👤 Lei Xiao

Neurodegenerative and psychiatric disorders share overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and neurotransmitter dysregulation. Essential oils from Lavandula angustifolia (TLEO) and Rosa rugosa (PREO) contain neuroactive compounds with therapeutic potential, but their mechanisms remain poorly defined. This study aimed to elucidate the shared and distinct molecular targets and pathways of TLEO and PREO using a multi-scale computational strategy. Compounds identified by GC-MS were evaluated through ADMET profiling, target prediction, and disease-target intersection analysis. Enrichment, network, docking, and dynamics analyses were performed on shared protein-coding targets between essential oils and twelve brain disorders, including seven neurodegenerative conditions (Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy) and five psychiatric disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia). A total of 110 compounds yielded 252 common targets, with CHRM2 (GPCR) and NR1H3 (non-GPCR) identified as key hubs. Docking suggested strong binding affinities for caryophyllene oxide at CHRM2 (-7.3 kcal/mol) and α-himachalene at NR1H3 (-8.5 kcal/mol). Molecular dynamics simulations confirmed stable, compact complexes with low RMSD and SASA values. MM/PBSA free energy calculations quantitatively validated these interactions, revealing favorable binding energetics driven predominantly by van der Waals and hydrophobic contributions, consistent with the terpenoid chemical profiles. Functional enrichment highlighted involvement in cholinergic signaling, lipid metabolism, and inflammatory regulation. This study demonstrates that PREO and TLEO can modulate multiple targets relevant to brain disorders through both GPCR and non-GPCR mechanisms. These findings provide a computationally inferred mechanistic framework for the potential neuroprotective synergy of these oils and highlight essential oil-derived compounds as promising leads for further experimental investigation. Show less

Glaucoma is a leading cause of irreversible blindness, yet the circulating proteins and metabolic pathways that causally contribute to different glaucoma subtypes remain poorly defined. We analyzed baseline plasma proteomics in 1485 glaucoma cases (447 primary open‑angle glaucoma [POAG], 177 primary angle-closure glaucoma [PACG], 120 normal-tension glaucoma [NTG]) in the UK Biobank using Cox models with graded adjustment. We then integrated five independent protein quantitative trait loci resources with FINLAND R12 genome-wide association study data to perform two‑sample Mendelian randomization (MR) and cross‑cohort meta‑analysis for overall glaucoma and each subtype. To prioritize effector genes and pathways, we conducted summary-data-based Mendelian randomization (SMR) using eQTLGen and two‑step mediation MR using metabolite quantitative trait loci data for ∼1400 plasma metabolites from the Canadian Longitudinal Study on Aging cohort. In fully adjusted Cox models, 484 proteins were associated with incident glaucoma, 135 with NTG, 59 with POAG, and 1 with PACG (false discovery rate <0.05). Multicohort MR and meta‑analysis identified eight proteins with robust causal effects: NRP2, TSPAN1, and HAVCR2 for overall glaucoma; NRXN3 for PACG; MANSC4 for NTG; and LTBP2, CD69, and SMAD1 for POAG. SMR supported NRP2 (overall glaucoma) and SMAD1 (POAG) as causal genes. Mediation MR revealed that sphingomyelins, acylcarnitines, and bile acid-related metabolites partially mediated the effects of several proteins, defining shared (e.g., sphingolipid) and subtype‑specific metabolic pathways. By integrating epidemiologic, proteomic, genetic, and metabolomic data, we identify convergent systemic protein and metabolic signatures associated with glaucoma susceptibility and its clinical subtypes. These findings nominate NRP2, SMAD1, and related pathways as promising biomarkers and therapeutic targets and support a systems‑level view of glaucoma pathogenesis beyond intraocular pressure alone. Show less

