Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon-like peptide 1 re Show more
Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist for the treatment of diabetes, has a role in attenuating CRC growth. TZP significantly inhibited colon cancer cell proliferation promoted apoptosis in vitro and induced durable tumor regression in vivo under hyperglycemic and nonhyperglycemic conditions across multiple murine cancer models. As glucose metabolism is known to critically regulate colon cancer progression, spatial metabolomics results revealed that glucose metabolites are robustly reduced in the colon cancer regions of the TZP-treated mice. TZP inhibited glucose uptake and destabilized hypoxia-inducible factor-1 alpha (HIF-1α) with reduced expression and activity of the rate-limiting enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK-1). These effects contributed to the downregulation of glycolysis and the tricarboxylic acid (TCA) cycle. TZP also delayed tumor development in a patient-derived xenograft (PDX) mouse model accompanied by HIF-1α mediated PFKFB3-PFK-1 inhibition. Therefore, the study provides strong evidence that glycolysis-blocking TZP, besides its application in treating type 2 diabetes, has the potential for preclinical studies as a therapy for colorectal cancer used either as monotherapy or in combination with other anticancer therapies. Show less
Endothelial-to-mesenchymal transition (EndMT) induced by dysfunctional pulmonary artery endothelial cells (PAECs) is regarded as an initiating and pivotal factor in pulmonary hypertension (PH). This s Show more
Endothelial-to-mesenchymal transition (EndMT) induced by dysfunctional pulmonary artery endothelial cells (PAECs) is regarded as an initiating and pivotal factor in pulmonary hypertension (PH). This study focuses on identifying a novel therapeutic target for regulating EndMT in PH. A comprehensive analysis of 2 hypoxic PAECs datasets yielded 310 overlapping upregulated and 229 downregulated differentially expressed genes (DEGs). These upregulated DEGs were primarily enriched in HIF-1 signalling pathway and glycolysis/gluconeogenesis, while downregulated only in spliceosome, as indicated by KEGG. Through PPI network analysis and the application of MCC algorithms, 5 hub genes were identified among these upregulated DEGs: GAPDH, LDHA, ALDOA, PFKL, and PFKP. Their enrichment in the 2 aforementioned pathways was confirmed by cross-pathway DEGs analysis and ClueGo. Among the hub genes, LDHA was chosen as the key gene based upon expression and correlation analysis of the validation set from PH patients. Subsequent GSEA also revealed the enrichment of LDHA in these 2 pathways. Additionally, the increased expression of LDHA protein in tissues and cells was confirmed, and the elevated enzymatic activity of LDHA in clinical serum samples was also verified. From 2 online databases, 4 LDHA inhibitors were filtered out, and the stable binding between the inhibitors and the LDHA protein was confirmed through molecular docking and molecular dynamics simulation. Finally, the experimental results indicated that one of the inhibitors FX11 reversed EndMT by inhibiting the lactate-SNAI1 axis, thereby alleviating hypoxia-induced PH. The potential of LDHA as a therapeutic target for PH by modulating EndMT was proposed in this study. Show less
Perimenopause is a critical turning point in women's life cycle, and the issue of sleep disturbance during perimenopause not only affects individual health, but also has profound implications for fami Show more
Perimenopause is a critical turning point in women's life cycle, and the issue of sleep disturbance during perimenopause not only affects individual health, but also has profound implications for family functioning, socioeconomic status, and public health policies. Therefore, this study aims to explore different potential profiles of sleep quality in perimenopausal women in the community and analyze the influencing factors of different profiles. A cross-sectional study was conducted from July 2024 to December 2024, and a total of 281 perimenopausal women in the community were recruited from 4 communities in Bengbu by convenience sampling. The participants completed the pittsburgh sleep quality index (PSQI), and self-rating anxiety scale (SAS), self-rating depression scale (SDS) and simplified coping style questionnaire (SCSQ). Latent profile analysis(LPA) was employed to identify latent profiles of sleep quality of perimenopausal women in the community. The predictors of sleep quality in different latent profiles were assessed via multinomial logistic regression analysis. One-way ANOVA, chi-square test or Fisher exact test, and the Kruskal-Walis test were used to compare the PSQI scores of perimenopausal women in the community under different latent profile characteristics. The mean age of 281 perimenopausal women was 50.09 ± 5.08 years, and the prevalence of sleep