As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, Show more
As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, particularly atherosclerosis, remain unclear. This study aimed to explore the effects of IL-38 on atherosclerosis progression and its mechanisms in regulating macrophage function during the atherosclerotic process. To evaluate the therapeutic potential of IL-38 in atherosclerosis, we performed histopathological examinations and biochemical analyses in vivo. In vitro, we used primary bone marrow-derived macrophages (BMDMs) stimulated with oxidized low-density lipoprotein (ox-LDL) to assess the anti-inflammatory effects of IL-38 and quantified its impact on ox-LDL-induced macrophage polarization. To further elucidate the specific mechanisms by which IL-38 regulates macrophage function, we conducted mRNA sequencing and validated downstream regulatory signaling pathways. IL-38 exhibited therapeutic potential in atherosclerosis by reducing atherosclerotic plaque formation, modulating plaque composition, suppressing the production of proinflammatory cytokines within plaques, and potentially regulating macrophage cholesterol metabolism. Moreover, IL-38 exerted significant anti-inflammatory effects on macrophages both in vivo and in vitro. Notably, it inhibited the polarization of macrophages toward the proinflammatory M1-like phenotype in both settings. Additionally, IL-38 impeded the phosphorylation and nuclear translocation of p65 in BMDMs and reduced ox-LDL-induced macrophage apoptosis. IL-38 holds therapeutic potential for atherosclerosis, as it alleviates disease progression, inhibits macrophage polarization toward the M1-like phenotype, suppresses nuclear factor-κB (NF-κB) signaling activation, and reduces macrophage apoptosis. This study provides new insights into the anti-inflammatory mechanisms by which IL-38 mitigates atherosclerosis. Show less
The incidence of Type 2 Diabetes Mellitus (T2DM) continues to rise steadily, significantly impacting human health. Early prediction of pre-diabetic risks has emerged as a crucial public health concern Show more
The incidence of Type 2 Diabetes Mellitus (T2DM) continues to rise steadily, significantly impacting human health. Early prediction of pre-diabetic risks has emerged as a crucial public health concern in recent years. Machine learning methods have proven effective in enhancing prediction accuracy. However, existing approaches may lack interpretability regarding underlying mechanisms. Therefore, we aim to employ an interpretable machine learning approach utilizing nationwide cross-sectional data to predict pre-diabetic risk and quantify the impact of potential risks. The LASSO regression algorithm was used to conduct feature selection from 30 factors, ultimately identifying nine non-zero coefficient features associated with pre-diabetes, including age, TG, TC, BMI, Apolipoprotein B, TP, leukocyte count, HDL-C, and hypertension. Various machine learning algorithms, including Extreme Gradient Boosting (XGBoost), Random Forest (RF), Support Vector Machine (SVM), Naive Bayes (NB), Artificial Neural Networks (ANNs), Decision Trees (DT), and Logistic Regression (LR), were employed to compare predictive performance. Employing an interpretable machine learning approach, we aimed to enhance the accuracy of pre-diabetes risk prediction and quantify the impact and significance of potential risks on pre-diabetes. From the China Health and Nutrition Survey (CHNS) data, a cohort of 8,277 individuals was selected, exhibiting a disease prevalence of 7.13%. The XGBoost model demonstrated superior performance with an AUC value of 0.939, surpassing RF, SVM, DT, ANNs, Naive Bayes, and LR models. Additionally, Shapley Additive Explanation (SHAP) analysis indicated that age, BMI, TC, ApoB, TG, hypertension, TP, HDL-C, and WBC may serve as risk factors for pre-diabetes. The constructed model comprises nine easily accessible predictive factors, which prove highly effective in forecasting the risk of pre-diabetes. Concurrently, we have quantified the specific impact of each predictive factor on the risk and ranked them based on their influence. This result may serve as a convenient tool for early identification of individuals at high risk of pre-diabetes, providing effective guidance for preventing the progression of pre-diabetes to T2DM. Show less
The benefits of plant essential oils (EO) on the health of animals have been frequently reported, but their alteration of lipid metabolism in obese pigs has yet to be explored. This study aimed to ass Show more
