👤 Xin Xiang

This study aimed to explore the effect and mechanism of polyphyllin Ⅱ in improving di(2-ethylhexyl)phthalate(DEHP)-induced learning and memory impairment. In the experiment, male C57BL/6 mice were randomly divided into five groups: a control group, a model group(exposed to 5 mg·kg~(-1) DEHP), and polyphyllin Ⅱ groups(5 mg·kg~(-1) DEHP + 0.5 mg·kg~(-1) polyphyllin Ⅱ, DEHP + 1 mg·kg~(-1) polyphyllin Ⅱ, and DEHP + 2 mg·kg~(-1) polyphyllin Ⅱ). The learning and memory function of mice was tested using the Morris water maze. The hippocampal neuron structure was detected by Nissl staining. The expression of casein kinase Ⅱ subunit beta(CK2b), protein kinase B(Akt)-cAMP response element binding protein(CREB) pathway-related proteins, as well as postsynaptic density protein 95(PSD95) and synapsin 1 was determined by immunofluorescence and Western blot. The brain-derived neurotrophic factor(BDNF) expression was measured by enzyme-linked immunosorbent assay(ELISA). The results showed that compared with the control group, DEHP induced learning and memory impairment, as well as hippocampal neuronal apoptosis in mice. Additionally, DEHP downregulated CK2b, inhibited the Akt-CREB pathway, and downregulated the PSD95, synapsin1, and BDNF expression. After polyphyllin Ⅱ administration, DEHP-induced learning and memory impairment was significantly improved, with inhibited hippocampal neuronal apoptosis, restored CK2b expression, reactivated Akt-CREB pathway, as well as restored expression of PSD95, synapsin1, and BDNF. Furthermore, the surface plasmon resonance(SPR) experiment of N2a cells demonstrated that polyphyllin Ⅱ targeted CK2b and stabilized its expression. After using siRNA to inhibit CK2b, the neuroprotective effect of polyphyllin Ⅱ was also significantly inhibited, and neuronal apoptosis was reinduced. In conclusion, polyphyllin Ⅱ can ameliorate DEHP-induced learning and memory impairment, with its potential mechanism involving the Akt-CREB pathway activation via CK2b upregulation, which leads to restored PSD95 and synapsin1 expression, and synaptic plasticity, as well as inhibited neuronal apoptosis, ultimately exerting a neuroprotective effect. This study suggests that polyphyllin Ⅱ possesses a neuroprotective effect and has potential application value in improving cognitive impairment. Show less

Critical limb ischemia (CLI) represents a severe vascular complication of type 2 diabetes, primarily driven by impaired angiogenic capacity, and frequently results in limb amputation or mortality. Here, we investigated the therapeutic potential of tirzepatide in promoting perfusion recovery in diabetic hindlimb ischemia and delineated the underlying molecular mechanisms. Human umbilical vein endothelial cells (HUVECs) exposed to high glucose were employed to evaluate tirzepatide's effects on endothelial proliferation, migration, and tube formation, alongside the activation of Akt, endothelial nitric oxide synthase (eNOS), and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, assessed by western blotting. Knockdown of GLP-1R or GIPR abrogated the pro-angiogenic effects of tirzepatide, while pharmacological inhibition of the Akt/eNOS or ERK1/2 pathways attenuated endothelial responses. In vivo, tirzepatide treatment significantly enhanced perfusion recovery and increased capillary density in the ischemic limbs of diabetic mice, corroborating its angiogenic effects. Collectively, these findings demonstrate that tirzepatide facilitates angiogenesis and accelerates ischemic limb revascularization through dual GLP-1R/GIPR activation and subsequent engagement of Akt/eNOS and ERK1/2 signaling pathways, highlighting its potential as a therapeutic strategy for diabetic CLI. Show less

As a complex physiological and psychological phenomenon, pain has a wide impact on the quality of life of patients. Chronic pain represents one of the most challenging public health issues, and ensuring effective pain management is not only a fundamental right of individuals but also a sacred duty of healthcare providers. This review focuses on recent advancements (within the past five years) in understanding how electroacupuncture (EA) alleviates pain-related affective disorders, such as anxiety and depression. By integrating findings from clinical trials and mechanistic studies, we highlight three key mechanisms: (1)Brain functional regulation: EA modulates brain regions (e.g., prefrontal cortex, insula, thalamus) and networks (default mode network, salience network) via functional magnetic resonance imaging (fMRI)-observed functional connectivity changes. (2)Neurotransmitter and receptor modulation: EA regulates pain and emotions by altering BDNF, β-endorphin, TRPV1, NMDARs, and P2Y12 receptor signaling, supported by studies on chronic pain and depression models. (3)Immune factor adjustment: EA reduces neuroinflammation by targeting TLR4/NF-κB pathways and pro-inflammatory cytokines (IL-1β, TNF-α), improving pain-related affective disorders. Clinical and preclinical evidence demonstrates EA's safety, efficacy, and multi-target effects, however, optimal treatment parameters and individualized strategies require further investigation. Future research should combine multi-omics, large-scale multi-center clinical studies , and precision medicine approaches to deepen understanding of EA's mechanisms and clinical applications. Show less

