👤 Chunfu Wu

Obesity is closely associated with cognitive dysfunction, and markedly increases the risk of developing neurodegenerative diseases. Currently, obesity-related cognitive impairment lacks effective therapeutic interventions. Shenling Baizhu Powder (SLBZ) is a classical formula used to strengthen the spleen and promote the ascent of clear qi in traditional Chinese medicine (TCM). According to the TCM, this formula has great potential for the treatment of obesity-related cognitive impairment. However, research on SLBZ has focused primarily on its gastrointestinal effects, leaving its neurocognitive mechanisms largely unexplored. This study aimed to elucidate the therapeutic mechanisms of SLBZ in obesity-related cognitive impairment. Obese mice were obtained by subjecting male mice to a 16-week high-fat diet (HFD, 60 kcal % fat). During the final four weeks of the study, a SLBZ decoction (10 and 20 g/kg/day) was administered orally. The mice were then subjected to two behavioral tests and a glucose tolerance test. To evaluate the therapeutic effects of HFD on metabolic dysregulation, neuroinflammation, and intestinal barrier impairment, a range of analytical techniques, including biochemical analysis, immunofluorescence, RT-qPCR, and Western blotting, were used. Subsequently, 16S rRNA gene sequencing and metabolomic profiling were used to detect changes in the gut microbes and metabolite levels. Finally, fecal microbiota transplantation was performed to assess the functional link between SLBZ remodeling of the gut microbiota, metabolic alterations, and hippocampal cognitive function. Our study demonstrated that HFD-fed mice developed significant cognitive impairment, supporting the notion that obesity adversely affects cognitive function. In the Morris water maze and open-field tests, SLBZ administration effectively ameliorated HFD-induced cognitive dysfunction. This improvement was accompanied by the restoration of the hippocampal synaptic ultrastructure and the recovery of the key synaptic proteins BDNF and PSD95. In agreement with this, SLBZ suppressed microglial activation and associated neuroinflammatory responses in HFD-fed mice. In the colon, SLBZ administration markedly alleviated HFD-induced gut barrier impairment, as evidenced by increased colonic mucus thickness and elevated expression of tight junction proteins, ZO-1, Occludin, and Claudin-1. Furthermore, SLBZ reduced endotoxin translocation and downregulated the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. Notably, HFD-induced gut microbiota dysbiosis was remodeled by the SLBZ treatment, which was characterized by an increased capacity for microbial vitamin B6 synthesis. SLBZ increased the serum levels of vitamin B6 in HFD-fed mice. Intriguingly, fecal microbiota transplantation from SLBZ-treated HFD-fed mice facilitated the amelioration of cognitive deficits, including superior performance in behavioral tests and synaptic repair in the hippocampus compared to recipients of HFD-microbiota. Our findings highlight that SLBZ is a promising therapeutic agent mitigating obesity-related cognitive impairment via the "gut microbiota-vitamin B6-neuroprotection" axis. Show less

Deoxynivalenol (DON), a secondary metabolite produced by Fusarium, can widely contaminate foods and feeds, endangering human and animal health. DON can cause anorexia in animals. However, the specific mechanism is unclear. In this study, in vivo and in vitro experiments were conducted in mice and mouse intestinal organoid, respectively. Specific antagonists NPS2143, U73122, Xestospongin C, TPPO, EGTA, and Nitrendipine were selected to inhibit CaSR, PLCβ2, IP3R, TRPM5, extracellular calcium, and L-type VSCCs to explore the effect of the CaSR-TRPM5 signaling axis in DON-induced anorexia and secretion of brain-gut peptide. The results showed that these antagonists attenuated the DON-induced anorexia and secretion of the brain-gut peptides CCK, PYY, GLP-1, and GIP. DON could significantly increase the expression of hypothalamic anorectic genes MC4R, POMC, and CART. Blocking the CaSR-TRPM5 signaling axis could attenuate these changes. The mouse small intestinal organoid can be induced to differentiate into EECs by blocking the Wnt/Notch/Mek pathway. DON-induced brain-gut peptides secretion was attenuated by inhibition of CaSR-TRPM5 signaling axis in mouse intestinal organoid. In summary, DON could act on enteroendocrine cells to induce secretion of brain-gut peptide and activate the hypothalamic anorectic genes to evoke anorexia through the CaSR-TRPM5 signaling axis. Show less

