As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphism Show more
As a result of individual genetic variations, some patients show no response to initial antidepressant medications. This study aims to investigate the association between specific genetic polymorphisms and the efficacy of antidepressant drugs and to improve the accuracy and effectiveness of treatment under the guidance of genetic testing. A retrospective screening was conducted on medical records from, Suixian People's Hospital between January 2022 and December 2024. A total 202 patients with depression carrying the CYP2C19 gene were selected after the application of exclusion criteria. They were assigned to three groups in accordance with their genetic metabolism types: the rapid metabolism group (Group A, n = 65), the intermediate metabolism group (Group B, n = 94) and the poor metabolism group (Group C, n = 43). All three groups were treated with sertraline for a six-week treatment cycle. The observation indicators included scores on the Hamilton Depression Scale (HAMD); onset time of drug effect; rates of response and remission; scores on the Clinical Global Impression-Improvement (CGI-I) scale; levels of the neurotransmitter factors 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF); incidence of adverse events; and scores on the Morisky Medication Adherence Scale-8 (MMAS-8). The baseline data of the three groups of patients were comparable before medication (p > 0.05). Compared with those in Groups A and B, patients in Group C showed a significantly greater reduction in HAMD scores (all p < 0.05), along with higher response rates (all p < 0.05) and remission rates (all p < 0.05). Amongst the three groups, Group C had a shorter onset time of drug effect (all p < 0.05); more significant improvement in CGI-I scores (all p < 0.05); and more prominent upregulation of neurotransmitter factors, namely, 5-HT (all p < 0.05), GABA (all p < 0.05) and BDNF (all p < 0.05). Regarding the incidence of adverse events, Group C had the highest rate, whereas Group A had the lowest (10.8% vs. 24.5% vs. 41.9%). Compared with other groups, Group B exhibited a more significant increase in MMAS-8 scores (all p < 0.05). Metabolic phenotype exerts substantial effects on the therapeutic outcome of sertraline in patients with depression carrying the CYP2C19 gene. Amongst groups, Group C showed better therapeutic efficacy but an elevated incidence of adverse events and lower medication adherence; Group A had relatively poor efficacy; and Group B demonstrated superior adherence. In clinical practice, individualised treatment can be implemented on the basis of CYP2C19 metabolic typing to improve therapeutic efficacy and reduce adverse events and medical burden. Show less
l-Pipecolic acid (l-PA) and its hydroxylated derivatives (hydroxypipecolic acids, HPAs) are non-proteinogenic amino acids that serve as valuable chiral building blocks for pharmaceuticals, antibiotics Show more
l-Pipecolic acid (l-PA) and its hydroxylated derivatives (hydroxypipecolic acids, HPAs) are non-proteinogenic amino acids that serve as valuable chiral building blocks for pharmaceuticals, antibiotics, and natural products. Conventional chemical synthesis of these compounds often suffers from operational complexity, poor environmental compatibility, and insufficient stereochemical control, driving a shift toward biosynthetic approaches. This review covers recent advances in enzyme engineering and synthetic biology aimed at enabling sustainable and efficient production of l-PA and HPAs. For l-PA biosynthesis, various metabolic engineering strategies to enhance its production in microbes are introduced, and enzyme cascades, single enzyme strategy, and immobilized enzyme strategy involved in l-PA production are discussed. Regarding HPAs biosynthesis, which involves the regioselective hydroxylation of l-PA, their structural features, catalytic mechanisms, and recent progress in the biosynthesis of diverse HPAs, the protein engineering of proline hydroxylase is emphasized. Finally, we present future perspectives to accelerate the biosynthetic production of l-PA and HPAs. Show less
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term tre Show more
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term treatments of the existing drugs suffered safety concerns. Show less
Nurses in traditional Chinese medicine (TCM) departments face significant sleep challenges associated with occupational stressors. However, person-centered analyses classifying these sleep patterns re Show more
