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Hepatic intercellular communication is the driving force for the progression of chronic Hepatitis B virus (CHB)-associated hepatopathologies, with the dynamic molecular mechanisms largely unknown. Combining scRNA-seq and spatial transcriptomic analysis, the kinetic landscape of the liver microenvironment across time and space in AAV-HBV mice, which develop from inflammation to ultimately hepatocellular carcinoma is generated. Kupffer cells (KCs), originally resided within the peri-portal area, are persistently recruited to the HBV-enriched peri-central region via increased CXCL9 produced by endothelial cells, facilitating the interaction between KCs and HBV Show less

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

Circadian rhythms have been reported in a variety of physiological processes that may influence cardiovascular disease, while little is known about the effects of circadian rhythm-related genes (CRRGs) on acute myocardial infarction (AMI). The genome-wide association study (GWAS) data of AMI (ukb-a-533) and expression quantitative trait loci (eQTL) data of CRRGs were downloaded from the integrative epidemiology unit Open GWAS database. The relationship between the CRRGs and AMI was assessed by the two-sample Mendelian randomization (TSMR) analysis. The hub genes that could directly affect AMI were identified based on the inverse variance weighted (IVW) algorithms. Subsequently, the TSMR results were evaluated via sensitivity analyses and MR-Steiger filtering. Then, the expression in immune cells and tissues was predicted from the Human Protein Atlas and Genotype-Tissue Expression databases. Finally, the molecular regulatory networks were generated based on the hub genes. In TSMR results, NR1H3 (IVW: odds ratio (OR) = 1.0009, 95% confidence interval (CI) = 1.0005-1.0013), SREBF1 (IVW: OR = 1.0015, 95% CI = 1.0007-1.0022), SIRT1 (IVW: OR = 1.0007, 95% CI = 1.0001-1.0013), and HIF1A (IVW: OR = 1.0022, 95% CI = 1.0004-1.0039) were risk factors for AMI patients, while NCOA1 (IVW: OR = 0.9984, 95% CI = 0.9969-0.9998) was a protective factor for AMI patients (P < .05). Importantly, the 5 hub genes could affect AMI occurrence in one direction. The expression levels of HIF1A, NCOA1, and SREBF1 were highest in neutrophils than the other immune cells. Also, HIF1A and SREBF1 had higher expression in the heart (left ventricle and atrial appendage) and artery (aorta, tibial, and coronary). Moreover, the transcription factor, NFKB1, might regulate the hub genes except for NCOA1. Generally, 4 risk genes (NR1H3, SREBF1, SIRT1, and HIF1A) and 1 protective gene (NCOA1) associated with circadian rhythm for AMI patients were identified, providing new insights into the diagnosis and treatment of AMI. Show less

The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined its association with inflammatory endotypes and clinical outcomes in CRSwNP. Efferocytosis-related marker expression between nasal polyps and healthy nasal mucosa was detected by quantitative real-time PCR and immunohistochemistry. Public single-cell RNA sequencing profiles of CRS were reanalyzed to dissect efferocytosis at single-cell resolution. Associations between efferocytosis and tissue inflammation were evaluated by Spearman correlation. Regression models and receiver operating characteristic analyses assessed the predictive capability of efferocytosis for CRSwNP recurrence. Compared with controls, CRSwNP exhibited widespread efferocytosis deficiency, including "find me" signals (CX3CR1, S1PRs, P2RY2, GPR132), "eat me" signals (ITGAV, MerTK, Tim1, ADGRB1), "don't eat me" signal CD300a, postengulfment signals (ABCA1, NR1H3/2, PPARδ/γ), and bridging molecule MFGE8. Macrophages, the principal efferocytic cells, shifted from homeostatic C3 Insufficient phagocytosis and increased antiphagocytosis activity are hallmarks of efferocytosis deficiency in CRS and are associated with the severity of inflammation and the clinical outcome of CRSwNP. Show less

Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 Show less

Liver X receptors (LXRs), transcription factors belonging to the nuclear receptor superfamily, exist as two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), that orchestrate cholesterol absorption, transport and excretion. Beyond their canonical roles in lipid homeostasis, LXRs modulate glucose metabolism, inflammatory responses and cellular proliferation. Emerging evidence implicates dysregulated LXRs activity in the pathogenesis of chronic liver diseases (CLDs), including viral hepatitis, metabolic dysfunction‑associated steatotic liver disease and hepatocellular carcinoma. However, the therapeutic potential of LXRs modulation remains paradoxical: While activation mitigates hepatic injury by maintaining cholesterol homeostasis and suppressing inflammation, concurrent upregulation of sterol regulatory element‑binding protein 1c exacerbates lipogenesis, potentially aggravating hepatosteatosis. The present review synthesized current insights into the dual regulatory mechanisms of LXRs in CLDs, critically evaluates their context‑dependent roles and highlights the imperative to balance therapeutic efficacy with metabolic side effects in future drug development. Show less

Postmenopausal metabolic syndrome and its associated liver injury have attracted considerable research interest, yet their underlying mechanisms and treatment strategies remain insufficiently elucidated. This study aimed to investigate the relationship between aberrant lipid metabolism and hepatic injury in ovariectomized (OVX) females and to evaluate the therapeutic potential of ingenol (Ing), a natural diterpenoid, via the SIRT1-LXRα signaling pathway. Data from 3047 females in NHANES (2017-2020) were analyzed to compare serum triglyceride (TG) and liver injury markers between OVX and non-OVX women. An OVX mouse model was established to examine hepatic lipid metabolism and SIRT1 expression. Molecular docking, dual luciferase assays, and SIRT1 silencing were performed to evaluate Ing-SIRT1 binding and regulation. HepG2 cells were used to assess Ing's effects on lipid levels and expression of LXRα, CYP39A1, CPT1, and ACOX1. In vivo studies in OVX mice confirmed the therapeutic effects of Ing and further investigated its mechanism via the SIRT1-LXRα pathway. NHANES data indicated that OVX women had significantly higher serum TG levels and more severe liver injury. OVX mice exhibited downregulated SIRT1 expression and disrupted lipid homeostasis. Ing showed high binding affinity to SIRT1, outperforming several known agonists. In HepG2 cells, Ing reduced intracellular TG and total cholesterol (TC), while upregulating LXRα, CYP39A1, CPT1, and ACOX1. In OVX mice, Ing treatment notably attenuated weight gain, reduced TG and TC levels, and ameliorated liver histopathological damage. These effects were mediated through the SIRT1-LXRα pathway. Ing effectively mitigates OVX-induced liver injury by activating SIRT1 and modulating downstream LXRα-mediated lipid metabolic pathways. These results support Ing as a promising therapeutic candidate for liver injury in postmenopausal or OVX women. Show less

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility toward a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in patients with ME/CFS ( Show less

Prednisone is used clinically during pregnancy. This study investigates whether prenatal prednisone exposure (PPE) affects susceptibility to high-fat diet (HFD)-induced metabolic dysfunction-associated fatty liver disease (MAFLD) in adult offspring and explores underlying mechanisms. Pregnant Kunming mice were administered prednisone (0.25 or 1 mg/kg; PPE-L or PPE-H) or vehicle control (5% carboxymethyl cellulose; Ctrl) by daily gavage from gestational days 0-18. Offspring were assessed metabolically, histologically, and via RNA-Seq. Primary hepatocytes were treated with fatty acids with or without the epigenetic inhibitors to evaluate Nr1h3 expression and lipid deposition. Offspring body weight was similar in PPE-L vs Ctrl, but was reduced in PPE-H group followed by delayed growth. After 6-week HFD feeding, PPE-L offspring showed mild metabolic issues, while PPE-H males exhibited significant glucose/lipid disorders and hepatic steatosis compared to controls. RNA-Seq showed upregulation of hepatic lipid pathways in the PPE-H male offspring when challenged by HFD. The liver X receptor alpha (LXRα)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway and the expression of genes involved in de novo fatty acid synthesis were increased in PPE-H offspring under HFD. A485 significantly downregulated the expression of Nr1h3 in primary hepatocytes from male PPE-H offspring and alleviated lipid deposition in these hepatocytes treated with fatty acids. The H3K27ac level in the Nr1h3 promoter in the PPE-H offspring's liver was significantly upregulated. PPE-L impairs offspring glucose/lipid homeostasis, whereas PPE-H increase MAFLD risk of the offspring by epigenetic programming of the hepatic LXRα-SREBP1 pathway, especially in the males. Show less

