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Cancer remains one of the leading causes of global mortality, necessitating novel therapeutic strategies. Liver X Receptors (LXRα and LXRβ) and the Farnesoid X Receptor (FXR) are nuclear receptors that regulate lipid and cholesterol homeostasis, bile acid metabolism, inflammation, and immune response pathways intricately linked to cellular dysregulation in oncogenesis. Despite their therapeutic potential, these receptors remain underexplored targets in cancer research. This study implements an extensive suite of computational strategies to identify and evaluate potential modulators of LXRα/β and FXR, through virtual screening using resveratrol as the lead scaffold, followed by drug-likeness evaluation and toxicity profiling. Molecular docking (MVD, AutoDock and ML-PLIC) identified C144 (AZD7762), a well-established CHK1 kinase inhibitor, as the top-ranked ligand, demonstrating superior binding affinity and conformational stability via convergent interaction mechanisms. Additionally, reactivity descriptors derived from density functional theory (DFT) and frontier molecular orbital (FMO) analyses further substantiated its favorable electronic properties and chemical stability. Structural pharmacophore mapping using LigandScout confirmed pharmacophoric alignment with receptor active sites, while bioactivity profiles predicted high efficacy. Extensive quantum mechanical analyses (MEP, NBO, Mulliken/NPA, NCI, RDG, ELF, LOL, BSA, HAS) revealed favorable electronic characteristics, stability, charge distribution, and interaction potential. CLC-Pred, biotransformation (RA), pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA and Shermo-based thermodynamic predictions further validated its biostability and systemic compatibility. These findings position C144 (AZD7762) as a promising anticancer candidate targeting LXRα, LXRβ, and FXR pathways. Further optimization and validation through in vitro and in vivo studies are essential for advancing these findings toward clinical application. Show less

Xenopus embryo is an ideal model for teratogenesis assays to assess the effects of any compounds on the cellular processes crucial for early development and adult tissue homeostasis. In our screening of a chemical library with frog embryo to identify novel compounds that exert specific effects on key cellular signaling pathways, perillic acid (PA) was found to disrupt germ layer specification in early development. Thus, the mechanism underlying this effect was investigated. Embryos were exposed to PA during a specific period of early development to observe stage-specific morphological alterations induced by this compound. Whole-mount in situ hybridization was performed to examine its effects on ectodermal and mesodermal differentiation and the anterior-posterior patterning of neural tissue. Western blotting analysis was employed to identify the signaling pathways through which PA influences germ layer formation in Xenopus development. PA-treated embryos exhibited the shortening of the anterior-posterior body axis, truncation of craniofacial structures and malformation of neural crest (NC). These severe morphological defects occurred when embryos became exposed to PA during the gastrula stages. Consistent with these phenotypes, treatment with PA caused significant expansion of neural tissue concomitant with a reduction of epidermal and NC cell fates. Furthermore, PA induced the caudalization of neural fate and expressions of paraxial mesodermal genes, recapitulating the activity of the FGF/MAPK signals in germ layer specification. In line with this, ERK activation could be induced by PA treatment, which was mediated by the FGFR1 pathway. PA affects the anterior-posterior neural patterning and mesodermal specification by activating the FGF/MAPK signaling pathway. Show less

Neuroblastoma (NB), a common childhood solid tumor, is the leading cause of childhood cancer deaths. Transgelin (TAGLN) is an actin-binding protein of the calponin family, and it is involved in cell motility and migration. The TAGLN gene expression was induced in NB cell lines, such as GOTO, SK-N-SH, and TGW, by gene overexpression using a retroviral Tet-On inducible expression system, and was repressed by RNA interference (RNAi) treatment. TAGLN overexpression repressed cell growth and migration and induced cell arrest and differentiation. On the other hand, RNAi-mediated TAGLN repression activated cell growth. Cells overexpressing TAGLN showed decreased levels of undifferentiated cell markers, such as SOX2, OCT4, KLF4, and ID2. Single-cell analysis after TAGLN overexpression revealed a distinguishable cluster characterized by expression of POSTM, APOE, PDGFRA, IGFBP3, SMAD5, and IGFBP7. In TH-MYCN mice, which have a high frequency of NB development, Tagln overexpression by induction of the murine Tagln gene significantly reduced tumor formation and prolonged survival. In conclusion, these in vitro and in vivo analyses suggest that TAGLN is a candidate tumor suppressor gene in NB. Show less

Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients. Show less

FGF, VEGFR-2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg In the prevention experiment, treatment with 6.25 or 12.5 mg·kg Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg Show less

In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor-positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy. Show less

Obesity is one of the most prevalent chronic metabolic alterations worldwide being highly related to an increased risk for further associated co-morbidities. Current evidence indicates that subjects with obesity have a distinct gut microbiota signature, emphasizing gut microbiota composition as a potential mediating factor. The aim of this research is to evaluate the potential effects of viable and heat-inactivated Lactobacillus rhamnosus GG in the prevention of diet-induced obesity in a rat model. The administration of the probiotic or its heat-inactivated postbiotic partially prevented diet-induced WAT increase in a similar manner. While viable probiotic administration resulted in a reduced lipid uptake (LPL) and de novo lipogenesis (FAS), along with enhanced lipolysis (ATGL) in WAT, its heat-inactivated postbiotic mainly acted reducing de novo lipogenesis. Additionally, the obtained results demonstrated that probiotic administration enhanced thermogenesis (UCP1) and fatty acid oxidation (CPT-1b) on BAT, as well as upregulated several markers involved in mitochondrial biogenesis (p38 MAPK, NRF1 and CS). By contrast, despite the administration of the postbiotic upregulated thermogenesis and fatty acid oxidation in a comparable manner as the probiotic, these results were not accompanied by changes in mitochondrial biogenesis markers. These results indicate that under the specific experimental conditions tested, both the administration of viable and heat-inactivated Lactobacillus rhamnosus GG present valuable potential for preventing diet-induced WAT mass increase in rats. While both treatments exerted similar effects on WAT and BAT, subtle differences that may derive from bacterial viability were observed in the involved mechanisms of action. Show less

The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less

Perfluorooctanoic acid and perfluorooctane sulfonate are well-known eight-carbon per- and polyfluoroalkyl substances (8C-PFAS) potentially toxic for the human liver. However, direct experimental evidence demonstrating their toxicity on the human liver remains limited. Consequently, this study aimed to extrapolate the 8C-PFAS liver toxicity mechanisms by leveraging omics data to integrate mouse and human findings. Through integration analyses of nine datasets (one human, six murine, and two rat), we identified 199 genes with known biological functions that are commonly affected by 8C-PFAS across species. We delineated a comprehensive regulatory network of 8C-PFAS toxicity, demonstrating that 8C-PFAS may trigger fatty liver disease by up-regulating CD36 and PPARα pathway; dysregulate xenobiotic metabolism by disrupting CAR and CYP family genes; and induce cancer by dysregulating WNT, TGFβ, FGF21, and P53 pathways. We also identified ATF3, EGR1, ESR1, NFATC4, SNAI2, TP53, and EZH2 as transcriptionally regulated by 8C-PFAS, along with PPARα, RXRα, FGFR1, TCF3, and SMAD3 as potentially functionally impacted. Collectively, these factors account for over 90 % of 8C-PFAS-affected key genes. This study not only developed a novel method for extrapolating human toxicity risks by integrating scattered toxicity evidence based on transcriptomics data, but also proposes new mechanisms by which 8C-PFAS contributes to fatty liver disease and cancer. Show less