The mechanisms by which the autosomal dominant disorder tuberous sclerosis complex (TSC) results in liver fibrosis remain poorly understood. KDM6A, a histone demethylase, has been implicated in the pathogenesis of fibrosis in multiple tissues. This study aimed to elucidate the molecular mechanism by which KDM6A contributed to TSC-associated fibrosis. We observed fibrogenesis, epithelial-mesenchymal transition (EMT) induction and upregulation of Kdm6a in vivo and in vitro upon Tsc1 or Tsc2 deficiency. Knockdown of Kdm6a attenuated both fibrosis and EMT phenotypes. Mechanistically, Kdm6a depletion reduced phosphorylation of ERK1/2 and downregulated Snai1 expression. Activation of the MAPK/ERK pathway with PMA restored EMT-related protein expression, confirming the functional involvement of this signaling axis. Furthermore, Tsc1 or Tsc2 deficiency promoted Kdm6a expression via the mTORC1 pathway, while Kdm6a knockdown conversely suppressed mTORC1 activity by reducing mTOR protein expression, suggesting a positive feedback loop between Kdm6a expression and mTORC1. These findings indicate that Kdm6a promotes fibrosis in TSC through the activation of the MAPK/ERK/SNAI1 signaling pathway. Moreover, the combination of mTORC1 and KDM6A inhibitors results in marked regression of fibrosis and liver lesions in TSC models, unveiling a potential treatment for TSC patients with inadequate response to mTORC1 inhibitors. Show less

Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease. Show less

Myocardial hypertrophy is one of the most prominent features of heart failure. SET domain-containing protein 7 (Setd7), a catalytic enzyme responsible for histone H3K4 methylation, has been implicated in various cardiac diseases. In this study we investigated whether Setd7 contributed to the development of cardiac hypertrophy. Male mice were subjected to a hypobaric hypoxic environment for 8 weeks; neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia for 6 h. We showed that hypoxic stimulation significantly upregulated the expression levels of Setd7 along with the expression of hypertrophic markers ANP and BNP in NRCMs. By conducting loss- and gain-of-function assays, we demonstrated that Setd7 modulated the hypertrophic and inflammatory markers in hypoxic cardiomyocytes. We further revealed that Setd7-mediated activation of E2F1 (E2 promoter binding factor 1) triggered the expression of E3 ubiquitin protein ligases WWP2, which catalyzed the ubiquitination and degradation of glutathione peroxidase 4 (GPx4), a critical lipid peroxide-reducing enzyme. This degradation drove extensive lipid peroxidation, thereby exacerbating pathological cardiac hypertrophy. Notably, GPx4 inhibition by ras-selective lethal small molecule 3 (RSL3) abolished the antihypertrophic effects of Setd7 knockdown in cardiomyocytes, underscoring the pivotal role of lipid peroxidation in Setd7-mediated hypertrophic responses. In summary, Setd7 promotes hypoxia-induced cardiac hypertrophy through the Setd7-E2F1-WWP2-GPx4 signaling pathway, suggesting that targeting Setd7 is a promising therapeutic strategy to alleviate hypoxia-induced myocardial hypertrophy. Show less

Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave adaptation by comparing brain transcriptomes of sympatric cave-dwelling ( Show less

In response to extracellular ligands, G protein-coupled receptors (GPCRs) undergo conformational changes that induce coupling to intracellular effectors such as heterotrimeric G proteins that trigger various downstream signaling pathways. These events have been shown to be highly regulated by concerted effects of post-translational modifications (PTMs) that occur in a ligand-dependent manner. Most notably, phosphorylation of residues in the C-terminal cytoplasmic tail of GPCRs has been strongly implicated in promoting receptor interactions with β-arrestins (βarrs), which are cytosolic adaptor proteins that modulate G protein coupling, receptor internalization, and perhaps also serve as signaling modules in their own right. Here, we use proteomic methods to identify C-tail residues that are phosphorylated in the glucagon family of class B1 GPCRs (GLP-1R, GCGR, and GIPR) upon agonist addition. We demonstrate that the phosphorylation of GLP-1R and GIPR is a critical determinant in the formation of GPCR-βarr complexes. However, our results suggest that ligand-induced βarr recruitment to GCGR proceeds in a phosphorylation-independent manner. These findings highlight the importance of recognizing phosphorylation as a component in the regulation of class B1 GPCR signaling but also the need to consider how such phenomena may not necessarily yield identical effects on intracellular signaling cascades. Show less

