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(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

Alzheimer's Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid. Employing the PPM, we re-stratify patients precisely using baseline data and demonstrate significant treatment effects; that is, 46% slowing of cognitive decline for slow progressive patients at earlier stages of neurodegeneration. In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials. Show less

This study explored latent mental health profiles among adolescents in southwestern China and the association with emotional regulation using the dual-factor model framework. 1,682 junior middle school students completed the LPA revealed three profiles: Troubled (31.51%, high negative symptoms/low well-being), complete mental health (61.30%, low negative symptoms/high well-being), and more troubled (7.19%, severe negative symptoms/extremely low well-being). Cognitive reappraisal positively predicted complete mental health (vs. Troubled; Three distinct profiles emerged, differing from the traditional dual-factor model. Cognitive reappraisal protects mental health, while expressive suppression correlates with poorer outcomes, highlighting the need for targeted interventions promoting cognitive reappraisal. Show less

Hypertrophic cardiomyopathy (HCM) represents the most prevalent form of hereditary cardiomyopathy, and mutation in the cardiac myosin-binding protein C (MYBPC3) gene have been identified as a major contributor to the pathogenesis of HCM. While the desmoplakin (DSP) gene is primarily associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), its role in HCM has been less frequently documented. This case report describes a Chinese patient with obstructive HCM harboring rare variants in both the MYBPC3 and DSP genes. These findings provide valuable insights for future investigations into the genetic underpinnings and disease associations. Show less

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. Show less

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) inhibitors have shown promise in treating Alzheimer's disease (AD) by reducing amyloid-beta (Aβ) production. However, clinical trials of inhibitors such as atabecestat, verubecestat, and lanabecestat have faced challenges, including limited efficacy and significant adverse effects. This narrative review discusses randomized-controlled trials of BACE1 inhibitors. Literature searches were conducted using PubMed and Web of Science for studies from 2010 to 2024. Association with BACE1's widespread expression beyond the brain shows adverse effects such as anxiety, depressive symptoms, and hepatotoxicity. The trial results underscore the need for CNS-specific BACE1 inhibitors to reduce adverse effects. Future research should focus on optimizing drug design and identifying additional therapeutic avenues, such as prostate cancer and insulin resistance. Show less

Low-grade glioneuronal tumors of the cranial nerves are rare, with only a few case reports describing their association with trigeminal neuralgia and no prior reports including genetic analysis. We present a case of a low-grade glioneuronal tumor located adjacent to the trigeminal nerve root in a 70-year-old man who had been experiencing severe left-sided trigeminal neuralgia for several months. He had initially presented with cranial polyneuropathy, for which oral steroid therapy was initiated. Magnetic resonance imaging of the head revealed the left superior cerebellar artery running near the left trigeminal nerve; however, no mass lesions were detected. During microvascular decompression, an 8-mm white tumor was identified on the trigeminal nerve and subsequently removed. Histopathological examination of the surgical specimen revealed round tumor cells with slightly eosinophilic or vacuolated cytoplasm, arranged in nests or rosettes. Foci of calcification, hemorrhage, and hemosiderin deposition were present, but eosinophilic granular bodies, Rosenthal fibers, necrosis, pleomorphism, or mitosis was absent. The tumor cells were immunopositive for synaptophysin and anti-Neuronal Nuclei, focally positive for glial fibrillary acidic protein and S-100 protein, and immunonegative for Olig2 and epithelial membrane antigen, with a Ki-67 labeling index of < 1%. Molecular analyses confirmed the fusion of KIAA1549 exon 16 with BRAF exon 9, with no mutations detected in IDH1/2, H3F3A, BRAF (V600), or FGFR1. These findings provide novel molecular and embryological insights into low-grade glioneuronal tumors of the trigeminal nerve, which may aid in their classification and understanding of the development of the tumor and neuralgia. Show less

This study aimed to investigate the expression and clinical significance of interleukin-27 (IL-27) and forkhead box P3 (Foxp3) in oral squamous cell carcinoma (OSCC) tissues, analyze their co-expression correlations, and explore their potential as prognostic biomarkers and therapeutic targets for OSCC. Immunohistochemistry (IHC) was used to detect the expression of the two subunits of IL-27, IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), and Foxp3 in OSCC tissues and normal tissues. Chi-square test was used to analyze the correlation between the expression of the three in OSCC tissues and the clinical pathological parameters of patients. The IHC results showed that the expressions of IL-27p28, EBI3 and Foxp3 proteins in OSCC tissues were all higher than those in normal control tissues( The expression levels of IL-27p28, EBI3 and Foxp3 in OSCC tissues are significantly upregulated, indicating that the three play important roles in the occurrence and development of OSCC tumors. Furthermore, its high expression is associated with various clinicopathological characteristics of OSCC patients and can be used as a potential indicator for evaluating the prognosis of OSCC patients. Show less

