Point-of-care diagnostic tools, such as lateral flow assays (LFAs), play a critical role in disease management and outbreak control. LFAs detect the presence of target antigens in disease-relevant biofluids, utilizing nanoparticles (termed detection probes) to produce colorimetric readouts. However, significant intra- and interpatient variation in the biochemical composition of biofluids has downstream consequences for assay performance. Robust LFAs must be able to function alongside such variability to produce reliable and reproducible test outcomes. Beyond this, biofluids (such as serum) contain significant amounts of proteins, which can interact with detection probes used in LFAs to form a protein corona. The consequences of protein corona formation on LFA performance are poorly understood. Using a model antigen-biofluid LFA (human epidermal growth factor receptor 2 (HER2) and human serum), we observed significant discrepancies in LFA performance when using conventional nanoparticle functionalization methods, including the use of generic, nonhuman protein blocking agents. To overcome these performance differences, we developed a methodology for Bionano interface Optimization for LFA Design (termed BOLD). The BOLD workflow employs mass spectrometry-based proteomics to characterize the native protein corona, followed by formation of an engineered corona to produce an optimized bionano interface. We identified a specific protein (kininogen-1, KNG1) that demonstrated negative interference, significantly reducing the observed LFA test line intensity. This experimental finding is complemented by Molecular Dynamics simulations, which probe the binding modes of KNG1 to platinum nanoparticles. Further, through the employment of an apolipoprotein engineered corona (apolipoprotein A1, B, and C3), a robust LFA was developed, increasing test line intensity and significantly reducing intersample variation (with over a 4-fold improvement in the coefficient of variation). Overall, the BOLD workflow presents a method for the rational optimization of detection probes in LFAs through the characterization of the bionano interface to produce robust LFAs.

BackgroundOsteoarthritis (OA) pathogenesis involves dysregulated extracellular matrix (ECM) remodeling and inflammation. Apolipoprotein A4 (APOA4), while known for lipid metabolism, has an uncharacterized role in OA.MethodsClinical samples including infrapatellar fat pad (IFP) (n=3), synovial fluid (n=11), and serum (n=11) from patients with and without OA were analyzed via immunohistochemistry (IHC) and ELISA. In vitro, human chondrocytes (C28/I2) were treated with recombinant APOA4 (5 nM), siRNA knockdown (si-APOA4), or overexpression (OE-APOA4). Functional assays (qPCR, RNA-seq, CCK-8, colony formation) and inflammatory modeling (IL-1β ± APOA4) assessed chondrocyte responses. Wnt pathway involvement was probed via Wnt3a rescue.ResultsAPOA4 expression was significantly elevated in OA IFP tissues, synovial fluid, and serum vs. controls (p < 0.05). APOA4 treatment upregulated the level of anabolic markers (COL2, p=0.0006; ACAN p=0.0055) and downregulated catabolic factors (MMP3, p=0.0249; MMP13, p=0.0214), while enhancing chondrocyte proliferation. OE-APOA4 mimicked these effects, whereas si-APOA4 reversed them. APOA4 attenuated IL-1β-induced inflammation, preserving COL2/ACAN and suppressing MMPs. RNA-seq implicated Wnt/β-catenin suppression (NES = −1.314; p = 0.008) as a key mechanism. Wnt3a treatment partially reversed APOA4’s chondroprotective effects.ConclusionAPOA4 mitigates OA progression by promoting ECM anabolism, inhibiting inflammation, and suppressing Wnt/β-catenin signaling. It represents a novel therapeutic target for OA.