The β-secretase β-site APP cleaving enzyme 1 (BACE1) is a major drug target for Alzheimer's disease (AD). Clinically tested BACE1 inhibitors induced unexpected cognitive side effects that may stem from their cross-inhibition of the homologous protease BACE2. Yet, little is known about BACE2 functions and substrates in vivo, and no biomarker is available to monitor the extent of BACE2 inhibition in vivo, particularly in cerebrospinal fluid (CSF). To identify a potential CSF biomarker for monitoring BACE2 activity, we analyzed the CSF proteome changes in non-human primates after treatment with a BACE1-selective inhibitor (a brain-targeted monoclonal antibody) in comparison to verubecestat, a clinically tested small-molecule drug inhibiting both BACE1 and BACE2. Acute treatment with either the antibody or verubecestat similarly reduced CSF abundance of the cleavage products of several known BACE1 substrates, including SEZ6, gp130, and CACHD1, demonstrating similar target engagement in vivo. One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD. Show less

Biallelic loss of function variants in ESAM (endothelial cell adhesion molecule) have recently been reported in 14 individuals (9 families) presenting with prenatal intracranial hemorrhage. Here, we describe four patients from two unrelated families in whom three of them presented with variable onset encephalopathy and seizures while one only displayed profound delay without seizures. Brain MRI showed variable onset intracranial hemorrhage that evolved to hydrocephalus in 3 patients, whereas hemosiderin deposits, white matter volume loss, and porencephalic cysts were noted in one patient. Unlike the majority of described cases, the youngest brother of the first family did not show microcephaly and failure to thrive. Exome sequencing identified two novel homozygous ESAM variants. A splice variant (c.731-2A>G) was identified in one family which was confirmed by investigating the patient's mRNA to result in exon skipping and early protein truncation. In addition, a missense variant (c.561G>C; p.Trp187Cys) was identified in the other family, which is the first disease causing missense variant to be described in patients with ESAM deficient phenotype. In addition, a maternally inherited pathogenic MC4R variant (c.811T>C; p.Cys271 Arg) was also identified in the youngest brother of the first family. Variants in the MC4R gene are associated with a non-syndromic form of obesity that could explain the unusual macrocephaly and obesity. Our work establishes ESAM as a tight junction gene that can present with variable neuroradiological and clinical phenotypes when mutated. Moreover, it refines the phenotype of this ultrarare syndrome and extends the number and type of variants described to date. Show less

Obesity has become a common public health problem all over the world today. In recent years, studies on the genetic etiology of obesity have gained importance. As a result of these studies, 127 obesity-related loci have been identified. The aim of this work was to screen obesity-related genes and review the literature. In this retrospective study, 41 obesity-related genes were screened in 116 patients by next-generation sequencing. These genes are Seventy-six of our patients were female, and 40 were male. As a result, 43 variants were detected in 39 (34.4%) patients. Of these, Understanding the genetics of obesity is an essential step toward treating and preventing this disease, which has become a global health problem. With this study, we wanted to contribute to the literature by reporting previously reported and novel variants we detected in our patients with obesity. Show less

People with HIV and chronic hepatitis C may develop metabolic complications after sustained virologic response (SVR), possibly due to persistent molecular alterations induced by HCV. This study aimed to identify baseline (pre-treatment) lipid and immune biomarkers associated with post-SVR metabolic events in HIV/HCV-coinfected participants with compensated advanced chronic liver disease (cACLD) receiving long-term suppressive antiretroviral therapy. We conducted a retrospective study of 56 HIV/HCV-coinfected participants with cACLD. Untargeted lipidomic profiling was performed on baseline plasma samples using a liquid-chromatography-mass spectrometer. The outcome was the development of metabolic events (diabetes mellitus and/or hyperlipidemia) during follow-up, up to seven years post-HCV treatment. Statistical analyses included orthogonal partial least squares discriminant analysis (OPLS-DA), Cox regressions models, and Spearman correlations with inflammation-related biomarkers and immune checkpoint proteins, with multiple comparison corrections using the false discovery rate. 25% participants developed metabolic events after SVR. OPLS-DA identified 163 lipid species (VIP scores≥1) associated with these events, and adjusted Cox regression confirmed significant associations for 24 of them. Lysophosphatidylcholines (LPCs) were the most prevalent, with higher baseline levels linked to increased metabolic risk. Participants who developed events also had higher levels of plasmalogens LPC (O-LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI), lysophosphatidic acid (LPA), and phosphosphatidylcholine (PC). Several lipid species correlated positively with the pro-inflammatory cytokine IL-18, the anti-inflammatory suppressor IL-1RA, and the immune checkpoint proteins IDO and S100A8/A9. Pre-treatment lipid and immune dysregulation was associated with post-SVR metabolic events in HIV/HCV-coinfected participants, suggesting that HCV may leave a lasting metabolic imprint that contributes to adverse outcomes after viral clearance. Show less

