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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

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

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

Adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive tumor arising from Rathke's pouch remnants, which is molecularly distinct from the other subtype, papillary craniopharyngioma (PCP). Despite advancements in surgery and radiotherapy, treatment outcomes remain unsatisfactory due to the tumor's invasiveness and resistance to conventional therapies. This review systematically examines the molecular pathogenesis of ACP and evaluates current and emerging therapeutic strategies to improve clinical management. ACP is driven by CTNNB1 mutations and dysregulated Wnt/β-catenin signaling, alongside inflammatory and senescence-associated pathways. Current pharmacological approaches, including interferon-α, IL-6 inhibitors (e.g., tocilizumab), and intracystic agents (e.g., bleomycin), exhibit limited efficacy. Promising emerging therapies target the angiogenesis (e.g., bevacizumab) and MAPK/ERK pathway, which is activated by somatic BRAF V600E mutations in PCP, has been successfully targeted with BRAF/MEK inhibitors, demonstrating significant efficacy in the majority of treated PCP patients. whereas immune checkpoint inhibitors and SHH pathway modulators face significant challenges. Additionally, ACP-related endocrine dysfunction and hypothalamic obesity require tailored interventions, such as GLP-1 receptor agonists and MC4R-targeted therapies. Precision medicine, informed by molecular subtyping and multi-omics data, holds transformative potential for ACP treatment. Future strategies should focus on combinatorial therapies to address tumor heterogeneity, microenvironment modulation, and senolytic approaches. Collaborative multidisciplinary efforts are crucial to translating these insights into clinical practice, ultimately enhancing patient outcomes and quality of life. 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

A female patient from India was diagnosed with diabetes at 16 years of age and presented to a tertiary care diabetes clinic nine months later with hyperglycemia and dyslipidemia (hypercholesterolemia and hypertriglyceridemia), while on insulin and statin therapy. The striking feature was the presence of lipodystrophy on both her upper and lower limbs. Both her elder brother and mother showed the presence of dyslipidemia and a normal phenotype on cascade screening. All three of them had a normal BMI. Managing the case was challenging due to the suboptimal response of dyslipidemia to the various combinations of medication. Genetic testing revealed a rare mutation in the LPL gene, causing familial combined hyperlipidemia (FCH) with an unusual association of lipodystrophy. A similar heterozygous mutation was found in the mother. We report the first case of FCH with lipodystrophy from India and share the challenges encountered during the three years of follow-up. 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

The liver plays essential roles in maintaining systemic glucolipid homeostasis under ever changing metabolic stressors. Metabolic dysregulation can lead to both adaptive and maladaptive changes that impact systemic physiology. Here, we examined disparate genetic and environmental metabolic stressors and identified apolipoprotein A4 (ApoA4) as a circulating protein upregulated in liver-specific KOs for carnitine palmitoyltransferase 2 and pyruvate carboxylase. We found this upregulation to be exacerbated by fasting and high-fat or ketogenic diets. Unique among these models was a concomitant increase in activating transcription factor 3 (Atf3). Liver-specific overexpression of Atf3 resulted in increased ApoA4 expression in a sex-dependent manner. To understand the requirement of Atf3 to metabolic stress, we generated liver-specific Atf3, Cpt2 double KO mice. These experiments demonstrated the requirement for Atf3 in the induction of ApoA4 mRNA, ApoA4 protein, and serum triglycerides that were also sex-dependent. These experiments reveal the roles of hepatic Atf3 and ApoA4 in response to metabolic stress in vivo. Show less

Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs. Show less

During mammalian spermatogenesis, the cytoskeleton system plays a significant role in morphological changes. Male infertility such as non-obstructive azoospermia (NOA) might be explained by studies of the cytoskeletal system during spermatogenesis. The cytoskeleton, scaffold, and actin-binding genes were analyzed by microarray and bioinformatics (771 spermatogenic cellsgenes and 774 Sertoli cell genes). To validate these findings, we cross-referenced our results with data from a single-cell genomics database. In the microarray analyses of three human cases with different NOA spermatogenic cells, the expression of TBL3, MAGEA8, KRTAP3-2, KRT35, VCAN, MYO19, FBLN2, SH3RF1, ACTR3B, STRC, THBS4, and CTNND2 were upregulated, while expression of NTN1, ITGA1, GJB1, CAPZA1, SEPTIN8, and GOLGA6L6 were downregulated. There was an increase in KIRREL3, TTLL9, GJA1, ASB1, and RGPD5 expression in the Sertoli cells of three human cases with NOA, whereas expression of DES, EPB41L2, KCTD13, KLHL8, TRIOBP, ECM2, DVL3, ARMC10, KIF23, SNX4, KLHL12, PACSIN2, ANLN, WDR90, STMN1, CYTSA, and LTBP3 were downregulated. A combined analysis of Gene Ontology (GO) and STRING, were used to predict proteins' molecular interactions and then to recognize master pathways. Functional enrichment analysis showed that the biological process (BP) mitotic cytokinesis, cytoskeleton-dependent cytokinesis, and positive regulation of cell-substrate adhesion were significantly associated with differentially expressed genes (DEGs) in spermatogenic cells. Moleculare function (MF) of DEGs that were up/down regulated, it was found that tubulin bindings, gap junction channels, and tripeptide transmembrane transport were more significant in our analysis. An analysis of GO enrichment findings of Sertoli cells showed BP and MF to be common DEGs. Cell-cell junction assembly, cell-matrix adhesion, and regulation of SNARE complex assembly were significantly correlated with common DEGs for BP. In the study of MF, U3 snoRNA binding, and cadherin binding were significantly associated with common DEGs. Our analysis, leveraging single-cell data, substantiated our findings, demonstrating significant alterations in gene expression patterns. Show less

The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The mitochondrial intermembrane bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the mitochondrial contact site and cristae organization system (MICOS). However, the interaction between Myo19, Miro1 and Miro2 (hereafter Miro1/2), and the MIB-MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB-MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for the connection between MIB-MICOS and the Myo19 and Miro1/2 proteins. Deleting Miro1/2 mimics the effects of Myo19 deficiency on ER-mitochondria contacts and cristae structure, whereas Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites. Show less

Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca Show less

The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic Data regarding circulating lipid traits and hepatic Hepatic This study identifies Show less

Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation. Show less

Pediatric hypertrophic cardiomyopathy (HCM) is a rare condition, particularly in neonates, and is characterized by rapid and extensive myocardial hypertrophy, often leading to severe clinical outcomes. HCM can arise from variants in sarcomeric genes, which are essential for myocardial contractions, as well as non-sarcomeric gene variants. Although genetic modifiers and oligogenic inheritance have been implicated in congenital heart disease and cardiomyopathy, their complexity in HCM has not been fully elucidated, especially in familial cases with variable phenotypes. Hence, this study aims to investigate the genetic architecture in a family with a history of cardiac disease and neonatal HCM, focusing on oligogenic inheritance of non-sarcomeric variants. Clinical data and blood samples were collected for genetic analysis. Whole genome sequencing (WGS) and bioinformatic analyses identified compound heterozygous variants in the MYO19 gene. Maternally inherited variants were analyzed because the proband's mother was also diagnosed with HCM. WGS was performed on the patient's maternal grandfather and aunt, who have cardiac disease, revealing candidate genetic variants that may contribute to the cardiac phenotype. Compound heterozygous MYO19 variants were identified in the neonatal patient. Missense c.203C > G (p.A68G) and frameshift c.275₂₇₆del (p.E92Vfs*19) variants were identified, which were located in the myosin motor domain, a functionally crucial region of the MYO19 protein. Maternally inherited missense variants were identified in SURF1 and ETFDH. All three genes are associated with mitochondrial function, and in silico prediction tools suggest that these variants are likely damaging. Other candidate genetic variants possibly contributing to the cardiac phenotype were also detected in the extended maternal family. To the best of our knowledge, this study represents the first report proposing MYO19 as a candidate gene for HCM and highlights the potential role of oligogenic inheritance in the etiology of the disease. Furthermore, plausible candidate variants of other mitochondria-related genes, such as MYO19, SURF1, and ETFDH, were identified, and other family members were investigated to support the pathogenesis of HCM further. Given the limited understanding of the genetics of pediatric HCM, these findings contribute valuable insights into its genetic basis in pediatric patients. Show less

