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
Oxymatrine is an alkaloid with the property of immunomodulation. Recent studies have demonstrated that oxymatrine inhibits experimental autoimmune encephalomyelitis (EAE), an animal model of multiple Show more
Oxymatrine is an alkaloid with the property of immunomodulation. Recent studies have demonstrated that oxymatrine inhibits experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by promoting the production of interferon-β (IFN-β). However, the mechanism through which oxymatrine regulates the production of IFN-β remains unclear. The aim of this study was to investigate the pharmacological effects and related molecular mechanisms of oxymatrine in the treatment of EAE through in vivo and in vitro experiments. Oxymatrine alleviated neurological dysfunction, demyelination, and inflammation in EAE mice. It reduced microglia/macrophage infiltration and polarization, lowered pro-inflammatory cytokine levels (iNOS, TNF-α), and enhanced the expression of IL-10 and IL-27. Additionally, oxymatrine upregulated the STING/TBK1/IRF3 signaling pathway in EAE mice, promoting IFN-β production by microglia. Similarly, in LPS-induced BV2 cells, oxymatrine suppressed inflammatory factors and activated the STING/TBK1/IRF3 pathway to enhance IFN-β production. Notably, treatment with the STING inhibitor, C176, reversed these effects in both EAE mice and LPS-induced BV2 cells, confirming the pathway's critical role in the mechanism of oxymatrine therapy. Oxymatrine promotes IFN-β production in microglia by upregulating the STING/TBK1/IRF3 signaling pathway, thereby alleviating the neurological dysfunction of EAE and reducing pathological and inflammatory events. This study identifies a novel anti-EAE mechanism of oxymatrine: promoting IFN-β production in microglia by activating the STING/TBK1/IRF3 pathway. However, it lacks clinical sample verification. If validated later, oxymatrine may provide a more economical, convenient endogenous IFN-β induction regimen for MS patients. 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
Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herba Show more
Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herbal preparation consisting of Panax ginseng C.A.Mey (Hongshen) and Ophiopogon japonicus (Thunb.) Ker Gawl (Maidong), traditionally used for qi-replenishing, collapse-stabilizing, and lung-moistening therapy. Although clinically utilized in the management of SA-ALI, the specific mechanisms by which it acts against SA-ALI necessitate further investigation. The present study endeavors to comprehensively determine the therapeutic efficacy of SMI against SA-ALI through an integrated approach combining network pharmacology, metabolomics, metagenomic sequencing, and experimental validation. In this study, murine SA-ALI was established using lipopolysaccharide (LPS) and Poly(I:C). Results indicated that SMI administration significantly attenuated pulmonary inflammation, restored blood-gas barrier integrity, reduced serum pro-inflammatory cytokines and suppressed NF-κB pathway activation in SA-ALI mice. Network pharmacology elucidated the multi-targeted mechanism of SMI in modulating steroid hormone biosynthesis. Integrated metabolomics and target analysis revealed that ophiopogonin A/B and luteolin in SMI alleviates metabolic dysregulation by targeting key enzymes, including AKR1C3, HSD17B1/2, and SULT1E1. Metagenomic profiling demonstrated SMI-mediated gut microbiota remodeling, marked by suppression of pathogenic Chlamydiaceae (particularly Chlamydia abortus) and enrichment of commensal Lactobacillaceae. Correlation analysis showed that intestinal androstenedione and androsterone levels during SMI treatment recovery were negatively correlated with Chlamydia abortus abundance. In conclusion, SMI enhances the recovery from sepsis-associated SA-ALI by dual modulation of gut microbial ecology and host metabolic homeostasis, thereby establishing its potential as a multi-mechanistic therapeutic candidate for sepsis-related organ injury. 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
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
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
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
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
The treatment and prognosis of cardiac amyloidosis (CA) depend heavily on the accurate identification of amyloid protein types. Histopathological methods are the most commonly used approach, but often Show more
The treatment and prognosis of cardiac amyloidosis (CA) depend heavily on the accurate identification of amyloid protein types. Histopathological methods are the most commonly used approach, but often produce inconclusive results. The application of mass spectrometry with laser microdissection mass spectrometry based on non-targeted proteomics in CA diagnosis is gradually being recognized, but it is expensive, time-consuming, and still in the early stages of scientific research applications. This study aims to establish a novel typing method based on targeted semi-quantitative proteomics to address the shortcomings of existing methods. Formalin-fixed, paraffin-embedded (FFPE) myocardial tissue samples from 52 CA and 52 hypertrophic cardiomyopathy (HCM) patients were analyzed. A semi-quantitative typing method was developed using triple quadrupole mass spectrometry, with laser microdissection mass spectrometry (LMD-MS) serving as the reference standard. A total of 52 peptides were analyzed. Key amyloid-associated proteins (AAPs) -apolipoprotein A-IV (apo A-IV), apolipoprotein E (apo E), and serum amyloid P component (SAP) - showed high diagnostic accuracy, with AUC values of 0.964, 0.999, and 0.923, respectively. Transthyretin (TTR), immunoglobulin light chains- κ (IGL - κ), and IGL-λ were semi-quantified using normalized scores (NS) adjusted for microdissection and peptide peak areas. An NS This targeted semi-quantitative mass spectrometry method has high consistency with non-targeted LMD-MS typing, with an accuracy higher than IHC (100 % vs. 30.8 %), while compensating for the shortcomings of non-targeted proteomics. It provides a practical method for CA typing in routine clinical laboratories and may help identify rare subtypes of amyloidosis in the future. 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
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
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
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
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
William Stewart, Bin Hu, Fengqiao Li+6 more · 2025 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabete Show more
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction. Show less