Dyslipidemia is a major risk factor for the development of NAFLD, atherosclerosis and cardiovascular diseases. Rosuvastatin (ROS) is a lipid-lowering drug that protects against the development of NAFLD and atherosclerosis. However, the mechanism of this protection remains obscure. Therefore, the current study aims to explore the mechanism by which ROS-loaded glycerosomes (ROS-GLY) protect against NAFLD and atherosclerosis. Hence, for this purpose, hepatic lncRNA-H19/miR-130a/PPAR-γ and aortic PPAR-γ/LXRα/ABCA1 signaling pathways were assessed. In addition, these target pathways were predicted using molecular docking analysis. Thirty-five male Sprague Dawley rats were separated into control, dyslipidemic (poloxamer 407 (P 407)), P 407+ROS-GLY, P 407+NC, and P 407+ROS-GLY+NC groups. ROS-GLY improved lipid profile, hepatic MDA, SOD, catalase and total antioxidant capacity (TAC) in compared to P 407 group. In the dyslipidemic group, ROS-GLY downregulated hepatic lncRNA-H19 expression which leads to an upregulate of the miR-130a level and subsequent reduction of the PPAR-γ level. Consequently, the hepatic expression level of lipogenic genes such as, ACC-1, FASN and SCD-1 was significantly downregulated in the ROS-GLY group than the dyslipidemic one. Aortic PPAR-γ/LXRα/ABCA1 signaling pathway was significantly upregulated in the ROS-GLY group compared to the dyslipidemic group. Furthermore, ROS-GLY modulated IL-6 and IL-10 immunoprotein expression in hepatic and aortic tissues. Interestingly, ROS showed a substantial binding affinity with PPAR-γ, LXR-α, and FASN, according to a molecular docking study. The current study indicated that ROS-GLY protected against the progression of NAFLD and atherosclerosis in dyslipidemic rats via modulation of lipid profile, oxidative stress, pro-/anti-inflammatory cytokines, hepatic lncRNA-H19/miR-130a/PPAR-γ, and aortic PPAR-γ/LXRα/ABCA1 signaling pathways. Show less

This study aimed to systematically elucidate the antihyperlipidemic mechanism of paeoniflorin, and we adopted an integrated multi-omics strategy to screen the key molecular targets and regulatory pathways involved in its action, followed by experimental validation to verify the potential regulatory effects of paeoniflorin on the screened targets and metabolic processes. Rats with high-fat diet-induced hyperlipidemia received paeoniflorin treatment. Liver histopathology was evaluated using hematoxylin-eosin and Oil Red O staining. Serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bile acids, activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen were measured using a biochemical analyzer. Integrated multi-omics analyses were performed to investigate paeoniflorin's lipid-lowering mechanism. Critical pathways and targets identified were validated using Western blotting. Paeoniflorin alleviated pathological liver damage in hyperlipidemic rats and improved blood lipid levels, coagulation function, and liver function markers. Multi-omics analyses verified that paeoniflorin downregulated the expression of TREM-1, TLR4, NF-κB, TNF-α, and IL-1β, thereby alleviating hepatic inflammation. Paeoniflorin also upregulated the expression of low-density lipoprotein receptors (LDLR), liver X receptor alpha (LXRα), and ATP-binding cassette subfamily G member 1 (ABCG1), while downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, contributing to balanced cholesterol metabolism. Paeoniflorin normalized glycerophospholipid and branched-chain amino acid metabolism, which correlated with reduced inflammation and improved cholesterol metabolism. Paeoniflorin ameliorates hyperlipidemia through multitarget mechanisms, potentially by suppressing the TREM-1-TLR4-NF-κB signaling pathway to reduce inflammation and by regulating cholesterol metabolism via the PCSK9-LDLR and LXRα-ABCG1 pathways. Show less

