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This study aimed to investigate serum inflammatory factor levels of polycystic ovary syndrome (PCOS) in female patients with bipolar disorder (BD) to explore the related inflammatory molecular mechanisms preliminarily. The study recruited 72 female drug-naïve patients with BD and 98 female healthy controls (HCs). Demographic information, menstrual cycles, sex hormone levels, and ovarian ultrasound data were collected from them. Additionally, their serum inflammatory factor levels and the proteomics of peripheral blood mononuclear cells were analyzed. The levels of interleukin (IL)-8 and IL-13 were significantly higher in patients with BD than in HCs (p < 0.05), and the IL-8 level was higher in BD patients with PCOS than in those without (adjusted p = 0.07). Bioinformatics analysis revealed that downregulated genes with significant differences between the two groups were all involved in immune-inflammatory-related pathways, and the expression of downregulated genes BTN3A2, MAP2K5, JCHAIN-B, and DMAP1 showed substantial differences and consistent trends between the two groups. IL-8-related chronic inflammatory response is closely associated with PCOS in BD patients, and genes such as BTN3A2 may mediate this chronic inflammatory response by negatively regulating the abnormal differentiation of T helper 17 cells, serving as one of the mechanisms underlying its pathogenesis. Show less

Diabetic retinopathy (DR) is the leading manifestation of diabetic microangiopathy. However, effective biomarkers and therapies are lacking. Circular RNAs (circRNAs) have been implicated in various diseases including DR. However, the role of circRNAs in DR remains elusive. In the present study, circNXN was upregulated in high glucose (HG)-treated human retinal microvascular endothelial cells (hRMECs). circNXN knockdown inhibited the proliferation, migration, and angiogenesis of hRMECs and promoted apoptosis. In addition, circNXN acted as a sponge for miR-338-3p to facilitate the FGFR1 (fibroblast growth factor receptor 1) expression. Furthermore, rescue assays revealed that the reduced promoting effect on hRMECs induced by the knockdown of circNXN could be reversed by a miR-338-3p inhibitor in HG-treated hRMECs. Additionally, in a DR rat model, circNXN downregulation ameliorated retinal vasculature changes. Our findings reveal a new therapeutic strategy for DR that may provide a new approach to clinical DR therapy. Show less

White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored. We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals. Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease. Show less

Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and theophylline derived compounds were designed and synthesized by applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane ( Show less

The phosphorylation of signal transducer and activator of transcription 3 (STAT3) monomer at S727 promotes its mitochondrial localisation and regulates mitochondrial function, thus exerting a protective effect on tumour cells. However, no inhibitor drugs targeting mitochondrial STAT3 (mitoSTAT3) or S727-STAT3 phosphorylation have been identified. Here, we report a novel diterpenoid extracted from Isodon sculponeatus, sculponeatin A (sptA), induces mitochondrial dysfunction in non-small cell lung cancer (NSCLC) by targeting mitoSTAT3 degradation. xCELLigence real-time cell analysis assay and high-content analysis were performed to measure cytotoxicity. Mitochondrial function was assessed by transmission electron microscopy, mitochondrial permeability transition pore opening and Seahorse cellular flux assays. The effects of sptA on the upstream signalling pathway of mitochondrial dysfunction were measured by Western blot, gene alterations and other approaches. Immunofluorescence and live cell imaging were performed to visualise the expression and position of mitoSTAT3. Nude mice and zebrafish were modelled with subcutaneous xenografts. Pharmacokinetics of sptA were examined in rats. Drug toxicity was evaluated in zebrafish. sptA inhibited mitochondrial respiration in NSCLC cells. sptA induced mitochondrial dysfunction by promoting the degradation of mitoSTAT3. sptA promoted WW domain containing E3 ubiquitin protein ligase 2 (WWP2)-mediated ubiquitination and degradation of mitoSTAT3 through direct binding. sptA inhibited tumour growth in vivo. Evaluation of drug toxicity in zebrafish showed that overdose of sptA may cause heart damage. These findings suggest that pharmacological targeting the degradation of mitoSTAT3 by sptA may provide therapeutic benefits against NSCLC. Show less

