This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each part Show more
This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each participant underwent PET/CT scanning using [ A total of 101 participants were included (mean age 63.267 ± 9.344 [range 39-86 years]). In benign lung lesions, [ [ Show less
Existing depression assessment tools inadequately detect rapid symptom changes after antidepressant treatments. This study aimed to translate, validate, and explore the clinical application of the Chi Show more
Existing depression assessment tools inadequately detect rapid symptom changes after antidepressant treatments. This study aimed to translate, validate, and explore the clinical application of the Chinese version of the McIntyre and Rosenblat Rapid Response Scale (CMRRRS) for use during the treatment of rapid-onset depression. The McIntyre and Rosenblat Rapid Response Scale was translated and culturally adapted for use in Chinese settings. Briefly, 71 patients with major depressive disorder who were receiving intravenous esketamine were assessed using the CMRRRS and other validated scales. Properties were examined, including internal consistency, construct validity, and responsiveness to change. For patient classification, Latent Profile Analysis (LPA) and Kernel Density Estimation (KDE) curves were used. The Minimum Clinically Important Difference was computed to explore the smallest change related to clinical improvement. The CMRRRS showed high reliability and robust validity. Factor analysis explained over 60% of the total variance. LPA distinguished three patient classes, while KDE curves determined that a cut-off of 5 points was optimal for detecting clinically meaningful changes. The CMRRRS is a reliable, valid, and sensitive tool for monitoring rapid symptom changes in patients with depression treated with esketamine. It allows real-time symptom monitoring and personalized treatment adjustments. Further studies are warranted to explore its broader applicability. Show less
Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse ca Show more
Observational studies have reported an association between visceral obesity and asthma. However, the causal direction of this relationship remains uncertain due to potential confounding and reverse causality. Furthermore, the underlying mediating factors and potential therapeutic targets underlying this association are poorly understood. This study aimed to investigate the causal effect of visceral adipose tissue (VAT) on asthma risk, identify potential mediators, and quantify their effects using a Mendelian randomization (MR) framework. In this study, we employed MR approach to elucidate the impact of VAT on asthma and to assess the potential mediators. Subsequently, the association between seven lipid-lowering medication targets and asthma risk was investigated using the drug target MR method. Lastly, we conducted an observational study involving 12,120 participants to evaluate the relationship between visceral adiposity index (VAI) and asthma. The univariable MR analysis demonstrated that each standard deviation increase in genetically predicted VAT was associated with a 46 % higher risk of asthma (IVW: OR = 1.460, 95 % CI: 1.351-1.578, p = 1.471E-21). This association remained significant after adjusting for BMI in multivariable MR (OR = 1.137, 95 % CI: 1.023-1.262, p = 0.017). Mediation analysis revealed that HDL-C accounted for 4.3 % of this effect (OR = 1.016, 95 % CI: 1.001-1.033, p = 0.038). Drug-target MR indicated that activation of HMGCR and LDLR reduced asthma risk (OR = 0.846 and 0.866, respectively; both p < 0.01), whereas LPL activation increased risk (OR = 1.080, p = 0.015). Observational analysis of NHANES data (n = 12,120) confirmed that higher VAI was associated with increased asthma prevalence (OR = 1.290, 95 % CI: 1.101-1.479, p = 0.010). Our results reveal a significant association between increased visceral adipose tissue and elevated risk of asthma, which is partially mediated by high-density lipoprotein cholesterol. 3-hydroxy-3-methylglutaryl coenzyme A reductase, low-density lipoprotein receptor, and lipoprotein lipase exhibit potential as therapeutic targets for asthma. Show less
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompl Show more
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less
As global population aging intensifies, mental health issues in older adults are increasingly prominent, with depression being particularly prevalent and detrimental. The study investigated how substi Show more