The benefits of plant essential oils (EO) on the health of animals have been frequently reported, but their alteration of lipid metabolism in obese pigs has yet to be explored. This study aimed to assess the impact of EO blends (oregano, cinnamon and lemon oils) on growth performance, meat physicochemical parameters, intestinal health and lipid metabolism in the small intestine of weaned Bamei (a kind of obese-type pig) piglets. One hundred and forty-four male 60-day-old weaned Bamei piglets were randomly assigned to three groups of six replicates each: CON (basal diet), T1 (basal diet + 250 mg/kg EO), and T2 (basal diet + 500 mg/kg EO) over 28 days. The results showed that T1 trended to improve the average daily gain and feed intake to body gain ratio (p < 0.1), reduced water loss (p < 0.05), and increased the redness of meat (p < 0.05) compared to the CON. In addition, a significant change in the proportion of C17:0 and C20:1 was observed in the meat of T1 (p < 0.05). Improved intestinal health was evidenced by the reduced crypt depth, improved villi-to-crypt length ratio, and better superoxide dismutase activity in T1 (p < 0.05). Further study on intestinal lipid metabolism showed that duodenal lipase activity and the mRNA expression levels of lipid transport-related genes in the jejunum (FABPs, APOA1, APOB and ACSL3) were significantly reduced, alongside diminished serum lipid metabolites (Total protein and triglyceride) in the groups fed with EO (p < 0.05). In short, EO supplementation especially at 250 mg/kg improved intestinal health and inhibited lipid metabolism, which had a positive effect on the overall performance of Bamei piglets. This new evidence contributes to understanding the early regulatory role of EO in obese pigs and their potential to alleviate adolescent obesity. Show less
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic mo Show more
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic modalities to revolutionize clinical management and enhance patient outcomes. The recent seminal discovery by Swamynathan et al. has unveiled menadione, a vitamin K precursor, as a potent inducer of triaptosis-a novel regulated cell death pathway mediated through the oxidative modulation of phosphatidylinositol 3-kinase PIK3C3/VPS34. This mechanistically distinct cell death paradigm, characterized by its intimate association with endosomal dysfunction and oxidative stress-induced cellular catastrophe, has demonstrated remarkable therapeutic efficacy in preclinical prostate cancer models, outperforming conventional therapeutic regimens and emerging as a potential paradigm-shifting strategy in oncology. This comprehensive review provides a critical synthesis of the triaptosis discovery landscape, elucidating its molecular intricacies and pathophysiological implications. We systematically examine the multifaceted roles of endosomal biology in oncogenesis and tumor progression, while offering a nuanced perspective on redox homeostasis in malignant cells and the therapeutic potential of oxidative stress modulation. Furthermore, we address the inherent dichotomy of oxidative stress induction in cancer therapy, balancing its therapeutic promise against potential adverse effects. Looking toward the horizon of cancer research, we explore transformative therapeutic strategies leveraging triaptosis induction and its potential applications beyond oncology, aiming to catalyze a new era of precision medicine that ultimately enhances patient survival and quality of life. Show less
To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Show more
To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Disease Neuroimaging Initiative. Edge time series (ETS) were obtained based on resting-state functional magnetic resonance data. The top 10% co-fluctuation signals of all time points in ETS were extracted to construct the high-amplitude frame networks, and the co-fluctuation signals from the remaining time points were used to construct the low-amplitude frame networks. In both network states, the graph theory and network-based statistics (NBS) analyses were used to compare SCD and HC. The correlation of the imaging indicators with cognitive scores and apolipoprotein E (APOE) ε4 genes was performed by Spearman correlation analysis. SCD exhibited lower peak amplitude and longer trough-to-trough duration (TTD) compared to HC. In both network states, the normalized clustering coefficient, normalized characteristic path length, small-worldness, and global efficiency of SCD were significantly reduced, and the altered nodal centralities of SCD predominantly exhibited a decreasing trend. However, the high-amplitude frame network identified more altered brain regions compared to the low-amplitude frame network. Furthermore, a SCD-related subnetwork was found in the high-amplitude frame network, which was composed of 11 brain regions and 13 edges. TTD was positively related to the number of APOE ε4 genes; the normalized characteristic path length, the betweenness centrality of right postcentral gyrus, and the connection between bilateral angular gyrus were correlated with cognitive scores. Our findings demonstrate that the edge-centric network framework reveals details of brain network alterations in SCD through different perspectives, and these alterations hold potential as novel biomarkers for SCD. Show less