disorders was 31.3%. The sleep quality of perimenopausal women in community could be divided into three different latent profiles: good sleep quality group (68.7%), falling sleep and maintenance difficulty group (24.2%), and poor sleep quality with sleep disorder group (7.1%). Taking the good sleep quality group as the reference group, drinking history (OR = 2.061), chronic disease history (OR = 2.154), spouse's health status (OR = 1.871) and anxiety (OR = 4.390) were the risk factors to predict the difficulty in falling asleep and maintaining sleep in community perimenopausal women (P < 0.05). Spouse's health status (OR = 2.139) and anxiety (OR = 19.029) were the risk factors for poor sleep quality and sleep disorders in community perimenopausal women (P < 0.05). There are three qualitatively different potential profile categories of sleep quality in perimenopausal women in the community, and drinking history, chronic disease, poor spouse health and anxiety have predictive effects on their profile categories. In the future, community nursing staff can take targeted interventions according to different categories of sleep quality in perimenopausal women to improve sleep quality and level of health promotion. Show less
Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yo Show more
Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yolk percentage, we performed integrated transcriptome and metabolome analyses on the liver, ovary, and magnum tissues of Rhode Island Red chickens with high and low yolk percentages. A total of 322 differentially expressed genes (DEGs) and 128 significantly differential metabolites (SDMs) (VIP>1, P < 0.05) were identified in the liver, whereas 419 DEGs and 215 SDMs were detected in the ovary, and 238 DEGs along with 47 SDMs were found in the magnum. In the liver, genes such as HMGCR, DHCR7, MSMO1, and CYP7A1 were linked to cholesterol metabolism, essential for steroid hormone synthesis and yolk formation, while ACACB, ACSL1, ACSL4, LPL, and SGPP2 were involved in fatty acid biosynthesis, a key process for supplying energy and structural components of the yolk. In the ovary, COL6A6, COMP, CHAD, ITGA7, THBS2, and TNC contributed to extracellular matrix-receptor interactions, which are fundamental for follicle development and oocyte maturation. In the magnum, UGT1A1, MAOB, and ALDH3B2 participated in drug metabolism-cytochrome P450 and amino acid metabolism, ensuring a proper environment for egg white formation and potentially influencing nutrient allocation to the yolk. Metabolic pathway enrichment revealed that steroid hormone biosynthesis, glycerophospholipid metabolism, and betaine metabolism were predominant in the liver; pyruvate, taurine, and hypotaurine metabolism in the ovary; and phenylalanine metabolism in the magnum. Moreover, integrated analysis highlighted key metabolites and genes potentially regulating yolk deposition, including 7,8-dihydroneopterin and Pg 38:4 in the liver (related to immune modulation and lipid metabolism, respectively), thalsimine in the ovary, as well as DL-glutamine in the magnum, all of which may be crucial for maintaining metabolic homeostasis and supporting egg formation. Collectively, these findings deepen our understanding of how distinct molecular and metabolic pathways in the liver, ovary, and magnum orchestrate yolk proportion and deposition. Such insights may advance future strategies to improve egg quality and productivity in poultry breeding programs. Show less
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-se Show more
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC Show less
Growing evidence indicates that healthy diets are associated with a slower progression of Alzheimer's disease (AD). Flavonoids are among the most abundant natural products in diets beneficial to AD, s Show more
Growing evidence indicates that healthy diets are associated with a slower progression of Alzheimer's disease (AD). Flavonoids are among the most abundant natural products in diets beneficial to AD, such as the Mediterranean diet. However, the effect and mechanism of these dietary flavonoids on AD remains incompletely understood. Here, we found that a representative dietary natural flavonoid, chrysin (Chr), significantly ameliorated cognitive impairment and AD pathology in APP/PS1 mice. Furthermore, mechanistic studies showed that Chr significantly reduced the levels of amyloid-β (Aβ) and phosphorylated tau (p-tau), along with dual inhibitory activity against β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase 3β (GSK3β). Moreover, the effect of Chr was further confirmed by EW233, a structural analog of Chr that exhibited an improved pharmacokinetic profile. To further verify the role of Chr and EW233, we utilized our previously established chimeric human cerebral organoid (chCO) model for AD, in which astrogenesis was promoted to mimic the neuron-astrocyte ratio in human brain tissue, and similar dual inhibition of Aβ and p-tau was also observed. Altogether, our study not only reveals the molecular mechanisms through which dietary flavonoids, such as Chr, mitigate AD pathology, but also suggests that identifying a specific constituent that mimics some of the benefits of these healthy diets could serve as a promising approach to discover new treatments for AD. Show less
