Maternal circulating lipid concentrations impact the risk of pregnancy complications and infant health outcomes. The associations between physical activity and circulating lipids during pregnancy rema Show more
Maternal circulating lipid concentrations impact the risk of pregnancy complications and infant health outcomes. The associations between physical activity and circulating lipids during pregnancy remain inadequately understood. A study was conducted from July 2024 to March 2025, involving the recruitment of 520 pregnant women in Wuhan, China. The Pregnancy Physical Activity Questionnaire (PPAQ) scores were evaluated in trimesters. Circulating lipid profiles, including total triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (APOA1) and apolipoprotein B (APOB) concentrations, were assessed at each trimester. The daily energy expenditure of physical activity (EEPA) during the first, second, and third trimesters was recorded as 11.35, 9.07, and 9.48 metabolic equivalents-hour/day (METs-h/d). The EEPA in the first trimester was significantly greater than that in the second ( This study suggests that increased physical activity during pregnancy is associated with lower lipid levels. Moreover, maternal age appears to have a significant impact on physical activity and the metabolism of circulating lipids during pregnancy. Show less
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were appr Show more
Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; howev Show more
Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; however, its specific regulatory mechanisms in PD remain unclear. This study utilized single-cell and bulk RNA sequencing data to identify core genes and investigate their potential roles. We utilized single-cell RNA sequencing data and applied 4 algorithms - area under the curve cell level enrichment, U-statistics-based single-cell signature scoring, single-sample gene set scoring, and AddModuleScore - to assess mitophagy activity and identify candidate genes. Subsequently, based on bulk RNA-seq data, 5 machine learning algorithms, including Least Absolute Shrinkage and Selection Operator Regression, random forest, Boruta, gradient boosting machine, and eXtreme Gradient Boosting, were employed to further screen core genes from the candidate gene set. Finally, immune infiltration analysis, cell communication analysis, and gene interaction network construction were integrated to systematically elucidate the regulatory mechanisms of core genes in the progression of PD. Single-cell RNA sequencing combined with multiple algorithms revealed significantly elevated mitophagy activity in PD tissues, particularly in monocytes/macrophages and endothelial cells. Additionally, we identified 4 core genes: BNIP3L, VPS13C, CTTN, and MAP1LC3B. BNIP3L and CTTN were downregulated in periodontitis, correlating negatively with disease prevalence, immune infiltration, and inflammatory pathways, whereas VPS13C and MAP1LC3B were upregulated, showing positive correlations. CellChat analysis highlighted monocytes/macrophages and endothelial cells with high core gene expression as key mediators of intercellular communication. This study identified BNIP3L, VPS13C, CTTN, and MAP1LC3B as core mitophagy-related genes associated with PD, and highlighted the pivotal roles of monocytes/macrophages and endothelial cells in disease progression. These findings provide new insights into the pathogenesis of PD and offer a theoretical foundation for mitophagy-targeted diagnosis, biomarker identification, and precision therapy. Show less
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted Show more
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less
Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells ( Show more
Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC). POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC. Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling. Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC. Show less
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immun Show more
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensiv Show more
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in inn Show more
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mech Show more
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis. Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 ( A six-gene prognostic model was established, comprising downregulated genes ( Show less
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as Show more
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance. We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors. A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size ≤2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size ≤10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with ≥4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window. Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size ≤2 cm, solid component ≤10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity. Show less
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain uncl Show more