Transcription factor EB (TFEB) is a key transcription factor that orchestrates the cellular response to stress. Dysregulation of TFEB is associated with a range of human diseases, and understanding the regulatory mechanisms of TFEB is crucial for identifying potential drug targets. In this study, we used Show less

BackgroundThe α-Klotho is known to be involved in longevity and various age-related diseases, including cognitive impairment. BACE1, an important enzyme associated with the pathological process of Alzheimer's disease (AD), serves as a biomarker for predicting changes in cognitive function. Although both proteins are closely linked to age-related cognitive function, the mechanism of their interaction remains unclear.ObjectiveTo identify the enzymatic digestion relation between α-Klotho and BACE1 and the specific cleavage site.MethodsThirty elderly and forty-five young individuals were recruited. The cleavage product was identified by Coomassie blue staining, western blot, and MALDI-TOF mass spectrometry. The concentrations of plasma proteins were measured by ELISA.ResultsA new protein product was identified after the digestion reaction. BACE1 cleaved the α-Klotho peptide 951-981 at the F-T residues. When the F-T residues were replaced with K-K, BACE1 was unable to cleave the mutant peptide. The plasma levels of α-Klotho were significantly lower in elderly participants than in young participants (p < 0.0001). However, there was no significant difference in plasma BACE1 levels between elderly and young participants (p = 0.164). In elderly adults, there was a significant positive correlation between plasma BACE1 and α-Klotho protein levels (p = 0.009, r = 0.469), while this correlation was not observed in young adults (p = 0.170, r = -0.208).ConclusionsThe anti-aging protein α-Klotho is a substrate of BACE1 with a specific cleavage site at F-T. The BACE1/α-Klotho pathway may serve as a common axis for age-related cognitive decline. Show less

Sex differences in patients with hypertrophic cardiomyopathy have been elaborated by many studies. However, large studies of the association of patient sex with outcomes after surgical myectomy are scarce. This study evaluated sex disparities in a large Chinese cohort undergoing hypertrophic cardiomyopathy surgery. The cohort encompassed 1613 patients, including 627 (38.9%) women who underwent septal myectomy between 2009 and 2018. At the time of surgery, women were 6 years older and had 1 year longer disease onset-to-surgery delay than men. They were more frequently in New York Heart Association class III/IV and had more severe left ventricular outflow tract obstruction. Compared with men, women had a notably higher left ventricular wall thickness index and a lower extent of late gadolinium enhancement. Women also had more mutations in In patients with obstructive hypertrophic cardiomyopathy, women had a similar fatal outcome but a worse nonfatal outcome than men after surgery. Measures improving quality of life may further enhance the event-free survival of female patients. Close monitoring and follow-up are warranted, especially in younger men and older women. Show less

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry. We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry. For clinically diagnosed AD, we identified 14 new loci-five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing-based GWAS of diverse cohorts. We used whole-genome sequencing data from large and diverse cohorts. We found novel genome-wide association study findings based on whole-genome data. We performed a multiancestry meta-analysis and incorporated results from underrepresented groups. Show less

Childhood obesity (OB) is influenced by complex gene-environmental interaction. While genetics of adult OB have been extensively studied, polygenic childhood OB in non-European populations is still underexplored. Furthermore, in a developing nation such as India, how the environmental component strongly modulated by the socioeconomic status (SES) shapes the genetic susceptibility is crucial to understand. A two-staged genome-wide association study (GWAS; N = 5673) and an independent exome-wide association study (ExWAS; N = 4963) were performed using a generalized linear model assuming additive effect to identify the common and rare genetic variants respectively associated with childhood OB. Rare-variant burden testing was also performed. We used the gene expression profiles and regulatory data from public databases to explain the novel associations. The implications of SES as a potential modifier of genetic susceptibility were evaluated. GWAS identified novel associations in TCF7L2, IMMP2L, IPMK, CDC5L, SNTG1, and MX1, whereas ExWAS uncovered CNTN4, COQ4, TNFRSF10D, FLG-AS1, and BMP3. Both GWAS and ExWAS validated known associations in FTO and MC4R. Furthermore, rare-variant testing highlighted the role of 101 genes. We also observed that SES can modulate the inherent susceptibility to OB. Our study identified genetic variants associated with childhood OB and highlighted the gene-environmental interaction in childhood OB. Show less