Neuropathic pain (NP) frequently co-occurs with depression (DP), exhibiting complex pathogenesis and limited clinical treatment options. This study aims to investigate the efficacy of Eupalinolide B (EB) in alleviating NP co-occurring with DP and its potential molecular mechanisms. Combining network pharmacology, molecular docking, and molecular dynamics simulations to screen potential targets for EB, validated through transcriptomic data. Using a sciatic nerve branch-preserving injury (SNI) mouse model, we assessed pain and depression-like behaviors through von Frey testing, hot plate testing, tail suspension testing, forced swimming testing, and open field testing. Concurrently, Western blotting, immunofluorescence, and Nissl staining were employed to analyze relevant molecules and neuropathological alterations. Network pharmacology and bioinformatics analysis identified EGFR, PTGS2, and JUN as the key targets for EB in treating NP combined with DP. Behavioral studies showed that 20 mg/kg of EB significantly alleviated pain in SNI mice and improved depressive-like behaviors. Mechanism research indicated that EB downregulated the expression of EGFR and PTGS2, inhibited the activation of microglia and astrocytes, and reduced neuronal damage. Additionally, EB could upregulate the expression of synaptic proteins (PSD95, SYN1, and BDNF) in the hippocampus. EB alleviates neuroinflammation by reducing EGFR and PTGS2 protein expression, modulates synaptic plasticity, and improves pain-depression comorbidity. EB may represent a promising therapeutic approach for pain-related depression. Show less

Patients with type 2 diabetes mellitus (T2DM) face a significantly elevated risk of developing cognitive impairment (CI), which has been recognized as an independent risk factor for dementia. Current glucose-lowering medications are limited by poor central nervous system penetration, delayed intervention, and single-target approaches, highlighting an urgent need for safe and effective complementary strategies. Exercise therapy, leveraging its advantage in "metabolic-neural bidirectional regulation," demonstrates considerable potential in ameliorating T2DM-related CI. This article systematically reviews basic and clinical research from the past decade, revealing that: ① Aerobic exercise, Tai Chi, and dual-task training can all significantly improve global cognitive scores (MoCA, MMSE), with effect sizes increasing over longer intervention periods; ② Tai Chi yields the most comprehensive benefits in memory, executive function, and balance-fall prevention, with an adherence rate as high as 79.6%; ③ Exercise exerts its effects through multi-target mechanisms, including upregulation of BDNF/IGF-1, suppression of IL-6/TNF-α, restoration of blood-brain barrier integrity, remodeling of the gut microbiota-butyrate-brain axis, and enhancement of mitophagy. Future research should focus on large-sample, multi-center, long-term follow-up studies to establish personalized exercise prescriptions based on genetic-metabolic-microbiota profiles. Integrating digital health technologies will enable remote monitoring and precise implementation, thereby providing an evidence-based foundation for constructing an integrated "metabolic-cognitive" prevention and treatment model. Show less

Fatty acid-binding proteins (FABPs) influence cellular energy metabolism by regulating fatty acid kinetics. They also play a vital role in neuronal apoptosis following cerebral infarction. Resveratrol (RSV) has demonstrated neuroprotective effects in ischemic stroke; however, its regulatory impact on FABPs and associated pathways requires further investigation. This study aimed to explore the potential mechanisms by which RSV protects ischemic stroke neurons by regulating fatty acid metabolism. A weighted gene co-expression network analysis revealed significant enrichment of FABP5 in fatty acid metabolism-related pathways in rats with middle cerebral artery occlusion (MCAO). Modulating FABP5 expression level may influence post-infarction neuronal recovery. Molecular docking experiments demonstrated that RSV exhibited strong binding affinity with FABP5. In the MCAO-group of rats, administering different doses of RSV led to a significant decrease in cerebral infarct area and improved neurological function with increased RSV doses. Concurrently, the expression of FABP5 and neuron-specific enolase in brain tissue decreased, whereas the expression of the brain-derived neurotrophic factor increased and neuronal morphology improved. Further experiments using FABP5 overexpression and inhibition models revealed that FABP5 overexpression exacerbated neuronal apoptosis and suppressed the expression of adenosine monophosphate (AMP)-activated protein kinase (AMPK) protein, whereas FABP5 inhibition reduced neuronal apoptosis and enhanced AMPK protein expression. RSV downregulates FABP5 expression in cerebral infarction tissues and potentially mediates the AMPK-related pathways to ameliorate neuronal apoptosis. Show less

