mice, increasing bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone mineral density (BMD), and reducing trabecular number (Tb.N), bone surface-to-bone volume ratio (BS/BV), indicating healthier bone quality, mechanistically attributed to CD44 signaling axis attenuation. Show less

Dyslipidemia remains a central modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, as well as ezetimibe, fibrates, and omega-3 fatty acids have established roles in lipid lowering, significant residual risk persists in many patients due to insufficient low-density lipoprotein cholesterol (LDL-C) reduction, elevated triglyceride-rich lipoproteins, and genetically determined elevations of lipoprotein(a) (Lp(a)). Recent years have witnessed remarkable advances in therapeutic modalities, including next-generation small molecules, monoclonal antibodies, protein-based infusions, and ribonucleic acid (RNA)-based strategies. These agents target diverse pathways such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C-III, apolipoprotein B, cholesteryl ester transfer protein (CETP), and Lp(a), achieving potent lipid modulation with improved convenience and safety. Clinical outcome trials have validated bempedoic acid, PCSK9 inhibitors, and icosapent ethyl, while large-scale programs are ongoing for obicetrapib, oral PCSK9 inhibitors, Lp(a)-targeted oligonucleotides, and ANGPTL3-directed RNA therapeutics. This review summarizes the mechanisms, pivotal trials, and clinical implications of innovative lipid-lowering therapies, highlighting how they may reshape future treatment algorithms for ASCVD prevention. Show less

Overweight and obesity are widespread in Mexico, often linked to dyslipidemia and higher cardiovascular risk. The search for safe and effective treatments has promoted interest in natural supplements such as Ashwagandha (Withania somnifera), recognized for its adaptogenic and potential lipid-lowering properties. To assess the impact of Ashwagandha supplementation on serum lipid profiles and anthropometric parameters in Mexican adults with overweight and obesity. A double-blind, randomized, placebo-controlled pilot clinical trial was carried out with 43 adults (n = 17 in the control group and n = 21 in the intervention group) over 40 days. Participants followed a monitored diet and received one daily capsule containing 500 mg of Ashwagandha or a placebo, in addition to a guided unrestricted dietary plan. Anthropometric and biochemical measurements were taken at baseline and after the intervention. In silico analysis was also performed to examine the binding affinity of Ashwagandha bioactive compounds to key proteins involved in lipid metabolism. Ashwagandha supplementation did not produce statistically significant changes in body weight, body mass index (BMI), or waist circumference (WC). However, significant reductions were observed in triglyceride and VLDL-c levels (p = 0.0082 and p = 0.0321, respectively). In silico results supported these findings, showing favorable interactions between compounds such as withanolide A and lipid metabolism targets, including AMPK, CETP, and LPL. Ashwagandha supplementation improved serum lipid profiles in adults with overweight and obesity, suggesting potential lipid-lowering effects when combined with a prescribed dietary plan. Also, it was possible to elucidate some metabolic pathways in which Ashwagandha composition has an influence on producing the reported effects. Further long-term studies with controlled dietary intake are needed to confirm these findings and clarify the underlying molecular mechanisms. Show less

Cholesterol metabolism (CM) plays essential roles in human disease. Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with significant morbidity and healthcare burden. However, the role of CM in UC remains unclear. Gene expression data of UC patients and control samples were retrieved and merged from GSE75214, GSE92415, GSE16879, and GSE48958. Differential analysis was performed for the identification of cholesterol homeostasis-related differentially expressed genes (DEGs), followed by machine learning for cholesterol homeostasis-related hub DEGs. Five cholesterol homeostasis related genes were identified. We further assessed the related pathways of 5 hub genes. Five overlapped cholesterol homeostasis related genes were identified by DEGs analysis. LIPC, LIPG, CETP, ABCB11, and APOH were identified as hub genes. The current study identified 5 cholesterol homeostasis related genes, LIPC, LIPG, CETP, ABCB11, and APOH, that might play key roles in the development of UC. These findings offer new insights for further exploring UC and its underlying mechanisms. Show less