As global population aging intensifies, mental health issues in older adults are increasingly prominent, with depression being particularly prevalent and detrimental. The study investigated how substituting sedentary behavior (SB) and sleep (SLP) with physical activity (PA) affects depression risk in this population. Meta-analysis was conducted by searching four databases: PubMed, Scopus, SPORTdiscus, and PsycINFO (via EBSCOhost platform) for relevant studies published until January 2025. Regression coefficients (β) with 95% confidence intervals (CIs) for depressive symptoms were estimated. Publication bias was assessed using funnel plots and Egger's tests, and heterogeneity was evaluated using Q tests and the I Among 18,912 participants (53.45% female, ≥60 years) across nine studies, replacing SB with MVPA significantly reduced depression (β = -0.12, 95% CI: -0.20, -0.04), subgroup analyses indicated that reallocating 10, 30 and 60 min/day of SB to MVPA ( Substituting SB and SLP with MVPA is significantly associated with a reduction in depression, whereas no significant association is observed when replaced by LPA. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=546666, identifier CRD42024546666. Show less
One serious consequence of diabetes mellitus is diabetic retinopathy (DR), which impairs eyesight to the point of blindness. While glucocorticoid medications are commonly employed in the management of Show more
One serious consequence of diabetes mellitus is diabetic retinopathy (DR), which impairs eyesight to the point of blindness. While glucocorticoid medications are commonly employed in the management of DR, their therapeutic efficacy requires enhancement. Due to the tight association between glucocorticoid-related genes and the onset and development of DR, a comprehensive examination of its root cause of activity may be able to overcome the drawbacks of existing treatment approaches. R programming tools were used to examine the single-cell RNA sequencing (scRNA-seq) dataset GSE178121, which was obtained from the Gene Expression Omnibus (GEO) database. To evaluate glucocorticoid activity, a gene set related to glucocorticoid phenotypes was sourced from the Molecular Signatures Database (MSigDB), followed by the identification of key cellular populations within DR tissues. Subsequently, these key cells underwent pseudotime analysis, transcription factor (TF) evaluation, cell-cell communication assessment, differential gene screening, and the construction of a regulatory network. Our investigation demonstrated that vascular endothelial cells (VECs) in DR tissue exhibited markedly elevated glucocorticoid activity. KLF4 is among the TFs that are intimately linked to the onset of DR, and hydroxyurea could be a beneficial medication. Cell-cell communication analysis highlighted the PTN and ANGPTL signaling pathways as important signaling pathways in DR. In the meanwhile, we identified 25 Hub genes, including DUSP6, AP1S2, and PTPRB, which were verified to be differentially expressed in DR. In conclusion, our comprehensive study elucidated the complex interactions of glucocorticoids in the pathogenesis of DR, thereby revealing potential signaling pathways and therapeutic targets. Show less
Mitophagy plays a critical role in maintaining mitochondrial quality and cellular homeostasis. But the specific contribution of mitophagy-related E3 ubiquitin ligases to prognoses remains largely unex Show more
Mitophagy plays a critical role in maintaining mitochondrial quality and cellular homeostasis. But the specific contribution of mitophagy-related E3 ubiquitin ligases to prognoses remains largely unexplored. In this study, we identified a novel mitophagy-related E3 ubiquitin ligase prognostic signature using least absolute shrinkage and selector operator (LASSO) and multivariate Cox regression analyses in breast cancer. Based on median risk scores, patients were divided into high-risk and low-risk groups. Functional enrichment analyses were conducted to explore the biological differences between the two groups. Immune infiltration, drug sensitivity, and mitochondrial-related phenotypes were also analyzed to evaluate the clinical implications of the model. A four-gene signature (ARIH1, SIAH2, UBR5, and WWP2) was identified, and Kaplan-Meier analysis demonstrated that the high-risk group had significantly worse overall survival (OS). The high-risk patients exhibited disrupted mitochondrial metabolism and immune dysregulation with upregulated immune checkpoint molecules. Additionally, the high-risk group exhibited higher sensitivity to several drugs targeting the Akt/PI3K/mTORC1 signaling axis. Accompanying mitochondrial metabolic dysregulation, mtDNA stress was elevated, contributing to activation of the senescence-associated secretory phenotype (SASP) in the high-risk group. In conclusion, the identified signature provides a robust tool for risk stratification and offers insights into the interplay between mitophagy, immune modulation, and therapeutic responses for breast cancer. Show less