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and increasingly associated with gut microbiota alterations. Roseburia intestinalis (R. intestinalis) is consistently reduced in PD; however, its functional contribution remains unknown. We performed two complementary mouse experiments using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. In the primary intervention experiment, mice received live or heat-killed R. intestinalis, followed by behavioral assessments and multi-layer analyses, including immunofluorescence, western blotting, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, 16S rRNA sequencing, metabolomics, and transcriptomics. In a separate mechanistic experiment, subdiaphragmatic vagotomy was introduced to interrogate vagus-dependent gut-brain communication, with key behavioral and inflammatory endpoints assessed. Live R. intestinalis improved rotarod, pole, and grip strength performance and preserved tyrosine hydroxylase-positive neurons in the substantia nigra; however, these effects were not observed in the heat-killed group. Live R. intestinalis treatment also reduced glial reactivity, restored brain-derived neurotrophic factor expression, and maintained blood-brain barrier integrity. Systemically, R. intestinalis lowered serum lipopolysaccharide, tumor necrosis factor-α, and interleukin-6 levels; preserved colonic structure; and restored mucin-secreting goblet cell function. MPTP-induced dysbiosis was partially corrected. Metabolomic profiling revealed restoration of several acyl-carnitines and higher acetic acid levels. Transcriptomic analysis showed increased immediate early genes after MPTP, and the elevated c-Fos in the substantia nigra was partially normalized by R. intestinalis. Importantly, vagotomy abolished the central neuroprotective and anti-inflammatory effects but did not affect peripheral cytokine suppression, indicating both vagus-dependent and vagus-independent pathways. R. intestinalis supplementation alleviated motor impairments, reduced neuroinflammation, preserved dopaminergic neurons, and improved intestinal and metabolic alterations in mice with an MPTP-induced PD model. Its protective actions may involve both central and peripheral mechanisms, potentially including gut-brain communication pathways. R. intestinalis may be a promising candidate for microbiota-based strategies against PD. Show less

Pancreatic cancer (PC) exhibits an extremely poor prognosis due to its high heterogeneity. The senescence-associated secretory phenotype (SASP), a distinct secretory profile displayed by senescent cells, has been increasingly studied. However, the role of SASP in PC prognosis and treatment remains unclear. Transcriptomic sequencing data from PC patients were analyzed using consensus clustering based on SASP genes. A prognostic signature was subsequently constructed Consensus clustering based on SASP genes identified two SASP-associated clusters (SASPclusters), with cluster B demonstrating significantly worse prognosis than cluster A. Thirty-three SASP genes showed significant associations with PC prognosis, and a 7-gene SASP-based prognostic signature was established. High-risk patients exhibited significantly higher mutation rates. Distinct immune cell infiltration patterns, immune functions, checkpoint expression levels, and chemosensitivity profiles were observed between risk groups. Besides, we found that ANGPTL4 could promote PC cell proliferation, migration, and invasion. Molecular subtyping and risk stratification based on SASP genes effectively predict PC prognosis and reveal heterogeneity in mutational burden, immune microenvironment, and therapeutic sensitivity. These computational findings deepen our understanding of potential role of SASP in PC and provide a theoretical foundation for personalized treatment strategies. Show less

Significant interindividual variability in radiosensitivity poses a major challenge to conventional radiation protection and radiotherapy. Current prediction strategies relying on DNA damage or genomic analysis have inherent limitations, underscoring the need for minimally invasive serum biomarkers. While serum apolipoproteins are crucial regulators of lipid transport, metabolism, and cellular stress response, their role as biomarkers for radiosensitivity remains largely unexplored. A 7.3 Gy ⁶⁰Co γ-ray whole-body irradiation mouse model (with training and independent validation cohorts) was established to assess individual radiosensitivity. Pre-irradiation peripheral serum samples underwent high-throughput proteomics analysis to identify differential proteins (DEPs) linked to 30-day post-irradiation survival. KEGG and GO enrichment analyses were conducted to characterize DEP-associated pathways. An XGBoost machine learning model was built using candidate biomarkers, with SHAP analysis to define their predictive contributions; Cox proportional hazards and Pearson correlation analyses were applied to evaluate survival associations. DIA-based proteomics identified 580 DEPs in the training cohort and 449 in the validation cohort. KEGG and GO enrichment analyses confirmed that these DEPs were predominantly enriched in the cholesterol metabolism and reverse cholesterol transport pathways. The predictive model based on an apolipoprotein panel (ApoA1/ApoA2/ApoA4), established using the XGBoost algorithm, exhibited exceptional performance in the training cohort (AUC = 1) and maintained robust generalizability in an independent validation cohort (AUC = 0.833). Compared with non-survivors, survivors exhibited significantly elevated serum levels of ApoA1 and ApoA2 but markedly reduced levels of ApoA4. Cox proportional hazards regression analysis established ApoA1 and ApoA2 as independent protective factors, whereas high ApoA4 expression was an adverse prognostic indicator. Notably, ApoA4 levels also demonstrated a strong negative correlation with post-irradiation survival time. The serum apolipoprotein profile (ApoA1/ApoA2/ApoA4) serves not only as a promising minimally invasive biomarker for predicting individual radiosensitivity in mice but also reveals a critical link between the cholesterol metabolic pathway and radiation response. This finding lays a theoretical foundation for translating predictive, cholesterol metabolism-related biomarkers to support radiation response assessments. Given the limitations of animal models, subsequent studies are required to validate the clinical applicability of this panel in human cohorts, with the aim of offering an effective tool for personalized radiation protection and precise radiotherapy. The online version contains supplementary material available at 10.1186/s12944-026-02868-8. Show less