Autophagy regulates intermittent hypoxia (IH)-induced obstructive sleep apnea-hypopnea syndrome (OSAHS). We investigated the effects of IH and its withdrawal on cognitive function, autophagy, and lyso Show more
Autophagy regulates intermittent hypoxia (IH)-induced obstructive sleep apnea-hypopnea syndrome (OSAHS). We investigated the effects of IH and its withdrawal on cognitive function, autophagy, and lysophagy in OSAHS. An OSAHS rat model was established, and rats were divided into five groups: normoxia control, IH-4w (4-week IH), IH-6w (6-week IH), IH-8w (8-week IH), and IH-8w + 4w (8-week IH and 4-week normoxia). The cognitive behavior; mitochondrial and lysosomal morphology of the hippocampal tissue; mitochondrial respiratory function, permeability, and membrane potential; lysosomal function; autophagy- and lysophagy-related protein levels; and hypoxia-associated autophagy gene expression in rats were assessed. The cognitive function of rats in the IH-4w, IH-6w, and IH-8w groups was significantly impaired. In IH-8w cells, mitochondrial function was damaged with swollen morphology and decreased quantity, respiration, permeability, and membrane potential, along with significantly increased mitophagy-related protein ATG5 and LC3II/LC3 levels and decreased p62 levels. Expression of hypoxia-associated autophagy genes Becn1, Hif1, Bnip3, Bnip3l, and Fundc1 was significantly higher in the IH-8w group. Significantly increased LAMP2, CTSB, and ACP2 levels in IH-8w cells further indicated impaired lysosomal function. Lysophagy-related protein LAMP1, LC3II/LC3I, and TFEB levels were significantly increased in the IH-8w group, whereas p62 level was significantly decreased. The above listed evidence indicated damage to the mitochondria and lysosomes, as well as stimulation of mitophagy and lysophagy in IH-treatment OSAHS rat model. After withdrawing IH and culturing for 4 weeks in normal conditions, the cognitive function of rats improved, and mitophagy and lysophagy decreased. Our findings indicate that IH impairs cognitive function and promotes mitophagy and lysophagy in an OSAHS rat model, and IH withdrawal recovered the above effects. Show less
Neovascular age-related macular degeneration (nAMD) is an advanced stage of AMD and is associated with an increased risk of visual impairment. Disturbances in lipid metabolism have been proposed as a Show more
Neovascular age-related macular degeneration (nAMD) is an advanced stage of AMD and is associated with an increased risk of visual impairment. Disturbances in lipid metabolism have been proposed as a major contributing factor to the pathogenesis of AMD. This study aims to investigate whether lipid profiles in the serum and components of dyslipidemia can be used as indicators for predicting progression to nAMD. A retrospective analysis was conducted involving 125 participants with nAMD. 125 non-AMD controls, matched by age, sex, and BMI, were incorporated into the study. The comparative analysis between the groups involved six lipid biomarkers in the serum: HDL-C, LDL-C TG, TC, ApoA1, and ApoB. Moreover, the existence of dyslipidemia and its constituents was assessed through t-tests, as well as univariate and multivariable logistic regression models. Individuals with nAMD exhibited significantly higher serum HDL-C (P = 0.02) compared to the controls without AMD. Furthermore, the concentrations of ApoB were significantly less in the nAMD cohort (P < 0.01) when compared to the control group. During the investigation of the correlation between levels of serum HDL-C (P < 0.01) and serum ApoB (P < 0.01) with nAMD through logistic regression analysis, notable findings indicated a significant association between both variables and nAMD. However, by multivariate logistic regression analysis, neither serum HDL-C nor serum ApoB was an independent risk factor for nAMD. While individuals with nAMD demonstrated elevated serum HDL-C and reduced serum ApoB levels, these lipid markers may not be suitable as biomarkers for monitoring or preventing nAMD. Show less
Yunxi Li, In-Hee Lee, Sek Won Kong · 2025 · medRxiv : the preprint server for health sciences · Cold Spring Harbor Laboratory · added 2026-04-24
Despite widely acknowledged sex differences in lipid metabolism and risks for cardiovascular disease, genetic associations contributing to such differences remain incompletely characterized. Here, we Show more