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2C We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD. Show less

Gene discoveries in obesity have largely relied on homogeneous populations, limiting their generalizability across ancestries. We performed a gene-based rare variant association study of BMI on 839,110 individuals from six ancestries across two population-scale biobanks. A cross-ancestry meta-analysis identified 13 genes, including five novel ones: Show less

Head and neck squamous cell carcinoma (HNSC) is a significant global health challenge. While traditional risk factors are well-established, the role of environmental pollutants in HNSC development remains unclear. To investigate the causal relationship between environmental pollution factors and HNSC risk using Mendelian Randomization (MR) analysis. Two-sample MR analysis was performed using genome-wide association study data from the IEU OpenGWAS project and HNSC RNA-seq data from TCGA. Environmental pollution-associated genes (MRGs) were identified and analyzed along with autophagy-related genes (ATGs) in HNSC samples. Cox proportional hazards models were used to develop a clinical prediction model. MR analysis revealed significant causal relationships between nitrogen dioxide air pollution, nitrogen oxides air pollution, PM2.5, and increased HNSC risk. Nine MRGs were identified, with four (IRF4, LINGO1, PTHLH, RSRC1) differentially expressed in HNSC. A six-factor clinical prediction model (IRF4, LINGO1, PTHLH, RSRC1, Age, USP10) showed good predictive performance for HNSC survival (C-index = 0.63, 10-year AUC = 0.761). Tumor mutation burden and immune cell infiltration analyses provided further insights into HNSC biology. This study provides evidence for causal relationships between specific air pollutants and HNSC risk, and identifies potential gene targets for further investigation. The developed clinical prediction model may aid in HNSC prognosis and personalized treatment strategies. Show less

Upon spinal cord injury, axons attempting to regenerate need to overcome the repulsive actions of myelin-associated inhibitors, including the myelin-associated glycoprotein, Nogo-A, and the oligodendrocyte myelin glycoprotein. These inhibitors bind and signal through a neuronal receptor/co-receptor/transducer complex composed of NgR1, Lingo-1, and p75. Consequently, p75 is cleaved by alpha secretase followed by gamma-secretase, triggering downstream signaling that inhibits axonal regrowth. ADAM10 and ADAM17 are both known to function as alpha secretases in neurons. Here we show that ADAM17, and not ADAM10, is the alpha secretase that recognizes and cleaves p75, when it is a part of a 5-component neuron-myelin signaling complex comprising NgR1, Lingo-1, p75, GT1b, and a myelin inhibitor. Importantly, we demonstrate the ability of inhibitory anti-ADAM17 mAbs to abrogate the cleavage of p75 in a neuroblastoma-glioma cell line and reverse the neurite outgrowth inhibition by myelin-associated inhibitors. Show less

Pulmonary hypertension is often a difficult to diagnose condition, in particular in younger population of patients. Early diagnosis and treatment of this condition is crucial to prevent further morbidity and mortality. A 32-year-old woman with a history of Ebstein anomaly (EA) and secundum atrial septal defect (ASD), who underwent transcatheter ASD closure at age 19, presented with progressive fatigue and exertional dyspnoea. Further evaluation revealed presence of compression of right pulmonary veins (rPVs) by the ASD device resulting in post-capillary pulmonary hypertension (PHTN) and worsening of right ventricular (RV) failure. Following surgical explantation of the ASD device, PHTN resolved with improvement of patient's functional status. This case depicts a rare haemodynamic entity of worsening PHTN in a 32-year-old patient with EA post-ASD closure. It illustrates a rare complication of compression of rPVs by the ASD device. Therefore, suspicion should be high for evaluating rPVs in EA with worsening PTHN and RV failure post-ASD closure. Show less

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. However, the genetic basis linking sociability with DMN function remains underexplored. This study aimed to elucidate the shared genetics and causal relationship between sociability and DMN-related resting-state functional MRI (rs-fMRI) traits. We conducted a comprehensive genomic analysis using large-scale genome-wide association study (GWAS) summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits ( Significant local genetic correlations were identified between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the cingulate and angular/temporal cortices. MR analyses suggested potential causal effects of sociability on 12 rs-fMRI traits. Seventeen genes were highly prioritized, with By combining genomic and transcriptomic data, our gene prioritization strategy may serve as a blueprint for future studies. Our findings can guide further research into the biological mechanisms underlying sociability and its role in the development, prognosis, and treatment of neuropsychiatric disorders. Show less