In retinopathy of prematurity (ROP), preventing avascular dysplasia may be more critical than inhibiting abnormal neovascularization. While hypoxia-inducible factors (HIFs) are implicated in angiogenesis, their role in preventing ROP remains unclear. Oxygen-induced retinopathy (OIR) model and hyperoxic cell model were used in this study. Immunofluorescence, western blot, ELISA, cell counting kit-8 (CCK-8), and flow cytometry were applied to assess the effects of hyperoxia on the astrocytes. Co-culture of astrocytes with retinal microvascular endothelial cells (RMECs) was used to observe the effects of astrocyte inactivation on the RMECs. Overexpression of HIFs in astrocytes was used to investigate the mechanism. The OIR model revealed a decreased number of retinal astrocytes and the expression of dystrophin and R-cadherin in hyperoxic environments (P12), which was reversed after room air rearing (P17-P21), with an upward trend in RMECs (P21). In vitro hyperoxia induced significant apoptosis in astrocytes at 24 h. Moreover, the expression of angiogenesis-related factors (VEGF and ANGPTL4), vascular stabilization, and development-related factors (Laminin-β2, Dystrophin, R-cadherin) was decreased. Co-culture of astrocytes and RMECs yielded similar conclusions, with astrocyte inactivation decreasing the tube-forming capacity of RMECs. Overexpression of HIFs in astrocytes promoted the expression of VEGF, ANGPTL4, and Laminin-β2 under hyperoxic conditions. Emphatically, HIF-1α was more effective than HIF-2α in promoting the expression of integrin β1, dystrophin, and R-cadherin. Overexpression of HIFs in astrocytes reverses hyperoxia-induced retinal astrocyte inactivation and retinal vascular structural disruption and dysplasia. Strikingly, HIF-1α is a more suitable therapeutic target for ROP prevention than HIF-2α. Show less

Animal models are used widely to study pulmonary hypertension (PH). The cell populations that respond to disease-inducing stimuli in these models and their relationship to human disease remain incompletely defined. This study analyzed the relationship between several rodent models of PH and human disease at single-cell resolution. scRNA-seq was performed on lungs from mice exposed to hypoxia or Sugen/hypoxia, rats exposed to monocrotaline, and controls. A cross-species single-cell dataset was integrated with human lung cell atlas (HLCA) and single-cell dataset from idiopathic pulmonary arterial hypertension (IPAH) to identify overlapping cell subsets between experimental and human disease and species. High levels of overlap were found between species and models of PH, HLCA, and IPAH datasets. Cell subsets perturbed in rat and mouse PH were similar to those found in human disease, with macrophages and endothelial cells being most affected. A novel We established a comprehensive cross-species single-cell atlas of mainstream rodent PH models, highlighting several novel macrophage and endothelial subtypes and signaling motifs potentially contributing to human disease. Show less

Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less

The aim of the present study was to investigate the dietary effects of replacing corn with different proportions of fermented straw on the growth performance and intestinal health of finishing pigs. A total of 275 healthy commercial finishing pigs aged 126 days (average body weight, 82.96 ± 3.07 kg) were randomly allocated into three groups: the control (CTR, basal diet) group, the 5% fermented straw (FJJG5, replacing 5% of the corn) group, and the 10% fermented straw (FJJG10, replacing 10% of the corn) group. There were six replicates in each group and 14-16 pigs per replicate. On day 39 of the experiment, one animal from each replicate was slaughtered for sampling and for further analysis. The results showed that the finishing pigs in the FJJG10 group had a reduced average daily weight gain and an increased feed-to-gain ratio. The FJJG5 group had reduced total cholesterol, high-density lipoprotein, and low-density lipoprotein in their serum, while the FJJG5 and FJJG10 groups had reduced contents of lactate dehydrogenase. In addition, the FJJG5 group exhibited increased T-SOD activity and MDA content in the colon, while the FJJG10 group also showed increased T-AOC activity in their serum and increased contents of MDA in the colon. The FJJG5 group exhibited increased activities of jejunal disaccharidase and lipase, while the FJJG10 group exhibited decreased jejunal crypt depths. Moreover, the FJJG5 group presented an increased relative expression of Show less

Genome-wide association studies (GWAS) have identified nearly 100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular functions of these variant alleles remain elusive, particularly when they occur in non-coding regions. Here we profiled the chromatin accessibility landscape of liver nuclei from MASLD individuals, and demonstrated these accessible genomic sites were bound by cell type-specific transcription factors (TFs) and enriched for MASLD risk variants, highlighting lineage- and disease state-specific regulation. Using a massively parallel reporter assay (MPRA), we identified hundreds of differential activity variants (DAVs) that operate in a cell type-specific manner or in a stimulus-dependent context by disrupting liver pathogenesis-associated transcriptional regulatory network. Integrative analyses combining liver eQTLs, chromatin looping, and single-cell CRISPRi screening linked these DAVs to functional target genes. Notably, we demonstrated that DAVs located near Show less