Ischemic injury induces a partial mesenchymal shift in endothelial cells (ECs), contributing to impaired vascular regeneration. However, the molecular regulators of this transitional state remain poor Show more
Ischemic injury induces a partial mesenchymal shift in endothelial cells (ECs), contributing to impaired vascular regeneration. However, the molecular regulators of this transitional state remain poorly defined. To address this, we performed circular RNA profiling of endothelial cells under ischemic-like conditions and identified a marked upregulation of a circular RNA, named circATXN1. Functional studies revealed that circATXN1 knockdown modulates endothelial phenotype and vascular response after ischemia. Functional studies have shown that knockdown of circATXN1 can regulate the endothelial cell phenotype and vascular response after ischemia. Mechanistically, circATXN1 knockdown enhances the demethylase protein ALKBH5 to reduce the RNA methylation level of the key transcription factor SLUG, thereby stabilizing SLUG. In animal models, suppression of circATXN1 enhances angiogenesis and improves recovery following ischemic injury. Here, we show that circATXN1 regulates partial endothelial-to-mesenchymal transition (EndMT) and angiogenesis by controlling SLUG mRNA methylation dynamics, highlighting its potential as a therapeutic target in ischemic disease. Show less
The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed Show more
The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed beak bean phenotypes of duck at 10, 20, 30 and 40 days of age, revealing that the most common type is the black beak bean, characterized by melanin deposition on the beak surface. This study performed single nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) to investigate the genetic basis of beak bean color, identifying signals on chromosome 1. The copy number variation region-based GWAS revealed a consistent candidate region overlapping with the SNP-based GWAS signals, further supporting the importance of this genomic region. Locus zoom analysis further refined the candidate regions to 48.5-50.5 and 50.8-52.8 Mb. Functional enrichment analysis highlighted six candidate genes within these regions: KITLG, DUSP6, GALNT4, MGAT4C, ATP2B1 and NTS. Notably, KITLG and DUSP6, which are linked to melanin production, were identified as key candidate genes for beak bean color. Our finding revealed the genetic basis of the bean color traits for the first time in ducks, providing a theoretical foundation and technological framework for enhancing duck beak coloration. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
To investigate the impact of obesity on brain structure and cognition using large neuroimaging and genetic data. Associations between body mass index (BMI), gray matter volume (GMV), whiter matter hyp Show more
To investigate the impact of obesity on brain structure and cognition using large neuroimaging and genetic data. Associations between body mass index (BMI), gray matter volume (GMV), whiter matter hyper-intensities (WMH), and fluid intelligence score (FIS) were estimated in 30283 participants from the UK Biobank. Longitudinal data analysis was conducted. Genome-wide association studies were applied to explore the genetic loci associations among BMI, GMV, WMH, and FIS. Mendelian Randomization analyses were applied to further estimate the effects of obesity on changes in the brain and cognition. The observational analysis revealed that BMI was negatively associated with GMV (r = -0.15, p < 1 The phenotypic and genetic association between obesity and aging brain and cognitive decline suggested that weight control could be a promising strategy for slowing the aging brain. Show less
This study aims to identify oxidative stress-related genes (OSGs) in papillary thyroid carcinoma (PTC) and their common targets with resveratrol. Oxidative stress-related differentially expressed gene Show more