A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease. Show less

Apolipoproteins (APOs) are essentially structural and functional components of lipoproteins, which are composed of 22 members and their effects on certain types of cancer have been studied. However, their roles in endometrial cancer (EC), which is one of the most common malignant tumors in gynecology were unclear and rarely investigated. We investigated the expression levels of APOs genes in EC. Furthermore, we explored the roles of APOs in prognostic value, and immune infiltrates in EC patients by using different bioinformatics databases. Nine APO genes (APOC1, APOC2, APOC4, APOD, APOE, APOL3, APOL4, APOLD1, and APOO) were found differently expressed between EC and control tissues by the GEPIA2. However, APOC4 was not included in the subsequent analysis due to its low expression in EC tissues. Moreover, mRNA expression levels of APOs were found correlated with the clinicopathological characteristics of EC, including stage, grade, molecular subgroups, p53 mutant conditions, PTEN mutant conditions, and expression levels of ESR1 and ESR2. Meanwhile higher expression levels of APOs were significantly correlated with better (APOD, APOL3) or poorer (APOC1, APOE, APOLD1) OS. ssGSEA showed 7 TILs in EC which differed significantly from those in adjacent noncancerous tissues were correlated with prognosis of EC patients. The expression levels of both APOD and APOE were positively correlated with all 7 TILs. Finally, western blotting showed that 17β-estradiol (E2) increased APOE protein expression level and reduced APOD protein expression level. Furthermore, APOE was identified to promote the cell migration by scratch assay. The expression of APOs may be a promising prognostic biomarker and is associated with immune invasion as a potential target for endometrial cancer. Show less

Vitiligo pathogenesis involves progressive melanocyte loss and keratinocyte dysfunction, which are driven primarily by oxidative stress resulting from excessive ROS accumulation. We engineered a temporally controlled hydrogel microneedle system that integrates ginseng-derived exosomes (G-Exos) with biomimetic polydopamine nanoparticles (PDA@PEGs) to concurrently target the pathogenic triad of vitiligo, including oxidative stress, inflammation, and melanocyte deficiency. This system employs methacrylated hyaluronic acid (HAMA) hydrogel microneedles for rapid PDA@PEG release while utilizing glyceryl monostearate micelles to achieve matrix metalloproteinase-9 (MMP-9)-responsive G-Exo release at inflammatory foci, enabling intelligent spatiotemporal control. Functionally, G-Exos help restore redox homeostasis and suppress inflammation through bioactive constituents, thereby protecting melanocytes and enhancing keratinocyte proliferation. Moreover, PDA@PEG promotes repigmentation through the dual mechanisms of exogenous melanin deposition and endogenous melanogenesis stimulation. In murine models, this strategy achieves significant repigmentation within 3 weeks by activating follicular stem cells, upregulating melanogenic markers (Tyr/Mc1r), increasing antioxidant defense (ApoE), and suppressing inflammatory signaling (IL-17). This natural-biomimetic hybrid design leverages biocompatible materials to co-target multiple pathological axes, offering a novel self-adaptive approach for microenvironmental rehabilitation in vitiligo. Show less

Atherosclerosis is a leading cause of worldwide cardiovascular morbidity and mortality, and endothelial ferroptosis has emerged as a key mechanism in driving vascular injury. This study aimed to investigate whether quercetin (QCT), a natural dietary flavonoid with potent anti-oxidant activity, protects against atherosclerosis-associated endothelial dysfunction by modulating ferroptosis. In order to test this, ApoE[Formula: see text] mice fed a high-fat diet were treated with QCT or ferrostatin-1, and their aortic plaque burden, stability, and macrophage infiltration were then assessed. To evaluate ferroptosis, human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (Ox-LDL), with or without QCT, and their reactive oxygen species (ROS), Fe[Formula: see text] accumulation, and heme oxygenase-1 (HMOX-1) expression were measured. While functional assays examined endothelial barrier integrity and monocyte adhesion, gene modulation studies explored the role of phosphofurin acidic cluster sorting protein 2 (PACS2). QCT treatment markedly reduced plaque area, necrotic core size, and macrophage infiltration while enhancing plaque stability. Show less