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain unclear. This study integrated bioinformatics and experimental validation to identify key genes in OA synovium and their association with immune infiltration. Analysis of the GSE82107 dataset (10 OA, 7 controls) revealed 909 differentially expressed genes (525 upregulated, 384 downregulated). WGCNA identified the "midnightblue" module, and its intersection with DEGs yielded 122 genes enriched in cytokine-cytokine receptor interaction, JAK-STAT signaling, and autophagy pathways. Protein-protein interaction analysis highlighted FLT3LG, MC4R, CXCL10, CARTPT, and LHX2 as core genes (AUC 0.743-0.871). Immune infiltration analysis showed elevated M0 macrophages in OA, with CXCL10 showing a strong positive correlation with M1 macrophage infiltration (r = 0.74), and MC4R correlating with the presence of follicular helper T cells (r = 0.85). In vitro, OA-derived fibroblast-like synoviocytes exhibited CXCL10 upregulation, MC4R downregulation, and increased IL-6, IL-8, and TNF-α secretion, which were markedly reduced by CXCL10 knockdown or MC4R overexpression. Synovial tissue assays confirmed these expression patterns. CXCL10 and MC4R may represent promising diagnostic markers and therapeutic targets, offering new insights into OA immunopathogenesis and precision intervention. Show less
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced Show more
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less
Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and a Show more
Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-κB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-κB, and inflammasome (NLRP3/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-κB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART-treated macaque revealed macrophage-rich plaques with p21 Show less
Little is known about the association between physical activity and the risk of pre-sarcopenic obesity (pre-SO) among adolescents. Hence, this study aimed to examine the association between physical a Show more
Little is known about the association between physical activity and the risk of pre-sarcopenic obesity (pre-SO) among adolescents. Hence, this study aimed to examine the association between physical activity and pre-SO in a sample of 2143 adolescents aged 12 to 18 years from Yinchuan, China. The pre-SO was defined by three criteria: low skeletal muscle mass adjusted by weight (SMM/W) combined with body mass index (BMI), fat mass percentage (FMP), and waist circumference (WC). After adjusting for age, smoking, drinking, sleep time, and high-fat food consumption, participants with high physical activity (HPA) had a lower risk of pre-SO compared to those with low physical activity (LPA) according to the obesity criteria of FMP (OR 0.63, 95% CI, 0.48-0.83, P < 0.05), and WC (OR 0.71, 95% CI, 0.52-0.96, P < 0.05). Additionally, restricted cubic spline models showed a linear dose-response association between total physical activity (TPA) and pre-SO no matter what obesity criteria were adopted (all P overall trend < 0.05, all P non-linear > 0.50). Subgroup analyses revealed that individuals with higher TPA levels exhibited a decreased risk of pre-SO in boys according to the obesity criteria of FMP, and WC. In conclusion, HPA is associated with a reduced risk of pre-SO in adolescents, especially among boys. Show less
Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to Show more
Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to be established. This study investigated the relationship between Lp(a) concentrations and cardiovascular outcomes in Taiwanese individuals, stratified by pre-existing ASCVD status. We conducted a retrospective analysis of 51,934 subjects from the Chang Gung Research Database (January 2004 to June 2019), comprising 49,363 individuals without ASCVD and 2,571 with established ASCVD. The primary outcome was major adverse cardiovascular events (MACEs), encompassing acute myocardial infarction, ischemic stroke, revascularization procedures, peripheral arterial interventions, and cardiovascular mortality. Individuals were followed until their last visit to our institutions or December 31, 2019. During a mean follow-up of 6.6 years (standard deviation: 5.0 years), the study population demonstrated a median Lp(a) of 9.6 mg/dL (interquartile range: 4.6-18.5). In ASCVD-free individuals, Lp(a) concentrations ≥30 mg/dL were associated with increased MACE risk (adjusted subdistribution hazard ratio [aSHR]: 1.24; 95% confidence interval [CI]: 1.07-1.43). Similarly, in the ASCVD cohort, elevated Lp(a) predicted higher MACE occurrence (aSHR: 1.36; 95% CI: 1.07-1.74). Restricted cubic spline analysis confirmed a progressive risk elevation beyond the 30 mg/dL threshold in both groups. Lp(a) levels ≥30 mg/dL independently predicted adverse cardiovascular outcomes, regardless of baseline ASCVD status. This threshold appears suitable for cardiovascular risk stratification in both primary and secondary prevention settings. Show less
Elevated red blood cell distribution width (RDW) is associated with increased risk of rheumatoid arthritis (RA), but the potential interactions of RDW with genetic risk of incident RA remain unclear. Show more