Based on the special role of mitochondria in tumour energy metabolism. We hope to explore the pathogenesis and potential therapeutic targets of Hepatocellular carcinoma by analysing the expression of 1136 mitochondrial proteins in hepatocellular carcinoma and their mechanisms in the Human.MitoCarta3.0 database. The expression of 1136 mitochondrial proteins in HCC was analysed by the TCGA database. We selected the top eight mitochondrial proteins among the highly expressed mitochondrial proteins that had not been studied in HCC and were statistically (P < 0.05) significant, according to fold change. Protein expression was verified by real-time quantitative reverse transcription polymerase chain reaction in tumours and adjacent paracancerous tissues of 34 pairs of HCC patients. Further in HCC cells, the expression of FDPS, DNA2 and MYO19 was verified. Clinical correlations of FDPS, DNA2 and MYO19 were analysed by UALCAN and KM-plot databases. Immune correlation of FDPS, DNA2 and MYO19 was analysed by TIMER2.0 and Sangerbox3.0 online databases. Mitochondrial proteins were expressed on all 24 chromosomes. More than 2/3 of the mitochondria were 100-600 bp long, of which 204 were secondary transmembrane proteins. 1136 mitochondrial proteins, of which 202 are not included in the TCGA database. Of the 934 mitochondrial proteins included in the TCGA database, 706 were highly expressed and 228 were poorly expressed in HCC. Further validated by HCC tissues and cells, the study found that significantly high expression of FDPS, DNA2 and MYO19 was negatively correlated with the prognosis of HCC patients. The results of the immune correlation analysis showed that DNA2 and MYO19 may be involved in regulating the infiltration of immune cells. 934 out of 1136 mitochondrial proteins in the Human.MitoCarta3.0 database were differentially expressed in HCC, suggesting that mitochondrial proteins play an important biological role in the development of HCC. Further experimental validation and bioinformatics analyses showed that functional mitochondrial proteins are potential pathophysiological mechanisms for malignant progression of HCC. Mitochondrial proteins, in the future, have the potential to be valuable therapeutic targets for HCC. Show less

Mitochondrial dynamics are important for cellular health and include morphology, fusion, fission, vesicle formation, transport and contact formation with other organelles. Myosin XIX (Myo19) is an actin-based motor, which competes with TRAK1/2 adaptors of microtubule-based motors for binding to the outer mitochondrial membrane receptors Mitochondrial Rho GTPases 1/2 (Miro). Currently, it is poorly understood how Myo19 contributes to mitochondrial dynamics. Here, we report on a Myo19-deficient mouse model and the ultrastructure of the mitochondria from cells of Myo19-deficient mice and HEK cells, Miro-deficient HEK cells and TRAK1-deficient HAP1 cells. Myo19-deficient mitochondria in MEFs and HEK cells have morphological alterations in the inner mitochondrial membrane with reduced numbers of malformed cristae. In addition, mitochondria in Myo19-deficient cells showed fewer ER-mitochondria contact sites (ERMCSs). In accordance with the ultrastructural observations, Myo19-deficient MEFs had lower oxygen consumption rates and a reduced abundance of OXPHOS supercomplexes. The simultaneous loss of Miro1 and Miro 2 led to a comparable mitochondria phenotype and reduced ERMCSs as observed upon the loss of Myo19. However, the loss of TRAK1 caused only a reduction in the number of cristae, but not ERMCSs. These results demonstrate that both actin- and microtubule-based motors regulate cristae formation, but only Myo19 and its membrane receptor Miro regulate ERMCSs. Show less

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic-pituitary-adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day ( Show less

This study aims to develop a receptor-dependent 4D-QSAR model to overcome key limitations of traditional QSAR, including its dependency on molecular alignment and poor performance with small datasets, by integrating ligand - target interaction information. Angiogenesis-related receptors, including VEGFR2, FGFR1-4, EGFR, PDGFR, RET, and HGFR (MET) were chosen based on the biological relevance in cancer. Ligand datasets with known IC₅₀ values were extracted from PubChem. One hundred docked conformers per ligand were generated using AutoDock. Protein - ligand interaction fingerprints were computed and encoded as 4D-descriptors. After evaluation via multiple classification algorithms, Random Forest was selected for model construction. The results shown that the proposed model outperformed traditional 2D-QSAR approaches across all targets. Accuracy exceeded 70% in most datasets, including those with fewer than 30 compounds. Besides, the model performance was significantly improved via using all conformers versus using a single best pose. The model demonstrated robust predictive power across varying receptor classes under consistent assay conditions. The proposed receptor-dependent 4D-QSAR model provides enhanced accuracy and generalizability for small, diverse datasets. Its integration of LTI-derived descriptors makes it a valuable tool for early-stage lead optimization and supports rational multi-target drug design in oncology. Show less