Apolipoprotein A2 (ApoA2) and ANGPTL3 modulate LPL activity and inflammatory cytokine secretion, resultantly influencing TG metabolism and inflammatory response. However, any associations that exist between those modulators were not explored. The study aimed to elucidate the functions of ApoA2 in modulating ANGPTL3 on the metabolism of TG and inflammatory cytokine secretion. A case-control hospital-based clinical study was conducted. A total of 50 patients with diagnosed CAD and 50 healthy control individuals were enrolled. Levels of ApoA2, ANGPTL3, and several pro-inflammatory cytokines were measured. The levels of ANGPTL3 and ApoA2 exhibited no significant discordance between the CAD group and control group. Both ANGPTL3 and ApoA2 were associated with TG (r = 0.249, P = 0.002; r = 0.379, P = 0.001, respectively). Additionally, ApoA2 were inversely associated with hs-CRP (r = -0.079, P =0.003), TNF-α (r = -0.119, P = 0.001), and IL-1β (r = -0.103, P = 0.004). Regression analysis confirmed that ApoA2 was an independent modulator of TG and inflammatory cytokines independent of ANGPTL3 (standardized β = 0.196, P < 0.001). ANGPTL3 and ApoA2 correlate with TG levels, with ApoA2 identified as an independent contributor via stepwise regression, and ANGPTL3 exerts its TGregulating effect mainly by inhibiting LPL activity through multiple mechanisms, suggesting its potential anti-inflammatory role, though conflicting findings in existing studies indicate the need for further clarification of this relationship. ApoA2 influences ANGPTL3 in modulating catabolism of TG and atherosclerotic-related inflammatory cytokines, suggesting a vital role of ApoA2 in promoting pathological progression of CAD.

Oyster mushrooms (Pleurotus ostreatus, PO) are rich in β-glucans and other ingredients with cholesterol-lowering potential. While human intervention studies suggest that PO intake may reduce total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides, current evidence remains limited due to methodological limitations of the studies. Thus, this study investigated whether regular intake of PO powder affects LDL-C concentrations in adults with moderately elevated LDL-C (primary aim). Moreover, the study explored the effect on other lipids (TC, high-density lipoprotein cholesterol, triglycerides), on apolipoproteins A1 and B and possible underlying mechanisms of action (secondary aims). In a double-blind, randomized controlled trial, 46 adults (37 female, 9 male) with moderately elevated LDL-C (116-190mg/dL) consumed a beverage containing 8.4g PO powder providing 3g of β-glucans or a beverage without PO daily over 4 weeks. Plasma concentrations of LDL-C, other lipids and apolipoproteins were measured before and after intervention. The concentrations of noncholesterol sterols in serum, normalized to cholesterol, were determined as validated surrogate markers for cholesterol absorption (sitosterol, campesterol, and 5α-cholestanol), cholesterol synthesis (lathosterol), and bile-acid synthesis (7α-hydroxycholesterol), along with ergosterol, a fungal-specific sterol. Expression of selected target genes involved in cholesterol metabolism was analyzed in blood. Statistical analysis included comparisons of the changes between the groups (treatment effect) and linear modeling. PO treatment did not modulate LDL-C; no treatment effect was observed for other lipids, apolipoproteins or gene expression (P ≥ 0.05 for all). However, after adjustment for sex, linear model analysis showed a reduction in markers of cholesterol absorption, especially in females (P < 0.05 for all). No effects were observed on markers of cholesterol and bile-acid synthesis (P ≥ 0.05 for all). Ergosterol was detectable in all serum samples after PO intake, confirming high compliance with PO treatment. Daily consumption of 8.4g of PO powder over 4 weeks has no impact on LDL-C concentrations in adults with moderately elevated LDL-C concentrations. However, post-hoc analysis indicates a sex-dependent reduction in cholesterol absorption by PO consumption, especially in females, suggesting that PO may have the potential to beneficially modulate cholesterol metabolism. Registration at German Clinical Trials Register; DRKS-ID: DRKS00033943; registration date: 21/03/2024. https://drks.de/search/de/trial/DRKS00033943 .