Elevated red blood cell distribution width (RDW) is associated with increased risk of rheumatoid arthritis (RA), but the potential interactions of RDW with genetic risk of incident RA remain unclear. This study aimed to investigate the associations between RDW, genetics, and the risk of developing RA. We analysed data from 145,025 healthy participants at baseline in the UK Biobank. The endpoint was diagnosed rheumatoid arthritis (ICD-10 codes M05 and M06). Using previously reported results, we constructed a polygenic risk score for RA to evaluate the joint effects of RDW and RA-related genetic risk. Two-sample mendelian randomization and bayesian colocalization were used to infer the causal relation between them. A total of 675 patients with RA were enrolled and had a median followed up of 5.1 years, with an incidence rate of 0.57/1000 person-years. The hazard ratio of RA was 1.89 (95% CI: 1.45, 2.47) in highest RDW quartile group compared with the lowest RDW quartile group. Individuals within the top quintile of PRS showed a significantly high risk of RA. Moreover, Participants with high genetic risk and those in highest RDW group exhibited a significantly elevated hazard ratio (7.67, 95% CI: 3.98, 14.81), as opposed to participants with low genetic risk and those in lowest RDW group. Interactions between PRS and RDW on the multiplicative and additive scale were observed. Mendelian randomization provided suggestive evidence of a bi-directional causal relationship between RDW and RA. Loci near IL6R, IL1RN, FADS1/FADS2, UBE2L3 and HELZ2 showed colocalization. Increased RDW is associated with elevated risk of incident RA especially in the high genetic risk populations, but only suggestive evidence supports a causal relationship between them. Show less
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) ag Show more
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), accelerated ammonium metabolism of HLCs, which was derived from adipose derived mesenchymal stem cells (ADSCs). Human ADSCs were seed in flat bottom plate, then our differentiation protocol was used for 21 days. OCA treatment had been performed in Step3 for 10days. Then, 1) hepatic maturation, 2) urea cycle genes, 3) urea production, and 4) ammonium metabolism was compared depend on the presence or absence of OCA. HLCs had been successfully produced for 21 days. HLCs with OCA showed significantly higher mRNA expressions of AAT than those without OCA. HLCs with OCA showed significantly higher mRNA expressions of urea cycle genes such as SLC25A13, CPS1, and OTC. Urea production was also tended to be upregulated by OCA addition. HLCs with OCA showed significantly higher clearance of NH4Cl at 6hr and 24 hr after addition of NH4Cl. FXR agonist, OCA, accelerates ammonium metabolism of ADSCs derived HLCs. HLCs could be one of treatment options of hepatic encephalopathy of patients with liver failure or urea cycle disorder in the future. J. Med. Invest. 72 : 54-59, February, 2025. Show less
Lewy body dementia (LBD) is the second common dementia, with unclear mechanisms and limited treatment options. Dyslipidemia has been implicated in LBD, but the role of lipid-lowering drugs remains und Show more
Lewy body dementia (LBD) is the second common dementia, with unclear mechanisms and limited treatment options. Dyslipidemia has been implicated in LBD, but the role of lipid-lowering drugs remains underexplored. This study aims to investigate the association between lipid traits, drug targets, and LBD risk using Mendelian Randomization (MR) analysis. We performed univariable and multivariable MR analyses to evaluate the causal effects of lipid traits on the risk of LBD. Then, drug-target MR analysis and subtype analysis were conducted to evaluate the effects of lipid-lowering therapies on LBD. In univariable MR, genetically predicted low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) levels were associated with an increased risk of LBD. Mediation analysis suggested a potential interaction between LDL-C and RC in influencing LBD risk. Drug-target MR analysis identified significant associations between genetically proxied inhibition of ANGPTL3, CETP, and HMGCR and LBD risk. This MR analysis provided evidence that elevated LDL-C and RC may increase the risk of LBD. Additionally, targeting ANGPTL3, CETP, and HMGCR may represent potential therapeutic strategies for the prevention or treatment of LBD. Show less
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphon Show more
In school settings, nomophobia-a newly identified form of problematic mobile phone use characterized by anxiety and discomfort experienced when an individual is unable to use or access their smartphone-poses significant challenges to students' learning and daily life. Prior research on nomophobia has predominantly adopted a variable-centered perspective. However, if nomophobia is heterogeneous across subgroups, acknowledging this heterogeneity may inform the advancement of more tailored and productive therapeutic methods. Latent profile analysis (LPA) was conducted separately among high school students (N = 446) and college students (N = 667) to identify potential subgroup heterogeneity in nomophobia. To examine cross-group similarities in nomophobia profiles, a multi-group LPA was employed. Based on multiple model fit criteria, a three-profile solution-high nomophobia, moderate nomophobia, and low nomophobia-was identified for both groups. However, the multi-group LPA provided only partial support for the similarity of nomophobia profiles across educational stages, specifically in terms of configural and dispersion similarity. While similar nomophobia profiles emerged across groups, the partial equivalence suggests that intervention strategies for nomophobia may not be universally applicable across different educational levels. Additional studies should investigate the mechanisms underlying students' nomophobia profiles and to inform differentiated interventions for educators, institutions, and policymakers. Show less