The development of BACE-1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors is a crucial focus in exploring early treatments for Alzheimer's disease (AD). Recently, graph neural networks (GNNs) have demonstrated significant advantages in predicting molecular activity. However, their reliance on graph structures alone often neglects explicit sequence-level semantic information. To address this limitation, we proposed a Graph and multi-level Sequence Fusion Learning (GSFL) model for predicting the molecular activity of BACE-1 inhibitors. Firstly, molecular graph structures generated from SMILES strings were encoded using GNNs with an atomic-level characteristic attention mechanism. Next, substrings at functional group, ion level, and atomic level substrings were extracted from SMILES strings and encoded using a BiLSTM-Transformer framework equipped with a hierarchical attention mechanism. Finally, these features were fused to predict the activity of BACE-1 inhibitors. A dataset of 1548 compounds with BACE-1 activity measurements was curated from the ChEMBL database. In the classification experiment, the model achieved an accuracy of 0.941 on the training set and 0.877 on the test set. For the test set, it delivered a sensitivity of 0.852, a specificity of 0.894, a MCC of 0.744, an F1-score of 0.872, a PRC of 0.869, and an AUC of 0.915. Compared to traditional computer-aided drug design methods and other machine learning algorithms, the proposed model can effectively improve the accuracy of the molecular activity prediction of BACE-1 inhibitors and has a potential application value. Show less

Neurological disorders arising from structural and functional disruptions in the nervous system present major global health challenges. This review examines the intricacies of various cellular signaling pathways, including Nrf2/Keap1/HO-1, SIRT-1, JAK/STAT3/mTOR, and BACE-1/gamma-secretase/MAPT, which play pivotal roles in neuronal health and pathology. The Nrf2-Keap1 pathway, a key antioxidant response mechanism, mitigates oxidative stress, while SIRT-1 contributes to mitochondrial integrity and inflammation control. Dysregulation of these pathways has been identified in neurodegenerative and neuropsychiatric disorders, including Alzheimer's and Parkinson's diseases, characterized by inflammation, protein aggregation, and mitochondrial dysfunction. Additionally, the JAK/STAT3 signaling pathway emphasizes the connection between cytokine responses and neuroinflammation, further compounding disease progression. This review explores the crosstalk among these signaling networks, elucidating how their disruption leads to neuronal decline. It also addresses the dual roles of these pathways, presenting challenges in targeting them for therapeutic purposes. Despite the potential benefits of activating neuroprotective pathways, excessive stimulation may cause deleterious effects, including tumorigenesis. Future research should focus on designing multi-targeted therapies that enhance the effectiveness and safety of treatments, considering individual variabilities and the obstacles posed by the blood-brain barrier to drug delivery. Understanding these complex signaling interactions is crucial for developing innovative and effective neuroprotective strategies that could significantly improve the management of neurological disorders. Show less

Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies. Show less

The objective of this study was to evaluate the effects of the dietary lysine (Lys)/ methionine (Met) ratio in a low-protein diet on short-chain fatty acid (SCFA) profiles, villus morphology, antioxidant capacity, and immune status of the jejunum in Tibetan sheep. A total of 90 weaned Tibetan sheep, each 2 months old with an initial weight of 15.37 ± 0.92 kg, were randomly divided into three treatment groups. These groups were supplemented with different Lys/Met ratios of 3 [low protein-high methionine (LP-H)], 2 [low protein-medium methionine (LP-M)], and 1 [low protein-low methionine (LP-L)] in the basal diet (10% crude protein). The feeding trial lasted 100 days, including a 10-day acclimation period and a 90-day experimental period. The hematoxylin-eosin (H&E) sections showed that the LP-L group had a significantly increased villus height compared to the LP-M and LP-H groups ( Collectively, our results suggest that the dietary Met/ Lys ratio could affect the jejunal SCFA concentration by modulating the microbial community and regulating metabolism, thereby contributing to jejunal barrier function. Our findings provide a theoretical basis for the application of Lys/Met diet supplementation in the nutritional management of Tibetan sheep, particularly when reducing the dietary crude protein (CP) level. Show less