The chimeric cytokine IC7Fc conveys the metabolic signaling properties of the glycoprotein 130 receptor cytokines interleukin-6 and ciliary neurotrophic factor via membrane-bound signaling. IC7Fc was previously shown to slow the progression of type 2 diabetes mellitus, and here, we demonstrate its effect on atherosclerotic development. In APOE*3-Leiden.CETP mice, an atherosclerosis-prone model with a humanized lipoprotein metabolism, IC7Fc markedly lowered plasma triglyceride and total cholesterol levels. This was mechanistically explained by an inhibition of de novo lipogenesis in the liver, increased synthesis of bile acids from cholesterol, and down-regulated apolipoprotein B synthesis, which resulted in decreased cholesterol secretion in very low-density lipoprotein particles. As a consequence, IC7Fc treatment considerably reduced atherosclerotic lesion formation and vascular inflammation compared with current antihyperlipidemic therapy. In conclusion, IC7Fc is a promising pharmacological treatment for cardiometabolic diseases targeting hyperlipidemia and inflammation. Show less

Obicetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor with promising lipid-lowering effects. While earlier CETP inhibitors have shown inconsistent cardiovascular outcomes and safety concerns, the efficacy and safety of obicetrapib remain under active investigation. We systematically searched PubMed, Embase, and Cochrane Central databases for randomized controlled trials (RCTs) comparing obicetrapib versus placebo in adults with dyslipidemia or at high cardiovascular risk. We pooled mean differences (MDs) with 95 % confidence intervals (CI) with a random effects model. We used R software version 4.4.2 for statistical analysis. We included 7 RCTs comprising 3381 participants, of whom 2151 (63 %) received obicetrapib. The mean age was 64.3 years, and 36 % were women. Compared with placebo, obicetrapib significantly reduced mean LDL-C (MD: -37.21 %; 95 % CI: -41.53 to -32.90; Among patients with dyslipidemia and/or high cardiovascular risk, obicetrapib significantly reduces LDL-C, lipoprotein(a), apolipoprotein B, and non-HDL-C. No significant differences were observed in adverse events, supporting the favorable safety profile of obicetrapib. Show less

Little is known, how life-long hyperlipidaemia affects vascular ageing, before atherosclerosis. Here, we characterise effects of mild, life-long hyperlipidaemia on age-dependent endothelial dysfunction (ED) in humanised dyslipidaemia model of E3L.CETP mice. Vascular function was characterised using magnetic resonance imaging in vivo and wire myograph ex vivo. Plasma endothelial biomarkers and non-targeted proteomics in plasma and aorta were analysed. Early atherosclerosis lesions were occasionally present only in 40-week-old or older E3L.CETP mice. However, age-dependent ED developed earlier, in 14-week-old male and 22-week-old female E3L.CETP mice as compared with 40-week-old female and male C57BL/6J mice. Acetylcholine-induced vasodilation in 8-week-old E3L.CETP, especially female mice, was blocked by catalase and attributed to H Show less

Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that significantly lowers low-density lipoprotein cholesterol (LDL-C). Additive reductions in LDL-C occur when obicetrapib is combined with ezetimibe. The impact of obicetrapib and ezetimibe fixed-dose combination (FDC) on coronary plaque burden is unknown. Favorable changes in noncalcified coronary atherosclerotic plaque volume (NCPV) may indicate a potential beneficial effect on atherosclerotic cardiovascular disease (ASCVD) events. REMBRANDT is a placebo-controlled, double-blind, randomized trial designed to assess the efficacy of obicetrapib and ezetimibe FDC on coronary plaque burden. Individuals aged 45 years or older with ASCVD (imaging evidence of vascular disease or clinically manifested ASCVD) and an LDL-C of ≥70 mg/dL despite maximally tolerated lipid-modifying therapy are eligible to participate. Eligible participants (N = 300) will be randomized in a 1:1 ratio to obicetrapib 10 mg and ezetimibe 10 mg FDC once daily or placebo tablet once daily. The primary efficacy outcome of REMBRANDT is percent change in total NCPV from baseline to 18 months as assessed by coronary computed tomographic angiography (CCTA). Secondary endpoints include absolute change in total NCPV, percent and absolute change in NCPV in the most diseased coronary segment, percent change in LDL-C, and change in perivascular fat attenuation index from baseline to 18 months. The REMBRANDT trial will determine whether the favorable effects of obicetrapib and ezetimibe FDC on LDL-C translate to a reduction in coronary plaque burden as a potential mechanism for ASCVD risk reduction. NCT06305559. Show less