Osteoarthritis (OA) often coexists with metabolic traits (MTs), causing significant disability. Our study aims to uncover the shared genetic mechanisms between OA and MTs, revealing novel OA-MT related genes, proteins and pathways. We first explored the clinical associations between OA and MTs based on UK Biobank data. Using GWAS statistics for 9 OA subtypes and 51 MTs, we identified both global and regional genetic correlations. Multi-trait GWAS helped revealed credible genes and relevant pathways through various methods. Protein-level analyses were also conducted to identify key proteins. We developed polygenic scores (PGS), machine learning models and drug repurposing strategies were explored to translate these findings into clinical applications. We identified 152 trait pairs with significant associations and 709 local regions linked to OA-MT. Key SNVs like rs13135092 (SLC39A8) and rs34811474 (ANAPC4) were associated with multiple OA-MT pairs. Lipid and glucose metabolism emerged as central pathways, with tissue-specific enrichment analyses revealing key gene clusters in hepatocytes, arteries, and brain regions. Protein-level analyses identified 205 protein subgroups. PGS integrating MTs outperformed model based solely on OA, improving AUC by 17.5%. Causal gene-based models showed strong diagnostic accuracy (average AUC = 0.875 in external cohorts). Drug prediction highlighted fenofibrate as a promising treatment among 71 candidates. This study provides new insights into the genetic links between OA and MTs. We identified genes, proteins, and pathways related to comorbidities, revealing shared mechanisms, highlighting the potential of integrating metabolic factors to improve OA prediction, diagnosis, and treatment. Show less

As the most common microvascular complication of diabetes, diabetic retinopathy (DR) has become a leading cause of blindness among the global diabetic population. The pathogenesis of DR is not yet fully understood, and current clinical treatment options are limited and have suboptimal efficacy. A detailed investigation of the intercellular communication mechanisms during the progression of DR is of paramount importance. In this study, we first synthesized findings from various studies on classical pathways, including VEGF signaling, oxidative stress, inflammatory cascades, the polyol pathway, PKC signaling, and the Wnt/β-catenin pathway, with a focus on elucidating the cell-type specificity of each pathway and the interactions among them. Subsequently, we explored emerging mechanisms identified in recent years, such as the ethanolamine pathway, ANGPTL4, Lrg1, and Norrin-FZD4, to expand our understanding of the pathogenesis of DR. Through a systematic investigation of multiple pathways, we propose that the progression of DR is not driven by the effect of a single pathway but rather results from the dynamic interplay among these signaling networks. Additionally, we described recent advances in the clinical translation of related pathways, including multitarget therapeutic strategies and precision interventions mediated by pathway-specific biomarkers. This review aims to provide a comprehensive and integrative perspective on the mechanisms underlying DR, thereby establishing a theoretical foundation for experimental research and clinical translation. Show less

Cancer-associated fibroblasts (CAFs) drive immunosuppression in hepatocellular carcinoma (HCC). However, their metabolic regulation remains poorly defined. We investigated the role of nicotinamide N-methyltransferase (NNMT) in CAFs. High NNMT expression in CAF tissues was confirmed by western blotting and immunofluorescence staining. Primary CAFs from HCC patients, single-cell RNA-seq (GSE149614), patient-derived organoids (PDOs), and fibroblast-specific NNMT-knockout mice were integrated by metabolomic analyses. NNMT in CAFs binds EZH2 and impedes its nuclear translocation, thereby reducing H3K27me3 enrichment at the promoter of angiopoietin-like 4 (ANGPTL4) to increase ANGPTL4 secretion. Secreted ANGPTL4 engages GLUT1 in HCC cells, activating aerobic glycolysis and increasing histone H3K18la levels. This epigenetic reprogramming transcriptionally upregulates PD-L1 expression, thereby facilitating tumor immune evasion. Additionally, CAF-derived ANGPTL4 promotes angiogenesis in HCC. Therapeutically, targeting the NNMT-ANGPTL4 axis restored CD8 We identified an NNMT-ANGPTL4-driven metabolic-epigenetic cascade in CAFs that induces PD-L1-mediated immune evasion, providing a therapeutic strategy to overcome resistance to immunotherapy in patients with HCC. Show less

Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence. Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry. Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6 INTS6 The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival. Show less

Anoikis resistance and epithelial-mesenchymal transition (EMT) are crucial factors in tumor invasiveness and metastasis in lung adenocarcinoma (LUAD). Identifying anoikis-EMT-related genes could be beneficial for predicting prognosis and immunotherapeutic efficacy in patients with LUAD. This study aims to establish and validate a novel prognostic signature based on anoikis-EMT-related genes for LUAD and to identify the potential biomarkers encapsulated within it. Anoikis-related genes and EMT-related genes were retrieved from the GeneCards and dbEMT 2.0 databases. Univariate Cox regression analysis and principal component analysis (PCA) were conducted to define anoikis and EMT levels. Gene expression and clinical information of patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Univariate Cox regression and multivariate Cox regression analyses were conducted to construct a risk score model. Immune correlation and drug sensitivity analyses were performed to investigate the association of the risk score with the immune profile and antitumor treatment. Three essential genes in the model were examined for messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR) and for protein levels via the Human Protein Atlas (HPA) database. LUAD patients demonstrating low Anoikis Potential Index (API) combined with high EMT Potential Index (EPI) exhibited the poorest overall survival (OS). We further constructed a nine-gene prognostic risk model that combines anoikis and EMT. High-risk patients demonstrated significantly shorter survival duration. The clinical-prognostic nomogram accurately predicted outcomes at 1, 3, and 5 years. In addition, patients in low-risk group demonstrated superior immune responses to treatment and were more sensitive to commonly used chemotherapy drugs. Our validation studies confirmed upregulated expression of ANGPTL4, SLC2A1, and BIRC5 in LUAD, observed at both transcriptional and translational levels. The anoikis-EMT-based risk model effectively forecasts both OS and immunotherapy response in LUAD patients, accelerating the identification of groundbreaking molecular biomarkers and prospective molecular targets. Show less

Volatile fatty acids (VFAs) provide more than 70% of the energy source for the ruminants. Understanding the host-microbiota regulation of VFAs production and utilization is highly important for optimizing the feed energy utilization efficiency of ruminants. Here, we conducted whole-genome resequencing, rumen transcriptome sequencing, 16S rRNA gene amplicon sequencing, and VFA concentration determination in 530 Holstein bulls. We treated VFA concentrations as complex traits to perform multi-omics association analyses. The host genetics, rumen microbiota, and rumen expressed genes, on average, explained 23%, 58%, and 61% of the variations in VFAs with the same diet, respectively. We found that the rumen microbial composition and community structure differed significantly between the high and low VFA individuals. We further identified 11 microbes with potential causal relationships with rumen VFAs via the Mendelian randomization method, among which Bacteroidales_RF16_group, Prevotella, Clostridia_UCG-014, and [Eubacterium]_ventriosum_group were positively correlated with acetic acid, propionic acid, and butyric acid. Conversely, rumen epithelial genes involved in fatty acid β-oxidation (e.g., HSD17B4, ACADVL, ACADL, CPT1A, and ANGPTL4) were negatively correlated with the main VFAs and VFA-producing bacteria. These candidate microbes and genes suggest that the host-microbe coregulating mechanism facilitates the efficient production and utilization of rumen VFAs in ruminants. Our study provides a comprehensive perspective on the complex dynamic regulatory patterns of rumen VFAs, highlighting the crucial role of host-microbe interactions in optimizing the feed utilization of ruminants. Show less