Nurses in traditional Chinese medicine (TCM) departments face significant sleep challenges associated with occupational stressors. However, person-centered analyses classifying these sleep patterns remain scarce. This study aimed to identify heterogeneous sleep disturbance subgroups via latent profile analysis (LPA) and evaluate the performance of explainable machine learning models in discriminating these subgroups based on demographic and occupational features. A cross-sectional survey enrolled 7721 nurses from 130 TCM healthcare institutions in Liaoning Province (December 2024). Data encompassed demographic, occupational, and psychological variables obtained via self-administered questionnaires, including the Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance short form 8a. LPA was employed to categorize sleep disturbance patterns. Recursive feature elimination with random forest (RFE-RF) was used to select features associated with subgroup membership for five machine learning models. Models were trained on 70% of the data and evaluated on a 30% independent test set. The optimal classification model (XGBoost) underwent interpretability analysis using Shapley additive explanations (SHAP). LPA identified three subgroups: mild-stable (29.8%), moderate-fluctuating (60%), and severe-persistent (10.2%). Machine learning models achieved test AUCs of 0.71-0.84, with XGBoost demonstrating the highest discriminatory performance (AUC = 0.84, 95%CI: 0.83-0.85) in classifying subgroups. SHAP analysis indicated that monthly income, organizational support, hospital level, self-compassion, and resilience were the top five features contributing to the model's classification output. This study characterized three distinct sleep disturbance subgroups among TCM nurses, with the majority exhibiting moderate symptoms. The sequential application of LPA and explainable machine learning demonstrated robust performance in distinguishing sleep disturbance patterns. Identifying correlates-such as lower income and resilience-may assist nurse managers in stratifying risk and tailoring interventions for those most likely to fall into the severe subgroup. Future longitudinal studies are required to validate the stability of these subgroups and establish causal relationships. Show less
Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic pe Show more
Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic performance and adverse side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising, safe, and noninvasive alternative intervention with demonstrated neuromodulatory efficacy. Nevertheless, its mechanisms remain unclear. This study investigated whether the antidepressant properties of taVNS are associated with the microbiota-gut-brain axis, focusing on the potential crosstalk between differentially expressed hippocampal proteins and the gut microbiota. A chronic unpredictable mild stress (CUMS) rat model of depression was established, and taVNS was administered for 14 days. Hippocampal proteomic profiling was performed using data-independent acquisition. Fecal metagenomic sequencing was conducted to characterize alterations in gut microbial communities. Key signaling pathways were validated using Western blot, qRT-PCR, HE staining, and transmission electron microscopy, all of which were employed to systematically assess behavioral, proteomic, microbial, and molecular changes. Proteomics and molecular analyses revealed that taVNS upregulated hippocampal expression of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GluN1) and brain-derived neurotrophic factor (BDNF), while simultaneously restoring mitogen-activated protein kinase (MAPK) signaling activity. Metagenomic profiling demonstrated that taVNS increased the abundance of TaVNS significantly alleviated depression-like behaviors in CUMS-exposed rats. The underlying mechanism may involve the restoration of synaptic function of glutamatergic neurons by regulating the GluN1/MAPK/BDNF signaling pathway. In addition, taVNS reshaped the gut microbiota, markedly increasing the abundance of Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current ther Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD. Show less
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating Show more
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less
The response rate to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) remains unsatisfactory, and the mechanisms of resistance are not fully understood. Here, we investigated the rol Show more
The response rate to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) remains unsatisfactory, and the mechanisms of resistance are not fully understood. Here, we investigated the role of fibroblast growth factor receptor 1 (FGFR1) in shaping the tumor microenvironment (TME) and mediating ICB resistance. An anti-PD-1-resistant HCC model was established in mice, followed by single-cell RNA sequencing to profile TME alterations. We observed that ICB resistance was associated with FGFR1 upregulation, which activated MAPK signaling and induced SPP1 expression. This cascade promotes macrophage infiltration and M2-type polarization, while simultaneously suppressing T cell recruitment and cytotoxic function, thereby fostering an immunosuppressive microenvironment. SPP1 knockdown or neutralization significantly reduced macrophage accumulation and restored intratumoral T cell infiltration. Importantly, pharmacological inhibition of FGFR1 using BGJ398 synergized with anti-PD-1 therapy, resulting in enhanced antitumor efficacy in preclinical models. Analysis of clinical datasets further revealed that high FGFR1 expression correlated with poor responses to ICB of HCC patients. Collectively, these findings identify FGFR1 as a key mediator of ICB resistance in HCC. Targeting FGFR1 represents a promising strategy to reprogram the immunosuppressive TME and enhance response to immunotherapy, with potential additional value as a predictive biomarker. Show less