The integrity of blood-brain barrier (BBB) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ clearance and neurotoxic compound exclusion. Hyperlipidemia exacerbates AD by impairing the BBB function. Inclisiran, a PCSK9-targeting siRNA, reduces cholesterol levels; however, its neuroprotective effects remain unclear. Here, we report the novel discovery that Inclisiran attenuates AD-like changes through the PCSK9-ferroptosis axis in brain microvascular endothelial cells (BMECs). First, integrated bioinformatics analysis and experimental validation of cortical tissues from patients with AD and healthy controls revealed a coordinated upregulation of PCSK9 and β-amyloid (Aβ), accompanied by increased iron deposition and significant activation of the ferroptosis pathway. Interestingly, these changes are located in the BMECs of the blood-brain barrier rather than in the brain parenchyma. Second, in hyperlipidemic ApoE Show less

Atherosclerosis (AS) is a chronic vascular disease and the principal cause leading to ischemic cardiomyopathy (ICM). It involves complex metabolic dysregulation beyond the resolution of single-omics. Emerging evidence implicates arginine-proline metabolism (APM) in driving inflammation and impairing efferocytosis, yet the cellular basis of plaque instability remains elusive. We employed a five-stage analytical framework. First, metabolomic profiling revealed shared pathways between AS and ICM. Second, single-cell RNA sequencing identified APM-enriched macrophage subtypes in both diseases. Pseudotime analysis, Scissor algorithm, and cell-cell communication analyses linked these subtypes to APM signaling, stroke prognosis, and key ligand-receptor interactions. Third, cNMF and unsupervised clustering defined APM-related gene signatures in macrophages, validated by survival analysis. Fourth, spatial transcriptomics confirmed their spatial distribution and colocalization within unstable plaques. Finally, key biomarkers were validated in atherosclerotic lesions using ApoE Metabolomic profiling revealed APM as a shared dysregulated pathway in AS and ICM. We identified a macrophage subset (SPP1⁺ macrophages and mono-macrophages), termed APM_high macrophages, enriched in the fibrous cap and characterized by elevated collagenase activity, heightened inflammation, and disrupted cholesterol homeostasis. Spatial and cell-cell communication analyses revealed strong interactions with dendritic cells via the MIF-(CD74 + CXCR4) axis, potentially contributing to plaque destabilization. Transcriptomic clustering uncovered a high-APM plaque subtype associated with worse ischemic outcomes. Six diagnostic biomarkers were identified through machine learning and validated across multiple cohorts and in ApoE In summary, our study decodes the metabolic basis of inflammation shared between AS and ICM, suggesting an APM_high macrophage-centered regulatory axis across multiple omics layers. This work advances our understanding of the cardio-metabolic axis and suggests new avenues for targeted therapy. Show less

Recently, macrophage senescence has been identified as an important pathological risk factor for atherosclerosis (AS). Oxymatrine (OMT) has demonstrated potential in ameliorating cellular senescence. This study aims to investigate the pharmacological properties and underlying mechanisms of OMT in alleviating AS progression. High-fat diet-fed ApoE Show less

FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less

Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain incompletely understood. Here, we demonstrate that GBM cells outcompete NK cells for branched-chain amino acid (BCAA), leading to BCAA depletion, suppression of NK and CD8 Show less

N-carbamylglutamate (NCG) is an activator of arginine biosynthesis, but its specific role in crustaceans remains poorly understood. This study aimed to investigate the effects of NCG on arginine biosynthesis capacity, metabolism, digestion, and the gene expression of the mTOR signaling pathway in Eriocheir sinensis. In Experiment 1, hepatopancreas was cultured in vitro with NCG medium (0, 65, 75, and 85 mg/L NCG). In Experiment 2, crabs were fed either regular feed or NCG feed (content: 302.96 ± 4.07 mg/kg) for 14 days. In Experiment 1, NCG significantly upregulated pyrroline-5-carboxylate synthase (p5cs) gene expression (P < 0.05), an enzyme that is related to arginine biosynthesis. Similarly, dietary NCG upregulated p5cs expression and significantly increased the activities of carbamoyl-phosphate synthase-1 (CPS-1) and P5CS in the hepatopancreas and intestine (P < 0.05). Metabolomics analysis indicated that NCG altered the metabolic profile of the hepatopancreas, promoting cholesterol metabolism, and arginine and proline metabolism. In the intestine, trypsin and α-amylase activities were significantly elevated (P < 0.05). NCG also altered the composition of intestinal microflora, with an increase in Proteobacteria and in the ratio of Firmicutes to Bacteroidota. Additionally, NCG increased the content of signaling molecule nitric oxide (NO) and upregulated the expression of genes in the mTOR signaling pathway (P < 0.05). In conclusion, NCG supplementation enhanced arginine biosynthesis capacity, stimulated intestinal enzymatic activities, and upregulated mTOR signaling pathway gene expression in Eriocheir sinensis, indicating the potential for improved metabolism and digestion. Show less