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti-vascular endothelial growth factor (VEGF) therapy remains the first-line treatment; however, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of patients with PDR, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1, prospero homeobox 1, and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in mice with oxygen-induced retinopathy alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells. Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cell proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, a finding that suggests a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune-vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction. Some patients with proliferative diabetic retinopathy (PDR) have poor responses to anti-vascular endothelial growth factor (anti-VEGF) therapy. This situation highlights the need for additional therapeutic approaches. In proliferative diabetic retinopathy, what is the role of ANGPTL4 that differs from VEGF? We found that ANGPTL4 is elevated in the vitreous humor of patients with PDR who are poorly responsive to anti-VEGF therapy. ANGPTL4, particularly its C-terminal fragment, causes retinal lymphatic-like remodeling in diabetic mice. This study provides novel insights into the complex interplay between immune activation, neovascularization, and lymphatic-like remodeling in PDR. Our findings deepen our understanding of PDR pathophysiology and propose a promising therapeutic target. Show less

Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial-derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular-osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron-derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single-cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line-1 in vitro through the FAK-AKT-VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular-mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration. Show less

Tumor budding (TB) is a well-established prognostic indicator in various epithelial malignancies. Chordoma, although a rare mesenchymal tumor, paradoxically exhibits prominent epithelial-like characteristics, as demonstrated in previous studies. In particular, it remains unclear whether TB-like (TBL) structures are present in chordoma, as well as the molecular mechanisms driving their formation and their functional impact on tumor progression, representing a critical gap in current knowledge. Tumor budding-like grades were defined and evaluated in tumor specimens from 481 chordoma patients across 4 large cohorts using hematoxylin-eosin and immunohistochemical staining. Multi-omics profiling, encompassing GeoMx digital spatial profiling, spatial transcriptomics, bulk RNA sequencing, single-cell RNA sequencing, single-cell ATAC sequencing, and multiplex quantitative immunofluorescence, was integrated to delineate TBL cell subpopulations (TBLCs) and their interactions with cholesterol-metabolic tumor-associated macrophages (CM-TAMs). Organoid models and in vitro/in vivo functional assays were employed for mechanistic investigation and validation. Tumor budding-like structures were prevalent in chordoma, and higher TBL grades were associated with unfavorable clinical outcomes and aggressive phenotypes. Mechanistically, BACH1 in CM-TAMs drove ANGPTL4 secretion, which targeted the SDC4 receptor on TBLCs, thereby enhancing stem-like properties, promoting cholesterol accumulation, and accelerating malignant progression. Pharmacological inhibition of cholesterol metabolism or disruption of the BACH1-ANGPTL4-SDC4 signaling axis markedly reduced tumor invasiveness in both preclinical models and chordoma organoids. BACH1-driven CM-TAMs activate TBLCs via the ANGPTL4-SDC4 signaling axis, promoting stemness and cholesterol accumulation, ultimately driving malignant progression in chordoma. These findings uncover a previously unrecognized tumor-immune-metabolic interaction and suggest potential therapeutic targets for this disease. Show less

Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4, a non-canonical pro-angiogenic mediator, impaired angiogenesis. In a first-in-human, single-center, phase 1 dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over 3 years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA. Show less

Modifying nanomedicines with targeting ligands represents an encouraging strategy for active tumor targeting, but its clinical failure underscores ongoing challenges. Herein, a series of liposomes with different targeting ligands (e.g., PEGylation, folic acid, mannose, RGD peptide, and melittin) were rationally designed to investigate the principles and mechanisms governing tumor targeting and penetration profiles. In primary and lung metastatic breast cancer models, these liposomes exhibited a systematic tendency of intratumor distribution, with melittin-modified liposomes showing optimal tumor targeting and therapeutic performance. Further studies revealed that the ligand modifications in liposomes could modulate the composition of their protein corona, particularly the level of Apolipoprotein A4 (ApoA4), which, in turn, influenced tumor targeting and intratumor distribution, ultimately affecting the therapeutic outcome of tumor inhibition and survival prolongation. This research provided a distinct correlation between ligand modification of liposomes and their Show less