Parents of children with congenital heart disease (CHD) face chronic stress impairing family functioning and well-being. As a key protective factor, family resilience aids their adaptation. However, e Show more
Parents of children with congenital heart disease (CHD) face chronic stress impairing family functioning and well-being. As a key protective factor, family resilience aids their adaptation. However, existing research predominantly measures general family resilience, neglecting heterogeneous resilience patterns and subgroup profiles. Our study uses person-centered Latent Profile Analysis (LPA) to identify latent family resilience classes in Chinese culture to provide tailored support. This study adopted a cross-sectional survey design. From October 2024 to July 2025, convenience sampling was used to recruit 426 eligible parents of children with CHD from two tertiary hospitals in Yunnan Province, China. Data were collected using the General Information Questionnaire, Family Hardiness Index (FHI), Simplified Coping Style Questionnaire (SCSQ), and Social Support Rating Scale (SSRS). LPA was applied to classify the family resilience levels of these parents. Subsequently, univariate and multivariate ordinal logistic regression analyses were conducted to explore the factors associated with different latent classes of family resilience. A total of 400 valid questionnaires were collected, with an effective response rate of 93.9%. The mean total score for family resilience in parents of children with CHD was 58.13 ± 5.79, suggesting a moderate overall level of family resilience in this group. The family resilience of parents of children with CHD was classified into three latent profiles: “High family resilience responsibility-anchored type” ( Parents of children with CHD demonstrate heterogeneity in family resilience. Healthcare professionals should pay attention to the family resilience differences among parents of children with CHD and implement targeted intervention measures based on the characteristics of different subgroups, thereby enhancing parents’ family resilience and further promoting family well-being. The online version contains supplementary material available at 10.1186/s12889-025-26143-0. Show less
Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson's disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the SNCA gene. Gene Show more
Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson's disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the SNCA gene. Genetic risk factors strongly influence LBD susceptibility, including SNCA multiplication, particularly triplication, and the apolipoprotein E ε4 allele (APOE4), the strongest common genetic risk factor for LBD. While SNCA is predominantly expressed in neurons and APOE primarily in glial cells, how these genetic factors converge to impact neuronal vulnerability and regional pathology in the human brain remains poorly understood. Here, we applied spatial transcriptomics to postmortem temporal cortex tissue from LBD cases with SNCA triplication or different APOE genotypes, alongside age- and sex-matched controls, to map gene expression within intact cortical architecture. We identified layer 5 of the gray matter as a particularly vulnerable region, characterized by elevated SNCA expression, pronounced synaptic and metabolic dysregulation, and exacerbation of these alterations in APOE4 carriers. Reelin signaling emerged as a core Lewy body-associated pathway disrupted across cortical layers, validated in independent postmortem cohorts and human-induced pluripotent stem cell (iPSC)-derived cortical organoids. In contrast, white matter exhibited distinct molecular alterations, including disrupted myelination pathways, with APOE4 carriers showing increased myelin debris and glial responses compared with non-carriers. Cell-type deconvolution informed by single-nucleus RNA sequencing further revealed APOE4-associated impairments in neuronal vulnerability and intercellular communication. Together, these findings define spatially and cell-type-specific mechanisms through which SNCA dosage and APOE4 genotype impact LBD pathology, providing insight into regionally distinct disease processes and potential targets for genetically stratified therapeutic interventions. Show less
Hereditary Multiple Osteochondromas (HMO) is a rare autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in EXT1 or EXT2, which encode glycosyltransferases essential Show more