Short bowel syndrome (SBS) arises from the surgical removal of extensive portions of the small intestine and is associated with high morbidity, including intestinal failure-associated liver disease (IFALD). Earlier studies revealed that orally administered systemic liver X receptor (LXR) agonist suppresses IFALD in mice and implicated intestinally derived high-density lipoprotein (HDL) in liver protection. Here we aimed to move away from the use of systemic LXR agonists because they have failed in clinical trials due to hepatic steatosis and hyperlipidemia, to determine if a gut-restricted LXR agonist could provide hepatoprotection in SBS. We synthesized and characterized WUSTL0717, an amide analog of GW3965, as a putative gut-restricted LXR agonist, and evaluated its potential to improve the outcomes in a preclinical mouse model of SBS. WUSTL0717 exhibited exceptional intestinal retention in pharmacokinetic analyses and activated LXR target genes in the small intestine but not the liver. Whereas small bowel resection lowered many lipid metabolites in portal venous plasma, WUSTL0717 treatment increased portal venous Apolipoprotein A1 (ApoA1), the core protein of HDL, and spared portal venous phospholipids known to be enriched on HDL. Accordingly, intestinal ApoA1 deficiency exacerbated IFALD, and in wild-type mice, portal venous ApoA1 and phospholipids inversely correlated with hepatic collagen accumulation. In addition, WUSTL0717 improved nutrient absorption and promoted body weight restoration in SBS. These data underscore the potential of gut-restricted LXR agonists to preserve metabolic health in the context of SBS. By acting locally in the intestine, WUSTL0717 positively mitigates profibrotic liver injury while avoiding systemic availability.

The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by the ABCA1 pathway is relatively well understood. However, additional research is needed to confirm the clinical significance of this pathway. It is also important to determine how, and whether, the antioxidative, immunologic, and anti-inflammatory properties of HDL subspecies, including those containing low-abundance proteins, contribute to cardioprotection.

Pharmacological control of leukotriene biosynthesis is well established in mammals, but its translational value for teleost inflammation remains unclear. We evaluated oral 5-lipoxygenase (5-LOX) inhibition with zileuton in Nile tilapia challenged with a bacterin of A. hydrophila to induce acute aerocystitis. Fish received vehicle or zileuton (2.25 or 4.50mg/kg) before challenge. Outcomes were assessed at 6, 24, and 48h post-inoculation (hpi) to investigate cellular profiles in exudates and blood, reactive oxygen species (ROS), acute-phase proteins (APPs), and the formation of splenic melano-macrophage centers (MMCs). Zileuton significantly reduced exudate granulocytes and thrombocytes at 6 hpi and macrophages at 24 hpi. Systemically, treatment attenuated transient peaks in neutrophils and lymphocytes (6 hpi) and thrombocytes (24-48 hpi). We observed correlations between lower ROS production and reduced blood neutrophil counts and macrophages in the exudate, suggesting a restrained oxidative burst. Zileuton down-modulated positive APPs (ceruloplasmin, complement C3, α2-macroglobulin, haptoglobin) in time- and dose-dependent patterns, while negative APPs (albumin, transferrin) and apolipoprotein A1 showed no consistent change. Histology revealed MMCs enlargement/remodeling with bacterin that was tempered by zileuton. The anti-inflammatory response was dose-dependent, since fish treated with 4.50mg/kg were more effective than 2.25mg/kg. Tilapia receiving 4.50mg/kg of zileuton exhibited a pronounced decrease in inflammatory cell accumulation in the exudate (granulocytes, lymphocytes, and macrophages), reduced ROS production, stronger suppression of positive acute-phase proteins (notably ceruloplasmin, complement C3, and haptoglobin), and more evident remodeling of splenic MMCs. No clinical adverse effects were observed. To our knowledge, this is the first demonstration in fish that oral 5-LOX inhibition by zileuton mitigates acute inflammatory reaction, and underscores leukotriene pathway as a promising lever for improving fish health outcomes.

Transcriptome sequencing reveals the regulatory mechanisms during the development of small white follicles to small yellow follicles in laying hens.