Despite widely acknowledged sex differences in lipid metabolism and risks for cardiovascular disease, genetic associations contributing to such differences remain incompletely characterized. Here, we performed a sex-stratified genome-wide association study (GWAS) for four lipid profiles to identify loci exhibiting differential effects between males and females. Using whole-genome sequencing data from All of Us Research Program comprising 124,920 participants of diverse ancestry, we conducted GWAS analyses separately in males, females, and a pooled cohort. Our analyses validated previous findings on genes associated with lipid metabolism. In addition, we have found 5 genes showing significant sex-heterogeneous effects, including Show less
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder Show more
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. Show less
Childhood cancer can disrupt family functioning, increase caregiver psychological distress, and impair caregiver quality of life. While family resilience is crucial for adaptation, most research has f Show more
Childhood cancer can disrupt family functioning, increase caregiver psychological distress, and impair caregiver quality of life. While family resilience is crucial for adaptation, most research has focused on individual-level factors, neglecting heterogeneity and multilevel influences on family resilience. Guided by the Social Ecological Model (SEM), this cross-sectional observational study used latent profile analysis (LPA) to identify distinct profiles of family resilience among caregivers of children with cancer and to explore factors associated with these profiles. Between July 2022 and March 2024, 292 caregivers were recruited. Family resilience was measured using the Family Resilience Assessment Scale. LPA was employed to identify resilience profiles, and binary logistic regression was used to explore influencing factors. Two latent profiles were identified: the Low Resources-Low Positivity profile (86%) and the High Internal Resilience profile (14%). The Low Resource-Low Positivity profile demonstrated generally lower scores, especially in utilizing social and economic resources and maintaining a positive outlook. The High Internal Resilience profile showed higher scores across all family resilience dimensions, particularly in communication/problem solving, positive outlook, and meaning-making, while the use of external social and economic resources remained relatively lower. Univariate analysis showed significant differences between profiles in residence, number of siblings, caregiver education, individual resilience, social support, caregivers' physical and psychological well-being and child communication (caregiver-reported). Binary logistic regression identified having more than one child (OR = 3.184, 95% CI: 1.437 ~ 7.057, P = 0.004) and higher individual resilience (OR = 1.095, 95% CI: 1.028 ~ 1.165, P = 0.005) as significant predictors of High Internal Resilience profile. This study identified two distinct family resilience profiles among caregivers of children with cancer. Limited use of social and economic resources was common, while caregiver resilience and having multiple children predicted higher family resilience. Interventions should enhance caregiver coping capacity, support one-child families through peer and family programs, and improve access to social support, flexible employment, and affordable care to strengthen family resilience. Not applicable. Show less
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a de Show more
In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strat Show more
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less
Zijun Zhu, Rongxing Wei, Hailong Li+5 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Inflammatory bowel disease (IBD) with the two predominant endophenotypes-Crohn's disease (CD) and ulcerative colitis (UC)-represents a group of chronic gastrointestinal inflammatory conditions. Since Show more
Inflammatory bowel disease (IBD) with the two predominant endophenotypes-Crohn's disease (CD) and ulcerative colitis (UC)-represents a group of chronic gastrointestinal inflammatory conditions. Since most genetic associations with IBD are often limited to independent subtypes, we reported a genome-wide association study (GWAS) cross-trait analysis combined with CD and UC to enhance statistical power. Initially, we detected 256 association signals at 54 genomic susceptibility loci and further characterized the functionality of variants within these regions. Subsequently, we revealed tissue and cell-specific heritability enrichment, particularly in whole blood, small intestine terminal ileum, spleen, lung, and colon transverse. Leveraging multi-omics datasets, we adopted a two-pronged approach comprising summary data-based Mendelian randomization (SMR) and transcriptome-wide association study (TWAS) to pinpoint likely causal genes and variants. Further, RNA-seq analysis facilitated the evaluation of differential expression and co-expression in intestinal tissues. Through a multi-stage prioritization strategy, compelling evidence for putative targets was nominated; notably highlighting several potential susceptibility genes such as IL27 and SBNO2. Finally, we utilized Mendelian randomization (MR) analysis with diverse datasets to verify the convergence of these two endophenotype-driven genes. Our investigation yields valuable insights to inform genetic mechanisms in IBD and reveal potential causal gene targets. Show less