Sudden sensorineural hearing loss (SSNHL) has serious harm to human hearing health, where blood lipid and inflammatory levels may play a key role in it. Thus, the purpose of this investigation was to assess the connection between inflammatory and lipid variables and SSNHL. Patients diagnosed with SSNHL had an analysis of serum lipid parameters, such as total cholesterol (TC), triglycerides, HDL-C, LDL-C, apolipoprotein A (apo A), apolipoprotein B (apo B), and lipoprotein A (Lp(a)), as well as inflammatory factors like TNF-α and IL-10. After that, risk factor analysis was carried out utilizing univariate, multivariate regression, and LASSO retrospective modeling. In all, 72 SSNHL patients and 67 healthy control individuals were involved. The LDL/HDL, total cholesterol, ApoB, LP(a), IL-10, TNF-α, and IFN-γ considerably higher in the SSNHL group than in the healthy control group, however, nervonic acid and coenzyme Q were decreased significantly in SSNHL than Control group. The multivariate logistic regression model's analysis using multifactorial retrospective modeling revealed significant changes in LDL, LDL/HDL, IL-10, and TNF-α. In addition, in the LASSO regression model, the model demonstrated high discrimination, as evidenced by the C-index for the cohort's prediction nomogram, which was 0.998 (95% CI, 0.154-1.115) and confirmed to be 0.925 following bootstrapping validation. Finally, IL-10 and LDL/HDL were the main risk factors in SSNHL. LDL/HDL and IL-10 may be closely related to SSNHL's progress and should be evaluated promptly before treating patients with SSNHL. Show less

To investigate the direct and indirect relationships between statin use, low-density lipoprotein cholesterol (LDL-C) levels, and intracerebral hemorrhage (ICH), providing new insights into this complex scientific question. In this cohort study, UK Biobank data from 2006 to 2010 were used to construct Structural Equation Models of statin use, LDL-C, and ICH, including 414,253 participants with LDL-C data. Published Genome-Wide Association Studies data were used for drug-target Mendelian Randomization analysis. The study included 414,253 participants, comprising 225,454 women (54.4%) with a mean age of 56.07 (8.11) years. During a median follow-up of 14.01 years, 2973 patients experienced ICH. Structural Equation Modelling showed the indirect effect (path a∗b) of statin on ICH was 0.003 (P < 0.001), the direct effect (path c') was -0.001 (P = 0.568), the total effect (path c) was 0.002 (P = 0.391), and the mediation proportion of LDL-C (a∗b/c) was 150.0%. Mendelian Randomization showed a negative association between LDL-C levels and ICH (β: -0.663, SE: 0.229, P = 0.004), with no causal relationship between statin use and ICH (β: -1.454, SE: 3.133, P = 0.643). Drug-targeted Mendelian Randomization revealed LDL-C levels, predicted by variants in or near HMGCR, PCSK9, CETP, ABCG8/5, and LAP, were negatively associated with ICH risk. This study confirmed that statins increase the risk of ICH primarily through their LDL-C-lowering effects, rather than the direct effects of the statins themselves. LDL-C is negatively associated with ICH, an association not confined to the effects of the HMGCR loci. This advance provides evidence for the controversy between statin use, LDL-C levels, and ICH risk. Show less

The intramuscular fat (IMF) content, as an important meat quality trait, can directly affect the tenderness, juiciness, and flavor of pork. Reasonably increasing the IMF content can improve the palatability of pork. Therefore, identification of important factors for the lipid accumulation among muscles is the breakthrough point for improving meat quality. FGF21, identified as a novel metabolic regulator, has been found to regulate glucose and lipid metabolism in 3T3-L1 adipocytes, but its function in porcine adipocytes remains unclear. In this study, we discovered that the administration of recombinant FGF21 protein promotes adipogenic differentiation and increases triglyceride accumulation in porcine adipocytes. While the expression of FGFR1 in adipocytes under muscle conditions is inhibited, affecting the signal transduction of FGF21. This inhibitory effect is accompanied by activation of the AhR signaling pathway. When treated with the AhR antagonist CH223191, there was a partial restoration of FGFR1 expression levels. This indicates that muscle cells suppress the expression of FGFR1 in adipocytes by activating the AhR signaling pathway, thereby affecting the signal transduction of FGF21. Our results reveal the regulatory role of FGF21 in pig adipocyte differentiation and the regulatory mechanism of muscle environment on FGFR1 expression, providing new theoretical basis for IMF content improvement from the perspective of FGF21-FGFR1 signaling transduction. Show less