Artificial sweeteners (ASs) are widely used sugar substitutes, but chronic exposure is linked to male infertility. We integrated computational prediction, network analysis, and wet-lab validation to explore mechanisms. Seven ASs were screened in AdmetSAR 3.0; high-confidence positives were prioritized. Targets were predicted by SwissTargetPrediction, SEA, and TargetNet, and intersected with the top 50 % GeneCards testicular-injury genes to define candidate targets. STRING PPI and enrichment analyses were performed, followed by machine-learning feature selection and independent dataset validation. Ligand-target binding was evaluated by molecular docking and 100-ns molecular dynamics (MD) simulations. Single-cell RNA-seq (Male Health Atlas) mapped core-gene expression across testicular clusters. TM3 Leydig cells were exposed to aspartame (0.5-2 mM) for 48 h and analyzed by RT-qPCR. Aspartame, neotame, and sucralose showed high-confidence reproductive-toxicity signals. Ninety-one candidate targets were identified, and FGFR1 emerged as the core gene with good discrimination in two datasets. Docking and MD supported stable AS-FGFR1 binding, especially for aspartame. FGFR1 was enriched in Leydig and vascular-associated cells. Aspartame upregulated FGFR1, DUSP6, and SPRY2 and downregulated STAR. FGFR1-associated signaling may link AS exposure to impaired male reproductive function, warranting in vivo and protein-level validation. Show less

Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound Show less

Dairy cattle, particularly in Australia where dairy farming is predominantly pasture based, are experiencing an increased incidence of heat stress through rising global temperatures, causing a detrimental impact on productivity and welfare. Improving the thermotolerance of dairy cows through genetic selection is a potential proactive solution for mitigating the impact of heat stress for the dairy industry. Although heat tolerance breeding values for milk yield traits have been available to Australian dairy producers since 2017, considerable potential remains to develop genetic evaluation for heat tolerance of fertility and understanding of the underlying genetic architecture for heat tolerance. The objective of this study was to investigate the effect of heat stress measured as temperature and humidity index (THI) on fertility traits and to identify genomic regions associated with heat tolerance in 2 specific fertility traits: first service non-return rate (FNRR) and successful calving rate to first service (SCRFS). In this study, we assembled more than 892k phenotypic records of Holstein cows with THI and fertility traits and identified specific periods with respect to service day. The effect of heat stress on fertility was assessed using random regression (RR) sire model for estimating the change in genetic variance of fertility across various THI and obtaining heat tolerance solution (slope) for sires. Also, whole genome sequence genome-wide association studies (GWAS) were undertaken based on heat tolerance phenotypes of 5k Holstein bulls with at least 10 daughters with fertility data. The assessment of the different THI definitions based on different numbers of days before and after artificial service days on the fertility traits showed that the most prominent effect of THI on fertility outcomes was observed for THI 7 d preceding service (including the service day) and 6 d after service day. Heat tolerance (HT) traits with respect to FNRR and SCRFS are lowly heritable and ranged from 0.01 to 0.04 under moderate THI conditions ranging between 60 and 70. However, as the THI exceeded 70, the heritability increased to up to 0.08, indicating increased genetic variance as THI increased. Genetic correlations between extreme THI ranges were as low as 0.13, while correlations between consecutive THI ranges reached up to 0.98. This finding suggests the presence of genotype by environment interactions due to heat stress. Notable variation in heat stress sensitivity among sires was also observed for HT fertility. In total, 553 sequence variants were significantly associated HT fertility, and 52 of them were identified as independent QTL. Some of QTL regions were located near or within the genes that are involved in oxidative stress, inflammation, and fertility (e.g., TRPC5, CDK5RAP2, MGAT1, COMMD10, PRR7, GRK6, CUGBP1, MAFG, HERC2, NAPRT, HSD17B12, THRB, and EEF1D). The findings in this study will further aid in understanding genetic architecture and provide valuable information for improving the accuracy of genomic prediction of heat tolerance in dairy cattle. Show less

Probiotics such as The intestinal colonization ability of CIQ249 was assessed using cFDA-SE labeling and flow cytometry. Growth performance and intestinal morphology were evaluated in mice. Antimicrobial activity of CIQ249 cell-free supernatant was tested against various pathogens, and pathogen damage was visualized by scanning electron microscopy. Protective effects against CIQ249 demonstrated strong intestinal colonization and increased villus height and the villus-to-crypt ratio, contributing to improved growth performance. Its cell-free supernatant selectively inhibited enteropathogens and induced structural damage in CIQ249 enhances mucosal defense against enteropathogenic bacteria through a dual mechanism-strengthening the epithelial barrier and activating a coordinated DC-Tfh-IgA immune axis. These findings provide a multi-level mechanistic basis for its application as a microecological agent against intestinal infections. Show less