Scatophagus argus is a highly valuable aquaculture fish. Its artificial breeding faces problems in the induction of high quality eggs, thus necessitating studies on the regulation of ovarian development. As the centre of nutrient metabolism in fish, the liver provides the material basis for ovarian development. However, the molecular mechanism of the liver in ovarian development in S. argus is still unclear. In this study, a transcriptome analysis of adult S. argus livers at different stages of ovarian development (stages II, III and IV) was performed. 410, 1025 and 1867 differentially expressed genes (DEGs) were obtained between stages II and III, stages II and IV and stages III and IV, respectively. In GO and KEGG analyses, DEGs were mostly involved in vitellogenesis and egg envelope formation (e.g., erα, erβ1, vtga, vtgb, vtgc, zp3, zp4a and zp4b), lipid metabolism and energy metabolism (e.g., dagt1, dagt2, lpl, apob, hk1, acly, ogdh, pc, and fbp1), and hormone signaling (e.g., lepa and igfbp1). Additionally, genes that were significantly upregulated in the liver at stage IV of ovarian development, compared to stages II and III, were markedly enriched in steroid biosynthesis and metabolism pathways. These findings provide clues to understanding the mechanisms of liver action in teleost ovarian development. Show less

The quantity and quality of anti-Spike (anti-S) antibodies, rapidly elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are necessary for understanding the immune response induced by infection. Antibody avidity is a good indicator of the quality of antibody response. Interleukin (IL)-21 and IL-27 are two cytokines that play vital roles in the affinity maturation process. Therefore, we decided to investigate whether there are any relationships between the avidities of antibodies against spike and nucleocapsid (N) antigens of SARS-CoV-2 and serum levels of these cytokines in symptomatic and asymptomatic coronavirus disease 2019 (COVID-19) patients. Forty symptomatic COVID-19 patients and 40 asymptomatic carriers were enrolled. Anti-S and anti-N IgG avidity indices (AIs) were determined using a modified enzyme-linked immunosorbent assay (ELISA). Serum levels of IL-21 and IL-27 were quantified by specific ELISA kits. AI values of both anti-S and anti-N IgG were lower in the symptomatic group compared to asymptomatic cases, while only that of anti-N IgG was statistically significant. For IL-21 and IL-27 serum levels, no significant difference between the two groups was shown. Also, we could not find any correlations between cytokine levels and antibody AI values. However, an inverse correlation between anti-S AI value and IL-27 serum level was found in asymptomatic patients. Our study suggests that serum levels of IL-21 and IL-27 cannot predict differences in anti-S and anti-N IgG avidity between symptomatic and asymptomatic COVID-19 patients. Show less