Familial Hypercholesterolaemia (FH) is characterised by high cholesterol and premature cardiovascular disease. While hypercholesterolaemia and inflammation are both key drivers in the formation of ath Show more
Familial Hypercholesterolaemia (FH) is characterised by high cholesterol and premature cardiovascular disease. While hypercholesterolaemia and inflammation are both key drivers in the formation of atherosclerotic plaques, inflammation remains understudied in FH. Inflammatory (M1) macrophages contribute to plaque destabilisation and macrophage precursors, monocytes, can be skewed towards an inflammatory state. Aims: Determine; whether monocytes of FH individuals are inflammatory, if they readily form inflammatory macrophages, and whether this remains so in statin-treated individuals. Blood samples were collected from people with FH (statin-treated and untreated) and healthy controls. Lipid profile was obtained and monocyte inflammatory marker expression was determined by whole blood flow cytometry. Monocytes were cultured with autologous serum and resultant macrophage profile determined by flow cytometry. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were higher in the Untreated-FH group compared to the Treated-FH group and controls. In both Treated-FH and Untreated-FH groups, monocytes were inflammatory with high CD86 (M1). The ratio of inflammatory/anti-inflammatory markers (CD86/CD163) significantly correlated with LDL-C and ApoB/ApoA1 ratio across the cohort, indicating the high LDL-C of FH may promote an inflammatory monocyte profile. Monocyte-derived-macrophages from (Treated) FH individuals also had a more inflammatory profile (CD86 and CD86/CD163). Overall, monocytes show inflammatory skewing in FH individuals, even those with moderately-reduced cholesterol levels. These monocytes readily become inflammatory macrophages. This, along with subsequent inflammatory macrophage formation, could contribute to plaque destabilisation and downstream clinical events. This supports inflammatory monocyte targeting as a potential approach to reduce residual risk in FH individuals. 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
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
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
Ruotong Li, Wenye Zhao, Jiaxin Zhang+7 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its Show more
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its active metabolites have been implicated in muscle development and the transformation of muscle fiber types. However, conventional VA formulations are restricted by poor stability and low bioavailability. In this study, a stable Nano VA was utilized to systematically evaluate its effects on muscle development and exercise performance in mice, as well as to explore its underlying mechanisms. A total of 44 male C57BL/6J mice were randomly divided into four groups: (i) normal control (NC), (ii) 5 mg/kg Nano VA (5 NVA), (iii) 10 mg/kg Nano VA (10 NVA), and (iv) 10 mg/kg VA (10 VA). The 10 NVA group demonstrated significantly improved muscle strength and swimming endurance, compared with the NC group. Further examination suggested a significant increase in myofiber diameter, cross-sectional area, and the content of fast-twitch fibers. Additionally, Nano VA treatment improved glucose tolerance and insulin sensitivity. To elucidate the mechanism by which Nano VA enhances muscle locomotor ability, transcriptomics and metabolomics data identified 111 differentially expressed genes and 253 differential metabolites. Of these, Angptl4, Ppp1r3a, and Cyp26b1 were identified as candidate regulators of muscle development and myofiber type transformation. In conclusion, Nano VA regulates muscle development and promotes muscle fiber type conversion, thus improving muscle strength and endurance in mice. Moreover, Nano VA facilitates mitigating and improving myasthenia gravis-related conditions. Show less
Halide perovskite nanomaterials have emerged as a transformative platform for generating and manipulating polarized luminescence, offering unprecedented opportunities for next-generation optoelectroni Show more
Halide perovskite nanomaterials have emerged as a transformative platform for generating and manipulating polarized luminescence, offering unprecedented opportunities for next-generation optoelectronic technologies. This review comprehensively examines recent advances in engineering both linearly polarized luminescence (LPL) and circularly polarized luminescence (CPL) from perovskite nanostructures, focusing on structural design principles, chirality transfer mechanisms, and performance optimization strategies. Methods are systematically analyzed to achieve polarized emission, including anisotropic nanocrystal growth, chiral ligand functionalization, and liquid crystal-mediated alignment, while highlighting critical optical factors such as dissymmetry factors and photoluminescence quantum yield. Key challenges in enhancing the precision control over perovskite nanostructures, room-temperature CPL efficiency, and scalable assembly are discussed, with a forward-looking perspective on the integration of artificial intelligence (AI) to accelerate progress in the development of perovskite nanomaterials with customized polarized luminescence. By bridging fundamental insights with technological applications, this review outlines a roadmap for developing perovskite-based polarized light sources that combine high performance, stability, and manufacturability, which are key enablers for the future of quantum photonics, ultra-secure communication, and intelligent optical systems. 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
Mengru Pan, Yifan Qian, Linlin Jiang+2 more · 2025 · Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology · Taylor & Francis · added 2026-04-24
To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism. Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA Show more
To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism. Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA) were established to evaluate the impact of GIP on androgen synthesis Administration of GIP significantly reduced testosterone secretion in a DHEA-induced PCOS mouse model. Consistent with these findings, GIP treatment decreased testosterone release and downregulated the expression of GIP receptor (GIPR), steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1) in NCI-H295R cells. Notably, RNA-seq revealed that Our study demonstrated that the administration of GIP reduces androgen synthesis in PCOS mouse models and at the cellular level, suggesting its potential as a novel therapeutic target for managing PCOS. 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