Surface-enhanced Raman scattering (SERS) nanoprobe-based immunoassay is an emerging liquid biopsy modality for the detection of blood biomarkers. However, quantitative detection of blood biomarkers using SERS nanoprobe immunoassays remains challenging, primarily due to intrinsic stochastic fluctuations of SERS signals. Herein, Ag nanogap shells (AgNGS) encoded with Raman labels are prepared as SERS nanoprobes with single-particle sensing resolution and long-term structural and signal stability. Then, digital SERS nanoprobe immunoassays using AgNGS nanoprobes and magnetic nanoparticles conjugated with detection and capture antibodies for carbohydrate antigen 19-9 (CA19-9) and apolipoprotein A1 (APOA1) are developed for their quantitative detection in the clinical serum samples of pancreatic cancer (PC). Furthermore, digitization of the SERS intensity-based assay outcomes into On/Off states allows significant improvement in limits of detection and quantification for biomarker detection. Finally, the digital AgNGS nanoprobe immunoassay enables quantitative detection of both CA19-9 and APOA1 from the 150 clinical serum samples of PC patients, which are integrated with machine learning analysis via bootstrap sampling and logistic regression modeling for the diagnosis of early-stage PC, achieving a high AUC of 0.988. AgNGS nanoprobe immunoassays offer an effective liquid biopsy route for profiling various blood biomarkers associated with many diseases.

Patients who undergo percutaneous coronary intervention (PCI) remain exposed to residual lipid and inflammatory risk despite contemporary secondary prevention. Real-world longitudinal data describing how conventional lipids, apolipoproteins, small dense low-density lipoprotein (sdLDL), lipoprotein(a) [Lp(a)], and C-reactive protein (CRP) remodel together after PCI are limited. We evaluated serial post-PCI changes in a broad atherosclerotic biomarker panel and explored the dissociation between cholesterol control and inflammatory control. We performed a retrospective longitudinal study using a clinical laboratory dataset. Adults with at least one PCI-coded encounter and serial laboratory follow-up were included. The index date was defined as the first PCI-coded visit. Angiography-only patients without PCI were excluded. Biomarkers included triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), Lp(a), apolipoprotein E (ApoE), sdLDL, free fatty acids, glycation, and CRP. Paired baseline-to-latest comparisons were performed in 397 patients. The prespecified primary endpoint was the paired change in LDL-C from index PCI to latest follow-up. Secondary endpoints included paired changes in other lipid and inflammatory biomarkers. Longitudinal associations across follow-up windows were explored using generalized estimating equations adjusted for age, sex, body mass index, diabetes, hypertension, smoking, baseline statin intensity, and time-updated lipid-lowering regimen category. Among 1082 encounters from 526 individuals, 397 patients with PCI contributed 813 observations from index onward. Mean age was 62.0 ± 10.3 years, 77.8% were men, 69.5% had hypertension, and 35.0% had diabetes. Median follow-up was 393 days. Compared with index PCI, latest follow-up showed lower LDL-C (2.42 to 1.63 mmol/L; mean change - 0.79, 95% confidence interval [CI] -0.90 to -0.68; p < 0.001), non-HDL-C (3.07 to 2.11 mmol/L; mean change - 0.96, 95% CI -1.09 to -0.83; p < 0.001), ApoB (0.82 to 0.63g/L; mean change - 0.19, 95% CI -0.22 to -0.16; p < 0.001), ApoB/ApoA1 ratio (0.74 to 0.59; p < 0.001), and CRP (4.94 to 2.71mg/L; mean change - 2.23, 95% CI -3.36 to -1.09; p < 0.001). HDL-C rose modestly (1.07 to 1.11 mmol/L; p < 0.001). Lp(a), sdLDL, triglycerides, free fatty acids, and glycation changed little in paired analyses. In adjusted longitudinal models, lower LDL-C, ApoB, non-HDL-C, and log (CRP) persisted through 1 year, 1-2 years, and > 2 years, whereas Lp(a) showed little overall change, with only a modest decrease in the 1-2-year window. In expanded multivariable analyses, combination or PCSK9-containing regimen at latest follow-up was independently associated with dual attainment of LDL-C < 1.4 mmol/L and CRP < 2mg/L at latest follow-up. The proportion with both high LDL-C and high CRP fell from 42.3% at index to 15.4% at follow-up, but isolated residual inflammatory risk rose from 6.0% to 11.8%. After PCI, real-world biomarker remodeling was characterized by durable reductions in LDL-C, ApoB, non-HDL-C, and CRP, but incomplete convergence of cholesterol-related and inflammatory biomarker profiles. Lp(a) and several nontraditional lipid measures appeared relatively resistant to routine care pathways. Because conventional CRP rather than hsCRP was available and no adjudicated clinical outcome data were available, the translational relevance of these findings is limited and they should be interpreted cautiously as biomarker-level and hypothesis-generating observations.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy associated with heterogeneous prognosis. Preoperative differentiation from adrenocortical adenoma (ACA) remains challenging, and no serum tumor marker has been established. We aimed to identify circulating protein biomarkers that distinguish ACC from ACA using a stepwise, multiplatform proteomics strategy. We assembled discovery (ACC = 10, ACA = 67) and verification (ACC = 7, ACA = 11) cohorts from a tertiary center and profiled fasting plasma using liquid chromatography-mass spectrometry (LC-MS/MS) with data-independent acquisition. Differentially expressed proteins (DEPs) were defined by t-tests with P < .05 and |fold-change| >1.2; DEPs common to both cohorts were prioritized. Targeted validation by parallel reaction monitoring (PRM) used an expanded, two-center cohort including additional cases from Asan Medical Center (ACC = 31; ACA = 78). Orthogonal validation employed the Olink Explore 384 Inflammation II panel in an independent set (ACC = 15; ACA = 24). The discovery cohort yielded 67 DEPs (22 upregulated and 45 downregulated in ACC), and the verification cohort identified 17 DEPs. Three proteins, CD44, proteoglycan 4, and apolipoprotein A4 (APOA4), were common to both analyses and were underexpressed in ACC compared with ACA. In PRM, CD44 and APOA4 showed directionally concordant, significant decreases in ACC, prioritizing these markers for further evaluation. In the Olink analysis, 40 proteins differed between ACC and ACA after false discovery rate correction; APOA4 remained significantly lower in ACC. Across discovery, targeted, and orthogonal platforms, APOA4 consistently exhibited lower circulating levels in ACC, supporting its potential as a serum biomarker for the preoperative differentiation of ACC from ACA. External, multiethnic validation and clinically deployable assays, alone or within multimarker panels, are warranted.