Due to the growth in the global consumption of assisted reproductive technology (ART), it is possible that long-term health impacts on offspring have come into focus. ART has offered a welcome solution to infertility, but the fear has been on its effect on the metabolic health of children born on their behalf. Past studies indicate that ART-conceived individuals can have characteristic metabolic profiles relative to their naturally conceived (NC) peers and are therefore potentially predisposed to changes in lipid and glucose handling. Physiopathological glycolipid metabolism, a hallmark of cardiometabolic health, is believed to be modulated not only by environmental and other external factors but also by intracellular regulation proteins, including sterol regulatory element-binding protein (SREBP) and miR-33, although there is little evidence on the effects of ART on these regulatory pathways in early childhood. This paper sought to compare the glycolipid metabolic profile of the kids who are in preschool age and who were conceived through ART and kids who were NC. The second aim was to study the expression of SREBP-1/2 and miR-33 in peripheral blood and the possible nature of the role of these players in regulating early-life metabolism. A total of 220 children aged between 3 and 6 years were recruited of which complete data has been obtained from 206 children out of 98 that were conceived via in vitro fertilization/intracytoplasmic sperm injection (ICSI) (ART group) and 108 that were conceived naturally (NC group). Anthropometric measures-such as body weight, height, and waist circumference-to determine physical growth and obesity status were taken. Biochemical variables, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), fasting serum insulin (FINS), and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. A centrifugal column was used to obtain peripheral blood RNA, and relative gene expression levels of SREBP-1, SREBP-2, miR-33a, and miR-33b were measured by qPCR. Compared with the IVF group, children in the ICSI group had significantly lower weight, height, and waist circumference ( Our data suggest that although children born by means of ART are otherwise normal in their glycolipid metabolism, they are more prone to overweight and obesity and have different biochemical and molecular characteristics than NC children. The upregulation of miR-33b, SREBP-1, and SREBP-2 observed indicates that ART can play a role in regulating the process of glycolipid metabolism during early childhood at a molecular level. Such alterations might not present the form of a blatant metabolic condition at this age but may consist of initial symptoms of future troublesome metabolic health. Prolonged follow-up of the ART offspring and additional mechanistic work are desirable to be able to determine whether these early changes are the underlying reasons behind higher metabolic risk as adults. Show less

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, with prevalence increasing due to aging and risk factors like obesity and hypertension. The retina, rich in microvasculature, provides a unique opportunity to investigate microvascular dysfunction linked to CVDs and other systemic vascular diseases. This study used a multifaceted approach to assess the genetic correlation and causal relationship between retinal characteristics and CVDs. Linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) analyses were conducted using genome-wide association study (GWAS) data from the UK Biobank and FinnGen datasets. A cross-sectional study was also conducted to validate the findings, collecting optical coherence tomography (OCT) images from 124 eyes (89 with CVDs and 35 healthy controls). A prediction model is based on least absolute shrinkage and selection operator (LASSO) regression to assess the risk of CVD. Using LDSC and two-sample MR, we found genetic evidence consistent with a causal effect whereby genetically proxied thinner retinal nerve fiber layer (RNFL) was associated with higher risks of hypertension and myocardial infarction (MI), while genetically proxied thicker photoreceptor inner segment/outer segment (PR-IS/OS) was associated with coronary heart disease and MI (false discovery rate [FDR] thresholds as reported). Genetically proxied thinner retinal pigment epithelium (RPE) showed an inverse association with stroke risk. Several circulating biomarkers-including lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB-exhibited MR evidence of association with multiple CVDs. In a cross-sectional cohort, retinal layer differences and their relationships with lipids were directionally consistent with the genetic findings. Retinal structural traits measured by OCT-particularly RNFL, PR-IS/OS, and RPE thickness-are best interpreted as non-invasive markers that reflect systemic vascular biology. Our MR analyses support shared etiologic pathways between retinal microstructure and CVDs rather than implying that retinal damage clinically causes cardiovascular events. Findings warrant validation in larger and more diverse populations and should not be considered definitive proof of causality. Show less