The formation of subendothelial macrophage-derived foam cells is a key driver of atherogenesis and contributes to the onset and progression of atherosclerosis (AS). The METTL3 gene, a central mediator of N6-methyladenosine (m6A) RNA methylation, serves as a critical regulatory node at the inflammation-metabolism nexus in immune pathophysiology. This study aimed to investigate the METTL3-mediated regulatory mechanisms in subendothelial macrophage-derived foam cells formation and their association with necrosis and the pro-inflammatory properties of AS lesions. METTL3 expression was significantly higher in human carotid artery plaques compared to non-plaques. Macrophages treated with ox-LDL had an upregulated METTL3 expression, while its knockdown reduced lipid accumulation, foam cell formation, and inflammatory responses in macrophages. Myeloid Mettl3 knockout AS mice exhibited attenuated AS lesions. METTL3 knockdown elevated ABCA1, LXR-α, and ZNF771 expression. Gain- and loss-of-function studies demonstrated that METTL3 modulates lipid accumulation and inflammation partly through the ZNF771/LXR-α/ABCA1 axis. YTHDF2 knockdown increased ZNF771 levels, indicating that METTL3 cooperates with YTHDF2 to suppress ZNF771 expression, thereby inhibiting LXR-α transcription. Macrophage METTL3 exacerbates AS by suppressing cholesterol efflux and amplifying inflammation through YTHDF2-mediated downregulation of ZNF771, which attenuates the LXR-α/ABCA1 axis. Our study identifies a novel METTL3-dependent mechanistic link between foam cell pathology and plaque destabilization. Show less

The liver X receptor (LXR) is expressed as α and β subtypes (NR1H3/NR1H2), which play both separate and overlapping roles in cholesterol metabolism. As ligand-regulated transcription factors, LXRα and LXRβ are activated by oxysterol. The two isoforms have high percent identity, sharing nearly identical structures and binding pockets. With these similarities, it is not clear how ligands distinguish between LXRα and LXRβ binding pockets. Yet, the ability to design isoform-specific modulator is highly dependent on this knowledge. Here, we test the hypothesis that, despite high structural similarity, the dynamic behavior of the receptors is distinct and can reveal fundamental differences between the isoforms. Using molecular dynamics simulations on a library of 27 oxysterols, we compare dynamic contacts, fluctuations and allosteric signaling in the ligand binding domains of both receptors. We quickly identify stability differences linked to subtle changes in secondary structure and inter-residue contacts. Using our reconstructed sequence of ancestral vertebrate LXR, we reveal that both receptors inherited distinct structural and/or dynamical features of the ancestor which underlie their dynamic differences. Show less

Liver X receptors (LXRα and LXRβ) are nuclear receptors critical for lipid homeostasis and inflammation regulation, making them potential therapeutic targets for atherosclerosis and inflammatory diseases. While LXR agonists hold promise, their use is limited by adverse effects on hepatic lipogenesis. Riccardin C (RC) has shown promise as an LXRα partial agonist/ LXRβ antagonist with cell-type-selective properties. This study investigates the molecular mechanisms behind RC-induced LXRα activation. A series of LXRα/β chimera and point-mutated receptors was generated to identify the domains and residues required for RC-induced transactivation. Functional analysis revealed that mutating alanine-327 of LXRα to LXRβ-type histidine in helix 6 impaired RC-induced association with coactivator peptides, reducing transactivation. Conversely, mutating histidine-341 of LXRβ or the inactive chimera to the LXRα-type alanine partially restored the response to RC, highlighting the significance of the A327H mutation in selective LXRα activation by RC. Furthermore, in vivo experiments revealed that when administered orally to mice, RC selectively induced hepatic and intestinal Abca1 expression without stimulating hepatic lipogenic gene expression, thereby elevating HDL levels without increasing plasma and hepatic triglycerides. These findings offer valuable insights for the development of novel therapeutic agents. Show less

Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration. Show less

Metabolic (dysfunction)-associated steatotic liver disease (MASLD), the hepatic consequence of metabolic syndrome, affects 30% of the global population. Studies in animals and humans investigating the effect of fructose on MASLD present conflicting findings, while in vitro methods often fail to add meaningful evidence due to acute exposures (<72 h) and non-physiological concentrations. This study aimed to determine the effect of fructose on triglyceride (TG) accumulation in HepG2 cells following acute and chronic exposures and assess its effect on the expression of genes related to de novo lipogenesis (DNL). TG concentration was measured after 48 h in response to fructose (20 mM) or glucose (20 mM), with or without a fatty acid mixture (oleic acid/palmitic acid 110 µM/55 µM), in low (5.5 mM)- and high (25.5 mM)-glucose media. To model chronic exposure, cells were maintained in fructose, glucose, or fatty acids for 28 days and the TG concentration was determined every 7 days. The effect of fructose on DNL regulators ( Neither fructose nor glucose, with or without fatty acids, changed the TG levels in cells at 48 h and the media glucose concentration had no effect on this result. Similarly, fructose did not increase TG levels after 28 days. While fructose and glucose did not affect key DNL genes at 6 h, the fatty acid mixture reduced This study shows that fructose did not significantly impact TG synthesis or DNL gene expression in the HepG2 cell model. Future studies should consider using primary human hepatocytes or more complex in vitro models. Show less

This study was aimed at identifying the effects of liver X receptor alpha (LXRα) on sepsis-induced acute lung injury (ALI) and clarifying its novel regulatory mechanisms using bioinformatics and experimental methods. Bioinformatics analysis of the differentially expressed genes and functional annotations were performed. Lipopolysaccharide (LPS) was administered intraperitoneally for sepsis-induced ALI in a mouse model; then, the LXR agonist T0901317 (T0) was administered to the mice along with RAW264.7 macrophages for LXRα activation. We then performed hematoxylin and eosin staining, estimated the total protein in the bronchoalveolar lavage fluid, and detected the expressions of TNFα and IL6 by reverse transcription polymerase chain reaction to evaluate the inflammatory injury in the lung tissues. Autophagy was detected via immunohistochemistry, transmission electron microscopy, and Western blotting. RNA sequencing was then used to analyze the autophagy-related genes regulated by LXRα, and the cells were transfected with S100A8-siRNA to determine whether LXRα regulated inflammatory damage by regulating the autophagy-related gene S100A8. The clinical correlation between LXRα and S100A8 was determined through analysis of human transcriptome data. The bioinformatics analyses revealed that LXRα (NR1H3) was downregulated in sepsis-induced ALI models and that LXRα might regulate autophagy. The animal- and cell-based experiments further verified these findings. The LXR agonist T0 was found to alleviate lung damage and reduce the expressions of inflammatory factors in the lung tissues and cells. After inhibiting autophagy with 3-methyladenine, the protective effects of T0 on inflammatory damage were shown to be inhibited. Subsequently, RNA sequencing of the macrophages was performed, and four genes ( The findings of this study suggest that T0 attenuates sepsis-induced pulmonary injury by promoting macrophage autophagy via suppression of S100A8 expression. Show less

Impaired excretion of lipid deposits within vascular smooth muscle cell-derived foam cells (VSMC-FCs) contributes to the ongoing expansion of the plaque necrotic core. This study aims to explore the effects and underlying mechanisms of exosomes secreted by M2 macrophage (M2-exos) on lipid metabolism of VSMC-FCs and plaque stability. First, immunofluorescence was used to detect the expression levels of CD45 (a recognized differentially-expressed molecule of myeloid and VSMC-FCs) and the key proteins of cholesterol efflux pathway, ABCA1 and ABCG1, in human early and late plaques. Next, an in vitro foam cell model was used to assess the effect and mechanism of M2-exos on lipid metabolism in vascular smooth muscle cells by western blot, Oil red O staining and cell total cholesterol assays. RNA-seq and quantitative real-time PCR were employed to characterize the miRNA profiles within M2-exos. The dual-luciferase reporting system and gene silencing approaches were utilized to assess the regulatory effect of candidate miRNA on target genes and signaling pathways. Subsequently, the effect of M2-exos on plaque progression and stability in ApoE Immunofluorescence revealed that compared to early plaques, VSMC-FCs (CD45 M2-exos exerted an obvious atherosclerotic protective effect, and the underlying mechanism was closely related to MiR-7683-3p, which targeted the 3'UTR of HOXA1 mRNA and activated the PPARγ-LXRα-ABCG1 mediated cholesterol efflux in VSMC-FCs. Show less