Cardiovascular diseases caused by atherosclerosis (AS) are the leading causes of disability and death worldwide. Apolipoprotein B (ApoB), the core protein of low-density lipoproteins, is a major contr Show more
Cardiovascular diseases caused by atherosclerosis (AS) are the leading causes of disability and death worldwide. Apolipoprotein B (ApoB), the core protein of low-density lipoproteins, is a major contributor to cardiovascular disease-related morbidity and mortality, with apolipoprotein B (ApoB) playing a critical role in its pathogenesis. However, no bibliometric studies on the involvement of ApoB in AS have been published. This study aimed to conduct a comprehensive bibliometric analysis to explore the current and future trends regarding the role of ApoB in AS. Utilizing the Web of Science Core Collection, a thorough search was conducted for ApoB in AS-related papers related to research on ApoB in the field of AS during 1991-2023. The analysis focused on annual publication trends, leading countries/regions and institutions, influential authors, journal and key journals. CiteSpace and VOSviewer were employed to visualize reference co-citations, and keyword co-occurrences, offering insights into the research landscape and emerging trends. This bibliometric analysis employed network diagrams for cluster analysis of a total of 2105 articles and reviews, evidencing a discernible upward trend in annual publication volume. This corpus of research emanates from 76 countries/regions and 2343 organizations, illustrating the widespread international engagement in ApoB-related AS studies. Notably, the United States and the University of California emerge as the most prolific contributors, which underscores their pivotal roles in advancing this research domain. The thematic investigation has increasingly focused on elucidating the mechanistic involvement of ApoB in atherosclerosis, its potential as a diagnostic biomarker, and its implications for therapeutic strategies. This bibliometric analysis provides the first comprehensive perspective on the evolving promise of ApoB in AS-related research, emphasizing the importance of this molecule in opening up new diagnostic and therapeutic avenues. This study emphasizes the need for continued research and interdisciplinary efforts to strengthen the fight against AS. Furthermore, it emphasizes the critical role of international collaboration and interdisciplinary exploration in leveraging new insights to achieve clinical breakthroughs, thereby addressing the complexities of AS by focusing on ApoB. 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
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-th Show more
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while Show more
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while also assisting in the production and organization of new viral components. However, NSPs are not incorporated into viral particles, and their subsequent fate within host cells remains poorly understood. Additionally, their role in viral pathogenesis requires further investigation. This study aimed to discover the ultimate fate of NSP6 in host cells and to elucidate its role in viral pathogenesis. We investigated the effects of NSP6 on cell death and explored the underlying mechanism; moreover, we examined the degradation mechanism of NSP6 in human cells, along with analysing its correlation with coronavirus disease 2019 (COVID-19) severity in patient peripheral blood mononuclear cells (PBMCs). NSP6 was demonstrated to induce cell death. Specifically, NSP6 interacted with EI24 autophagy-associated transmembrane protein (EI24) to increase intracellular Ca This study reveals that KLHL22-mediated ubiquitination controls NSP6 stability and that NSP6 induces autophagic cell death via calcium overload, highlighting its cytotoxic role and suggesting therapeutic strategies that target calcium signaling or promote NSP6 degradation as potential interventions against COVID-19. Show less
Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. A cellular model of Show more
Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. A cellular model of steatosis was established by treating primary duck hepatocytes with OA. Transcriptome sequencing was performed to identify key signaling pathways and candidate genes. The role of Apolipoprotein A1 (APOA1) was investigated through overexpression and knockdown experiments. Intracellular triglycerides (TGs) were quantified commercially; lipid droplets were visualized by Oil Red O staining. Intracellular TG accumulation was induced by OA treatment in a dose-dependent manner. Through transcriptome analysis, 1045 differentially expressed genes (DEGs) were identified, with APOA1 being recognized as a key candidate within the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The content of TGs and lipid droplets was increased by APOA1 overexpression, whereas these effects were suppressed by APOA1 knockdown. The expression of acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) was upregulated by APOA1. Conversely, the expression of carnitine O-palmitoyltransferase 1 (CPT1), acyl-CoA oxidase 1 (ACOX1), and apolipoprotein B (APOB) was downregulated. This study demonstrates that OA upregulates APOA1, suggesting the involvement of the PPAR pathway and providing a theoretical basis for modulating hepatic fat deposition. Show less
End-stage renal disease (ESRD) is associated with high morbidity and mortality. Identifying patients with stage 4 chronic kidney disease (CKD) at risk of short-term progression to ESRD remains challen Show more
End-stage renal disease (ESRD) is associated with high morbidity and mortality. Identifying patients with stage 4 chronic kidney disease (CKD) at risk of short-term progression to ESRD remains challenging. Accurate prediction can improve advanced care planning and patient outcomes. This study aimed to develop and validate a machine learning (ML) model for predicting progression within 25 weeks (approximately six months) of ESRD in patients with stage 4 CKD. Electronic health records (EHRs) of patients with stage 4 CKD were analyzed. Nine ML models including Ridge regression (Ridge), random forest (RF), and eXtreme Gradient Boosting (XGBoost) were used to predict short-term progression to ESRD within 25 weeks. The models were trained and externally validated using the data of 346 and 105 patients. Of the 451 patients with stage 4 CKD, 219 developed ESRD. Among the evaluated models, XGBoost demonstrated the best overall performance. In the internal validation, it achieved an area under the curve (AUC) of 0.93, an accuracy of 0.90, and an F1 score of 0.89. In the external validation, XGBoost maintained the highest AUC (0.85), accuracy (0.79), and F1 score (0.79), along with the highest average precision (0.89) and a low log-loss (0.48), indicating strong discriminative ability and good generalizability. The top predictive features included high-density lipoprotein cholesterol, Alb, Cys C, ApoB, FGB, Bun, Neutrophil, and Total cholesterol. This study demonstrated the feasibility of ML for assessing ESRD prognosis based on easily accessible clinical features. XGBoost demonstrated superior performance in both internal and external validation, suggesting its potential for future patient screening. Show less
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive Show more
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive of its therapeutic potential against T2DM. In this study, we evaluated the protective effects of KA against apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (LDL) (AC3RL)-induced β-cell apoptosis and its underlying mechanism of action. ApoE Show less
To investigate the effects of Qihuang Jianpi Zishen Granules (QJZG) on renal injury in SLE mice, focusing on macrophage M1/M2 polarisation mediated by the AMPK/ULK1 signalling pathway. Parameters of r Show more
To investigate the effects of Qihuang Jianpi Zishen Granules (QJZG) on renal injury in SLE mice, focusing on macrophage M1/M2 polarisation mediated by the AMPK/ULK1 signalling pathway. Parameters of renal function and proteinuria were assessed. Pathological changes in the kidney were examined using H&E, periodic acid-Schiff and Masson's trichrome staining. Serum inflammatory factor levels were quantified using ELISA. The expression levels of the glycolysis rate-limiting enzymes hexokinase 2 (HK2) and glucose transporter 1 (GLUT1) were determined, and the transcriptional levels of AMPK/ULK1 pathway components were measured using quantitative PCR. The abundance of proteins associated with AMPK/ULK1 signalling was assessed via immunoblotting. Flow cytometry was used to quantify CD86+ M1 type and CD206+ M2 type macrophage populations. Dual immunofluorescence staining was employed to visualise F4/80+CD86+ and F4/80+CD206+ coexpression patterns. Compared with the Untreated group, mice in the PRED (prednisone acetate), QJZG and 2-Deoxy-D-glucose groups exhibited improved renal histopathology, reduced levels of creatinine, blood urea nitrogen, 24-hour RRO (24-hour urinary protein), ACR (Albumin-to-Creatinine Ratio), TPCR (Urine Total Protein-to-Creatinine Ratio), tumour necrosis factor alpha, interleukin (IL)-1β, IL-12, IL-23, IL-27, HK2, GLUT1, mTOR, CD86 and iNOS messenger RNA (mRNA), CD86 and iNOS proteins, M1 macrophages, M1/M2 macrophages and F4/80+CD86 expression (p<0.05). They also displayed increased expression of transforming growth factor-beta, IL-4, IL-10, C-C motif chemokine ligand 18, AMPK, ULK1, Atg13, CD206 and Arg-1 mRNA, AMPK, ULK1, CD206 and Arg-1 proteins, M2 macrophages and F4/80+CD206 (p<0.05). QJZG effectively improved renal injury in SLE by reducing inflammation and modulating the AMPK/ULK1 signalling pathway to suppress M1 macrophage polarisation. Show less