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of Show more
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn Show less
Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. Howe Show more
Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. However, their interplay in GC prognosis remains unexplored. We analyzed RNA-seq and clinical data from The Cancer Genome Atlas Program and Gene Expression Omnibus databases. Using univariate Cox, LASSO, and multivariate Cox regression, we identified candidate genes and constructed a prognostic signature. Immune contexture, genomic alterations and drug sensitivity were compared between high- and low-risk group. The metabolic and aging related risk score, comprising 4 genes (GNAI1, GSTA1, APOC3, and LOX), was developed. Validation across multiple cohorts confirmed its robust prognostic performance. The model also effectively stratified patients into distinct risk subgroups with differential immune profiles and responses to immunotherapy. Notably, high-risk patients showed reduced sensitivity to common chemotherapeutic agents but may benefit from targeting the PI3K/mTOR pathway. Metabolic and aging related risk score serves as a promising tool for individualized risk assessment and therapeutic guidance in GC, warranting further clinical validation. Show less
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less
Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics pro Show more
Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs themselves are elevated in the myocardium of patients with HF, potentially due to a defect in BCAA catabolic breakdown. The rate limiting step of BCAA catabolism is the decarboxylation by the enzyme branched chain ketoacid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically. Here, using two pre-clinical CKM models, the hyperphagic ZSF1 obese rat and the uninephrectomized SDT fatty rat with high salt drinking water, we applied unbiased proteomic, transcriptomic and metabolomic profiling to assess overall kidney gene expression and mitochondrial function. We show that BCAA catabolic impairment is associated with and may be causal to CKM and demonstrated impairment in BCAA catabolism within ZSF1 obese rat kidneys. In both CKM animal models, treatment with the BDK inhibitor BT2 improved urine protein content, kidney hypertrophy, and kidney pathology. Furthermore, coadministration of BT2 and the sodium-glucose cotransporter-2 inhibitor empagliflozin demonstrated additive effects to improve kidney parameters, kidney gene expression signatures, and kidney mitochondrial density and function. Our study suggests that in addition to its previously reported beneficial effects on metabolism and cardiac function, BDK inhibition may also improve kidney health and therefore could represent a new therapeutic avenue for CKM. Show less
Evidence is accumulating that links gut microbiota, a crucial component of the immune environment, to Sjogren's syndrome (SS). The mechanisms underlying the influence of gut microbiota on the onset an Show more
Evidence is accumulating that links gut microbiota, a crucial component of the immune environment, to Sjogren's syndrome (SS). The mechanisms underlying the influence of gut microbiota on the onset and development of SS are still not completely understood. To this end, we applied a Mendelian randomization (MR) framework to investigate whether inflammatory cytokines mediate the association of gut microbiota with SS. Our MR analysis leveraged publicly available GWAS data, including information on 211 gut microbiota taxa sourced from the MiBioGen consortium (18,340 participants), summary statistics for 91 inflammatory cytokines obtained from a study of 14,824 individuals, and genetic data for SS derived from the UK Biobank (407,746 participants). To investigate causal associations between gut microbiota and SS, we primarily employed the inverse variance weighted method, supported by additional techniques such as MR-Egger, simple mode, weighted median, and weighted mode for validation. The potential mediating effect of inflammatory cytokines in the gut microbiota-SS relationship was investigated using both mediation MR and multivariable MR (MVMR) analyses. MR analysis identified five microbiota taxa causally associated with SS. Particularly, class Gammaproteobacteria (OR = 3.468, 95% CI = 1.139-10.557, The findings suggest that certain gut microbiota is sociated with an increased risk of SS, mediated by specific inflammatory cytokines. Show less