This study aims to identify oxidative stress-related genes (OSGs) in papillary thyroid carcinoma (PTC) and their common targets with resveratrol. Oxidative stress-related differentially expressed genes (OS-DEGs) were identified by intersecting datasets. The screened core genes were utilized to construct a prognostic model, and their prognostic value, along with their associations with clinical pathological characteristics and immune infiltration, was assessed. Subsequently, the core targets at the intersection of resveratrol and oxidative stress (OS) in PTC were screened, and their binding properties with resveratrol were analyzed. By conducting cross-database analysis, 38 OS-DEGs were identified, and 3 core genes APOE、CDKN2A、APOD were determined. The prognostic model based on core genes exhibited robust prognostic capabilities. The core genes displayed significant correlations with various clinical pathological parameters and a range of immune cells. Additionally, 13 targets of resveratrol for antioxidative stress were screened from databases. 6 high-performing targets, JUN, TGFB1, BCL2, CDKN1A, FOS, ICAM1, were revealed by topological analysis, all exhibiting binding energies lower than - 5.0 kcal/mol. Our study is the pioneering research to provide new insights into the diagnosis, prognosis, and treatment of PTC through the analysis of OSGs, presenting potential clinical implications. Furthermore, this research reveals the molecular functions associated with resveratrol and its pharmacological targets regulating OS in PTC for the first time. Show less
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a m Show more
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a multifaceted role in the progression of cardiac hypertrophy and HF. Here, it is identified that a lncRNA forkhead box O6, opposite strand (Foxo6os) is significantly downregulated in murine HF model induced using transverse aortic constriction (TAC). Knockdown of Foxo6os accelerates cardiomyocyte hypertrophy, reflects as elevated expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain 7 (MYH7). Conversely, Foxo6os overexpression can improve cardiac function and alleviate adverse cardiac remodeling. Mechanistically, Foxo6os directly interacts with myosin-binding protein-C (MYBPC3), which then recruits protein kinase C alpha (PKC-α) to facilitate MYBPC3 phosphorylation, resulting in maintaining myocardial contractility and postponing HF progression. Therefore, these findings underscore the critical role of Foxo6os in preserving cardiomyocyte contractile function, suggesting a potential for Foxo6os as a novel therapeutic target of HF. Show less
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safet Show more
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safety of treatment with pemigatinib, an oral, potent, selective FGFR1-3 inhibitor, in patients with advanced FGFR-altered CNS tumors. FIGHT-207 was a single-arm, open-label, phase 2 study of pemigatinib in patients with advanced solid tumors harboring FGFR fusions/rearrangements or other mutations. Patients received pemigatinib 13.5 mg once daily until disease progression or unacceptable toxicity. Endpoints included tumor response and safety. Of the 13 patients with CNS tumors in FIGHT-207, 10 had glioblastoma. Fibroblast growth factor receptor alterations were FGFR3-TACC3 fusions (n = 9), FGFR1 K656E mutations (n = 2), FGFR1 N546K mutation (n = 1), and FGFR1-MITF fusion (n = 1). Three patients (23%) displayed objective responses (1 complete, 2 partial). Safety was consistent with the overall FIGHT-207 population. Pemigatinib had antitumor activity and a manageable safety profile in patients with CNS tumors. Show less
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute config Show more
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC 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
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of le Show more
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on c Show more
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on coagulation remains unclear. To investigate the effects of ApoA-IV on the coagulation system, including its interactions with potential targets and the underlying mechanisms. Plasma ApoA-IV levels in deep vein thrombosis patients were tested by enzyme-linked immunosorbent assay. The effects of ApoA-IV on coagulation were assessed through thromboelastography. Potential interactions and mechanisms were analyzed using surface plasmon resonance and AlphaFold 3. Mice bleeding and stroke models were employed to evaluate the effects on hemostasis and thrombosis. ApoA-IV levels were reduced in deep vein thrombosis patients and correlated with increased thrombotic risk. Thromboelastography showed that ApoA-IV treatment delayed clot reaction and kinetic times while decreasing thrombus generation angle and maximum amplitude, highlighting its crucial role in inhibiting coagulation