Hereditary Multiple Osteochondromas (HMO) is a rare autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in EXT1 or EXT2, which encode glycosyltransferases essential for heparan sulfate (HS) biosynthesis. Whether haploinsufficiency alone suffices or biallelic inactivation is required for osteochondroma formation remains a central unresolved question. In this study, we employed CRISPR/Cas9 combined with PiggyBac transposon technology to introduce a second pathogenic mutation (c.1883+1G>T) into patient-derived induced pluripotent stem cells (iPSCs) carrying a heterozygous EXT1 c.1126C>T mutation. This approach enabled the generation of isogenic iPSC lines: wild-type (WT), single-mutant (SM), and double-mutant (DM). These iPSCs were differentiated through induced mesenchymal stem cells (iMSCs) into chondrocytes. Biallelic EXT1 mutation in DM cells led to significant upregulation of SOX9, COL2A1, and ACAN, elevated glycosaminoglycan (GAG) levels, and markedly reduced HS, whereas SM cells remained indistinguishable from WT. Three-dimensional (3D) chondrogenic organoid cultures revealed that DM organoids were enlarged and structurally disorganized, partially recapitulating key histopathological features of osteochondromas. Transcriptomic analysis identified the Wnt signaling pathway as the most significantly enriched pathway among differentially expressed genes following EXT1 loss. Collectively, these findings provide direct human cellular evidence that complete EXT1 inactivation-not haploinsufficiency-drives aberrant chondrogenesis, likely through impaired sequestration of morphogen ligands, thereby supporting the Two-hit pathogenic model. Show less
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, w Show more
Autophagy supports clear cell renal cell carcinoma (ccRCC) progression, yet its upstream regulatory mechanisms remain to be fully defined. Integrating bulk, single-cell, and spatial transcriptomics, we identify a regulatory axis wherein the transcription factor ZBED6 activates the expression of the autophagy-initiating kinase PIK3C3 via the repression of IGF2, thereby driving pro-tumorigenic autophagy. Spatial analysis confirms the co-localization of ZBED6 and PIK3C3 in tumor tissues. Using genes associated with this axis, we develop a six-gene prognostic signature that stratifies patients with distinct survival outcomes and differential responses to immunotherapy and targeted therapy. Functional assays show that ZBED6 promotes ccRCC cell proliferation, migration, and invasion. This work elucidates a pathway governing autophagy in ccRCC and provides a framework for prognostic assessment and precision therapy. Show less
KRAS We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRAS Sustained tumor regression in four (33%) PDXs was observed while the remaining eight mode Show more
KRAS We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRAS Sustained tumor regression in four (33%) PDXs was observed while the remaining eight models were intrinsically resistant to AZD4625. Organoid responses to AZD4625 were concordant with their derived PDXs. Acute AZD4625 exposure significantly decreased gene expression of the ERK1/2 negative regulator, DUSP6, in all models while protein MAPK and AKT/mTOR signals were downregulated more frequently in the AZD4625-sensitive than AZD4625-resistant cohorts. Analyzing PDX transcriptomes and proteomes identified mTOR signaling as a putative mechanism of primary resistance to AZD4625. Our findings confirm AZD4625 as a highly active KRAS Show less
APOE polymorphisms are major genetic risk factors of Alzheimer's disease (AD). Compared with APOE3/E3, the APOE4/E4 genotype is associated with a > 14-fold increased risk. Therefore, we hypothesized t Show more
APOE polymorphisms are major genetic risk factors of Alzheimer's disease (AD). Compared with APOE3/E3, the APOE4/E4 genotype is associated with a > 14-fold increased risk. Therefore, we hypothesized that conversion of APOE4 to APOE3 would ameliorate AD-related pathologies. Accordingly, we generated a knock-in mouse model harboring an APOE4-FLEx (Flip-Excision) 4-to-3 construct enabling postnatal Cre-mediated APOE4-to-APOE3 switching. This construct comprised an APOE3 exon inserted in a reverse orientation downstream of the APOE4 exon, flanked by alternating loxP and mutant loxP sites, allowing Cre-mediated FLEx switching from APOE4-to-APOE3. For in vitro validation, HEK293T cells were transfected with APOE4-FLEx 4-to-3 plasmid, followed by AAV8-mediated iCre delivery. For in vivo studies, endogenous Apoe was replaced with the APOE4-FLEx 4-to-3 construct to generate APOE4-FLEx 4-to-3 knock-in mice, which were crossed with tamoxifen-inducible Rosa26-CreERT2 mice to yield Cre: APOE4-FLEx 4-to-3 double-knock-in mice. Tamoxifen was administered to induce APOE switching. Cre expression successfully induced APOE4-to-APOE3 switching in vitro. Tamoxifen administration in Cre: APOE4-FLEx 4-to-3 mice triggered APOE4-to-APOE3 switching in the liver, demonstrating the feasibility of postnatal isoform switching. However, brain APOE protein levels were below the detection limit. Investigation of the underlying cause involving transcript analysis revealed aberrant retention of intron 3 (APOE-I3). This abnormal splicing probably contributed to the decreased expression of fully spliced, translation-competent (mature) APOE mRNA, driving the subsequent protein reduction. Although APOE expression across organs in APOE4-FLEx 4-to-3 mice requires further optimization, our findings demonstrate that Cre-mediated FLEx switching can serve as a potential strategy to induce APOE genotype switching in vivo. Show less