Primary Sjögren's Syndrome (pSS) is a chronic autoimmune condition affecting lacrimal and salivary glands. While previous studies suggest potential associations between dyslipidemia and autoimmune diseases, the causal relationship between lipid-lowering medications and pSS remains unclear. This study employed drug-targeted Mendelian randomization (MR) analysis to assess the impact of lipid-lowering drugs on pSS risk, focusing on genetic targets including HMGCR, PCSK9, NPC1L1, APOB, CETP, and LDLR. Data were sourced from the Global Lipids Genetics Consortium and UK Biobank. Significant single-nucleotide polymorphisms linked to LDL cholesterol were utilized as instrumental variables. Causal effects were estimated using Inverse Variance Weighted, Weighted Median, MR Egger, Simple Mode, and Weighted Mode methods. Robustness was ensured through heterogeneity and sensitivity analyses. The inhibition of HMGCR and CETP genes was found to be significantly associated with an increased risk of developing pSS (HMGCR: OR = 3.602, 95% CI [1.051, 12.344], p = 0.041; CETP: OR = 12.251, 95% CI [2.599, 57.743], p = 0.002). HMGCR and CETP may affect pSS risk via non-lipid pathways, suggesting distinct mechanisms among different lipid-lowering drug targets. This study provides compelling evidence suggesting that lipid-lowering drugs may contribute to the risk of pSS, thus offering new insights for clinical intervention strategies. Show less

Apolipoprotein B (apoB) can be measured directly and accurately, and better predicts atherogenic risk than conventional lipid profiles. We aimed to investigate whether total and regional (trunk or leg) fat deposits are associated with apoB levels in general US adults. 4585 participants were enrolled from the US National Health and Nutritional Surveys from 2011 to 2016. Overall and regional body fat were measured using dual-energy X-ray absorptiometry. The associations of total and regional fat with apoB levels were evaluated using linear regression models. Following adjustment for demographic, lifestyle, and clinical risk factors, whole-body fat percentage was positively associated with apoB levels. Additionally, percent trunk fat was positively associated (highest vs. lowest tertile beta = 17.73 for men and 14.89 for women, respectively), whereas percent leg fat was inversely associated (highest vs. lowest tertile beta = - 4.84 for men and - 6.55 for women, respectively) with apoB levels in both sexes. The association for trunk fat and leg fat remained significant after further adjustment for body mass index or waist circumference. Higher percent trunk fat combined with lower percent leg fat was associated with particularly higher apoB. In conclusion, among general US adults, both elevated trunk fat and reduced leg fat are associated with higher levels of apoB. Further research is required to elucidate the underlying pathophysiological mechanisms. Show less

This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-protein (LP) diets. A total of 384 Hy-Line brown laying hens (32 weeks old) were divided into six groups: control (CON) diet with 16.5 % crude protein (CP), LP diet with 15 % CP, and LP diets supplemented with 3 %, 5 %, 7 %, and 9 % CM. Results showed that dietary CM supplementation of up to 5 % did not negatively affect the productive performance of laying hens fed LP diets. However, the groups receiving 7 % and 9 % CM exhibited a significant increase in the feed-to-egg ratio (P < 0.05). Additionally, dietary CM supplementation effectively enhanced egg yolk color in a dose-dependent manner (P < 0.05). Intestinal morphology analysis indicated that the 5 % CM group had a higher villus height-to-crypt depth ratio than the LP and 9 % CM groups (P < 0.05), with no significant differences among the other groups. Dietary supplementation with 3 %-7 % CM did not significantly affect serum and jejunal antioxidant capacity, and the 9 % CM group exhibited the highest levels of serum and jejunal malondialdehyde among the groups (P < 0.05). Dietary CM supplementation significantly increased anti-inflammatory cytokines (IL-4 and IL-10) and decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum and jejunal tissue of laying hens (P < 0.05). Moreover, CM supplementation significantly altered the cecal microbiota composition in laying hens, increasing the abundance of beneficial bacteria, such as Desulfovibrio and Megamonas. Furthermore, dietary CM supplementation significantly decreased serum triglyceride levels; downregulated liver mRNA levels of ACC, FAS, and SREBP-1C/2; and upregulated the mRNA levels of ACOX1, PPAR-α, Apob, and CPT in laying hens fed LP diets. In conclusion, CM supplementation should not exceed 5 % to avoid negative impacts on performance while supporting intestinal health and lipid metabolism. Show less

