Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. T Show more
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. This study aimed to observe the mechanism of EA as an adjunct therapy to escitalopram oxalate (EO) on depressed patients. This study was designed as a single-blinded, double-dummy randomized controlled trial. 61 participants were diagnosed with mild-to-moderate depression according to the International Classification of Diseases 10th Edition (ICD-10, F32) were randomly allocated to receive EA + EO placebo, EO + sham EA, or EA + EO for six weeks treatment. The clinical assessment including depression severity, quality of life (QOL) and clinical safety. Biological indicators of immune-inflammation, the brain-derived neurotrophic factor and glucocorticoid inducible genes in peripheral blood of participants were measured by using enzyme linked immunosorbent assay and real-time polymerase chain reaction respectively before and after treatment. Three interventions improved the depression severity and QOL (P < 0.05), and no inter-group difference was found in the 6th week (P > 0.05). Anxiety psychic and somatic general symptoms in the EA + EO group were improved significantly than those of the other two groups (P < 0.05). After six-week treatment of EA + EO, blood SGK1 mRNA, GILZ mRNA, and BDNF levels were increased significantly ( Show less
Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii. This study aims t Show more
Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii. This study aims to evaluate the neuroprotective effects of CF and elucidate the possible molecular mechanisms underlying its neuroprotective effects through in vivo and in vitro models of Parkinson's disease. 1-methyl-4-phenylpyridinium ions (MPP Following CF administration, the apoptosis rate and reactive oxygen species (ROS) levels in PC12 cells were significantly reduced. CF markedly upregulated the expression of proteins including dopamine, tyrosine hydroxylase, brain-derived neurotrophic factor (BDNF), while simultaneously downregulating the expression of proteins such as α-synuclein. Molecular docking results demonstrated favorable affinity between CF and proteins including p62. This compound not only ameliorated motor and cognitive impairments in Parkinson's disease mice but also markedly increased neuronal numbers within the substantia nigra region of these animals. CF exerts a neuroprotective effect in Parkinson's disease by modulating the p62-Keap1-Nrf2 signalling pathway. 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
To examine associations between the 24-h composition of movement behaviors (sedentary behavior [SB], light physical activity [LPA], moderate-to-vigorous physical activity [MVPA], and sleep) and physic Show more
To examine associations between the 24-h composition of movement behaviors (sedentary behavior [SB], light physical activity [LPA], moderate-to-vigorous physical activity [MVPA], and sleep) and physical and mental health in older adults using compositional data analysis. Data came from 4,150 adults aged ≥ 60 in the 2015 China Health and Nutrition Survey. Multiple‑balance isometric log‑ratio regression and compositional isotemporal substitution models were used to assess relative associations and the effect of time reallocation. The 24‑hour geometric mean composition was 43.1% sleep, 30.6% SB, 21.8% LPA, and 4.5% MVPA. LPA was positively associated with physical (β = 0.062, Replacing sedentary time or sleep with LPA, even in small amounts, is associated with better physical and mental health in older adults, supporting integrated 24‑hour activity guidelines that emphasize light‑intensity movement. Show less
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
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
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
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 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
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
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
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress respons Show more
Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress response. Accumulating evidence highlights its context-dependent regulatory roles in hepatocellular carcinoma (HCC)-the most prevalent primary liver malignancy with high mortality and limited therapeutic efficacy. This review systematically summarizes the core mechanisms by which TRIM21 orchestrates HCC progression: ① Autophagy regulation: TRIM21 modulates HCC autophagy via multiple axes, including CCR4-NOT complex (TNKS1BP1/CNOT4)-mediated substrate ubiquitination, ATG14-dependent autophagosome initiation, and RETREG1-driven reticulophagy, with context-dependent effects on tumor proliferation. ② Drug resistance: TRIM21 enhances oxaliplatin sensitivity by ubiquitinating and degrading G6PD (the rate-limiting enzyme of the pentose phosphate pathway), while its role in sorafenib resistance involves dual pathways-the MST1/YAP axis and the ApoE/cholesterol/PI3K-AKT cascade. ③ Metastasis suppression: TRIM21 restricts HCC invasion and metastasis by ubiquitinating key oncoproteins, preserving epithelial integrity and inhibiting mesenchymal transition. ④ Reactive oxygen species (ROS) balance: TRIM21 regulates oxidative stress in HCC via the SQSTM1/p62-Keap1-NRF2 axis, coordinating with HIF1α to modulate antioxidant responses and tumor cell survival. Additionally, we discuss the regulatory significance of TRIM21 in HCC associated with hepatitis B virus (HBV) infection (via HBx/DNA polymerase ubiquitination) and nonalcoholic steatohepatitis (NASH) (via suppressing lipogenic enzymes to reduce steatosis-driven carcinogenesis). This review provides a theoretical basis for TRIM21 as a potential diagnostic marker and therapeutic target for HCC. 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 increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reac Show more
The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. 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
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
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
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
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
The mechanisms by which Polycyclic Aromatic Hydrocarbons (PAHs) induce lipid metabolic disorder and inflammation in marine invertebrates remain poorly understood. This study utilized the clam Ruditape Show more
The mechanisms by which Polycyclic Aromatic Hydrocarbons (PAHs) induce lipid metabolic disorder and inflammation in marine invertebrates remain poorly understood. This study utilized the clam Ruditapes philippinarum during its reproductive stage as a model organism, integrating high-throughput omics, computational simulation, and confocal microscopy to elucidate the accumulation characteristics and toxicological pathways of PAHs. The results demonstrated that PAHs significantly accumulated in the digestive gland and gonads, primarily sequestered within lipid droplets. This tissue distribution was found to be dependent on a lipid-dependent transport mechanism mediated by ApoB, FATP, and FABP4. Mechanistically, PAHs activated SREBP1 and PPARα, β nuclear receptors by interfering with the neuroendocrine system and endoplasmic reticulum stress pathways. This activation resulted in dysregulated lipid metabolism (favoring synthesis over degradation) and subsequent abnormal lipid (TG, PL) deposition. Furthermore, PAHs induced low-grade inflammation by synergistically activating the NF-κB and AP-1 pathways, a response driven by both lipotoxicity and cellular organelle stress. This finding provides important scientific evidence for contaminant risk assessment in aquatic organisms. 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