Hypoglycemia is a commonly neglected complication in elderly diabetic patients, which can lead to cardiovascular events. Endothelial cell dysfunction is the primary inducer of cardiovascular events, a Show more
Hypoglycemia is a commonly neglected complication in elderly diabetic patients, which can lead to cardiovascular events. Endothelial cell dysfunction is the primary inducer of cardiovascular events, and it is associated with hypoglycemia-triggered cytokine release and inflammatory programmed cell death. A comprehensive understanding of lineage-specific variations in pathological vascular changes is essential to mitigate cardiovascular events and ensure therapeutic efficacy. Herein, unbiased clustering analyses and single-nucleus RNA sequencing are performed on cells of the thoracic aorta in db/db and insulin-induced hypoglycemic db/db mice. Comparative analyses show changes in lineage-specific genes, subpopulation composition, intercellular communication, and molecular biology in hypoglycemic diabetic mice. The analyses also revealed the changes of different cells, particularly endothelial cell PANoptosis, macrophage inflammatory polarization, and vascular smooth muscle cell (VSMC) fibrosis. Pseudo-time sequencing, differential expression, and regulation network analyses revealed the association of potential hub genes Klf2, ETS2, Elavl1, C3, and Nr4a1 with the mentioned pathological processes. It is demonstrated that hypoglycemia induces VSMC fibrosis in vivo, whereas Angptl4 knockdown can attenuate VSMC fibrosis in vitro. These findings demonstrate the hypoglycemic macroangiopathy mechanism and provide important references for future disease intervention and treatment. Show less
Skin color of poultry, an important economic trait, is related to breed, feed, environment, and other factors. In recent years, China's duck industry has developed rapidly, and duck products are welco Show more
Skin color of poultry, an important economic trait, is related to breed, feed, environment, and other factors. In recent years, China's duck industry has developed rapidly, and duck products are welcomed by consumers. Different skin colors of ducks have different cooking methods. Black skinned duck, such as Yulin black duck, is more popular in China because they are considered more suitable for making soup, while other skin colors, such as Pekin duck, is used for roasting. In order to gain a deeper understanding of the genetic factors associated with differences in duck skin color, the transcriptomes and metabolomes of skin between Yulin black duck and Pekin duck from 15 (BSE15 vs. PSE15), 21 (BSE21 vs. PSE21) and 27 (BSE27 vs. PSE27) days of incubation were compared and analyzed. The transcriptome results showed that a total of 187 (118 up-regulated and 69 down-regulated), 417 (91 up-regulated and 326 down-regulated) and 137 (55 up-regulated and 82 down-regulated) differentially expressed genes (DEGs) were identified from BSE15 vs. PSE15, BSE21 vs. PSE21 and BSE27 vs. PSE27, respectively. The significantly enriched GO terms of biological process were positive regulation of melanin biosynthetic process, melanin biosynthetic process, cuticle development, melanin biosynthetic process from tyrosine, and melanocyte differentiation, which were potentially related to skin growth and development. Eleven significant pathways, highly enriched by DCT, TYR, ASIP, TYRP1, KIT, PHOSPHO2, CERS3, SGPP2, SPTLC3, DEGS2, PATJ, RBP7, AOX1, ETNPPL, HPGDS, and GAD1, were melanogenesis, tyrosine metabolism, vitamin B6 metabolism, sphingolipid metabolism, protein digestion and absorption, tight junction, alpha-linolenic acid metabolism, arachidonic acid metabolism, linoleic acid metabolism, nicotinate and nicotinamide metabolism, and alanine, aspartate and glutamate metabolism, which participated in regulating the development of duck skin during embryonic stage. The significantly different metabolites (SDMs) were mainly organoheterocyclic compounds, lipids and lipid-like molecules, organic oxygen compounds, organic acids and derivatives, including L-tyrosine, N-arachidonyl maleimide, glycerophospho-N-palmitoyl ethanolamine, LPE 22:4, and PC(0:0/18:0). which were mainly enriched in glycerophospholipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, alpha-linoleic acid metabolism, and melanogenesis in metabolome, suggesting that these pathways may play important roles in skin development of duck during embryonic stage. Besides, the analysis of integrated transcriptome and metabolome indicated that the pathways, including glycerophospholipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, and alpha-linolenic acid metabolism, could contribute to regulating skin development in embryonic duck. Our findings could help elucidate the genetic mechanisms underlying the development differences in duck skin color. Furthermore, the candidate genes and metabolites can be used to provide a valuable breeding strategy for the selection of specific duck breeds with ideal skin coloration. Show less