Sertoli cells are well known as crucial orchestrators in guaranteeing normal spermatogenesis and male fertility. Circular RNA (circRNA) has increasingly been identified within spermatogenesis-related cells, attributed with key regulatory roles. However, the functions and mechanisms of circRNAs in spermatogenesis remain largely unexplored, particularly in domestic animals. The present study was conducted to explore the regulatory and functional roles of circKANSL1, a nucleus enriched circRNA, in proliferation and apoptosis of immature porcine Sertoli cells. The circKANSL1 was confirmed as a novel, stable, nucleus-enriched circRNA in immature porcine Sertoli cells using reverse transcription PCR, Sanger sequencing assays, and fluorescence in situ hybridization assays. Overexpression of circKANSL1 facilitated cell cycle progression, enhanced cell proliferation, and inhibited cell apoptosis in immature porcine Sertoli cells. Transcriptome analysis revealed 248 differentially expressed genes that were induced by circKANSL1 overexpression, and the parental gene KANSL1 of circKANSL1 was detected as a top one up-regulated gene. Mechanistically, circKANSL1 recruited the Vimentin protein to enhance its parental gene KANSL1 expression. Furthermore, siRNA-induced KANSL1 gene knockdown exhibited an opposite effect to that of circKANSL1 overexpression. Collectively, our findings provided a novel functional mechanism of circRNA in participating spermatogenesis through deciding the fate of Sertoli cells. Show less

Falls have long been a significant safety concern worldwide, not only compromising the physical and psychological health of older adults and limiting their social engagement but also imposing substantial economic and caregiving burdens. Evidence on fall risk perception among Chinese community-dwelling older adults remains limited, especially for those transitioning to community living after hospital discharge. This research examined the subtypes of fall risk perception of Chinese community-dwelling older adults in the post-discharge transition and to explore subgroup characteristics and associated factors. A cross-sectional survey was conducted between January 2024 to March 2025 in Hangzhou, Zhejiang Province. A self-designed questionnaire was used to collect demographic and health-related information, The Fall Risk Perception Scale for Community-dwelling Older Adults was used to assess the fall risk perception, the objective fall risk was assessed by Morse Fall Scale. Latent profile analysis (LPA) was performed to extract latent classes of fall risk perception, and multinomial regression analyses were used to identify differences between these categories. A total of 468 older adults were included, with 56.0% were male. Three fall risk perception subtypes were identified by LPA: Low Perception-Social Context Desensitized Type (29.2%), Moderate Perception - Balanced Type (43.4%), and High Perception - Bio-behaviorally Salient Type (27.4%). Individuals who were aged with 70-79 (OR = 0.46, 95% CI: 0.27-0.77), with college education or above (OR = 0.31, 95% CI: 0.13-0.76), those who underwent surgery during hospitalization (OR = 0.26, 95% CI: 0.15-0.43), reported difficulty falling asleep (OR = 0.40, 95% CI: 0.20-0.82), and those with a history of falls (OR = 0.44, 95% CI: 0.24-0.81) were significantly more likely to be in the High Perception - Bio-behaviorally Salient Type. Compared to objective fall risk level, a third of participants (31.4%) correctly estimated their fall risk, 23.1% overestimated it and 45.5% underestimated it. Most older adults possess a Moderate Perception - Balanced Type toward fall risk. Key determinants of heightened risk perception included advanced age, higher education, fall history, and recent surgical experience. Tailored, profile-specific risk communication strategies are essential to improve perceptual accuracy during the hospital-to-home transition may support post-discharge fall prevention. Show less

Myopia is a critical public health issue; however, the roles of multidimensional psychological resources (i.e., resilience and emotion regulation) and potential gender differences remain underexplored. This cross-sectional study aimed to investigate the association between latent psychosocial profiles and myopia severity, and to examine the moderating role of gender in this association among adolescents. In total, 1008 Chinese seventh-grade students completed assessments of psychological resilience, emotion regulation, and depressive and anxiety symptoms. Myopia was measured as spherical equivalent refraction (SER). Latent profile analysis (LPA) was used to identify distinct psychological profiles, and moderation analysis tested gender's role in the profile-myopia association. LPA revealed three distinct psychosocial profiles: "Low-Resource", "Emotion-Driven", and "Balanced-Adaptive". The Low-Resource profile exhibited the highest levels of depression, anxiety, and myopia severity. A significant moderating effect of gender was found. Among females, both the Emotion-Driven and Balanced-Adaptive profiles were associated with significantly less myopia severity compared to the Low-Resource profile-an association not observed in males. Specific psychological resource profiles were linked to myopia severity, a relationship that was significantly moderated by gender and was prominent only in female adolescents. These findings highlight the importance of person-centered approaches and gender-specific considerations in understanding the psychosomatic pathways of myopia. Show less