Breast cancer (BC) is the most common cancer diagnosed in the world and it is also the main leading cause of cancer deaths in women. Change in epigenetic mechanisms promotes BC initiation and progression. Histone deacetylase 8 (HDAC8) was found to act as a potential oncogene in different malignancies. For better understanding of the HDAC8 function in BC development, we investigated the effect of HDAC8 deletion on the expression of genes involved in signaling pathways. In this study, CRISPR technology was used to knockout the HDAC8 gene in MDA-MB-468, MDA-MB-231 and MCF-7 ​cell lines. For this purpose, two gRNAs were designed and cloned into the PX459 vector. The gRNA-containing vectors were transfected into the BC cell lines and then the effect of this deletion on the expression of genes involved in signaling pathway was determined using quantitative real-time PCR (qRT-PCR). Analysis of qRT-PCR results showed a reduction in the expression of studied genes in BC cell lines after deletion of the HDAC8 gene compared to untreated controls. Although this decline was not significant for FGF2 and FGFR1 genes, however the mTOR, IGF1R, INSR, VEGFA and VEGFR2 genes showed statistically significant reduction in the studied BC cell lines. In addition, the down-regulation of PDGFC and PDGFRA genes were only significant in the TNBC cell lines. Overall, our study showed that HDAC8 can exert its oncogenic effects by altering the expression level of molecules involved in some signaling pathways, and inhibiting HDAC8 can revert these effects. Show less

Apolipoprotein C-III (apoC-III) is an important regulator of triglyceride (TG) metabolism and a target for intervention. The present study examined the effects of gain-of-function (GOF) variants in APOC3 on apolipoprotein B kinetics to understand further how changes in the synthesis of this apolipoprotein impact triglyceride-rich lipoprotein (TRL) metabolism. Two groups of subjects were recruited by population screening, 9 carriers of known APOC3 GOF variants and 9 age-, sex- and BMI-matched non-carriers. The kinetics of TRL were determined using stable isotope tracers of apoprotein and triglyceride metabolism in a non-steady-state protocol involving administration of a fat-rich meal. APOC3 GOF carriers had 47 % higher plasma apoC-III levels compared to non-carriers (P = 0.022) and higher production rates for the apolipoprotein. Post-prandial response (total area-under-curve) for plasma TG was 108 % greater in GOF carriers compared to non-carriers (P = 0.002) due specifically to higher levels of VLDL APOC3 GOF carriers showed specific alterations in TRL metabolism (compared to matched non-carriers), namely slower lipolysis and delayed clearance of VLDL Show less

Myocardial infarction (MI) is one of the leading causes of mortality in Saudi Arabia, with individuals sharing genetic, lifestyle, and environmental risk factors. The present investigation aimed to review the literature on genetic susceptibility to MI among Saudi individuals, with a specific emphasis on genome-wide association studies (GWAS) for coronary artery disease (CAD) and MI. Studies have revealed the relationship between polymorphisms in genes such as proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), which are involved in lipid metabolism, inflammation, and endothelial function. This PROSPERO-registered systematic review and meta-analysis (CRD42024603752) evaluates genetic determinants of myocardial infarction among Saudi adults. Five databases were searched (1989-Oct 2024) according to PRISMA guidelines. Case-control and cohort studies that met the inclusion criteria were analyzed using random-effects models. Findings suggest that several polymorphic genes are highly associated with MI in Saudi citizens. There is strong evidence indicating that PCSK9, CETP, and CDKN2B-AS1 contribute to susceptibility to MI, though the effect of these polymorphic genes varies. The meta-analysis confirmed that MI is a polygenic disease, and genetic predisposition, in combination with individual lifestyle factors, determines disease progression. This study establishes that genetic factors significantly contribute to MI in Saudi Arabia. Integrating genetic screening with traditional cardiovascular risk assessments can enhance early intervention strategies. The findings highlight the need for MI prevention programs tailored to specific genotypes in the Saudi population. Show less

Despite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients. The registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5). We studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27-57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8-13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107-184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32-86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5-145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors. In Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets - even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101. Show less