A functional SNP rs12718466 in APOA1 promoter modulates gene expression via interaction with SOX7.

Effects of fenofibrate on angiopoietin-like 3/4/8 proteins and apolipoprotein A5.

Obesity and depression have a bidirectional relationship. Previous work has shown that obesity increases the risk of depression, while atypical depression can elevate the risk of obesity. This study aimed to investigate the associations between anthropometric markers, lipid and insulin resistance biomarkers, inflammatory cytokines, and adipokines with depressive symptom severity in individuals with newly diagnosed metabolic syndrome (MetS). 88 treatment-naïve adults with newly identified MetS, without known coronary artery disease, were included. Clinical assessments comprised anthropometric measures, while laboratory analyses measured lipid metabolism markers, insulin resistance indicators, inflammatory cytokines, and adipokines. Depressive symptom severity was assessed using the von Zerssen Depression Scale (DS), validated for the Bulgarian population. To explore latent structures within biomarker domains, principal component analyses (PCA) were performed. Associations between depressive symptoms and biomarkers were then examined in two steps: first, using linear regression with PCA-derived component scores, and second, through hierarchical multiple regression focusing on selected individual biomarkers, controlling for covariates such as age and gender. PCA identified distinct latent structures within anthropometric, lipid, insulin resistance, and cytokine domains, though regression analyses using PCA-derived component scores did not yield significant associations with depressive symptoms (all p > 0.050). Hierarchical multiple regression with selected biomarkers showed that lower low-density lipoprotein cholesterol (LDLc)/Apolipoprotein B (ApoB) ratios were consistently associated with higher depressive symptom severity (Model 1: β = -0.332, p = 0.011; Model 2: β = -0.326, p = 0.012; Model 3: β = -0.319, p = 0.013), while higher interleukin-6 (IL-6) levels were independently linked to greater symptom severity (Model 1: β = 0.217, p = 0.052; Model 3: β = 0.230, p = 0.033). ApoB/apolipoprotein A1 (ApoA1) ratios and age showed weaker or non-significant effects. LDLc/ApoB ratio and IL-6 levels are independently associated with depressive symptom severity in newly diagnosed MetS, highlighting their potential as clinically relevant biomarkers. These findings highlight perspectives for integrating lipid and inflammatory profiles in the assessment of depression risk within MetS populations.