The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether Show more
The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable. To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial. A prospective longitudinal cohort study. Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3). 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data. Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1-6 additional Aβ PET scans every 1.5-3 years. Those < 5 CL were classified as PET- and 5-20 CL as PET At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PET Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5-20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials. 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. Show more
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
Yiming Li, Wenxin Zou, Yan Zhang+5 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Atherosclerosis (AS) is a chronic disease characterized by lipid deposition in the vascular intima. As the pathological basis of cardiovascular diseases, AS represents a major contributor to global mo Show more
Atherosclerosis (AS) is a chronic disease characterized by lipid deposition in the vascular intima. As the pathological basis of cardiovascular diseases, AS represents a major contributor to global morbidity and mortality. While Gualou Huoxue Jiedu Decoction (GHJD) has been widely used in clinical practice for the treatment of AS, the molecular mechanisms remain unclear. To investigate the anti-atherosclerotic effects and underlying mechanisms of GHJD. Apoe GHJD alleviated plaque formation, improved lipid metabolism, and suppressed inflammation in vivo. Multi-omics analysis revealed that DNA methylation of Mfap4 could be a pivotal target of GHJD efficacy. In vitro assays confirmed that GHJD suppressed Mfap4 transcription and translation, leading to downregulation of integrin receptor family expression and inhibition of VSMC phenotypic switching. GHJD exerts anti-atherosclerotic effects through epigenetic modulation of Mfap4 and downstream integrin/FAK signaling pathway, thereby inhibiting VSMC phenotypic switching. These findings provide pharmacological evidence supporting GHJD as a potential therapy for AS and, for the first time, validate MFAP4 as a pharmacological target, offering new insights into AS prevention and treatment. Show less
Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In Show more
Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4, a non-canonical pro-angiogenic mediator, impaired angiogenesis. In a first-in-human, single-center, phase 1 dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over 3 years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA. Show less
The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous Show more
The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH-AM-PEG-ApoE (PAPA) nanoparticles (PAPA/siRNA NPs), which facilitates BBB penetration. In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1-siRNA and GSK3β-siRNA. The PAPA/siRNA NPs were prepared through self-assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice. The prepared PAPA/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in vitro cell experiments, the PAPA/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual-loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3β and BACE1 genes. In vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half-life of siRNA but also greatly reduced the generation of pathological β-amyloid and phosphorylated microtubule-associated protein tau, showing excellent therapeutic effects in the treatment of AD. In this study, we successfully constructed a brain-targeted siRNA nanocarrier delivery system for double-gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in the clinical treatment of AD and is expected to bring new breakthroughs and changes to the conquest of this disease. Show less
Wenjie Li, Chen Li, Xing Li+1 more · 2026 · The aging male : the official journal of the International Society for the Study of the Aging Male · Taylor & Francis · added 2026-04-24
Prostate cancer (PCa) is a leading cause of male cancer-related death globally. While the gut microbiota is linked to PCa, its genetic association remains unclear. We screened genetic instruments rela Show more
Prostate cancer (PCa) is a leading cause of male cancer-related death globally. While the gut microbiota is linked to PCa, its genetic association remains unclear. We screened genetic instruments related to the gut microbiota and paired them with PCa genome-wide association study data to conduct Mendelian randomization (MR) analysis. Positive MR findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus (GEO) dataset to perform differential expression analysis, aiming to identify differentially expressed associated genes (DEAGs). We determined the importance scores of these DEAGs through four machine learning models and constructed a nomogram based on these findings, and then validated it in another group of the GEO dataset. MR analysis found 16 gut bacteria causally linked to PCa (7 risk, 9 protective), with 144 related genes. PLCL1, VSNL1, ROR2, NRXN3, and TEAD1 were identified as feature genes for constructing a nomogram that provides a quantitative prediction of the risk of PCa onset. This study indicates that there are causal links between the gut microbiota and PCa. Feature genes may affect the occurrence of PCa by inhibiting the epithelial-mesenchymal transition, proliferation, migration, and invasion of cells. Show less