Addition of the PCSK9 inhibitor, evolocumab, to statin therapy promoted coronary plaque stabilization after an acute coronary syndrome. While apolipoprotein B (ApoB) has been proposed as a goal for lipid-lowering therapy in the prevention of cardiovascular disease, its association with plaque stability has not been studied. The High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS) used serial optical coherence tomography to assess coronary plaque phenotypes in patients with non-ST elevation myocardial infarction treated with evolocumab plus statin or placebo plus statin for 52 weeks. Changes in plaque composition were studied in patients according to achievement of a goal ApoB level <65 mg/dL. Of 112 patients, 67 (59.8 %) achieved the ApoB goal and had lower ApoB values at follow-up compared with those not at goal (37.1 ± 15.0 vs 92.7 ± 19.4 mg/dL, P < 0.001). Patients achieving the ApoB goal demonstrated a greater increase in minimum fibrous cap thickness (+44.6 ± 36.0 vs +24.9 ± 38.1 μm, P = 0.007) and a more pronounced decrease in lipid arc (-57.8 ± 52.8 vs -27.0 ± 59.2°, P = 0.005) at follow-up, compared with those who did not achieve the ApoB goal. At follow-up, thin-cap fibroatheroma (TCFA) was less prevalent among patients achieving the ApoB goal compared with those not at goal (9.0 vs. 40.0 %, P < 0.001). Multivariate analysis demonstrated that achieving an ApoB <65 mg/dL at follow-up independently associated with the absence of TCFA at follow-up (P = 0.004). Lower achieved ApoB levels associated with evidence of greater plaque stabilization even after controlling for low-density lipoprotein cholesterol levels. This highlights the importance of optimizing ApoB levels for the reduction of cardiovascular risk. NCT03570697. Show less

Lung cancer is one of the most common cancer and the leading cause of cancer-related death worldwide. Early detection of lung cancer can help reduce the death rate; therefore, the identification of potential biomarkers is crucial. Thus, this study aimed to identify potential biomarkers for lung cancer by integrating bioinformatics analysis and machine learning (ML)-based approaches. Data were normalized using the robust multiarray average method and batch effect were corrected using the ComBat method. Differentially expressed genes were identified by the LIMMA approach and carcinoma-associated genes were selected using Enrichr, based on the DisGeNET database. Protein-protein interaction (PPI) network analysis was performed using STRING, and the PPI network was visualized using Cytoscape. The core hub genes were identified by overlapping genes obtained from degree, betweenness, closeness, and MNC. Moreover, the MCODE plugin for Cytoscape was used to perform module analysis, and optimal modules were selected based on MCODE scores along with their associated genes. Subsequently, Boruta-based ML approach was utilized to identify the important genes. Consequently, the core genes were identified by the overlapping genes obtained from PPI networks, module analysis, and ML-based approach. The prognostic and discriminative power analysis of the core genes was assessed through survival and ROC analysis. We extracted five datasets from USA cohort and three datasets from Taiwan cohort and performed same experimental protocols to determine potential biomarkers. Four genes (LPL, CLDN18, EDNRB, MME) were identified from USA cohort, while three genes (DNRB, MME, ROBO4) were from Taiwan cohort. Finally, two biomarkers (EDNRB and MME) were identified by intersecting genes, obtained from USA and Taiwan cohorts. The proposed biomarkers can significantly improve patient outcomes by enabling earlier detection, precise diagnosis, and tailored treatment, ultimately contributing to better survival rates and quality of life for patients. Show less

To investigate the effects and underlying mechanism of ionizing radiation on the adipogenic of mesenchymal stem cells (MSCs). Mouse MSCs were cultured in vitro and treated with 2 Gy and 6 Gy radiation with Bulk RNA-seq suggested that ionizing radiation promotes adipogenic differentiation of MSCs and up-regulation of oxidative stress-related genes and pathways. The results of Oil Red O staining and qPCR showed that ionizing radiation promoted the adipogenesis of MSCs, with high expression of Ionizing radiation promotes adipogenesis of MSCs in mice, and oxidative stress pathway participates in this effect, blocking Show less