Atherogenic lipoprotein exposure during young adulthood increases the risk of atherosclerotic cardiovascular disease (ASCVD) later in life. The relationships between cumulative and usual yearly apolipoprotein B (apoB), low-density lipoprotein particle (LDL-P), and triglyceride-rich lipoprotein particle (TRL-P) exposure in early adult life and incident ASCVD was quantified. Follow-up data of young adults aged 18 to <40 years from the longitudinal population-based Coronary Artery Risk Development in Young Adults (CARDIA) cohort were used. Cumulative early adult exposure of apoB, LDL-P, and TRL-P were defined over a 22-year exposure period (18 to <40 years). 'Usual' exposure to atherogenic lipid particles was calculated by dividing the cumulative exposure to apoB, LDL-P, and TRL-P by 22 years, and the hazard ratio was calculated between a 1 SD higher cumulative lipoprotein exposure with incident ASCVD after age 40 using adjusted Cox regression models. Among 4366 CARDIA participants, there were 241 ASCVD events after age 40 (mean follow-up of 19.3 years). A 1 SD higher cumulative exposure to apoB, LDL-P, and TRL-P was associated with unadjusted HRs of 1.53 [95% confidence interval (CI) 1.36-1.72], 1.54 (95% CI 1.36-1.75), and 1.48 (95% CI 1.30-1.68) for incident ASCVD after age 40, respectively. Adjustment for covariates yielded HRs for each measure of approximately 1.30. The hazard ratio for ASCVD increased after a usual apoB exposure of approximately 75 mg/dL/year from age 18 to <40. Cumulative exposure to atherogenic lipid particles in young adulthood increases the risk for incident ASCVD later in life. Apolipoprotein B concentration <75 mg/dL may represent a goal to maintain low risk in young adults. Show less

A fibre rich diet is linked to a healthier cardiometabolic profile and may promote fatty acid oxidation to lower acylcarnitine accumulation. This study aimed to determine whether total dietary fibre intake was related to cardiometabolic risk markers as well as acylcarnitine levels in apparently healthy adults, which concurrently may be related to blood pressure (BP). This study included 983 adults from the African-PREDICT study (aged 24 ± 3 years). Total fibre intake was determined using 24-hr dietary recalls, and 24-hr ambulatory BP was measured. Acylcarnitines were analysed in spot urine samples using liquid chromatography-tandem mass spectrometry-based metabolomics. Lower dietary fibre intake was related to a higher waist circumference (WC) and body mass index (BMI) as well as higher total cholesterol, low-density lipoprotein-cholesterol (LDL-C), triglycerides, Apo-lipoprotein-B, C-reactive protein (CRP), free carnitine, and short-chain acylcarnitine (C2-, C4- and C5-carnitine) levels (all p trend <0.05). Concurrently, all traditional cardiometabolic risk markers (WC, BMI, total cholesterol, LDL-C, triglycerides, Apo-B, and CRP) correlated positively with 24-hr BP. In multiple regression analyses, 24-hr SBP was associated with WC (β = 0.44; p < 0.001) and total energy intake (β = 0.096; p = 0.002), while 24-hr DBP was associated with WC (β = 0.283; p < 0.001), triglyceride levels (β = 0.085 p = 0.008), dietary fibre intake (β = -0.120; p < 0.001) and total energy intake (β = 0.128; p < 0.001). There was no relationship between acylcarnitine levels and 24-hr BP. We demonstrate that participants consuming a higher fibre diet had a more favourable metabolic profile than those consuming a low fibre diet, which was ultimately associated with lower BP. Show less