Increased hepatic triacylglycerol (TG) storage in lipid droplets (LDs) is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Human carboxylesterase 1 (CES1) regulates TG storage and secretion in hepatocytes, but the mechanism remains to be elucidated. We performed studies in rat hepatoma McArdle RH7777 cells stably transfected with CES1 cDNA and in Ces1d-deficient mice using a variety of biochemical, pharmacological and cell biology approaches including the assessment of gene expression, confocal immunofluorescence microscopy, lipid synthesis measurements and quantitative mass spectrometry. CES1-expressing cells accrued more TG compared to cells lacking CES1 when incubated with oleic acid. CES1 increased the expression of Show less

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

Necrosis induced by sodium overload has recently been identified as a novel form of regulated cell death. However, the specific genes associated with sodium overload in breast cancer (BC) remain uncharacterized. We identified 753 differentially expressed sodium-overload-related genes (DESORGs) in BC. We performed pathway enrichment analyses, then used univariate Cox regression to select 67 prognostic DESORGs. To build prognostic models, we tested 101 combinations of ten machine learning algorithms. SHAP analysis was used to determine feature importance. Mendelian randomization (MR) was applied to assess causal effects. Experimental validation (in vitro) included overexpression and knockdown studies. GSEA/GSVA and molecular docking were conducted to explore downstream pathways and potential drug candidates. The ridge regression model showed optimal prognostic power. IFNG was identified as the key feature. The computed risk score was an independent prognostic factor, outperforming traditional clinical variables (AUC = 0.845), and a nomogram built with it yielded good calibration (C-index = 0.815). MR suggested a protective causal effect of NR1H3 in BC, and patients with high NR1H3 expression had significantly better overall survival (p = 0.02). These findings highlight NR1H3 as a novel DESORG and a promising therapeutic target in breast cancer. Show less

Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mechanisms in human Sertoli cells remain unclear. In this study, immortalized human Sertoli cells were exposed to BPS, and cell viability, proliferation, and transcriptomic changes were assessed, with bulk RNA sequencing integrated with single-cell transcriptomic profiles from non-obstructive azoospermia (NOA) testes to identify key regulatory factors. Potential BPS targets were predicted via pharmacophore mapping and confirmed through molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations, while functional validation was performed using NR1H3 knockdown and overexpression assays with luciferase reporter and Western blot analyses. BPS significantly inhibited cell viability and proliferation at concentrations ≥ 20 μM, inducing transcriptomic dysregulation involving cell cycle suppression, metabolic pathway alterations, and steroid biosynthesis disruption. Integration of computational and transcriptomic analyses identified NR1H3 as a direct BPS target, with docking and dynamics simulations demonstrating stable binding (-20.64 ± 2.26 kcal/mol), and experimental data showing that BPS reduced NR1H3 protein levels and transcriptional activity, while NR1H3 knockdown impaired cell survival and overexpression partially rescued BPS-induced cytotoxicity. These findings provide the first evidence that BPS impairs human Sertoli cell function by targeting NR1H3, revealing a critical role of NR1H3 in Sertoli cell survival and suggesting that BPS exposure may contribute to male infertility through NR1H3-mediated pathways. Show less

Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identify prognostic biomarkers associated with dexmedetomidine and dezocine (DD) in BRCA patients. Through Mendelian Randomization analysis, we screened four DD targets that had a causal relationship with BRCA. Subsequently, utilizing TCGA-BRCA data, univariate and Lasso Cox analyses revealed two significant prognostic biomarkers (NR1H3 and ADRB1) associated with BRCA patient prognosis, leading to the successful construction and validation of a prognostic risk model. Kaplan-Meier survival curves indicated that patients with higher NR1H3 and ADRB1 expression had longer overall survival (OS). Immunoinfiltration analysis showed that high-risk group patients exhibited increased infiltration levels of CD56 bright natural killer cells, CD56 dim natural killer cells, eosinophils, and plasmacytoid dendritic cells. Conversely, activated B cells and immature B cells demonstrated greater infiltration in the low-risk group. Correlation analysis revealed significant associations between prognostic biomarkers and various immune cells, including CD56 bright natural killer cells, CD56 dim natural killer cells, and activated CD8 T cells. NR1H3 was highly positively correlated with immune checkpoints such as TIGIT, PDCD1, CD274, CTLA4, LAG3, and HAVCR2 (|cor|≥0.3, The online version contains supplementary material available at 10.1007/s12672-025-03694-7. Show less

Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi-component activity. The effectiveness of these botanical extracts is thought to involve complex interactions among diverse constituents; however, the molecular basis of such interactions remains insufficiently understood. In this study, we explored the anti-inflammatory properties of the ethanol extract of Polygonum multiflorum (PME) through a combination of chemical profiling and computational analysis. PME was found to reduce the production of nitric oxide, inducible nitric oxide synthase, and interleukin-6 in LPS-stimulated RAW 264.7 macrophages. Using HS-SPME-GC-MS in conjunction with network pharmacology, we identified 32 volatile constituents, among which five core compounds were predicted to be associated with three inflammation-related targets: ESR1, FASN, and NR1H3. Dual-ligand molecular docking and molecular dynamics simulations suggested that the sequence of ligand binding may influence the stability and interaction patterns of protein-ligand complexes, offering insights into possible mechanisms of synergy and antagonism mediated by key residues such as ARG394 in ESR1. Overall, these findings contribute to a better understanding of how binding order and structural context may shape constituent-target interactions, providing a basis for the further development of multi-component natural product strategies against inflammation. This study underscores the relevance of incorporating multi-ligand dynamics into natural product research and presents an integrated experimental-computational framework to investigate the cooperative or competitive behaviors of functional food constituents, thereby supporting the rational design of optimized multi-target formulations. Show less

Propylene glycol (PG) is incorporated into ruminant diets to boost glucogenic energy availability, yet its precise effects on adipose tissue development remain incompletely defined. The study was designed as a 3 × 3 factorial experiment with two independent variables: dose of PG and duration of fattening. Three groups were formed, including a dose group of PG 1.5 mL/kg live weight (PG1.5), a dose group of PG 3 mL/kg live weight (PG3), and a group without PG (PG0). Gluteal adipose tissues were collected from animals slaughtered on days 60, 90, and 120. mRNA, protein, and fatty acid profiles were analyzed. Protein-protein interaction and gene set enrichment analysis were also performed. On day 60, FABP4 was approximately 3-fold higher at both mRNA and protein levels in PG3 compared to PG0, nearly 2-fold higher at the protein level in PG1.5, and SREBP-1c protein levels were reduced in PG1.5 compared to PG0. On day 120, FABP4, PPARγ, C/EBPα exhibited an increasing trend at both mRNA and protein levels in PG groups, whereas SREBP-1c was decreased in PG3. Fatty acid profiling revealed C16:0, C18:0, and C18:1 comprised over 70% of total lipids. PG supplementation shifted the profile toward unsaturated species, reducing saturated fatty acid proportions and enhancing nutritional indices, particularly in PG1.5. Findings at the bioinformatics levels demonstrate PG exerts clear dose- and time-dependent modulation of adipogenic transcription factors, fatty acid composition, and molecular interaction networks in lamb adipose tissue. Early PG3 feeding elevates FABP4 and suppresses SREBP-1c, whereas prolonged supplementation enhances PPARγ and C/EBPα and drives a favorable shift in lipid profiles. Network and pathway analyses reveal coordinated regulation via NR1H3/RXR and PPAR axes, suggesting PG not only optimizes energy partitioning but also supports cellular homeostasis. These results could contribute to the development of potential strategies aimed at supporting adipose tissue quality and metabolic health in sheep. Show less

Cordyceps has been clinically used to treat atherosclerosis (AS) since the 1980s. However, the active components responsible for its effects and the underlying mechanisms remain poorly understood. In this study, we aimed to explore the anti-AS effects and mechanisms of action of wild Cordyceps polysaccharides (WCP). The molecular weight, monosaccharide composition, and structural characteristics of WCP were analyzed. Furthermore, the anti-AS effects of WCP were evaluated using apolipoprotein E knockout ( Show less