The research on Apolipoprotein A-1 (ApoA-1), Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) ratio, and preterm birth was limited to the first and second trimesters. No studies have been conducted in the third trimester, and thus this study aimed to investigate the association between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth in patients with gestational diabetes mellitus (GDM) in the third trimester. This study collected the data of single pregnant women of age at pregnancy 16-49 years with GDM who were in the third trimester and gave birth in the Obstetrics department, Hangzhou Linping District Women & Children Hospital from December 1, 2023, to April 20, 2024. The patients were divided into preterm birth group and term birth group according to whether they had preterm birth or not. The restricted cubic spline analysis was used to explore whether there was a linear relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth. The relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth in patients with GDM was explored using trend analysis. The receiver operating characteristic and Decision Curve Analysis were conducted to evaluate the predictive efficacy and clinical benefits of ApoA-1, ApoB/ApoA-1 ratio in predicting preterm birth in patients with GDM. There was a linear relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth. The higher the ApoA-1 level, the lower the risk of preterm birth; the higher the ApoB/ApoA-1 ratio, the higher the risk of preterm birth. ApoA-1, ApoB/ApoA-1 ratio in pregnant women with GDM in the third trimester were associated with preterm birth. Show less

Foam cells derived from macrophages and smooth muscle cells (SMCs) play a pivotal role in the progression of atherosclerosis. While phytosterols (PS) have demonstrated cholesterol-lowering and anti-inflammatory properties, their impact on foam cells remains elusive. Here, we investigated the effects of PS on foam cell formation, inflammatory responses, and lipid metabolism using both single-cell RNA sequencing (scRNA-seq) and functional assays. scRNA-seq of aortic tissue from Show less

Atherosclerosis (AS) is a chronic inflammatory disorder driven by dysregulated lipid metabolism and remains a leading cause of cardiovascular morbidity. The Shen-Hong-Tong-Luo (SHTL) preparation has demonstrated clinical benefit in stabilizing atherosclerotic plaques, yet its molecular mechanisms are not fully defined. This research sought to elucidate the protective effects exerted by SHTL on AS progression. To investigate the impact of SHTL on macrophage function and plaque stability, we utilized ApoE SHTL markedly attenuated the progression of AS, demonstrated by reduced plaque formation within both the aortic root and aorta, diminished plasma lipid concentrations, and suppressed inflammatory responses. SHTL demonstrates significant anti-inflammatory and lipid-regulatory effects, attenuating AS progression through the PPARγ/Mfge8 pathway, thereby enhancing macrophage efferocytosis. These findings highlight a novel mechanism by which SHTL may contribute to preventing and treating atherosclerotic diseases. Show less

Alzheimer's disease (AD) and vascular dementia (VaD) account for most dementia cases. AD biomarkers remain costly and invasive, and no specific biomarkers exist for VaD. We analyzed plasma and brain proteomics in the UK Biobank (N=53,000) and ROSMAP (N=512) to identify shared and distinct proteomic signatures of AD and VaD and assess the influence of the APOE ε4 variant. We identified 55 AD-associated and 49 VaD-associated proteins, with 13 shared. AD proteins were enriched in glycosaminoglycan binding and cholesterol metabolism; VaD proteins in virus receptor activity, cytokine activity and metalloproteinases. Both showed IGF pathway dysregulation. APOE ε4 stratification revealed distinct AD proteomic signatures beyond GFAP and NeFL. Mendelian randomization suggested causal links for SNAP25 in AD, EDA2R and TIMP4 in VaD, and PVR in both. Findings underscore the importance of APOE genotype and highlight SNAP25, EDA2R, TIMP4, and PVR as potential biomarkers and therapeutic targets. Show less

This study aimed to investigate the anti-tumour effect and the possible molecular mechanism of Tianma granules on colorectal cancer (CRC). The therapeutic effect of Tianma granules on CRC cell lines (HT116 and SW480) and AOM/DSS-induced CRC mouse models was evaluated. Tianma granules can attenuate weight loss and increase the survival rate of CRC mice, restore reduced colon length, reduce tumour numbers and increase goblet cell numbers in CRC mice. Tianma granules also downregulated the level of CRC-specific markers (COX2 and MUC2), inhibited the inflammation (decreased TNF-α, IL-1β, IL-6 levels and increased INF-γ level), and promoted apoptosis (decreased TUNEL positive cell rate; decreased Bax and Cleaved caspase3 protein levels and increased Bcl2 level) in CRC mice. In vitro, Tianma granules can inhibit the viability, proliferation, migration and invasion of CRC cells, while promoting cell apoptosis, cell cycle arrest and cell senescence. Tianma granules promoted AXIN1 protein levels and inhibited p-GSK-3β, β-catenin, Wnt5a and Cyclin D1 and c-Myc protein levels. Moreover, the network pharmacology analysis and in vitro validation revealed berberine might be the key compound responsible for Tianma granules' pharmacological actions. In conclusion, Tianma granules can inhibit inflammation and tumour progression in AOM/DSS-induced CRC mice, as well as inhibit CRC cell malignant phenotype. The protection of Tianma granules against CRC may be achieved by inhibiting the Wnt signalling pathway. Show less