Nero Siciliano (NS) is an autochthonous pig breed reared in northeastern Sicily; despite its high-quality meat products, NS is currently endangered. This study aimed to evaluate the genetic variability at nine loci within candidate genes for meat traits-Melanocortin 4 Receptor ( Show less

Chronic cerebral hypoperfusion (CCH), a pathophysiological state linked to vascular dementia and cognitive impairment, involves the NgR1/Lingo-1/p75 signaling complex implicated in neurodegenerative processes. Resveratrol (RES), a neuroprotective compound, was investigated for its potential to mitigate CCH-induced cognitive deficits by targeting this pathway. This study examined RES's ability to improve cognitive impairment in CCH by suppressing the NgR1/Lingo-1/p75 complex and downstream RhoA-ROCK2 signaling. Rats were divided into five groups: Control, CCH + Ethanol (ETH), CCH, CCH + resveratrol (RES), and RES. Chronic cerebral hypoperfusion was induced via permanent bilateral carotid artery occlusion (2VO). Cognitive function was assessed using the Morris Water Maze (MWM). Hippocampal morphology in CA1, CA3, and dentate gyrus (DG) regions was analyzed via H&E staining. The expression levels of Lingo-1, NgR1, P75, RhoA, and ROCK2 signaling pathway were detected by western blot and quantitative real-time PCR (qRT-PCR). Chronic cerebral hypoperfusion rats showed elevated protein expression of Lingo-1, p75, RhoA, and ROCK2, though NgR1 remained unchanged. The RES treatment significantly reduced these protein levels. Similarly, mRNA levels of all five targets increased in CCH, but RES notably lowered Lingo-1 and NgR1 expression. The MWM tests revealed RES improved spatial learning and memory deficits in 2VO rats. H&E staining demonstrated RES's neuroprotective effects, preserving hippocampal neuron integrity. Resveratrol alleviates CCH-induced cognitive impairment by downregulating the Lingo-1/NgR1/p75 signaling axis and inhibiting RhoA-ROCK2 pathways. These findings highlight RES's potential as a therapeutic agent for vascular cognitive impairment associated with chronic hypoperfusion. Show less

Certain parents of children with febrile seizures have a high sense of perceived vulnerability, which may lead to overprotective behaviors. This study aimed to measure the latent profile types of perceived vulnerability in parents of children with febrile seizures and investigate the factors affecting these different profiles. A cross-sectional study was conducted from October 2023 to December 2024. Participants were surveyed using a general data questionnaire, the child vulnerability scale (CVS), parents' perception of uncertainty scale (PPUS), and perceived social support scale (PSSS). Latent profile analysis (LPA) was conducted to identify different types of perceived vulnerability among parents of children with febrile seizures. The influencing factors for each profile were identified using univariate and multivariate logistic regression analysis. In total, 400 participants were included in this study. The perceived vulnerability among parents of children with febrile seizures was divided into three latent profiles: "General Low Perceived Vulnerability Group" (37.9%), "Moderate Perceived Vulnerability Group" (32.8%), and "High Perceived Vulnerability Group" (29.3%). Multivariate analysis indicated that relationship with children, parents' age, educational attainment, marital status, body temperature during febrile seizures, PPUS, and PSSS were the factors affecting perceived vulnerability in parents of children with febrile seizures. The perceived vulnerability in parents of children with febrile seizures exhibited significant heterogeneity. To minimize the perceived vulnerability, medical professionals should provide tailored mental health counseling and intervention based on vulnerability characteristics. Show less

Polycystic ovary syndrome (PCOS) is a multifactorial disorder influenced by both environmental and genetic factors. The aim of this study was to evaluate associations between selected polymorphisms ( A total of 50 women (25 with PCOS and 25 healthy controls) were included. Genetic variants were identified using Polymerase Chain Reaction (PCR)-based methods. The frequencies of genotypes and alleles were compared between groups. Clinical symptoms such as irregular menstruation, hirsutism, acne, androgenetic alopecia, and overweight were assessed in relation to genotype. No significant differences were found in genotype distributions for Although most analyzed variants were not directly associated with PCOS in this cohort, the observed link between Show less