Cardiovascular-Kidney-Metabolic (CKM) syndrome is characterized by the interrelatedness of chronic kidney disease, cardiovascular disease, and metabolic disorders. Although physical activity is widely Show more
Cardiovascular-Kidney-Metabolic (CKM) syndrome is characterized by the interrelatedness of chronic kidney disease, cardiovascular disease, and metabolic disorders. Although physical activity is widely acknowledged as an effective intervention for improving the prognosis of chronic diseases, its impact on all-cause mortality among patients with CKM syndrome remains unclear. To investigate the impact of physical activity on all-cause mortality among patients with CKM syndrome. Data from the 2011 wave of the China Health and Retirement Longitudinal Study were used as the baseline, with follow-up conducted until 2013. According to the International Physical Activity Questionnaire criteria, weekly physical activity levels were divided into three categories: light-volume physical activity (LPA), moderate-volume physical activity (MPA), and vigorous-volume physical activity (VPA). Cox proportional hazards regression models were employed to assess the impact of varying levels of physical activity on all-cause mortality. Restricted cubic spline analysis was used to explore possible nonlinear relationships. A total of 3343 patients with CKM syndrome were enrolled in this study. During the 2-year follow-up period, 44 deaths were recorded. After adjusting for potential confounders, VPA was associated with a 54% lower risk of all-cause mortality (adjusted hazard ratios, 0.46; 95% confidence interval: 0.24-0.89). Dose-response relationships demonstrated that all-cause mortality decreased as physical activity increased, with a 5.8% reduction in all-cause mortality risk for every 1000 MET-min/week increment in physical activity levels. VPA was significantly associated with reduced all-cause mortality in patients with CKM syndrome. Encouraging patients with CKM syndrome to engage in increased physical activity may improve clinical outcomes. Key messages What is already known on this topic: Cardiovascular-Kidney-Metabolic (CKM) syndrome involves a complex interplay between cardiovascular disease, metabolic disorders, and chronic kidney disease. While prior studies have established that physical activity can decrease mortality risk in the general population as well as in patients with cardiovascular and metabolic syndromes, the evidence regarding its impact on individuals with CKM syndrome remains limited. Additionally, there is a lack of detailed dose-response analyses of physical activity specifically targeting this high-risk population. What this study adds: This study provides novel evidence indicating that vigorous-volume physical activity (>3000 MET-minutes/week) significantly decreases all-cause mortality by 54% among patients with CKM syndrome, whereas moderate-volume, and light-volume physical activities show no significant effects. Notably, a linear dose-response relationship was established, demonstrating that each 1000-MET increment corresponds to a 5.8% reduction in mortality risk. These findings address a critical knowledge gap by quantifying both the threshold and incremental benefits of physical activity specifically for individuals with CKM syndrome, a population characterized by unique multisystem pathophysiology. How this study might affect research, practice, or policy: The findings of this study have the potential to substantially impact clinical practice by offering evidence-based thresholds for physical activity recommendations in the management of CKM syndrome. The benefits associated with vigorous-volume physical activity (>3000 MET-minutes/week) may encourage guideline committees to formulate more precise exercise prescriptions tailored to this high-risk population. Additionally, these results can be incorporated into a multidisciplinary care framework designed for managing complex chronic conditions. 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
Ershen Wan (ESW), a classic traditional Chinese medicine (TCM) prescription composed of Psoralea corylifolia Linn. and Myristica fragrans Houtt., has been applied to treat gastrointestinal disorders i Show more