Alzheimer’s disease (AD) is the most common type of dementia. A major pathological feature of AD is the aggregation of amyloid-β (Aβ), primarily driven by β-secretase (BACE1) activity. However, the mechanisms underlying continuous Aβ accumulation remain unclear. Circulating extracellular vesicles (EVs) may play a crucial role in AD progression. Here, we investigate whether circulating EVs in AD promote Aβ generation and aggregation. In this study, we found that compared to WTEVs (circulating EVs isolated from WT mice), APPEVs (circulating EVs isolated from APP/PS1 mice) showed higher concentrations and activated the JAK2-STAT1 pathway in neurons, upregulating BACE1 expression and activity. This cascade promoted amyloid precursor protein (APP) β-cleavage in lipid rafts, inducing substantial Aβ generation. Proteomic analysis revealed complement C1q in APPEVs as a key protein activating the JAK2-STAT1-BACE1 pathway. Furthermore, in vivo experiments demonstrated that intravenously injected APPEVs crossed the blood-brain barrier without damaged the epithelial tight junction, promoting BACE1 expression in neurons, and enhancing Aβ production and aggregation in brain. Inhibition of C1q mitigated these effects in both in vitro and in vivo experiments. In conclusion, during the progression of AD, circulating EVs containing complement C1q are delivered to neurons, activating their JAK2-STAT1 signaling pathway. This activation upregulates the expression of BACE1, subsequently enhancing the β-cleavage of APP in lipid rafts. These events lead to a substantial increase in Aβ production, exacerbating the pathological progression of AD. The online version contains supplementary material available at 10.1186/s12974-025-03528-x. Show less

Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals. Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group). EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways. Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation. Show less

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD. Show less

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans. Show less

Kidney tubular cell injury is largely responsible for the pathophysiological features of diabetic kidney disease (DKD). Increased leucine levels in individuals with DKD have been associated with the progression of diabetes to end-stage renal failure, yet a comprehensive understanding of leucine metabolism in kidney tubules during the progression of DKD is lacking. Human kidney biopsies and mouse models were used to assess leucine metabolism during DKD progression. Enhancement of leucine degradation was achieved through genetic ablation or pharmacological inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK). Cultured kidney tubular epithelial cells were used to analyse the underlying cellular mechanisms. The association of urinary leucine with progression of DKD was determined in individuals with diabetes. Measurements of metabolites and enzymes suggested defective leucine degradation and increased BCKDK expression in kidney tubules during DKD progression. Enhancement of leucine degradation relieved glucose-induced metabolic remodelling in tubular cells and mitigated DKD in mouse models. Accumulation of leucine stimulated metabolic remodelling via the mTOR signalling pathway; this was relieved by blocking leucine uptake or enhancing its degradation. Restricting dietary leucine significantly decreased albuminuria, kidney hypertrophy and lipid accumulation in mouse models of diabetes. Additionally, we observed that rapid decline in kidney function correlated with a higher urinary leucine-to-creatinine ratio in both female and male individuals with diabetes. In summary, we identify defective leucine degradation in renal tubules of diabetic individuals and propose leucine as a causative factor for DKD, highlighting its potential as a therapeutic target for further investigation. The transcriptomic data supporting the findings of this study are openly available at the National Center for Biotechnology Information Sequence ReadArchive (SRA) ( https://www.ncbi.nlm.nih.gov/sra , identifiers: PRJNA1180888 and PRJNA1180923). The metabolomics data associated with the manuscript are available in the ESM. Show less

Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK-mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK-mediated phosphorylation of AKT decreases ubiquitin-mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient-derived organoids (PDOs), enhances doxorubicin-induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention. Show less