To establish an The 6-8-week-old C57BL/6N female mice and BALB/c female mice were used as the donor and recipient mice of the aGVHD model, respectively. Bone marrow transplantation (BMT) mouse model ( An The adipogenic differentiation capacity of MSCs is inhibited by aGVHD mouse serum. Show less

The characterization of physiological immune signatures in a population-based cohort is a prerequisite for identifying pathological immune signatures associated with inflammatory or autoimmune diseases. Here, 47 plasma cytokines, chemokines, and growth factors were quantified with a bead-based multiplex-assay (Merck HCYTA-60 K) using a FLEXMAP 3D™ instrument in 1175 individuals of the Study of Health in Pomerania (SHIP; TREND cohort, 532 men and 643 women, age: 20 to 81, BMI: 17.7 to 53.6). Associations of cytokine concentrations with age, sex, BMI, season, and blood cell parameters (BCP) were examined by multivariate regression models. The physiological cytokine concentrations differed strongly between analytes, with median concentrations ranging from 0.6 to 7820 pg/mL. Many cytokine levels showed a large dynamic range within the study population. Higher levels of the pro-inflammatory cytokines and chemokines IL-6, IL-8, CXCL9, CXCL10, IL-12p40, CCL2, CCL4, CCL11, IL-27, FLT3LG, and TNFα were significantly associated with increasing age. The strongest age-associated effects were seen for CXCL9 (β The generated cytokine atlas provides detailed information on cytokine variations in the general population and will provide a reference base for disease-related studies in the future. Furthermore, BCPs should be considered as potential confounders in association studies based on plasma cytokine levels. Show less

This study aimed to evaluate the effects of butyrate, butyric glycerides (BG) and their combination with sodium selenite (SeNa) or hydroxy-selenomethionine (OH-SeMet) on the performance and egg quality of the laying hens in post-peak period as well as the potential mechanism. A total of 900 45-week-old Hy-Line brown laying hens were randomly allocated to 5 treatment groups (n = 10 replicates/diet, 18 hens/replicate). The hens were fed the basal diet supplemented with 0.3 mg/kg selenium from SeNa (Control), Control plus 240 mg/kg butyric acid from coated butyrate (CB), Control plus 240 mg/kg butyric acid from butyric glycerides, basal diet supplemented with 0.3 mg/kg selenium from OH-SeMet plus coated butyrate (CB+OH-SeMet) or butyric glycerides (BG+OH-SeMet), respectively, for 20 weeks. Serum, liver, isthmus, uterus, and jejunum were collected at the end of the trial for biochemistry, histology, redox status, and gene expression analysis. Compared with Control, diets supplemented with BG, CB+OH-SeMet and BG+OH-SeMet increased (p < 0.05) the average egg weight (0.6-2.2 %), while only BG+OH-SeMet increased (p < 0.05) the total egg weight (7.1 %) and egg-laying rate (4.6 %) and decreased (p < 0.05) the feed/egg ratio (5.0 %) throughout the whole experiment. Furthermore, BG+OH-SeMet reduced (p < 0.05) the content of IL-6 and alanine aminotransferase (15.4-32.5 %), while elevated (p < 0.05) the content of IgA, IgY, IgM and total protein (18.7-26.8 %) in the serum in comparison to the Control. Notably, dietary supplementation of BG+OH-SeMet performed more effective antioxidant capacity in decreasing (p < 0.05) malondialdehyde (16.4-27.9 %) content and increasing (p < 0.05) the activity of total antioxidant capacity and glutathione peroxidase (17.6-36.3 %) in various tissues. Further experiment revealed that dietary BG+OH-SeMet regulated the lipid metabolism by increasing (p < 0.05) the expression of Carnitine palmitoyltransferase 1A (CPT1A) and Lipoprotein lipase (LPL) in liver. In conclusion, diets supplemented with BG and OH-SeMet could improve the laying performance via the enhancement of antioxidant capacity and regulation of lipid metabolism. Show less