Inhibition of angiopoietin-like protein 3 (ANGPTL3) has been proposed as a promising approach to reduce residual cardiovascular risk. We conducted a meta-analysis of randomized controlled trials (RCTs) to provide a comprehensive evaluation of the metabolic effects of ANGPTL3 inhibitors. Databases (PubMed, EMBASE, Web of Science, CENTRAL, ClinicalTrials.gov) were searched from inception to July 2025. Eligible studies were RCTs comparing ANGPTL3 inhibitors against placebo. Outcomes included triglycerides (TG), LDL-C, apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (ApoA1), apolipoprotein C3 (ApoC3), lipoprotein(a) (Lp(a)), remnant cholesterol (RC), ANGPTL3 and C-reactive protein (CRP). Pooled estimates of percentage change from baseline were obtained using fixed- and random-effects models. Subgroup analysis was performed based on the mechanism of action: monoclonal antibodies (mAbs, evinacumab), antisense oligonucleotides (ASOs, vupanorsen), and small interfering RNAs (siRNA, zodasiran and solbinsiran). Nine RCTs (1,254 participants) were included. ANGPTL3 inhibition significantly reduced TG (-47.1%), LDL-C (-21.6%), ApoB (-19.9%), non-HDL-C (-31.5%), TC (-32.8%), VLDL-C (-40.6%), and RC (-72.7%). Modest but consistent reductions were also observed in Lp(a) (-11.5%), ApoA1 (-18.3%), and ApoE (-16.4%). ANGPTL3 inhibitors markedly reduced circulating ANGPTL3 protein (-70.7%), with no significant effect on high-sensitivity CRP. Subgroup analyses demonstrated greater reductions in LDL-C, ApoB, non-HDL-C, and TC with evinacumab compared to the other groups, whereas small interfering RNAs produced more pronounced VLDL-C lowering compared with vupanorsen. ANGPTL3 inhibition offers broad lipid-lowering benefits, with particularly marked reductions in TG-rich lipoproteins.

Sex-specific differences in serum lipids are recognized, but their relationship with cardiovascular disease (CVD) has not been reliably quantified. We examined sex-specific associations of major lipids and apolipoproteins with incident CVD. We included 432 092 UK Biobank participants without CVD at baseline (2006-2010) and with ≥1 lipid measurement. Age-adjusted risks were estimated using Poisson regression. Multivariable Cox models estimated hazard ratios (HRs) and women-to-men ratios of HRs for 1-SD higher values of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apoB (apolipoprotein B), apoA1 (apolipoprotein A1), and Lp(a) (lipoprotein [a]). Over a mean 13.3 years of follow-up, there were 10 699 and 18 950 cases of CVD in women and men, respectively. CVD risk per 10 000 person-years was 33.4 (95% CI, 32.7-34.0) for women and 76.6 (95% CI, 75.5-77.7) for men. Low-density lipoprotein cholesterol, apoB, and log Lp(a) were associated with smaller HRs of CVD for women than men (ratio of HR, 0.94 [95% CI, 0.91-0.97], ratio of HR, 0.94 [95% CI, 0.92-0.97] and ratio of HR, 0.96 [95% CI, 0.93-0.99], respectively). Triglycerides were associated with larger HRs of CVD in women than men (ratio of HR, 1.06 [95% CI, 1.02-1.09]). The association of lower apoA1 with higher CVD risk was stronger in men than women (ratio of HR, 1.06 [95% CI, 1.03-1.10]). No sex difference was observed for high-density lipoprotein cholesterol (ratio of HR, 1.02 [95% CI, 0.98-1.06]). Men had a higher rate of CVD than women overall. Low-density lipoprotein cholesterol, apoB and Lp(a) had stronger associations with CVD risk in men, whereas triglycerides were stronger in women. ApoA1 was less protective for CVD in women than men.