Diet-based modulation of the gut microbiota has emerged as a promising strategy to alleviate obesity and its related complications. Our previous study demonstrated that polysaccharide derived from Cordyceps militaris (CMP) exerts anti-obesity effects, yet the specific mechanism linking gut microbiota to its metabolic impact remains unclear. Herein, we utilized murine models with distinct gut microbial profiles created via antibiotic cocktails to investigate these mechanisms. The protective effects of CMP against high-fat diet (HFD)-induced obesity and associated metabolic disturbances were substantially impaired in mice depleted of neomycin-sensitive gut bacteria. Metagenomic analyses further established that CMP required these bacteria to restore gut microbial homeostasis. Notably, we observed that CMP elevated hepatic levels of brassicasterol in a manner dependent on neomycin-sensitive gut bacteria. Brassicasterol treatment alone replicated the anti-obesity effects of CMP, as indicated by reduced body weight gain, improved lipid and glucose metabolism, and decreased inflammation. Through transcriptomic and functional analyses, we identified hepatic Apoa4 as a key downstream effector of brassicasterol. Our results indicated that brassicasterol upregulated Apoa4, facilitating lipid transport and suppressing inflammation both in vitro and in vivo. Collectively, our findings indicate that CMP exerts its anti-obesity effects through a neomycin-sensitive gut bacteria-brassicasterol-Apoa4 pathway. This work expands the mechanistic understanding of CMP and highlights a novel microbiota-metabolite-host regulatory axis for dietary intervention in metabolic disorders. Show less

Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. However, adaptive changes in respiratory metabolism and molecular mechanisms in lung tissues of small mammals under extreme water shortage conditions remain unclear. This study hypothesized that small desert mammals can adapt to extreme water shortage environments by regulating the plasticity of lung tissue gene expression and respiratory metabolism. Using 29 wild-caught Siberian jerboas ( Show less

Wilson disease (WD) and familial hypertriglyceridemia (FHTG) are both genetic metabolic diseases, and their comorbidity is extremely rare. This article reports a case of WD with FHTG in a 12-year-old Chinese boy. The patient was diagnosed due to elevated transaminase levels, combined with clinical manifestations, copper metabolism indexes, lipid profile analysis, and genetic testing results (pathogenic mutations of Show less

Apolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformation of lipoprotein lipase (LPL). LPL unfolding results in loss of catalytic activity and the detachment of LPL from the surface of cells. An Show less

Elevated lipoprotein(a) [Lp(a)] is a genetically determined and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is largely resistant to conventional lipid-lowering therapies. Novel Lp(a)-targeted agents, including small interfering RNA (siRNA), antisense oligonucleotides (ASO), and the oral small-molecule inhibitor muvalaplin, have shown potent efficacy in early trials. We conducted a systematic review and network meta-analysis to comprehensively compare their efficacy and safety. A total of 25 randomized controlled trials (RCTs) involving 7715 participants were included, evaluating six siRNA agents, four ASO agents, and one small-molecule inhibitor. The primary outcome was percentage change from baseline in Lp(a). Secondary outcomes included absolute change in Lp(a), percentage changes in apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C), and adverse events. SiRNA therapies achieved the greatest Lp(a) reductions (olpasiran: mean difference [MD] -92.1%, 95% CI -100.1 to -84.0%; zerlasiran: -80.6%, 95% CI -87.7 to -73.5%), followed by muvalaplin (-76.8%, 95% CI -90.3 to -63.2%) and ASO therapy (pelacarsen: -54.2%, 95% CI -72.2 to -36.2%; all P < 0.001). Most agents achieved absolute Lp(a) reductions exceeding 105 nmol/L, suggesting clinically meaningful benefit. Baseline Lp(a) levels significantly modified treatment response (P < 0.001), and concomitant proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use further enhanced LDL-C reduction (P = 0.024). All therapies were well tolerated, with injection-site reactions most frequent for injectables, while muvalaplin was well tolerated. These findings indicate that targeted Lp(a)-lowering therapies substantially reduce circulating Lp(a), with siRNA showing the greatest potency and muvalaplin offering a convenient oral alternative for personalized ASCVD risk reduction. Show less