Ershen Wan (ESW), a classic traditional Chinese medicine (TCM) prescription composed of Psoralea corylifolia Linn. and Myristica fragrans Houtt., has been applied to treat gastrointestinal disorders in clinical practices for thousands of years. However, its potential molecular mechanism in alleviating ulcerative colitis (UC) remains to be elusive. The purpose of the study is to explore the underlying mechanism of ESW in treating UC. The protective effect of ESW on dextran sodium sulfate (DSS)-induced UC mice was assessed by body weight, disease activity index (DAI), colon length, colon tissue pathology, and colonic inflammatory factors. Furthermore, network pharmacology was applied to dissect the possible targets and biological pathways regulated by ESW. The plasma and fecal metabolomics were comprehensively analyzed by UPLC-Q-TOF/MS. Subsequently, an efficient and feasible approach integrating network pharmacology, metabolomics, and molecular docking was used to explore the key targets obtained from the metabolite-reaction-enzyme-gene network. And the effect of ESW on the MAPK signaling mediated intestinal epithelial cell apoptosis was further investigated by in vitro and in vivo experiments. ESW could notably alleviate colon injury and inflammation of UC mice. Network pharmacology suggested that the bioactive components of ESW could mainly modulate signaling pathways associated with inflammation and metabolism. Consistently, plasma and fecal metabolomics further indicated that ESW could regulate the metabolic pathways of arachidonic acid, linoleic acid, sphingolipid, tryptophan, and glycerophospholipid. And the combined analysis of network pharmacology and metabolomics revealed that 14 pivotal targets were modulated by ESW, including PTGS1, PTGS2, CYP1A1, FADS1, CBR1, ALOX5, EPHX1, EPHX2, HPGD, PLA2G1B, PLA2G7, MGLL, ACHE, and SPHK1. Additionally, molecular docking suggested that bioactive components of ESW could bind well to these potential targets. And in vitro and in vivo experiments further verified that ESW could markedly ameliorate pathological symptoms of UC mice through inhibiting MAPK signaling mediated colonic epithelial cell apoptosis. Collectively, these findings indicated that ESW could effectively alleviate the pathological symptoms of UC mice, mainly involving in the modulation of lipid and amino acid metabolism pathways, and the suppression of MAPK signaling-mediated apoptosis. In this study, the potential mechanism of ESW for the treatment of UC was first clarified, which provided a solid scientific foundation for its clinical application. Notably, the proposed strategy facilitated a comprehensive prediction and validation of the efficacy and molecular mechanism of TCMs, and also provided a novel approach for revealing the intricate biological pathogenesis of diseases. Show less
The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidate Show more
The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidated. This study aims to examine the prognostic significance of genes associated with immune-stromal scores and to explore their underlying mechanisms in ccRCC. Data from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) were subjected to analysis to compute immune and stromal scores utilizing the ESTIMATE algorithm. The weighted gene co-expression network analysis (WGCNA) was employed to identify gene modules associated with these scores. Differentially expressed genes were assessed using the limma package. Prognostic biomarkers were subsequently identified through univariate, LASSO, and multivariate Cox regression analyses, culminating in the development of a risk score model. Gene expression was confirmed in ccRCC cell lines (786-O, Caki-1) and tumor tissues. Functional assays, such as wound healing and Transwell assays, were employed to evaluate tumor invasion and migration. The prognostic accuracy was assessed through ROC curve analysis, and a nomogram integrating risk scores with clinical variables was constructed. Analyses of immune infiltration, human leukocyte antigen (HLA) expression, immune checkpoint expression, immunophenoscore (IPS), tumor immune dysfunction and exclusion (TIDE) scores, and responses to six targeted therapies were conducted across different risk groups. Twelve critical prognostic markers, including CAPRIN1, CXCR3, FERMT3, HAPLN3, HBP1, MACF1, MPEG1, OSCAR, STAT1, UBA7, VAMP1, and VSIG4, were identified. The risk score model exhibited a high degree of predictive accuracy for survival outcomes in ccRCC. Immune profiling revealed significant differences in the TME between risk groups, with high-risk patients displaying elevated expression of HLA and immune checkpoints. Drug sensitivity analyses suggested that high-risk patients had a better response to erlotinib, temsirolimus, axitinib, and sunitinib, whereas low-risk patients demonstrated greater sensitivity to pazopanib. Variability in immunotherapy responsiveness between groups was observed based on IPS and TIDE analyses. This study highlights the prognostic value and TME-related mechanisms of immune-stromal score signatures in ccRCC, developing a risk score model and nomogram for predicting patient prognosis. Show less
Systemic delivery of adeno-associated virus serotype 9 (AAV9) to the central nervous system (CNS) is insufficient due to hindrance from the tight junctions of the blood-brain barrier (BBB). While pept Show more