Peptide hormone-receptor interactions serve as critical regulators of metabolic homeostasis, a paradigm exemplified by the clinical efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists. Building upon this framework, strategic design has yielded unimolecular dual and triple agonists targeting GLP-1R, glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GcgR), leveraging the sequence homology within the cognate native ligands of the class B G protein-coupled receptor (GPCR) family. However, the integration of Y2 receptor (Y2R) agonism─engaged by peptide YY (PYY) and belonging to the structurally divergent class A GPCR family─has remained an unaddressed challenge due to the topological and sequence disparities between these receptor classes. Y2R activation plays a pivotal role in appetite suppression, potentiating the metabolic benefits conferred by GLP-1R, GIPR, and GcgR agonism. Here, we report first-in-class, unprecedented tetra-agonists with high potency at GLP-1R, GIPR, GcgR, and Y2R. The chimeric peptides overcome the intrinsic sequence constraints imposed by class A and class B GPCR divergence, demonstrating the feasibility of rationally designed agonism mediated by single agents across receptor families. Lipidation of this template is well tolerated enhancing the promise of therapeutic viability. Furthermore, we show that biased agonism at GLP-1R selectively boosts cyclic AMP (cAMP) signaling while minimizing β-arrestin recruitment, thereby decoupling receptor desensitization from metabolic efficacy. Additionally, we introduce a tunable framework to modulate β-arrestin engagement without compromising cAMP potency, providing insight into the fine-tuning of GPCR-mediated signaling for next-generation peptide therapeutics. Show less

In patients who have achieved optimal LDL-C control, there remains a residual risk of atherothrombotic cardiovascular disease (ASCVD) related to alterations in lipid metabolism, among which alterations in triglyceride-rich lipoproteins and the cholesterol they contain, known as remnant cholesterol, play a major role. Remnant cholesterol is related to ASCVD risk that is independent of LDL-C and has been demonstrated in epidemiological and Mendelian randomization studies. Numerous epidemiological and genetic Mendelian randomization studies support that elevated triglyceride-rich lipoproteins (TRL) and remnant cholesterol are causally associated with ASCVD, myocardial infarction, ischemic stroke, aortic valve stenosis, and all-cause mortality. The remnant particles of triglyceride-rich lipoproteins are highly atherogenic due to their ability to enter and be retained in the arterial wall, their high cholesterol content, and their capacity to generate foam cells, induce endothelial dysfunction, a prothrombotic environment, and a vascular inflammatory response. Assessment of remnant cholesterol can provide information about residual ASCVD risk beyond that provided by LDL-C, non-HDL-C, and apoB, particularly in individuals with hypertriglyceridemia, type2 diabetes, or metabolic syndrome. Show less

The triglyceride-glucose (TyG) index is a novel diagnostic marker for various metabolic and cardiovascular diseases. However, little is known about the association of the TyG index with plasma atherogenicity, especially with its latent forms. The aim of this study was to assess the potential of the use of the TyG index as a marker of atherogenic risk. A total of 202 men with normolipidaemia, aged 20-60 years, were enrolled in this study. Fasting biochemical parameters were measured. The TyG index was calculated as ln[triglyceride(mg/dL)×glucose(mg/dL)]/2. The diagnostic ability of the TyG index for detecting atherogenic risk was tested by receiver operating characteristic (ROC) curve analysis. A substantial portion of normolipidaemic men had deviations from the reference values for the indices calculated using apolipoproteins. Unfavorable values for the apolipoprotein (apo) B/apoA-I ratio, low-density lipoprotein cholesterol/apoB (LDL-C/apoB) ratio, and the atherogenic index (ATH index) were observed in 32.7%, 31.7%, and 14.4% of men, respectively. The results of ROC curve analysis showed that the TyG index had good diagnostic ability for identifying unfavorable apolipoprotein indices in normolipidaemic men. Thus, the TyG index can be a valuable additional marker for assessing latent atherogenic risk; it can provide useful information for the diagnosis and treatment of early atherosclerosis. Show less