Background: Migraine frequently co-occurs with cardiovascular and metabolic diseases. Observational studies examining the association between conventional lipid profiles and migraine risk have yielded inconsistent results and cannot establish causality. This study aimed to investigate the causal effects of specific lipid species on migraine and its primary subtypes: migraine with aura (MA) and without aura (MO). Methods: Using a Mendelian randomization (MR) methodology, this study analyzed genome-wide association study (GWAS) data from the UK Biobank and FinnGen Consortium. Exposures comprised seven lipids and 179 lipid species while the outcomes were overall migraine and its subtypes. Pleiotropy and heterogeneity were assessed using sensitivity analyses such as MR-Egger, weighted median, and Pleiotropy Residual Sum and Outlier (MR-PRESSO). Results: Genetically predicted higher levels of high-density lipoprotein cholesterol (HDL-C; odds ratio (OR) = 0.88; 95% confidence interval (CI), 0.82–0.93) and apolipoprotein A1 (ApoA1, OR = 0.89; 95% CI, 0.84–0.95) were associated with a reduced risk of migraine. Conversely, higher triglycerides (TG) increased the risk of overall migraine. Lipidomic analysis revealed 15 specific lipid species causally associated with overall migraine. Subtype-specific analyses revealed divergent causal profiles for MO and MA. Seven triacylglycerol (TAG) species were specifically associated with an increased risk of MO, whereas only sphingomyelins (SM)(d36:1) was linked to an increased risk of MA. Conclusions: This study provides robust evidence for a causal relationship between lipid metabolism and migraine, demonstrating that these effects are highly specific to individual lipid molecules and migraine subtypes. These findings enhance our understanding of the lipid-mediated mechanisms in migraine pathogenesis and highlight potential subtype-specific pathways for developing future therapeutic and preventive strategies.

GBS (Guillain-Barré syndrome) is an acute immune-mediated peripheral neuropathy whose pathological mechanisms remain incompletely understood. Our study aimed to explore the intrinsic link and potential mechanisms between circulating dyslipidemia and immune metabolic remodeling of monocytes in GBS. Clinical data from 163 patients diagnosed with classic GBS and 169 healthy controls were analyzed to examine the correlations between their lipid profiles and immune cell features. Leveraging our team's previously published single-cell RNA sequencing (scRNA-seq) dataset for GBS, we characterized the subpopulations, functional features, and differentiation trajectories of peripheral blood monocytes. Furthermore, through transcriptional regulatory network analysis, we identified key transcription factors governing these processes. Compared to healthy controls, GBS patients displayed a distinct dyslipidemia characterized by elevated triglycerides (TG), very low-density lipoprotein (VLDL), and residual cholesterol (RC), but decreased high-density lipoprotein (HDL) and apolipoprotein A1 (APOA1). This lipid profile coincided with higher monocyte counts in peripheral blood, suggesting a synergistic relationship. The scRNA-seq analysis results indicate that the composition of peripheral blood monocyte subsets in GBS patients undergoes fundamental remodeling. This is characterized by a significant expansion of CD14+CD163+ monocytes lipid metabolism-active monocytes and pro-inflammatory CD14+CD169+ monocytes, while the proportion of classical monocytes sharply decreases. Pseudo-time trajectory analysis revealed a differentiation pathway from classical monocytes to CD14+CD163+ monocytes via CD14+CD169+ and intermediate monocytes. This pathway was characterized by an initial increase followed by a decrease in pro-inflammatory activity, coupled with a progressive enhancement in lipid metabolism activity. Transcriptional network analysis identified CEBPB as a core transcription factor potentially associated with the phenotypic conversion of monocyte subsets, likely mediated by synergistic regulation of genes involved in lipid metabolism and cell differentiation. In summary, GBS is characterized by synergistic dyslipidemia and monocyte remodeling. The pathological signature involves lipid metabolic reprogramming in the CD14+CD163+ monocytes and pro-inflammatory phenotypes in the CD14+CD169+ monocytes. The transcription factor CEBPB is associated with this phenotypic conversion by regulating lipid metabolism and differentiation genes, revealing molecular targets for precise GBS diagnosis and therapy.