In recent years, human exposure to p-phenylenediamine-derived quinone (PPD-Qs) has attracted great attention due to their potential toxic effects on humans. While, their potential health risks to the lipid metabolism in humans remain inadequately elucidated. This cross-sectional study analyzed blood samples for six PPD-Qs, lipid profiles, and mitochondrial DNA copy number (mtDNAcn), and investigated the association between PPD-Q exposure and lipid levels in a population-based cohort comprising 255 healthy Chinese adults. Results showed that PPD-Qs in human serum was dominated by 6PPD-Q (mean 1.8 ng/mL), followed by 77PD-Q (0.73 ng/mL) and DTPD-Q (0.60 ng/mL). Multivariate analyses demonstrated significantly positive correlations between exposure to specific PPD-Qs (i.e., 6PPD-Q, CPPD-Q, DPPD-Q, and DTPD-Q) and elevated serum concentrations of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Weighted quantile sum regression showed that mixed PPD-Q exposure was positively correlated with TG levels (β = 0.050, 95% CI: 0.009 -0.16), with 6PPD-Q showing the highest weight for TC (weight 0.27), TG (0.31), low-density lipoprotein (0.28), apolipoprotein A1 (ApoA1; 0.52), and apolipoprotein B (ApoB; 0.33). Bayesian kernel machine regression analysis confirmed dose-dependently positive relationships between combined PPD-Q exposure and TC, TG, LDL-C, ApoA1, and ApoB. Mechanistically, mtDNAcn mediated 34 (95% CI: 9.3 -138%)-70% (95% CI: 12 -266%) of the total serum TG-elevating effects induced by PPD-Q exposure, revealing a novel pathway through which these PPD-Qs disrupt lipid homeostasis. Findings of this study address critical knowledge gaps regarding the toxicological impacts of these emerging environmental contaminants on human metabolic health. Show less

Copper overload has been implicated in impaired A total of 117 patients with T2DM (mean age 55.15 ± 10.70 years; 62.4% male) were included. Whole blood copper concentration was measured using inductively coupled plasma mass spectrometry. Associations between blood copper and glycemic indicators, including glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG), were evaluated using multivariable linear regression models. Stratified and interaction analyses were performed according to apoB and other lipid-related parameters. After adjustment for potential confounders, a significant interaction between blood copper and apoB was observed in relation to HbA1c (P for interaction< 0.001). Stratified analyses showed that higher blood copper concentration was significantly associated with higher HbA1c levels among patients with lower apoB levels below the study median, whereas no significant association was observed among those with higher apoB levels. Exploratory analyses further indicated that apoB also influenced the association between blood copper and FPG (P for interaction< 0.05), showing a consistent pattern. In patients with T2DM, a significant association between blood copper concentration and glycemic control was observed among individuals with lower apoB levels, whereas no such association was found among those with higher apoB levels. These findings suggest that apoB status may influence the relationship between blood copper and glycemic control and merit further investigation in longitudinal studies. Show less

Staphylococcus aureus is a significant pathogen that poses a threat to both human and animal health. Its pathogenicity in humans has been extensively studied, however, the signaling pathways and key genes in Koi Carp responding to S. aureus from human rhinitis remain unclear. In this study, we established an intraperitoneal infection model in koi carp (Cyprinus carpio) using an S. aureus isolate from patients with rhinitis and integrated RNA-seq, qPCR, and ELISA to dissect the host response. Our findings reveal a dual-module immune evasion strategy employed by S. aureus in koi carp. Module I: The pathogen down-regulated the entire complement coagulation cascade (C3, C9, CFH, F7/9/10) and apolipoprotein-mediated opsonins (APOA1, APOB, APOC1/2), thereby crippling innate clearance. Module II: The host mounted a restricted but potent counter-response, characterized by type I IFN signalling (gvin1, MHC-I), NK/T-cell co-stimulation (CD244, SLAMF5), and the selective induction of IL-8 and IL-1β, while IL-6, IL-10, and TNF-α remained unchanged. Functionally, serum superoxide dismutase (SOD), catalase (CAT), and lysozyme (LZM) activities surged, confirming an oxidative burst, whereas splenic CD22R protein decreased, indicating B-cell disinhibition. These results establish a molecular basis for understanding the interaction between human-derived S. aureus and the immune system of aquatic organisms. Show less