A case of a 29-year-old female patient with a history of a single episode of hypertriglyceridemia-induced pancreatitis 4 years prior is reported. She had been treated with fibrates until 2 months before conception and required hospitalization at 33 weeks of gestation due to severe hypertriglyceridemia (6690 mg/dL) and gestational diabetes. Upon hospital admission, there was no evidence of pancreatitis. A comprehensive treatment approach was initiated, combining a low-fat diet, fibrates, omega-3 fatty acids (2 g/d), and continuous insulin infusion. This regimen resulted in a significant reduction of triglyceride levels to 960 mg/dL. The pregnancy progressed to full term without any maternal-fetal complications. Genetic analysis revealed 2 compound heterozygous mutations in the APOA5 gene, which encodes apolipoprotein AV. Notably, these specific mutations have not been previously reported as causative factors for familial chylomicronemia syndrome (FCS). The diagnosis of FCS was confirmed by the patient's markedly reduced lipoprotein lipase activity of 3.2%. Show less

This study employs animal-free Next Generation Risk Assessment (NGRA) principles to evaluate the safety of repeated dermal exposure to 2.5% (w/w) HC Yellow No. 13 (HCY13) hair dye. As multiple in silico tools consistently flagged hepatotoxic potential, likely due to HCY13's trifluoromethyl group, which is known to interfere with hepatic lipid metabolism, liver steatosis was chosen as the primary mode of action for evaluation. AOP-guided in vitro tests were conducted, exposing human stem cell-derived hepatic cells to varying HCY13 concentrations over 72 h. The expression of 11 lipid metabolism-related marker genes (AHR, PPARA, LXRA, APOB, ACOX1, CPT1A, FASN, SCD1, DGAT2, CD36, and PPARG) and triglyceride accumulation, a phenotypic hallmark of steatosis, were measured. PROAST software was used to calculate in vitro Points of Departure (PoD Show less

In recent years, the number of people suffering from lifestyle diseases such as hyperlipidemia and fatty liver disease has increased rapidly due to westernization of dietary patterns. Among fatty liver diseases, those that are not caused by alcohol are referred to as nonalcoholic fatty liver disease (NAFLD). Some NAFLD can progress to nonalcoholic steatohepatitis (NASH), and further progression of NAFLD can lead to cirrhosis and liver cancer. Although numerous studies have demonstrated the efficacy of dietary polyunsaturated fatty acids (PUFAs), particularly omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), against NAFLD, the detailed mechanisms by which these PUFAs exert their protective effects on the pathogenesis and progression of NAFLD are not well understood. Recent studies using knockout mouse models and genome-wide association studies have suggested a potential role for the enzymes responsible for the biosynthesis of PUFAs (FADS1, FADS2, ELOVL2, and ELOVL5) and their incorporation into phospholipids (LPCAT3/MBOAT5/LPLAT12 and LPIAT1/MBOAT7/LPLAT11) in the development of NAFLD. In this review, we summarize recent findings on the association of NAFLD and PUFAs with a focus on PUFA biosynthetic and metabolic enzymes to discuss the potential role of PUFAs in the prevention of NAFLD. Show less

Familial hypercholesterolemia (FH) is characterized by high serum low-density lipoprotein cholesterol (LDL-C) levels from birth, tendon/skin xanthomas, and premature coronary artery disease. The prevalence of FH is 1 per 300 individuals in the general population. FH is caused by a pathogenic (rare) variant in the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In Japan, there has been only one reported case of a family with FH caused by the known APOB p.(Arg3527Gln) variant. Those without pathogenic variants in the LDLR or PCSK9 genes account for approximately 36% of patients with FH. Novel causative genes/variants of FH have been explored in patients with FH worldwide, but no gene variants with a large effect size have been found. Polygenic hypercholesterolemia accounts for approximately 10% of patients with clinical FH. We performed whole-exome sequencing in 122 families without pathogenic variants in the LDLR and PCSK9 genes. However, we could not find novel causative genes/variants of FH via family analysis. We examined all the APOB variants and showed that the low-frequency APOB p.(Pro955Ser) variant has a moderate effect size in FH patients via functional analysis of hepatocytes. We also reported that low-frequency PCSK9 variants contribute to the severity of the FH phenotype in patients with FH harboring an LDLR pathogenic variant. Thus, the combination of low-frequency variants and age, environmental factors such as diet, or other genetic factors contribute to the severity of or variability in the FH phenotype. Show less