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson' Show more
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson's disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520-7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population. Show less
Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associ Show more
Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3 Overexpression of human ApoC3 in ApoC3 ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters. Show less
Families with children diagnosed with autism spectrum disorder (ASD) often encounter significant challenges, manifesting in elevated stress levels and compromised physical and mental well-being. This Show more
Families with children diagnosed with autism spectrum disorder (ASD) often encounter significant challenges, manifesting in elevated stress levels and compromised physical and mental well-being. This study employed Latent Profile Analysis (LPA) to comprehensively examine family resilience attributes among 328 Chinese parents of children with ASD. Drawing on Walsh's family resilience framework and the Double ABCX stress-adaptation model, the research examined how protective factors (social support, posttraumatic growth) and risk factors (family stressors) distinctively characterize resilience profiles and predict profile membership, alongside sociodemographic correlates. Through rigorous statistical analysis, the following three distinct family resilience profiles emerged: adversity (32.31%; characterized by low resilience), ordinary (46.65%; demonstrating moderate resilience) and growth (21.03%; exhibiting high resilience). Critically, the findings revealed that higher family income, perceived social support and posttraumatic growth were associated with higher family resilience, while family stressors were associated with lower family resilience. These insights underscore the importance of developing targeted, personalized intervention strategies that can effectively enhance familial coping mechanisms and psychological adaptation for families navigating the complex challenges of ASD. Show less
Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau tangles, and neuroinflammation. C-X3-C motif chemokine ligand 1 (CX3CL1, also known as fractalkine), a neuroimmune chemokine impl Show more
Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau tangles, and neuroinflammation. C-X3-C motif chemokine ligand 1 (CX3CL1, also known as fractalkine), a neuroimmune chemokine implicated in AD pathogenesis, shows inconsistent alterations in plasma/serum across studies. Specifically examining age-dependency and diagnostic utility, we investigated plasma CX3CL1 levels across the cognitive continuum (cognitively normal [CN], amnestic mild cognitive impairment [aMCI], AD) in a Chinese cohort. A total of 443 participants, including 130 patients with AD, 72 patients with aMCI, and 99 age-and sex-matched CN controls, as well as a cohort of 142 CN subjects of different ages, were enrolled from Chongqing General Hospital. Plasma CX3CL1 levels were determined using Enzyme-Linked Immunosorbent Assay (ELISA). Apolipoprotein E genotypes (APOE) were performed. The correlations between Plasma CX3CL1 levels and cognition test scores or age were analyzed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis. Plasma CX3CL1 levels significantly increased with age in CN individuals. No significant sex difference was found. Plasma CX3CL1 levels did not differ significantly between APOE ε4 carriers and non-carriers. Stepwise elevation across continuum: CX3CL1 levels showed a significant stepwise increase: CN controls (1.73 ± 0.51 ng/mL) < aMCI (2.40 ± 1.06 ng/mL) < AD (4.15 ± 1.24 ng/mL) (p < 0.001 between all groups). This pattern persisted in both male and female subgroups, between the AD group and the aMCI group, between the AD group and the CN control group (p < 0.001), between the aMCI group and the CN control group, and between the male and female subgroups (p < 0.05). CX3CL1 levels negatively correlated with Mini-Mental State Examination (MMSE) scores and positively correlated with age. Plasma CX3CL1 levels exhibit a significant age-dependent increase in cognitively normal individuals, peak in midlife (40-49 years), and demonstrate a stepwise elevation across the AD continuum (CN → aMCI → AD). Strong inverse correlations with cognitive scores in disease groups and high diagnostic accuracy for AD, particularly against CN, support its role as a biomarker reflecting both physiological aging and AD-related pathological decline. Its regulation appears independent of APOE ε4 status. The midlife peak suggests potential relevance for preclinical processes, warranting further investigation of CX3CL1 as a biomarker and therapeutic target. Show less