Lipid nanodiscs are synthetic nanoparticles capable of solubilizing lipophilic drugs and have been shown to improve the potency of the antifungal Amphotericin B (AmphB) against various fungal pathogens. In this study, the SpyCatcher–SpyTag covalent labeling system was used to couple AmphB-loaded Apolipoprotein A1 (ApoA1) lipid nanodiscs to the receptor domain of Dectin-1, which binds to β-1,3/1,6 glucans present in many fungal cell walls. Denaturing protein gel electrophoresis demonstrated that ApoA1-SpyTag003 lipid nanodiscs could be covalently labeled with SpyCatcher003-Dectin-1-superfolder GFP (sfGFP). In microtiter growth assays with Saccharomyces cerevisiae, Dectin-1 AmphB nanodiscs displayed an IC50 1.5-fold lower than uncoupled AmphB nanodiscs and 2.8-fold lower than AmphB-only controls. Nanodiscs without AmphB and SpyCatcher003-Dectin-1-sfGFP themselves did not inhibit yeast growth. Fluorescence microscopy showed that SpyCatcher003-Dectin-1-sfGFP binds to yeast cell walls and accumulated at hot spots, matching the budding scar enrichment pattern previously described for other Dectin-1 fusion proteins. Together these results indicate that Dectin-1 fusions can target AmphB-loaded lipid nanodiscs to fungal cell walls and improve drug delivery. The results here establish the use of a modular SpyCatcher–SpyTag coupling system for targeting drug-loaded lipid nanodiscs to different cells or tissues, thereby increasing drug retention at infection sites, increasing drug potency, and reducing harmful side-effects.

This study explored the relationship between clinical phenotypes and immuno-molecular features of systemic lupus erythematosus (SLE) using unsupervised machine learning and multi-omics integration. A multicentre cohort of 1065 SLE patients from five teaching hospitals was studied. Unsupervised clustering was performed using integrated clinical and laboratory data to identify distinct phenotypic clusters. Multi-omics profiling, including proteomics and transcriptomics, was conducted for each cluster, comparing with healthy controls. In addition, 899 patients were prospectively followed for over 1 year to assess therapeutic responses and remission outcomes. Unsupervised clustering identified five distinct clusters of SLE based on clinical phenotypes and immunological signatures, and an intrinsic association was found between each cluster and immune-inflammatory features. Cluster 1 (renal; 14.27%) had predominant renal involvement (87.5%) and high disease activity. Cluster 2 (mucocutaneous; 39.53%) exhibited mainly cutaneous manifestations (72.45%) with mild visceral involvement and the highest rates of achieving low disease activity state (46.42%). Cluster 3 (neuropsychiatric; 14.74%) had a high frequency of neuropsychiatric manifestations (96.18%) and anti-U1 ribonucleoprotein antibodies positivity (42.04%). Cluster 4 (haematologic; 22.63%) was characterised by haematologic involvement, predominantly cytopenia (95.85%), with frequent antiphospholipid antibody positivity and direct Coombs positivity (87.55%). Cluster 5 (cardiopulmonary; 8.83%) exhibited prominent cardiopulmonary involvement (97.87%) and serositis, with enrichment of inflammatory CD161+ regulatory T cells. Transcriptomic and proteomic analyses confirmed distinct molecular signatures and cluster-specific enrichment of biological pathways. Key molecule apolipoprotein A4 was validated using enzyme-linked immunosorbent assay. Regarding therapeutic outcomes at 1 year follow-up, Cluster 2 had the highest proportions achieving lupus low disease activity state (46.42%) and tapering glucocorticoids. Cyclophosphamide use was associated with greater clinical improvement (r=0.284; p=0.023) in Cluster 3, while in Cluster 5, rituximab use was associated with favourable responses (r=0.286; p=0.019). We identified five SLE clusters with distinct clinical, immunological features and treatment outcomes, demonstrating an intrinsic link between clinical involvement and immune-inflammatory alterations.