This study aims to examine the health characteristics of female sex workers (FSWs) in entertainment venues and to investigate the relationship between these characteristics and sleep quality. This study employed a cross-sectional design and was conducted from January to April 2024 in Wuhan, China. Participants were FSWs recruited through snowball sampling from entertainment venues, including hotels, restaurants, nightclubs, karaoke bars and dance halls. Data were collected via structured questionnaires covering sociodemographic information, work experience, psychological stress, health status, sleep quality and circadian rhythms. Latent profile analysis (LPA) was employed to identify health characteristic profiles among FSWs, and multivariate logistic regression was used to examine the associations between these profiles and sleep quality. Among the 1,036 FSWs surveyed, 45.1% had poor sleep quality. LPA classified FSWs’ health characteristics into three profiles: the high overall functioning group, the lower physical–emotional functioning group and the lower psychosocial functioning group. Multivariate logistic regression analysis showed that FSWs in the lower physical–emotional functioning group had higher odds of poor sleep quality (OR = 2.184) compared with those in the high overall functioning group. FSWs in the lower psychosocial functioning group had substantially higher odds of poor sleep quality (OR = 7.755) than that in the high overall functioning group. FSWs demonstrate substantial heterogeneity in health characteristics and exhibit lower overall sleep quality compared with the general population. Psychological and physiological factors are major influencing factors for their sleep quality, suggesting the importance of prioritising mental and physical health in this population. Show less

Observational studies have yielded conflicting evidence regarding the interdependence between lipoprotein(a) [Lp(a)]-related cardiovascular risk and systemic inflammation. It remains unclear whether combined targeting of Lp(a) and inflammation provides additive cardiovascular benefits. This study aimed to investigate the associations between genetically predicted lower Lp(a) and cardiovascular disease (CVD) across interleukin-6 (IL-6) signalling levels and the combined effects of lower Lp(a) and IL-6 signalling activity on CVD risk. This study included UK Biobank participants of European ancestry. Genetic scores for LPA and IL-6 receptor (IL6R)-mediated signalling were calculated to mimic the effects of therapies targeting Lp(a) and IL-6 signalling, respectively. We investigated the associations of separate and combined exposure to lower Lp(a) and IL-6 signalling with coronary heart disease (CHD), ischaemic stroke (IS), heart failure (HF), atrial fibrillation (AF), peripheral artery disease (PAD), and aortic aneurysm (AA), using Mendelian randomization analyses and validating the findings in observational analyses. This study included 408 687 UK Biobank individuals (mean age, 57 years; 54% women). Genetically predicted lower Lp(a) was associated with reduced risks of CHD [odds ratio (OR) per 50 mg/dL reduction in Lp(a) levels, 0.68; 95% confidence interval (CI), 0.65-0.71], IS (0.89, 0.80-0.98), PAD (0.68, 0.62-0.76), HF (0.82, 0.77-0.88), and AA (0.71, 0.61-0.82). Genetically lower IL-6 signalling was associated with lower risks of CHD (OR per 0.5 log[mg/L] reduction in log-transformed C-reactive protein levels, 0.67; 95% CI, 0.55-0.82), AF (0.72, 0.55-0.94), and AA (0.43, 0.23-0.83). The genetic association between Lp(a) and CVD was consistent among individuals with different IL-6 signalling activity (P for difference > 0.05). Combined exposure to genetically predicted lower Lp(a) and IL-6 signalling was associated with an additive decrease in CHD risk (lower Lp(a): 0.67, 0.63-0.71; lower IL-6 signalling: 0.61, 0.46-0.80; combined: 0.25, 0.21-0.30; P for interaction = 0.144). In observational analyses, IL-6 levels below the median and Lp(a) concentrations below 50 mg/dL were also independently and additively associated with lower CHD risk (Lp(a) < 50 mg/dL: hazard ratio, 0.82; 95% CI, 0.72-0.93; IL-6 < median: 0.79, 0.65-0.96; combined: 0.65, 0.56-0.74; P for interaction = 0.102). Lower Lp(a) levels were associated with a reduced risk of CVD, independent of IL-6 signalling activity. Combined exposure to genetic variants lowering Lp(a) and downregulating IL-6 signalling was associated with an additive reduction in cardiovascular risk. These findings indicate that concurrent Lp(a)-lowering and anti-inflammatory therapies may reduce residual cardiovascular risk through additive effects. Show less

Sepsis triggered by lipopolysaccharide (LPS) is a life-threatening condition. Inspired by the specific capture mechanism of innate proteins like LBP and CD14, we develop oxidized chitosan microspheres functionalized with hyperbranched polylysine (OCS-HBPL) as a sepsis detoxification agent. Isothermal titration calorimetry (ITC) reveals that HBPL-LPS binding is an enthalpy-driven process, distinct from the entropy-driven interaction of linear polylysine (LPL)-LPS. Validated by surface plasmon resonance (SPR), HBPL demonstrates superior affinity with a dissociation constant (K Show less