Lipoprotein lipase (LPL) is a key enzyme that hydrolyzes triglycerides (TGs) into free fatty acids. Several genetic variants of LPL are directly or indirectly associated with variations in lipid levels, causing different lipid metabolic disorders. Previous studies on the LPL gene have shown that exons and introns are essential for gene expression and regulation. However, mechanisms through which introns regulate gene expression and function remain unclear. In this study, we successfully designed a protocol to assess the function of LPL intron 3 in LPL regulation. This was accomplished by constructing luciferase reporter vectors, containing full and partial intron 3 fragments from a healthy human DNA sample. These recombinant constructs facilitated the analysis of transcriptional activity using dual-luciferase reporter assays in cell lines. The results showed that the luciferase activity of the chimeric firefly luciferase reporter construct containing the full-length LPL intron 3 was higher than that of other constructs. In this study, a successful protocol was developed to assess the function of LPL intron 3 in regulation of the LPL gene. This protocol provides a novel method for functional analysis of introns and intronic variants that can be applied to other genes. Show less

s: Cholesteryl ester transfer protein (CETP) inhibition has long been attracting a lot of attention if it could reduce the risk for coronary artery disease (CAD). A previous study has demonstrated that protein-truncating variants (PTVs) were associated with lower risk for CAD, which was dependent on lower LDL cholesterol in general population. We tested this hypothesis among Japanese heterozygous FH (HeFH) patients whose CAD risk was extremely high. We investigated the clinical data of 2344 patients diagnosed with HeFH (mean age = 50 years, males = 1,174, median LDL cholesterol = 244 mg/dL) who were examined for their genotype of CETP and phenotypes, including the presence of CAD from 1990 to 2024 at Kanazawa University Hospital. We investigated whether PTVs of the CETP were associated with plasma lipid levels and CAD among patients with HeFH. We identified 42 patients (1.8 %) with a PTV of CETP in HeFH patients. Compared with non-carriers, carriers of a PTV of CETP had higher HDL cholesterol (effect size, 17.6 mg/dL; 95 % confidence interval [CI], 11.4 to 23.8; P < 0.001), lower LDL cholesterol (-15.4 mg/dL; 95 % CI, -24.5 to -6.3; P < 0.001), and lower lipoprotein (a) [Lp(a)] (-7.8 mg/dL; 95 % CI, -12.5 to -2.5; P < 0.001). CETP PTV carrier status was associated with reduced risk for CAD (odds ratio, 0.64; 95 % CI, 0.38 to 0.90; P < 0.001). PTVs of CETP were significantly associated with higher HDL cholesterol, lower LDL cholesterol, lower Lp(a), and lower risk for CAD among patients with HeFH. Show less

Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB-containing lipoproteins stand out as abundant and bulky secretory particles with profound implications for human health and diseases. Recent insights into the specialized intracellular itinerary of lipoprotein metabolism and transport not only shed light on longstanding questions of lipid dynamics, but also highlight challenges faced by the COPII machinery in accommodating these complex, unconventional cargoes. Emerging evidence supports that tightly-regulated COPII condensation enables maximal capacity of cargo transport, providing a potential solution tailored for efficient lipoprotein delivery without affecting general protein secretion. This distinction suggests that targeting COPII condensation may provide new therapeutic strategies for lipid-associated diseases. Indeed, recent studies have identified manganese as a key modulator of this process, offering novel insights into its physiological relevance and potential translations. Show less

Lipoprotein (a) [Lp(a)] is an independent and causal risk factor for atherosclerotic cardiovascular disease. In this study we aimed at assessing the effect of currently available lipid-lowering therapies (LLTs) on Lp(a) plasma levels. A meta-analysis was performed according to the PRISMA guidelines. Databases were searched up to May 2025. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) comparing the effect of lipid-lowering drugs vs placebo (addition of the same drug to both intervention and control group was acceptable); (4) reporting the effects on Lp(a) levels; (5) intervention duration of more than 3 weeks. The between-group (treatment-placebo) Lp(a) absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 145,314 subjects from 147 RCTs were included. Statins, bempedoic acid, ezetimibe, omega-3 fatty acids, and fibrates did not affect Lp(a) concentration. Lp(a) levels were significantly reduced by PCSK9 monoclonal antibodies (PCSK9mAbs, -6.37 mg/dL [-7.26 to -5.47], a 29% reduction from baseline), inclisiran (-4.76 mg/dL [-5.83 to -3.69], a 22% reduction from baseline), CETP inhibitors (CETPi, -6.77 mg/dL [-8.67 to -4.88], a 46% reduction from baseline), and niacin (-7.06 mg/dL [-9.27 to -4.85], a 37% reduction from baseline). In the subgroup analysis by baseline Lp(a) levels, a larger absolute reduction of Lp(a) levels was observed with increasing baseline levels of Lp(a) for PCSK9mAbs, inclisiran, and CETPi. Among available LLTs, PCSK9mAbs, inclisiran, CETPi, and niacin significantly decreased Lp(a) levels. Further research is necessary to understand whether this effect would translate into a clinically relevant cardiovascular benefit. Show less