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, over Show more
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation Show less
Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain l Show more
Perioperative neurocognitive disorder (PND) is a common complication following thoracic surgery and often leading to poor outcomes. Despite ongoing research, effective treatments for late PND remain limited. Identifying reliable biomarkers for early diagnosis is, therefore, essential. A prospective cohort study was conducted with 60 elderly patients undergoing thoracic surgery. Serum samples were collected within 10 minutes prior to anesthesia and following extubation to measure adiponectin (APN), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), aquaporin-4 (AQP4) and brain-derived neurotrophic factor (BDNF). Among PND patients, serum APN, PKA, AQP4, and BDNF levels were markedly decreased compared with the normal group. While serum cAMP (HR = 1.087, p = 0.695, 95% CI [0.284-4.166]) and PKA (HR = 0.996, p = 0.09, 95% CI [0.491-0.947]) were not significantly correlated with PND, serum APN (HR = 0.307, 95% CI [0.113-0.835], p = 0.021), AQP4 (HR = 0.204, 95% CI [0.060-0.697], p = 0.011), and BDNF (HR = 0.382, 95% CI [0.177-0.823], p = 0.014) were protective factors against PND. ROC analysis demonstrated that APN (AUC = 0.68, 95% CI [0.51-0.87]), AQP4 (AUC = 0.73, 95% CI [0.59-0.87]), BDNF (AUC = 0.73, 95% CI [0.59-0.87]), and the model of combining those biomarkers (AUC = 0.91, 95% CI [0.83-0.99]) could predict PND. PND patients exhibited a lower protective stress response to surgical trauma. High serum APN, AQP4, and BDNF levels were independent protective factors for PND, and a combined model of these biomarkers showed predictive potential for PND. Show less
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insuffi Show more
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood. We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis. Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins ( Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN. Show less
This study aims to investigate the roles of the EXT1 and FGFR3 genes in the development of osteochondromas, focusing specifically on their potential interactions in chondrocyte proliferation, differen Show more
This study aims to investigate the roles of the EXT1 and FGFR3 genes in the development of osteochondromas, focusing specifically on their potential interactions in chondrocyte proliferation, differentiation, and tumor formation. In vitro, the ATDC5 chondroprogenitor cell line was used to examine the effects of inactivation of both EXT1 and FGFR3. In vivo, a mouse model with dual gene knockout of Ext1 and Fgfr3 was constructed to further explore these genes' roles in tumor formation by observing the incidence and distribution patterns of osteochondromas. The in vitro experiments demonstrated that ATDC5 cells with reduced expression of EXT1 and FGFR3 genes exhibited enhanced chondrogenic differentiation. In vivo, Fgfr3 The EXT1 and FGFR3 genes play crucial regulatory roles in the development of osteochondromas. Deficiencies in Ext1 and Fgfr3 can induce the formation of osteochondromas. Show less
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its anti Show more
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against Show less
This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glu Show more
This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). A prospective cohort of 150 diet-controlled GDM patients and 150 pregnant women with NGT, all delivering at our hospital, were selected based on predefined criteria. Data on demographics, physical parameters, and perinatal outcomes were compiled. Blood samples for fasting plasma glucose (FPG), homocysteine (Hcy), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and apolipoprotein A1 (apoA1) were collected before delivery. GDM patients exhibited higher levels of FPG, Hcy, and the apoB/apoA1 ratio, but lower HDL-C and apoA1 levels compared to the NGT group. Adverse outcomes such as macrosomia, premature rupture of membranes, and postpartum hemorrhage were more prevalent in the GDM group. In GDM patients, neonatal birth weight positively correlated with FPG and TG levels. Stratified Hcy analysis in GDM showed no significant differences in perinatal outcomes. However, the third quartile of the apoB/apoA1 ratio had a lower incidence of macrosomia compared to the first quartile, and the second quartile showed a higher incidence of birth asphyxia. GDM patients demonstrated increased levels of Hcy, FPG, and the apoB/apoA1 ratio, correlating with more adverse perinatal outcomes than healthy pregnant individuals. The relationships between Hcy, lipids, and these outcomes remain inconclusive, highlighting the need for further research. Show less
Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amy Show more
Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) plays a critical role in the production of Aβ, making it a key therapeutic target. In the current work, a CNS library of ChemDiv database containing 44085 compounds was screened against the BACE1 protein. Initially, a structure-based pharmacophore hypothesis was constructed, followed by virtual screening, with the screened hits docked to the BACE1 protein to determine the optimal binding modes. The docking results were examined using the glide gscore and chemical interactions of the docked molecules. The cutoff value of -5 kcal/mol was used to select hits with high binding affinities. A total of seven hits were chosen based on the glide g score. Furthermore, the possible binding mechanisms of the docked ligands were investigated, and it was discovered that all seven selected ligands occupied the same site in the predicted binding pocket of protein. The bioactivity scores of the compounds demonstrated that the chosen compounds possess the features of lead compounds. The toxicity risks and ADMET features of the selected hits were anticipated, and four compounds, J032-0080, SC13-0774, V030-0915, and V006-5608 were chosen for stability analysis. The selected hits were extremely stable and strongly bound to the BACE1 pocket, and conformational changes caused by RMSD, RMSF, and protein-ligand interactions were assessed using MD modeling. Similarly, principal component analysis revealed a large static number of hydrogen bonds. The MM/GBSA binding free energies maps revealed a significant energy contribution in the binding of selected hits to BACE1. The binding free energy landscapes indicated that the hits were bound with a high binding affinity. Thus, the hits could serve as lead compounds in biophysical investigations to limit the biological activity of the BACE1 protein. Show less
Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the Show more
Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the immune response. Current therapeutics are limited to palliative care, i.e., mechanical ventilators, thus highlighting the need to develop targeted therapeutic for ARDS. Interleukin-27 (IL-27) is a multifunctional cytokine with the capability for immune modulation. Our interest lies in exploring the properties of IL-27, particularly as an anti-inflammatory cytokine that functions as an antagonist of IL-6 signaling, as an inducer of anti-viral genes, as a promoter of tissue repair, and as a regulator of both the innate and adaptive immune responses, possessing promising potential as a therapeutic for ARDS. To overcome the challenge of repeated administration due to the short half-life of cytokines, we utilized a cell-based gene therapy approach. An IL-27-expressing plasmid was transfected into adipose mesenchymal stromal cells (ASC) that serve as the gene therapy carriers. For in vitro studies, we treated mono- and co-culture lung lipopolysaccharide (LPS)-induced lung epithelial and monocytes/macrophages cell line with IL-27-expressing ASC (IL-27 ASC) conditioned media (CM) to determine the effects on pro-inflammatory gene expression. For in vivo studies, male C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) and treated either PBS, ASC, or IL-27 ASC (5 × 10 IL-27 ASC CM reduced pro-inflammatory gene expression of lung epithelial and macrophages cultured in both mono- and co-culture systems. Additionally, IL-27 ASC were able to reduce pro-inflammatory markers, decrease cell infiltration into the lungs, promote genes and immune cells involved in tissue repair, and rebalance innate and adaptive immunity in an LPS-induced in vivo model. Collectively, our in vitro and in vivo results show promising potential for IL-27 cell-based gene therapy as a treatment for ARDS. Show less
Poor feather growth not only affects the appearance of the organism but also decreases the feed efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet t Show more
Poor feather growth not only affects the appearance of the organism but also decreases the feed efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet the exact mechanism involved remains insufficiently understood. A total of 180 1-day-old broilers were selected and randomly divided into 3 treatments: control group (0.45% Met), Met-deficiency group (0.25% Met), and Met-rescue group (0.45% Met in the pre-trial period and 0.25% Met in the post-trial period). The experimental period lasted for 56 d, with a pre-trial period of 1-28 d and a post-trial period of 29-56 d. In addition, Met-deficiency and Met-rescue models were constructed in feather follicle epidermal stem cell by controlling the supply of Met in the culture medium. Dietary Met-deficiency significantly (P < 0.05) reduced the ADG, ADFI and F/G, and inhibited feather follicle development. Met supplementation significantly (P < 0.05) improved growth performance and the feather growth in broilers. Met-rescue may promote feather growth in broilers by activating the Wnt/β-catenin signaling pathway (GSK-3β, CK1, Axin1, β-catenin, Active β-catenin, TCF4, and Cyclin D1). Compared with Met-deficiency group, Met-rescue significantly (P < 0.05) increased the activity of feather follicle epidermal stem cell and mitochondrial membrane potential, activated Wnt/β-catenin signaling pathway, and decreased the content of reactive oxygen species (P < 0.05). CO-IP confirmed that mitochondrial protein PGAM5 interacted with Axin1, the scaffold protein of the disruption complex of the Wnt/β-catenin signaling pathway, and directly mediated Met regulation of Wnt/β-catenin signaling pathway and feather follicle development. PGAM5 binding to Axin1 mediates the regulation of Wnt/β-catenin signaling pathway, and promotes feather follicle development and feather growth of broiler chickens through Met supplementation. These results provide theoretical support for the improvement of economic value and production efficiency of broiler chickens. Show less