Lanthanum (La), the second most produced rare earth element, is detected in various environmental and human samples. Epidemiological studies have reported a strong association between La exposure and liver injury. However, the effects of early La exposure on liver development and underlying mechanisms remain limited. Here, we evaluate the hepatotoxicity of LaCl Show less

Hypothyroidism, the most prevalent endocrine disorder globally, is associated with increased cardiovascular risk. This study aims to evaluate cardiovascular risk factors-including serum oxidized low-density lipoprotein (ox-LDL), serum homocysteine (Hcy), and lipid profiles-and their correlations with thyroid-stimulating hormone (TSH) levels. Early identification of these risk predictors may reduce the incidence and mortality of cardiovascular disease in hypothyroid patients. This cross-sectional study included 676 participants. Subjects were stratified into four groups: three corresponding to TSH quartiles within the reference range and a fourth comprising subclinical hypothyroidism (SCH) patients with TSH levels above this range. All participants underwent physical examinations and provided fasting blood samples for measurement of TSH, free thyroxine (FT4), free triiodothyronine (FT3), blood glucose, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein(a) [Lp(a)], ox-LDL, and Hcy. Across the four subgroups, LDL-C, ApoB, ox-LDL, and Hcy levels exhibited significant increasing trends (all The observed correlations between ox-LDL, Hcy, and dyslipidemia in subclinical hypothyroidism may indicate a proatherogenic state. Elevated ox-LDL and Hcy emerge as independent factors associated with accelerated atherosclerosis in this condition. Show less

This study aims to investigate the underlying pathophysiological relationship between obesity and osteoporosis (OP) in obese individuals, involving lipid metabolism, inflammation, and bone mineral density (BMD). Data from 318 patients diagnosed OP at our hospital between January 2023 to December 2025 were collected and analyzed. The basic information of the patient included gender, age, BMI, drinking and smoking history, diabetes, hypertension and bone mineral density (T-scores) were recorded. Baseline peripheral blood was employed to calculate lipid markers and inflammatory cytokines. Linear regression and mediation analyses were employed to assess the relevance and differences. Increased level of blood lipids and inflammatory cytokines were associated with increased risks of OP in obesity. Compared to normal-weight individuals, obese subjects exhibited significantly lower BMD. Dysregulated lipids (TC, TG, HDL-C, ApoB) negatively correlated with BMD in obesity. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) inversely associated with BMD, while anti-inflammatory IL-10 showed positive association. Hyperlipidemic obese individuals had elevated inflammatory cytokines (TNF-α, IL-1β) and exacerbated BMD loss. Mediation analysis revealed TNF-α mediated 41.91% and IL-6 mediated 33.20% of the TC-BMD association; TNF-α and IL-6 mediated 28.76% and 37.38% of HDL-C-BMD effects, respectively. Obesity-associated dyslipidemia drives BMD loss partly through inflammation-mediated pathways. Key inflammatory cytokines significantly mediate lipid metabolism’s impact on bone health. Targeting lipid-inflammatory crosstalk may optimize OP management in obese populations. Show less