and platelet aggregation. We identified ApoA-IV as a functional activator of activated protein C (APC), with critical interactions occurring at residues 144 to 148 within the exosite loop of the APC protease domain. In animal models, anti-ApoA-IV antibody administration shortened bleeding time but exacerbated ischemic stroke outcomes. Notably, inhibitory peptide HE5, which inhibits ApoA-IV-APC interaction, effectively counteracted the anticoagulant activity of ApoA-IV. These findings establish ApoA-IV as a pivotal regulator of coagulation and hemostasis, primarily through enhancing APC activity. This research advances our understanding of the interplay between inflammation, lipid metabolism, and thrombosis, offering insights for developing novel antithrombotic therapies. Show less
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty Show more
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Show less
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing Show more
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium. Show less
Thyroid cancer, the most common endocrine malignancy, is characterized by a unique and complex tumor microenvironment (TME). To unravel the high tumor heterogeneity and molecular mechanisms driving ca Show more
Thyroid cancer, the most common endocrine malignancy, is characterized by a unique and complex tumor microenvironment (TME). To unravel the high tumor heterogeneity and molecular mechanisms driving cancer progression, we performed single-cell RNA sequencing (scRNA-seq) analysis, enabling a comprehensive exploration of cellular diversity and molecular dynamics at single-cell resolution. We employed Principal Component Analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and subsequent identification of cellular clusters. Differential gene expression analysis across subclusters was conducted using the FindAllMarkers function, while the DoHeatmap function was utilized to visualize the distribution of differentially expressed genes. The AUCell algorithm was applied to evaluate pathway enrichment within specific cell subtypes. To decipher cellular communication networks, we integrated the CellChat and NicheNet algorithms, which revealed intricate intercellular signaling interactions. Finally, multiplex immunohistochemistry (mIHC) was performed to validate key cellular interactions identified in silico. By analyzing 405,077 single cells from 50 thyroid cancer samples (including papillary, anaplastic, and metastatic tumors) and 14 normal thyroid tissues, we identified four major cellular subpopulations through unbiased clustering based on gene expression patterns and representative cellular markers. The TME was found to encompass diverse immune, endothelial, and mesenchymal cell subtypes, including novel populations such as CD4 + HSPA1A + T cells. Functional pathway enrichment analysis highlighted the roles of abundant cell types in tumor progression. Cell-cell communication analysis uncovered potential immunotherapeutic targets and revealed critical crosstalk among hub niche cells, including APOE+ macrophages, EMT-like cancer-associated fibroblasts (CAFs), and RBP7+ endothelial cells. These findings were further validated by multiplex immunohistochemistry, confirming the spatial organization and interactions of these cell populations within the TME. Our study provides a comprehensive single-cell transcriptomic atlas of thyroid cancer, offering profound insights into tumor heterogeneity, the functional roles of key niche cells, and potential biomarkers for anticancer therapy. These findings not only enhance our understanding of thyroid cancer biology but also pave the way for the development of novel therapeutic strategies targeting the TME. Show less
Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, Show more
Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients. Show less
Idiopathic frozen shoulder (FS) can lead to difficulties in daily activities and significantly impact the quality of life. Early diagnosis and treatment can help alleviate symptoms and restore shoulde Show more