Ionizable lipids are critical for determining the potency of mRNA lipid nanoparticles (LNPs). Various mRNA therapies require LNPs that achieve efficient delivery while maintaining appropriate immunogenicity in vivo. While research has largely focused on screening the amine headgroups, linkers and hydrophobic tails of ionizable lipids, the role of tail unsaturation in influencing mRNA delivery and immunogenicity of LNPs has received less attention. Here, we utilized a four-component Ugi reaction (Ugi-4CR) system to synthesize a small library of 17 ionizable lipids with identical backbones but varying in degrees, positions, and types of unsaturation in hydrophobic tails. We systemically investigated structure-activity relationships and elucidated the influence of tail unsaturation on physicochemical properties, endosomal escape, mRNA delivery efficiency and immunogenicity of LNPs. The findings indicate that optimization of tail unsaturation could serve as a promising strategy to improve mRNA encapsulation and delivery efficacy while modulating LNP immunogenicity in vivo. Using interleukin-27 (IL-27)-encoded mRNA as a model, we demonstrated the potential of selected LNPs for protein supplementation therapies. These insights provide a foundation for the rational design of ionizable lipids, advancing the development of more efficient and safer mRNA delivery systems. Show less

Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have recently been shown to play a significant role in the treatment of diabetes and obesity. Better understanding of their signaling and mechanism of action could further improve their therapeutic effects. In the current study, we investigate the impact of biased cyclic AMP (cAMP) signaling of GLP-1R and GIPR, individually, as well as the combined effects of a unimolecular dually biased GLP-1R/GIPR agonist, CT-859, on glucose, food consumption, and body weight regulation. Our data demonstrate that biased agonism of either GLP-1R or GIPR leads to better glycemic regulation, greater food intake suppression, and weight loss. In addition, concerted biased activation of both GLP-1R and GIPR results in substantially higher efficacy. Activation of GLP-1R and GIPR with a combination of individually biased agonists or via a dually biased unimolecular approach with CT-859 may provide significant therapeutic advantages for the treatment of diabetes and obesity. Show less

Asian populations are underrepresented in the hypertrophic cardiomyopathy (HCM) genomic databases, which are currently largely dominated by Caucasian population. We aim to characterize the genetic landscape of HCM in patients from Hong Kong Chinese population. From March 2023 to March 2024, fifty-three unrelated patients with an unequivocal clinical diagnosis of HCM were enrolled at a single tertiary center in Hong Kong and underwent genetic testing using a standardized 19-gene panel. In this cohort study, we identified 13 patients (24.5%) with a predominant pathogenic or likely pathogenic (P/LP) variant and 12 patients (22.6%) with a predominant variant of unknown significance (VUS). Most of the P/LP variants identified were in Our study provided insight into the genetic landscape of HCM in Hong Kong Chinese population. We identified several recurrent variants and novel variants in our HCM cohort. Patients with P/LP variants were associated with an increased risk of developing left ventricular dysfunction. Future studies on the potential founder effects of these recurrent variants, cumulative effects of multiple variants, and longitudinal follow up of HCM patients would be useful. Show less

Genes associated with body mass index (BMI), including FTO rs9939609,MC4R rs17782313, and BDNF rs6265, may influence BMI and regulate energy metabolism. While previous studies have explored health-related behavior changes, few have investigated both biochemical and behavior changes resulting from perceived genetic risk. This study investigated whether recognizing BMI-related genes affects health-related behaviors and alters blood metabolite levels. Normal and overweight adults aged 25-35 years (n = 100) were randomly assigned to an intervention group (n = 65) informed about BMI-related genetic information (FTO rs9939609, MC4R rs17782313, BDNF rs6265) and an uninformed group (n = 35, CON). The intervention group was further divided into Intervention-high risk (IHR, n = 36) and intervention-low risk (ILR, n = 29) subgroups. Dietary intake and physical activity (PA) were assessed using a 3-day dietary record and the IPAQ-short form. Blood metabolites were analyzed through multivariate analyses to identify significant differences among the groups, with measurements taken at baseline, 3 months, and 6 months. The IHR group exhibited increased dietary fat and fast foods intake, along with enhanced vigorous and moderate PA. Six metabolites were selected as biomarkers that were distinguishable among groups, and the relative serum cholesterol levels significantly decreased in the IHR group at 3 months. These results demonstrate that recognizing the BMI-associated genetic risk resulted in a short-term increase in PA but did not improve dietary intake. Increased PA was significantly associated with reduced cholesterol concentration, suggesting the clinical importance of physical activity in the genetically at-risk group. This study was reviewed and approved by the Seoul National University Institutional Review Board (IRB #1901/001-004) and registered on the Clinical Research Information Service (CRIS), KCT0004650 ( https://cris.nih.go.kr/cris/search/detailSearch.do /14091, 2020/01/28). Show less