This study developed and validated a continuous metabolic syndrome (MetS) risk score (msRS) for adolescents and evaluated its clinical utility in identifying multiple clinical cardiovascular markers (CCMs) using dual adolescent populations. Adolescents aged 12‒18 from two stratified random samples were used: the nationwide Nutrition and Health Survey in Taiwan (NAHSIT, n = 1920) for development and the Adiposity‒Cardiovascular Disease Axis study in Southern Taiwan (adiCards, n = 3295) for validation. Four sex-and-age-specific msRS were developed through confirmatory factor analysis (CFA) utilizing five MetS components-waist circumference, high-density lipoprotein cholesterol, triglycerides, fasting glucose, and mean arterial pressure. Their discriminatory ability for clinical outcomes was validated using the area under receiver operating characteristic (AU-ROC) curve. The msRS demonstrated exceptional capability in detecting MetS in NAHSIT and adiCards cohorts (AU-ROCs: 0.954‒0.969). Adjusted for covariates, msRS explained higher variability in body-fat percentage, apolipoproteins B/A1, and homeostatic model assessment of insulin resistance (HOMA-IR) than binary MetS and abnormal components count (partial R The CFA-derived sex-and-age-adjusted msRS scheme provides an improving measure to assess and manage adolescent cardiometabolic health. Adolescent MetS components share a latent metabolic construct. A scoring system through confirmatory factor analysis captures sex-and-age specific metabolic heterogeneity. Continuous risk score accurately discriminates pediatric MetS. MetS risk score effectively detects pediatric cardiovascular risk. Consideration of population characteristics is essential when developing a continuous MetS score. Show less

Etamsylate, a commonly used clinical hemostatic agent, may cause false decreases in biochemical test results through inhibition of enzymatic activity or interference with chromogenic reactions. However, insufficient research on its interference mechanisms and correction methods increases the risk of clinical misjudgment. Serum samples were collected from three patients treated with etamsylate and analyzed using the Roche Cobas 8000 c701 automated biochemical analyzer. Samples were tested at undiluted (0-fold), 3-fold, 5-fold, and 10-fold dilution gradients to evaluate drug interference characteristics and the efficacy of dilution-based correction. Among the 46 routine biochemical assays evaluated, etamsylate exhibited significant negative interference on 12 parameters, including creatinine (CREA), albumin (ALB), and cholyglycine (CG). The interference diminished linearly with increasing dilution factors, demonstrating a dose-dependent recovery trend. CG demonstrated the most pronounced changes. No significant interference was observed for 12 other tests, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Following dilution, six parameters, including apolipoprotein A1 (APOA1), apolipoprotein A2 (APOA2), and apolipoprotein B (APOB), exhibited a paradoxical decrease in assay results, suggesting the presence of distinct interference mechanisms. The dilution method can effectively correct the false decrease interference of etamsylate on biochemical detection. However, it is necessary to optimize the dilution factors to avoid loss of sensitivity. It is recommended that laboratories establish a drug interference database, standardize the gradient dilution process, and promote multi-disciplinary collaboration to optimize the detection system. Show less

Obesity is a well-documented cardiovascular risk factor. Here, we sought to investigate whether obesity causes subclinical cardiac remodeling and heart failure (HF), and if so, to perform a systematic scan of the plasma protein for novel drug targets. We leveraged visceral adipose tissue (VAT), waist circumference (WC), and waist-to-hip ratio (WHR)-all adjusted for body mass index (BMI)-as indicators of obesity. Two-sample Mendelian randomization (MR) analyses were used to estimate the independent, causal effects of obesity on cardiovascular magnetic resonance (CMR)-derived cardiac traits and HF risk. Mediation analyses followed by druggability assessment were conducted to identify promising protein targets for therapeutic translation. Genetically determined VATadjBMI, WCadjBMI, and WHRadjBMI presented broad causal associations with alterations of distinct cardiac phenotypes, most of which remained significant after controlling for obesity-induced cardiometabolic risk factors, including hypertension, type 2 diabetes, and adverse lipid profiles. By contrast, WHRadjBMI is the only independent causal predictor for HF risk. Of 142 proteins with mediating effects, scavenger receptor class A member 5 (SCARA5), membrane cofactor protein (CD46), and alpha-1-antichymotrypsin (SERPINA3) may contribute to the early-stage adverse cardiovascular effect of obesity, whereas apolipoprotein C-III (APOC3), mitochondrial aldehyde dehydrogenase 2 (ALDH2), and chordin-like protein 2 (CHRDL2) may further promote the development of obesity-driven HF. Medications targeted at these candidate proteins are either approved or under evaluation in clinical trials. Our MR findings provided genetic evidence for the direct, causal associations of obesity with cardiac remodeling and HF, while also outlining druggable proteins as promising therapeutic targets. Show less