Idiopathic frozen shoulder (FS) can lead to difficulties in daily activities and significantly impact the quality of life. Early diagnosis and treatment can help alleviate symptoms and restore shoulder function. Therefore, we aimed to explore the diagnostic biomarkers and potential mechanisms of FS from a transcriptomics perspective. Total RNA was extracted from tissue samples of 15 FS and 11 controls. At the outset, we conducted differential expression analysis, weighted gene co-expression network analysis (WGCNA), and utilized the cytoHubba plugin, complemented by two machine learning algorithms, receiver operating characteristic (ROC) analysis, and expression level evaluation to identify biomarkers for FS. Subsequently, a nomogram was constructed based on the biomarkers. Additionally, we conducted enrichment and immune infiltration analyses to explore the mechanisms associated with these biomarkers. Finally, we confirmed the expression patterns of the biomarkers at the clinical level through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This study established a link between FS biomarkers that have strong diagnostic potential and specific immune responses, highlighting possible targets for diagnosing and treating FS. Show less
Qianzhu Jiang, Huiting Li · 2025 · Journal of bioenergetics and biomembranes · Springer · added 2026-04-24
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific Show more
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less
"Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers a Show more
"Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers are crucial for identifying patients eligible for AIS treatment. This study enrolled 141 AIS patients who exceeded the conventional treatment window. Using CT perfusion imaging, patients were categorized into "penumbra freezing" and "non-penumbra freezing" groups based on the EXTEND criteria. Multiple regression analysis assessed the association of nine baseline factors and five blood lipid indicators with "penumbra freezing." Diagnostic accuracy was evaluated using ROC curves. Mendelian randomization (MR) analysis validated these findings using blood lipid indicators as exposures and penumbra biomarkers as outcomes. Among AIS patients beyond the treatment window, males exhibited better penumbra preservation (OR=0.243, 95% CI=0.072-0.813, p=0.022), while those with hyperlipidemia showed poorer preservation (OR=2.429, 95% CI=1.027-7.747, p=0.043). In the "penumbra freezing" group, ApoA1 levels were significantly lower (1.29 ± 0.03 g/L) compared to the "non-penumbra freezing" group (1.42 ± 0.06 g/L, p=0.034). Conversely, Lp(a) levels were significantly higher in the "penumbra freezing" group (304.63 ± 52.44 mg/L) than in the "non-penumbra freezing" group (110.26 ± 40.71 mg/L, p=0.034). Higher ApoA1 levels increased the likelihood of "non-penumbra freezing" beyond the time window (OR=3.206, 95% CI=1.034-9.938, p=0.044), while elevated Lp(a) levels reduced this likelihood (OR=0.075, 95% CI=0.007-0.848, p=0.036). MR analysis confirmed genetic associations of ApoA1 and Lp(a) with penumbra biomarkers. ApoA1 and Lp(a) may be linked to ischemic penumbra status, but further validation is needed due to limitations in sample size and study methodology. ApoA1 and Lp(a) are promising biomarkers for identifying AIS patients eligible for "penumbra freezing," suggesting the potential to extend the treatment window. Show less
Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP Show more
Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160. Show less
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in A Show more
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis. First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking. According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy. Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients. Show less
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic A Show more
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Show less
Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer. miRNAs play an essential role in TNBC pathogenesis and prognosis. Obesity is linked with an increased ris Show more
Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer. miRNAs play an essential role in TNBC pathogenesis and prognosis. Obesity is linked with an increased risk for several cancers, including breast cancer. Obesity is also related to the dysregulation of miRNA expression in adipose tissues. However, there is limited knowledge about race- and obesity-specific differential miRNA expression in TNBC. We performed miRNA sequencing of 48 samples (24 tumor and 24 adjacent non-tumor tissues) and RNA sequencing of 24 tumors samples from Black (AA) and White (EA) TNBC patients with or without obesity. We identified 55 miRNAs exclusively associated with tumors in obese EA patients and 33 miRNAs in obese AA patients, each capable of distinguishing tumor tissues from obese from lean individuals within their respective racial groups. In EA, we detected 41 significant miRNA-mRNA correlations. Notably, miR-181b-5p and miR-877-5p acted as negative regulators of tumor-suppressor genes (e.g., Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying ef Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)-a bioactive glycoside from Show less