Systemic delivery of adeno-associated virus serotype 9 (AAV9) to the central nervous system (CNS) is insufficient due to hindrance from the tight junctions of the blood-brain barrier (BBB). While peptide-display-based AAV engineering has advanced CNS-targeting capsid development, traditional strategies inserting or substituting a 7-mer peptide remain limited by low success rates and scarcity of efficient variants. To address these issues, we developed the Multiple Capsid Mutation Strategies (MCMS) library, which enhanced sequence diversity by incorporating random peptide insertions flanked by AAV9 or variant-derived residues and peptide substitutions within the VR-VIII of the AAV9 capsid protein. Following capsid selection in mice, the leading AAV variant BRC06 was identified and validated across different mouse strains. BRC06 exhibited approximately 1.9-fold higher brain transgene expression than AAV.PHP.eB in C57BL/6J mice. In BALB/c mice, BRC06 achieved a 1,482-fold brain enhancement with a 92-fold liver reduction relative to AAV9. Sequence analysis revealed that BRC06 was derived from the MCMS library's substitution strategies. Additionally, host factor screening revealed AAVR-dependent entry with accessory factors like Show less
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focu Show more
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti Show more
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-κB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less
Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with increasing evidence implicating the oral microbiome and tumor microenvironment in its progression. However, the mechan Show more
Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with increasing evidence implicating the oral microbiome and tumor microenvironment in its progression. However, the mechanistic impact of OSCC patient-derived saliva on tumor development remains poorly understood. We established an orthotopic OSCC mouse model and topically applied saliva collected from OSCC patients to assess its effects on tumor progression. Multi-omics analyses, including 16 S rRNA sequencing, tumor transcriptomics (RNA-seq), and metabolomics (LC-MS), were performed to explore changes in the oral microbiota, gene expression profiles, and metabolic pathways. Treatment with OSCC patient saliva significantly accelerated tumor growth compared to controls. Saliva application altered the oral microbiota, most notably causing a significant enrichment of the genus Staphylococcus. Tumor transcriptomics revealed upregulation of genes associated with chronic neutrophilic inflammation (Mpo), cancer-associated fibroblast (CAF) activation, and extracellular matrix (ECM) remodeling (Angptl4, Col2a1). Metabolomic analysis demonstrated profound metabolic reprogramming within the tumors, including enhanced amino acid metabolism (tryptophan, glutamate), fatty acid oxidation, and accumulation of the oncometabolite succinate. Integrated analysis showed that Staphylococcus abundance was strongly correlated with these inflammatory and metabolic signatures. This study demonstrates that saliva from OSCC patients promotes tumor progression in vivo through a multifactorial mechanism involving inflammation, stromal remodeling, and metabolic rewiring. These findings highlight the tumor-promoting potential of salivary and microbial components, suggesting new avenues for diagnostic and therapeutic strategies targeting the oral microenvironment in OSCC. Show less
The entorhinal cortex (ERC) is implicated in early progression of Alzheimer's disease (AD). Here we investigated the impact of established biological risk factors for AD, including
Earthworms are valued as a dietary protein source in many regions. Earthworm protein can yield bioactive peptides, but enzymatic hydrolysis is inefficient by commercial proteases, and bioactivity deve Show more
Earthworms are valued as a dietary protein source in many regions. Earthworm protein can yield bioactive peptides, but enzymatic hydrolysis is inefficient by commercial proteases, and bioactivity development is still inadequate. This study developed a novel efficient method for degrading earthworm protein and investigated the lipid-lowering activity and mechanism of earthworm peptides. It was found that combining autolysis and alcalase exhibited a higher hydrolysis degree of earthworm protein of 43.64 ± 0.78% compared to using autolysis or alcalase only. The hydrolysate significantly reduced lipid accumulation in steatotic hepatocytes. LC-MS/MS results showed that the primary lipid-lowering peptides (EWPs) in the hydrolysate