Many studies have revealed the observational associations between lipoprotein(a) (Lp(a)) concentrations and the incidence of cardiovascular diseases (CVDs). However, the causal associations remain unclear. Public summary data were analyzed using a Mendelian randomization (MR) design to assess the causal associations between Lp(a) levels and risks of nine CVDs and evaluate the potential impact of aspirin on Lp(a) levels. The principal analysis was conducted employing the random-effects inverse-variance weighted (IVW) method. Furthermore, the weighted median and MR-Egger approaches were used as the sensitivity analysis. Additionally, the significantly associated single nucleotide polymorphisms (SNPs) in salicylic acid (INTERVAL and EPIC-Norfolk, n = 14,149) were chosen to assess the potential effects of aspirin on lowering Lp(a) levels. The IVW analysis showed that the per standard deviation (SD) increment in Lp(a) level was causally associated with a higher risk of coronary artery disease (odds ratio (OR), 1.237; 95% confidence interval (CI), 1.173-1.303), atrial fibrillation (OR, 1.030; 95% CI, 1.011-1.050), heart failure (OR, 1.074; 95% CI, 1.053-1.096), hypertension (OR, 1.006; 95% CI, 1.004-1.008), and peripheral artery disease (OR, 1.001; 95% CI, 1.001-1.001) (all A causal nexus was discerned between Lp(a) levels and an increased risk of conditions including coronary artery disease, atrial fibrillation, heart failure, hypertension, and peripheral artery disease. Furthermore, administering aspirin may be a potential therapeutic to reduce these CVD risks among individuals with elevated Lp(a) levels. Show less

The neurotoxicity of carbon monoxide (CO) to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Our previous study found that retinoic acid (RA) can suppress the neurotoxic effects of CO. This study further explores, in vivo and in vitro, the molecular mechanisms by which RA alleviates CO-induced central nervous system damage. A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO, and a DEACMP animal model was established in adult Kunming mice. Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin V/propidium iodide (PI) double staining. The transcriptional and protein expression of each gene was detected using real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Long noncoding RNA (lncRNA) RA at 10 and 20 μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes, downregulation of RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes, thereby reducing central nervous system injury and exerting neuroprotective effects. LncRNA Show less

Essential tremor (ET) is a common movement disorder characterized by persistent limb tremors. Currently, no effective treatment for ET exists. Natural plant-derived compounds, like the flavonoid, quercetin may provide therapeutic benefits, particularly when delivered in nanoemulsion formulations that enhance bioavailability and efficacy. This study evaluated the neuroprotective potential of quercetin nanoemulsion (Que-NE) in a harmaline-induced mouse model of ET. Thirty-two male Swiss mice were randomly divided into four groups (n = 8 each): Control, Harmaline (10 mg/kg, i.p., on days 3, 5, and 7), Que-NE (20 mg/kg, i.p., for 7 days), and Harmaline + Que-NE. Harmaline was used to reliably induce tremor via olivocerebellar hyperexcitability. Behavioral performance was assessed using the open field, elevated plus maze, tail suspension, wire grip, rotarod, and passive avoidance tests. Expression of NF-κB, TNF-α, IL-1β, IL-6, NMDA receptor, and Lingo-1 was determined by RT-PCR. Que-NE significantly reduced harmaline-induced tremor severity (p < 0.0001), decreased immobility time in the tail suspension test (p = 0.0003), and improved open field anxiety-like behaviors compared with harmaline alone (P = 0.0012). Que-NE downregulated pro-inflammatory mediators (P < 0.0001) and reduced Lingo-1 gene expression (P < 0.0001). However, Que-NE showed limited efficacy in severe motor coordination tasks (rotarod, wire grip) and passive avoidance memory. Que-NE exerts measurable anti-inflammatory, anxiolytic, and antidepressant-like effects in the harmaline model of ET. The impact of Que-NE on improving motor deficits, reducing inflammatory markers, and suppressing inhibitors of synaptic plasticity highlights the potential of Que-NE as a disease-modifying strategy. However, dose-response, protein-level, and long-term studies are needed to evaluate the therapeutic potential of Que-NE for ET management. Show less