Standard models of lexical production assume that speakers access representations of meaning, grammar, and different aspects of sound in a roughly sequential manner (whether or not they admit cascading or interactivity). In contrast, we review evidence for a parallel activation model in which these representations are accessed in parallel. According to this account, word learning involves the binding of the meaning, grammar, and sound of a word into a single representation. This representation is then activated as a whole during production, and so all linguistic components are available simultaneously. We then note that language comprehension involves extensive use of prediction and argue that comprehenders use production mechanisms to determine (roughly) what they would say next if they were speaking. So far, theories of prediction-by-production have assumed sequential lexical production. We therefore reinterpret such evidence in terms of parallel lexical production. Show less

Dysregulated lipid metabolism promotes the progression of various cancer types, including breast cancer. The present study aimed to explore the lipidomic profiles of patients with breast cancer, providing insights into the correlation between lipid compositions and tumor subtypes characterized by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Briefly, 30 patients with breast cancer were categorized into four groups based on their HR and HER2 status: HR+ no HER2 expression (HER2-0), HR+ HER2-low; HR+ HER2-positive (pos) and HR- HER2-pos. The lipidomic profiles of these patients were analyzed using high-throughput liquid chromatography-mass spectrometry. The data were processed through principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and random forest (RF) classification to assess the lipidomic variations and significant lipid features among these groups. The profiles of the lipids, particularly triglycerides (TG) such as TG(16:0-18:1-18:1)+NH Show less

Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by the presence of 2 pathogenic variants in the LDLR, APOB, PCSK9, or LDLRAP1 genes, which cause very high levels of LDL-cholesterol and premature atherosclerotic cardiovascular disease (ASCVD). To analyze the current situation regarding diagnosis, cardiovascular disease, lipid-lowering treatment, and degree of control of lipids in patients with HoFH in the National Dyslipidemia Registry of the Spanish Atherosclerosis Society. Subjects with HoFH, confirmed by the presence of 2 pathogenic variants in the genes mentioned above, included in the registry from 2013 to June 2023 with an updated review were analyzed. Of 71 included subjects with HoFH, 40.8% were women, aged 52 [24-62] years, 57 adults and 13 children. The median follow-up was 7 [4-13] years. Age of diagnosis was 14 [2-26] years, with 10% of ASCVD at diagnosis and 27% of current ASCVD at 40.6 (13.4) years of age; 38% were on PCSK9 inhibitors, 9 patients on lomitapide, 9 on LDL apheresis, and 1 patient on evinacumab. Subjects with more than 4 therapies achieved >80% reduction in LDLc. In the last visit, the median LDLc was 139.3 [89.4-204.2] mg/dL. ASCVD was strongly associated with male sex and family history of ASCVD, relative risk 5.26 (1.53-18.10) and 2.53 (1.03-6.26), P < .05, respectively. Only 18% and 10% meet the recommended LDLc goal in primary and secondary prevention respectively. The current situation of HoFH in Spain is better than expected, with marked reductions in LDLc levels with new treatments. In this population, recommended LDLc goals are difficult to achieve despite maximum lipid-lowering therapy. ASCVD has been reduced and delayed by 2 decades. Show less