were small molecule peptides with molecular weights of 500-1000 Da and chain lengths of 4-7 amino acid residues. Western blot results demonstrated that EWP regulated the expression of lipid metabolism-related proteins, including APOC3, HMGCR, PCSK9, SREBP1, C/EBP-α, NPC1L1, PPAR-γ, and CYP7A1. Transcriptomic analysis and validation experiments indicated that the lipid-lowering activity of EWP was associated with its suppression of inflammatory factors, such as IL-6. This study presents an efficient enzymatic hydrolysis strategy for earthworm protein utilization, laying the foundation for its application in functional foods such as protein supplements, nutraceutical capsules, hypoallergenic infant formulas, and sports nutrition products. Show less
Lipokines are a class of lipid-derived signaling molecules, playing essential roles in regulating metabolic homeostasis and systemic metabolism. In this review, we first comprehensively describe six m Show more
Lipokines are a class of lipid-derived signaling molecules, playing essential roles in regulating metabolic homeostasis and systemic metabolism. In this review, we first comprehensively describe six major lipokines, including palmitoleic acid (C16:1n7), 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), fatty acid esters of hydroxy fatty acids (FAHFAs), 12-hydroxyeicosapentaenoic acid (12-HEPE), lysophosphatidic acid (LPA), and 15-hydroxyeicosatetraenoic acid (15-HETE), focusing on their mechanistic roles in energy metabolism and inflammatory modulation as well as their cross-talk within different signaling pathways. These lipokines collectively contribute to metabolic homeostasis by regulating multiple pathways, including insulin signaling, AMPK activation, inflammatory modulation, and G-protein-coupled receptor-mediated pathways. Furthermore, we clarify the associations between lipokines and various diseases such as obesity, type 2 diabetes, cardiovascular diseases, non-alcoholic fatty liver disease, inflammatory disorders, and cancer, and discuss their potential as biomarkers and therapeutic targets. Despite current challenges, including functional complexity, limitations of model systems, and difficulties in clinical translation, lipokines demonstrate promising prospects in the prevention and treatment of metabolic diseases and application in precision medicine. Future research should prioritize the elucidation of the specific action mechanisms of different lipokines, development of highly sensitive detection methodologies, and large-scale clinical trials to facilitate the translation of the research results into practical medical applications. Show less
Hepatoid carcinoma of the ovary (HCO) is a highly uncommon and aggressive neoplasm originating from the surface epithelial cells of the ovary, characterized by hepatocyte-like differentiation. To date Show more
Hepatoid carcinoma of the ovary (HCO) is a highly uncommon and aggressive neoplasm originating from the surface epithelial cells of the ovary, characterized by hepatocyte-like differentiation. To date, most information on HCO is derived from case reports, with fewer than 50 documented cases globally. In this case report, we present a detailed account of the diagnosis, treatment, and prognosis of a patient diagnosed as having bilateral HCO, which is even rarer. Targeted next-generation sequencing revealed somatic mutations in PIK3C3 and TP53, with no BRCA1/2 alterations, and a molecular profile consistent with microsatellite stability and low tumor mutational burden. We also review the current literature to situate our findings within the broader context of existing knowledge. Given the rarity of bilateral HCO, our objective is to contribute to the existing body of knowledge by providing a comprehensive description of its clinical features, molecular characteristics, and treatment strategies. This effort may enhance understanding of this rare malignancy and offer insights to improve patient outcomes in clinical practice. Show less
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains Show more
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less
Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two la Show more
Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of neocortical interneurons, innervate the soma and/or proximal dendrites, and distal dendrites of pyramidal neurons, respectively. Using PV- and SST-specific knockout mouse models, we show that PV+ interneurons require FGFR2, which responds to FGF7, to drive PV+ inhibitory presynaptic maturation on perisomatic regions of Layer V pyramidal neurons. In contrast, SST+ interneurons rely on both FGFR1 and FGFR2, which respond to FGF10 or FGF22, to promote SST+ inhibitory presynaptic maturation on distal dendrites of pyramidal neurons in cortical Layer I. Mechanistically, FGF-FGFR signaling sustains VGAT protein levels in interneurons through PP2A and Akt pathways. Together, these findings demonstrate that distinct FGF ligand-receptor combinations regulate inhibitory presynaptic differentiation by PV+ and SST+ interneurons, contributing to the formation of compartment-specific synaptic patterns. Show less