Residual feed intake (RFI) has recently gained attention as a key indicator of feed efficiency in poultry. In this study, 800 slow-growing ducks with similar initial body weights were reared in an exp Show more
Residual feed intake (RFI) has recently gained attention as a key indicator of feed efficiency in poultry. In this study, 800 slow-growing ducks with similar initial body weights were reared in an experimental facility until they were culled at 42 d of age. Thirty high RFI (HRFI) and 30 low RFI (LRFI) birds were selected to evaluate their growth performance, carcass characteristics, and muscle development. Transcriptome and weighted gene co-expression correlation network analyses of pectoral muscles were conducted on six LRFI and six HRFI ducks. The results revealed that selecting for LRFI significantly reduced feed consumption (P < 0.05) and improved feed efficiency without affecting the growth performance, slaughter rate, or meat quality of ducks (P > 0.05). Moreover, compared with HRFI ducks, LRFI ducks had a lower pectoral muscle fat content (P < 0.05), larger muscle fiber diameter and area (P < 0.05), and lower muscle fiber density (P < 0.05). There were significant differences in gene expression between LRFI and HRFI ducks, with 102 upregulated and 258 downregulated genes, which were enriched in the PPAR signaling pathway, adipocytokine signaling pathway, actin cytoskeleton regulation, ECM-receptor interaction, and focal adhesion. The expression of genes associated with fat and energy metabolism, including ACSL6, PCK1, APOC3, HMGCS2, PRKAG3, and G6PC1, was downregulated in LRFI ducks, and weighted gene co-expression correlation network analysis identified PRKAG3 as a hub gene. Our findings indicate that reduced mitochondrial energy metabolism may contribute to the RFI of slow-growing ducks, with PRKAG3 playing a pivotal role in this biological process. These findings provide novel insights into the molecular changes underlying RFI variation in slow-growing ducks. 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
Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk predi Show more
Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk prediction methods for DM patients complicated with TB (DM-TB) are lacking. This study mined transcriptome data of DM-TB patients from the GEO database (GSE181143 and GSE114192) and used differential analysis, weighted gene co-expression network analysis (WGCNA), intersecting immune databases, combined with ten machine learning algorithms, to identify immune biomarkers associated with DM-TB. An early alert model for DM-TB was constructed based on the identified core differentially expressed genes (DEGs) and validated through a prospective cohort study and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for gene expression levels. Furthermore, we performed a detailed immune status analysis of DM-TB patients using the CIBERSORT algorithm. We identified 1090 DEGs associated with DM-TB and further pinpointed CETP (cholesteryl ester transfer protein) (AUC = 0.804, CI: 0.744-0.864), TYROBP (TYRO protein tyrosine kinase binding protein) (AUC = 0.810, CI: 0.752-0.867), and SECTM1 (secreted and transmembrane protein 1) (AUC = 0.811, CI: 0.757-0.864) as immune-related biomarkers for DM-TB patients. An early alert model was developed based on these three genes (AUC = 0.86, CI: 0.813-0.907), with a sensitivity of 0.80829 and a specificity of 0.75758 at a Youden index of 0.56587. External validation using the GSE114192 dataset showed an AUC of 0.901 (CI: 0.847-0.955). Population cohort research and RT-qPCR verified the expression levels of these three genes, demonstrating consistency with trends seen in the training set. KEGG enrichment analysis revealed that NF-κB and MAPK signaling pathways play crucial roles in the DM-TB pathogenic mechanism, and immune infiltration analysis showed significant suppression of certain adaptive immune cells and activation of inflammatory cells in DM-TB patients. This study identified three potential immune-related biomarkers for DM-TB, and the constructed risk assessment model demonstrated significant predictive efficiency, providing an early screening strategy for DM-TB. 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
β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completel Show more
β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy. Show less