Patients with chronic kidney disease frequently exhibit abnormalities in their lipid metabolism. Confounding factors in observational studies often obscure the causal relationship between these 2 diseases. This study investigated the causal relationships between genetically predicted levels of 6 key lipid parameters (total cholesterol (TC), triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB)) and circulating kidney injury molecule 1 (KIM-1) levels, using a comprehensive bidirectional Mendelian randomization (MR) analysis. Using genome-wide association study data, the primary analysis used the inverse-variance weighted (IVW) method, supported by MR-Egger regression and a weighted median estimator. Sensitivity analyses including heterogeneity, pleiotropy tests, leave-one-out, and reverse causality analyses were conducted. The IVW model revealed the following: TG (odds ratio (OR): 1.1843, 95% confidence interval (CI): 1.1178-1.2547, P = 9.5894e-09), TC (OR: 1.1096, 95% CI: 1.0178-1.2095, P = .0182), and ApoA1 (OR: 1.1820, 95% CI: 1.0741-1.3007, P = .0007) were found to have significant causal relationships with KIM-1, a biomarker of kidney tubular injury, and may be risk factors for renal tubular injury; No significant causal associations were observed between high-density lipoprotein cholesterol (HDL-C), (P = .2929), LDL-C (P = .2178), ApoB (P = .1836), and KIM-1; Horizontal pleiotropy was detected for ApoA1 (P = .0208). However, sensitivity analyses confirmed the robustness of the results after the removal of outliers; significant heterogeneity was observed across all lipid parameters (Cochran Q P < .05), which necessitated the use of random-effects IVW models; and reverse causality analyses (MR-Egger intercept P > .05, Steiger filtering) confirmed no evidence of reverse causation between lipid profiles and KIM-1. TG, HDL-C, and ApoA1 levels may be risk factors for renal tubular injury. However, no significant causal relationships were observed between HDL-C, LDL-C, and ApoB levels and renal tubular injury. To further explore the underlying mechanisms of the associations between TG, HDL-C, ApoA1, and KIM-1 and to inform lipid management strategies in tubulopathy-related conditions. Show less

Mercury (Hg) is a widespread environmental pollutant with known neurotoxic and cardiometabolic effects, and its influence on lipid metabolism during childhood remains insufficiently understood. Mitochondrial dysfunction is proposed as a potential mechanism linking Hg exposure to metabolic disruption. Mitochondrial DNA copy number (mtDNA-CN) is regarded as an indicator of mitochondrial biogenesis and functional capacity, where lower levels generally suggest mitochondrial damage or dysfunction. In contrast, ribosomal DNA (rDNA) and relative telomere length (RTL) reflect genomic stability and cellular aging. This study investigated the associations between blood Hg levels and serum lipid profiles in children and adolescents and assessed the mediating roles of mtDNA-CN, rDNA, and RTL. A cross-sectional study was performed among 352 children and adolescents aged 6–17 years in eastern China. Blood Hg levels were determined using inductively coupled plasma mass spectrometry (ICP-MS), and serum lipid markers, namely total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were assessed along with the genomic indicators such as mtDNA-CN, rDNA, and RTL. Multivariable linear regression and mediation analyses were conducted. Higher Hg levels were significantly related with increased TC (β = 0.144, Hg exposure in children and adolescents is linked to an atherogenic lipid profile, potentially through mitochondrial dysfunction. MtDNA-CN appears to be a sensitive molecular mediator of Hg-induced lipid disturbances, which highlights the relevance of mitochondrial health in early-life environmental epidemiology and cardiovascular risk prevention. The findings support early prevention strategies and environmentally focused health policies that reduce toxicant exposure and thus promote long-term cardiometabolic health in young populations. Show less