Mammalian scent glands mediate species-specific chemical communication, yet the mechanistic basis for convergent musk production remain incompletely understood. Forest musk deer and muskrat have indep Show more
Mammalian scent glands mediate species-specific chemical communication, yet the mechanistic basis for convergent musk production remain incompletely understood. Forest musk deer and muskrat have independently evolved specialized musk-secreting glands, representing a striking case of convergent evolution. Through an integrated multi-omics approach, this study identified cyclopentadecanone as a shared key metabolic precursor in musk from both forest musk deer and muskrat, although downstream metabolite profiles diverged between the two lineages. Single-cell RNA sequencing revealed that these specialized apocrine glands possessed unique secretory architecture and exhibited transcriptional profiles associated with periodic musk production, distinct from those in conventional apocrine glands. Convergent features were evident at the cellular level, where acinar, ductal, and basal epithelial subtypes showed parallel molecular signatures across both taxa. Notably, acinar cells in both species expressed common genes involved in fatty acid and glycerolipid metabolism (e.g., Show less
Pulmonary Hypertension (PH) is a significant contributor to cardiac mortality in Dilated Cardiomyopathy (DCM) patients. Inflammatory processes and oxidative stress play pivotal roles in the advancemen Show more
Pulmonary Hypertension (PH) is a significant contributor to cardiac mortality in Dilated Cardiomyopathy (DCM) patients. Inflammatory processes and oxidative stress play pivotal roles in the advancement of Pulmonary Hypertension (PH). The Monocyte-to-High-- Density-Lipoprotein Cholesterol Ratio (MHR), a newly identified biomarker indicative of inflammatory and oxidative stress, has not been extensively researched in the context of pulmonary hypertension, especially within the scope of dilated cardiomyopathy. Given the reason mentioned above, our research explores the correlation between the MHR and the severity of PH in patients suffering from DCM. In this study, we conducted a retrospective review of medical data from 107 individuals diagnosed with non-ischemic DCM, evaluating their clinical profiles, biochemical indicators, MHR, and echocardiographic parameters. We analyzed the relationships between Pulmonary Arterial Systolic Pressure (PASP) and the Ejection Fraction of the Left Ventricle (LVEF). Utilizing logistic regression analysis, we determined the predictors of PH. Findings indicated that the DCM-PH group exhibited a significantly larger male population and elevated New York Heart Association (NYHA) classification scores (both with p-values <0.001 and 0.01, respectively) compared to the DCM-only group. A positive association was observed between the PASP and parameters, such as the Dimensions of the Left Atrium (LAD) and Left Ventricle in Systole (LVDs), Monocyte (M) levels, Direct Bilirubin (DB), and MHR. Conversely, an inverse relationship was noted with serum lipid profiles, including Total Cholesterol (TC), HDL Cholesterol (HDL-c), and apolipoprotein A1. LVEF demonstrated positive linkage with the same lipid profiles and the Left Ventricular Posterior Wall Thickness (LVPWT) yet showed negative correlations with the NYHA classification, Red Blood Cell Distribution Width Standard Deviation (RDW-SD), Total Bilirubin (TB), Direct Bilirubin (DB), and dimensions of the left ventricle in diastole and systole, as well as MHR. Through logistic regression analysis, several factors were recognized as significant predictors for the severity of PH within the DCM cohort, with weight (OR1.20, CI 1.022-1.409, p=0.026), RDW-SD (OR1.988, CI 1.015-3.895, p=0.045), LVPW (OR3.577, CI 1.307-9.792, p=0.013), LVDd (OR1.333, CI 1.058-1.680, p=0.015), MHR (OR3.575, CI 1.502-8.506, p=0.032), and TB (OR1.416, CI 1.014-1.979, p=0.041) showing positive associations, while apoB (OR0.001 CI0.001-0.824, p=0.045) exhibiting negative associations, all with p-values <0.05. Higher MHR and LVD correlate with increased PASP and reduced LVEF in DCMPH patients. MHR and LVPW are independent predictors of PH severity, indicating their potential as novel severity markers in DCM-related PH. Show less