Despite preclinical evidence for berberine's antidepressant potential, its pharmacological effects remain controversial.This study therefore systematically reviews animal research to clarify its mechanisms and support future clinical trials. We searched PubMed, Embase, Web of Science, Cochrane Library, and OVID for studies on berberine in depression models up to March 20, 2025. Analysis used STATA 15.0 and Review Manager 5.4, with study quality assessed via SYRCLE's risk of bias tool. The meta-analysis included 18 studies (338animals). Overall, berberine significantly reduced depression-like behaviors in animal models.Specifically, BBR increased total locomotor activity in the open field test (SMD=2.79, 95% CI: 1.55, 4.02) and time spent in the center zone (SMD=2.49, 95% CI:1.61, 3.37), reduced immobility time in both the forced swim test and tail suspension test (SMD =-4.42, 95% CI:-5.77,-3.07; SMD=-4.46, 95% CI:-6.21, -2.71), increased sucrose intake in the sucrose preference test (SMD = 3.72, 95% CI: 2.37, 5.07), and reduced feeding latency in the novelty-suppressed feeding test (SMD=-5.72, 95% CI:-7.63, -3.82). However, BBR did not significantly alter the number of square crossings (SMD=1.36, 95%CI:-0.07 , 2.79) or rearing frequency (SMD=1.66, 95% CI: -0.29, 3.61) in the open field test. BBR also increased the levels of body weight, brain-derived neurotrophic factor, dopamine, serotonin, and norepinephrine,while reducing the levels of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. Preclinical studies suggest that berberine may represent a promising therapeutic agent for the treatment of depressive disorders. Its antidepressant effects appear to be closely associated with the modulation of neurotransmitter levels,reduction of oxidative stress, and inhibition of inflammatory responses.However, methodological limitations may constrain these findings. Larger, more rigorous preclinical studies are needed for confirmation. https://inplasy.com/inplasy-2025-6-0002, identifier INPLASY202560002. Show less

In heart failure (HF), atherogenic dyslipidemia and lipotoxicity contribute to adverse remodeling. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve HF outcomes, yet their lipid effects remain debated. This review aims to synthesize quantitative changes in lipid parameters and plausible mechanisms by which SGLT2i modulate lipoproteins in HF. Across trials and HF-focused cohorts, SGLT2i are associated with small increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and small decreases in triglycerides. Beyond concentrations, emerging data suggest qualitative remodeling - a shift toward less atherogenic LDL phenotypes (small-dense LDL (sd-LDL)↓) and increases in HDL2 - although evidence is limited and heterogeneous. Mechanistically, enhanced adipose lipolysis and hepatic β-oxidation/ketogenesis may raise ketone availability for the myocardium ("thrifty substrate"), while hepatic cholesterol pool-driven LDL receptor (LDLR) downregulation could explain modest LDL-C increases. These lipid shifts coexist with consistent reductions in HF events, independent of diabetes, implying benefits not captured by traditional lipid metrics alone. In HF, SGLT2i likely exert modest quantitative lipid changes but potentially meaningful qualitative lipoprotein remodeling alongside improved metabolic flexibility. Clinically, apolipoprotein B (ApoB)-targeted therapy (e.g., statins ± ezetimibe) remains essential when LDL-C/ApoB are above goal, with SGLT2i used for cardiorenal benefit. HF-specific trials powered for ApoB, sd-LDL, low-density lipoprotein particle number (LDL-P), HDL function, and lipidomics are lacking. In conclusion, SGLT2i produce small, mixed lipid changes in HF, but mechanistic and particle-level effects may align with improved outcomes; definitive HF-centric lipid studies are a priority. Show less

Individuals with familial hypercholesterolemia (FH) are at high risk of premature cardiovascular disease. A healthy lifestyle and lipid-lowering medication are essential to reduce this risk. We examined if adherence to a heart healthy diet provides additional risk reduction independent of lipid-lowering medication. The Dutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH (n=559 individuals with probable or definite FH) in the Copenhagen General Population Study(n=106,899) and the Copenhagen City Heart Study(n=7,451). Individuals were categorised by their level of heart healthy dietary adherence to Danish dietary guidelines, corresponding to international guidelines. Concentrations of low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, triglycerides, and lipoprotein(a) (Lp(a)), and risk of ischaemic heart disease (IHD) were assessed by clinical FH category and level of dietary adherence. Women had a higher heart healthy dietary adherence compared to men. Mean concentrations of LDL cholesterol, apoB, non-HDL cholesterol, remnant cholesterol, and triglycerides increased stepwise by lower dietary adherence category, regardless of clinical FH category. Lp(a) concentration did not change by adherence to dietary guidelines. Results were similar in individuals taking lipid-lowering medication. Risk of ischemic heart disease (IHD) was lower in individuals with a higher dietary adherence (ranging from 8 to 57 % lower risk) compared to individuals with a very low dietary adherence regardless of clinical FH category. Adherence to a heart healthy diet is associated with lower concentrations of atherogenic lipids and lipoproteins, and lower risk of IHD in individuals with clinical FH, independent of treatment with lipid-lowering medication. Dietary adherence should be emphasised as an important tool in addition to treatment with lipid-lowering medication in individuals with FH. Show less

Leucine Rich Repeat Containing 8A (LRRC8A) anion channels (VRACs) associate with NADPH oxidase 1 (Nox1) and support extracellular superoxide (O We assayed O KO cells were less permeable to extracellular O Loss of LRRC8A reduced O Show less