Lipid-associated disorders such as obesity are major global health challenges, primarily driven by dysregulated lipid metabolism and associated alterations in gene expression and protein interactions. Understanding these molecular mechanisms is essential for identifying new therapeutic targets. This study investigates the molecular landscape of lipid dysregulation through differential gene expression analysis in hyperlipidemic rat models. By integrating multiple datasets and computational tools, we aimed to identify key proteins involved in obesity pathogenesis, thereby contributing to the development of targeted therapeutic strategies for lipid-associated disorders. A comprehensive search was conducted to identify differentially expressed genes associated with lipid disorders by analyzing metadata from various public databases, leading to the curation of four distinct datasets. Gene Ontology (GO) analysis was performed using the G: Profiler server, and protein-protein interaction (PPI) networks were constructed using Cytoscape. Cluster analysis with MCODE identified densely connected subnetworks, while pathway enrichment analysis using KEGG-KASS explored gene involvement in biological pathways. GO analysis revealed critical pathways involved in lipid metabolism, particularly those related to lipid oxidation and homeostasis. Pathway enrichment analysis identified three pivotal genes-Akt1, Nr1h3, and Il6-with Nr1h3 emerging as a prominent target under treatment conditions. Il6 showed significance in both disease and treatment contexts, suggesting its potential as a therapeutic target. These genes were also linked to obesity, fatty liver disease, and atherosclerosis in rat datasets, with supporting evidence from previously published rodent and human studies. Show less

Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen presentation. A total of nine pigs from the 112-population were selected for RNA-seq analysis. To pinpoint key transcription factors (TFs) regulating gene expression in the lymph nodes, weighted Kendall's Tau rank correlation analysis was performed to link the TF binding potential with the extent of differential expression of target genes. CD8 These mutations may disrupt TFs binding to the ELK4 promoter, potentially reducing ELK4 expression and impairing antigen processing and presentation. Show less

Cholesterol-loaded macrophage foam cells are a key feature of atherosclerotic plaques. Oxysterol-binding protein-related protein 2 (ORP2) facilitates the transport of cholesterol from lysosomes to the plasma membrane in cultured cell lines. However, the role of ORP2 in macrophages and its involvement in atherosclerosis remain unclear. In this study, we found ORP2 expression was reduced in atherosclerotic vessels and in macrophages exposed to oxidized LDL (ox-LDL). Myeloid-specific human ORP2 overexpression (hORP2 Show less

By 2020, breast cancer (BRCA) surpassed lung cancer as the most prevalent cancer globally, exhibiting high morbidity and mortality. Given the emerging role of circadian rhythm in cancer progression, this study aimed to develop a prognostic signature based on circadian rhythm-related genes (CRRGs) to predict BRCA patient survival. Gene expression profiles and clinical data were sourced from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and the Molecular Signatures Database (MSigDB). A multigene signature was constructed using LASSO-penalized Cox regression. Patients were stratified into high- and low-risk groups based on median risk scores. Pathway activity was assessed via gene set variation analysis (GSVA). Prognostic performance was evaluated using ROC curves, Kaplan-Meier (K-M) analysis, and multivariate Cox regression. A 20-CRRG prognostic signature was identified, effectively stratifying patients into distinct risk groups (K-M *P* < .05). ROC analysis demonstrated high predictive accuracy (AUC > 0.7). Functional enrichment linked these CRRGs to circadian regulation, nuclear components, and DNA binding. Further refinement revealed a 9-gene subset (ADRB1, BHLHE41, BTG1, EGR3, NONO, NR1H3, NTRK3, OPN4, PIGF) with superior 5-year survival prediction (AUC 0.82) compared to 1- and 3-year outcomes. The CRRG-based signature, particularly the 9-gene subset, robustly predicts BRCA patient survival, offering potential clinical utility for long-term prognosis. These findings underscore the role of circadian rhythms in BRCA progression and highlight novel biomarkers for risk stratification. Show less