👤 Xiaofeng Peng

In our previous study, we found that both bombesin receptor-activated protein (BRAP) and its mouse homolog, BC004004, are expressed in the central nervous system, although their functions remain unclear. In feeding experiments, BRAP homolog knockout mice (BC004004 Show less

Yueju pill (YJ), a classical Traditional Chinese Medicine formula for "six stagnations", has long been used for mood disorders. We have previously demonstrated that YJ exerts rapid-onset antidepressant effects. However, the long-lasting antidepressant effects and its underlying neurobiological mechanisms remain elusive. To evaluate the sustained antidepressant efficacy of YJ in a chronic restraint stress model and elucidate its underlying molecular mechanisms through the integration of transcriptomic, pharmacological, and molecular biological analyses. We first assessed quality consistency of YJ via HPLC quantification. YJ's long-lasting antidepressant actions were conducted using behavioral paradigms (NSF, TST, FST, SPT, OFT) from 30 min 5 day in normal or chronic restraint stress model (CRS) mice after acute administration. Hippocampal key targets in mice affecting the therapeutic onset and long-lasting antidepressant efficacy of YJ were anchored through RNA-sequencing. The expression alterations of these identified targets in mouse hippocampus following YJ treatment were further confirmed by Western blot and PCR. Bidirectional causal validation was achieved by region-specific pharmacological antagonism (PACAP6-38) and RNA interference (AAV-PACAP-shRNA) in the dentate gyrus (DG), elucidating the necessity of this pathway for enduring antidepressant responses to YJ. Elisa was utilized to quantify hippocampal synaptic protein expressions in response to YJ and to assess its association with PACAP. Multi-component analysis via simultaneous identification and quantification of four marker constituents established the inter-batch homogeneity of YJ, with determined mean levels of shanzhiside methylester (0.2594 mg/kg), geniposide (44.2805 mg/kg), ferulic acid (0.1031 mg/kg), and gentiobioside (0.6720 mg/kg). In dose-response testing (1.0-2.5 g/kg), YJ at 1.0 g/kg exhibited the optimal antidepressant-like profile, characterized by rapid onset (reduced feeding latency in NSF at 30 min), short-term efficacy (decreased TST immobility at 3 h), and prolonged therapeutic effects (reduced immobility persisting up to 5 days). In the CRS model, acute YJ administration rapidly and robustly reversed stress-induced behavioral deficits, as evidenced by improved performance in NSF at 30 min, TST at 2 h, and SPT at day 1, with sustained antidepressant-like effects observed in FST at day 3. Notably, these behavioral changes occurred without alterations in locomotor activity or center time in OFT. Hippocampal transcriptomic analysis revealed distinct time-dependent molecular signatures following YJ administration. At 30 min, YJ induced a unique transcriptional shift characterized by qPCR-confirmed upregulation of ADCYAP1 (encoding PACAP). Conversely, at 3 days, a separate signature emerged with CSPG4 (NG2) identified and validated as upregulated. Furthermore, YJ treatment increased hippocampal PACAP levels at 30 min and NG2 expression at 3 days in CRS-exposed mice. Intra-dentate gyrus infusion of PACAP6-38 eliminated YJ's rapid antidepressant-like effects (NSF at 30 min; TST at Day 1) but left Day 3 FST efficacy and NG2 upregulation partially intact. However, AAV-shRNA-mediated PACAP knockdown in the dentate gyrus completely blocked both rapid and sustained behavioral benefits and abolished NG2 induction at 3 days and also blocked the acute YJ-induced enhancement of hippocampal synaptic proteins (synapsin 1 and PSD95) and BDNF expression at both 30 min and 3 days post-administration. Our study demonstrates that YJ achieves sustained antidepressant effects through a time-dependent hippocampal mechanism involving sequential PACAP and NG2 activation, ultimately converging on synaptic protein enhancement and BDNF signaling. This multi-component, multi-target, and multi-temporal mode of action embodies the holistic essence of TCM and offers a compelling alternative to current monoamine-based therapies with limited efficacy and delayed onset. Show less

Bupivacaine (BUP), a widely used amide-type local anesthetic, exhibits neurotoxic effects. This study aimed to explore the functions of brain-derived neurotrophic factor (BDNF) and methyltransferase Like 3 (METTL3) in BUP-induced hippocampal neuronal damage. HT22 cells and SH-SY5Y cells were treated with various concentrations of BUP. METTL3 and BDNF were manipulated using either overexpression or knockdown approaches to assess their functional roles. Cell viability, apoptosis, mitochondrial membrane potential and oxidative stress markers (Lactate Dehydrogenase (LDH), Reactive Oxygen Species (ROS), Superoxide Dismutase (SOD), Malondialdehyde (MDA)) were evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry, JC-1 staining and commercial kits. The expression of BDNF, METTL3, Caspase-9, Bax and Bcl-2 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The N6-methyladenosine (m6A) modification of BDNF mRNA was assessed using Methylated RNA Immunoprecipitation (Me-RIP) and commercial kits. BUP treatment dose-dependently reduced viability, while increasing oxidative stress and apoptosis in our cellular model. BDNF expression was down-regulated in BUP-induced cells. Additionally, BUP stimulation suppressed both total m6A levels and METTL3 expression in cell models. Overexpression of BDNF ameliorated BUP-induced cell damage. METTL3 stabilized BDNF through m6A modification, and the depletion BDNF reversed the protective effect of overexpressing METTL3 on BUP-induced neurotoxicity. Together, our results indicated that METTL3 attenuated BUP-induced neurotoxicity by enhancing BDNF expression via m6A modification. Show less

Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardiovascular events and long-term mortality. Existing treatment strategies have limitations, and clinical needs remain unmet. The gut-brain axis (GBA) serves as a core network regulating neuroimmune and endocrine responses, and its imbalance involves key links such as intestinal flora dysbiosis and neuroimmune crosstalk disorders. It is closely related to the pathogenesis of this complication, providing a novel perspective for targeted interventions. This review aims to systematically clarify the mechanism of GBA in PCPAD, comprehensively explore therapeutic strategies targeting this axis, and focus on the intervention value and application potential of natural products. The study was designed and conducted in strict accordance with the PRISMA 2020 guidelines. Relevant literatures were searched from PubMed, Web of Science Core Collection, ScienceDirect, Embase, Cochrane Library, and CNKI databases from their inception to December 2025. Literatures focusing on GBA-related mechanisms of PCPAD or investigating the mechanisms and clinical applications of natural products targeting GBA for PCPAD treatment were included. Conference abstracts, case reports, duplicate publications, and other ineligible literatures were excluded. Through quality control strategies including double independent screening and verification, priority inclusion of high-credibility evidence, and data cross-validation, 168 eligible literatures were finally included. The composition and functions of GBA, its imbalance mechanisms, and the basic and clinical evidence of natural product-based interventions were systematically analyzed. Studies have shown that GBA imbalance is the core pathogenesis of PCPAD, among which the inflammatory cascade initiated by intestinal flora dysbiosis, abnormal activation of the neuroendocrine axis, disorder of immune-nerve crosstalk, and abnormal gene and epigenetic regulation are key pathological links. In summary, GBA imbalance, especially gut microbiota dysbiosis and neuroimmune interactions, plays a critical role in the pathogenesis of PCPAD. Natural products (including traditional Chinese medicine (TCM) monomers, TCM compound prescriptions, patented TCM drugs, and natural products from other plant sources worldwide) can exert therapeutic effects by synergistically regulating GBA homeostasis through multiple targets. Specifically, they include increasing the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, promoting the production of anti-inflammatory metabolites such as short-chain fatty acids, repairing intestinal barrier function, inhibiting pro-inflammatory pathways such as NF-κB and NLRP3 inflammasome, and regulating the levels of neurotransmitters and neurotrophic factors such as 5-HT and BDNF. Basic and clinical studies have confirmed that these natural products have high biocompatibility and low toxic side effects, and are compatible with the safe medication needs of patients during the organ function recovery period after cardiac surgery. Several natural products have been proven to modulate GBA dysfunction, with potential for clinical therapeutic application. This review systematically elucidates a new paradigm of precise intervention for PCPAD via natural products that regulate GBA through multiple targets, addressing the limitation of traditional single-target therapies and providing a low-cost, easily promotable solution for clinical translation. Additionally, natural product-based interventions offer a novel approach for treating post-cardiac surgery complications. In the future, it is necessary to further conduct large-sample, multicenter clinical trials to clarify their mechanisms of action and standardized dosage regimens, strengthen toxicological research, facilitate the translation from basic research to clinical practice, and provide more precise therapeutic strategies for patients. Show less

Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD. 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 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

Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exert profound therapeutic effects in a rat model of moderate-to-severe CP established via bilateral carotid artery occlusion with hypoxia. Intravenously administered hUCMSC-Exos displayed sustained brain retention and significantly restored motor coordination and cognitive function. The recovery was primarily mediated through enhanced remyelination driven by promoted oligodendrocyte maturation and differentiation (elevated oligodendrocyte lineage transcription factor 2 and myelin basic protein). Concurrently, the treatment attenuated key pathological processes involving sustained neuroinflammatory responses (reduced ionized calcium-binding adapter molecule 1, tumor necrosis factor-α, and interleukin-6) while elevating brain-derived neurotrophic factor. Our findings establish hUCMSC-Exos as a promising dual-modality therapy for moderate-to-severe CP, mechanistically linked to robust remyelination and coordinated modulation of core disease mechanisms. Show less

Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abnormally elevated levels of amyloid-β (Aβ) deposition and tau phosphorylation. Given the rapid rate of population aging, many scientists are investigating AD, focusing on its pathogenic mechanisms and potential treatments. Unfortunately, to date, no highly effective therapeutic strategies have emerged. Intriguingly, multiple studies have revealed alterations in the gut microbiome of individuals with AD, suggesting it may serve as a novel avenue for investigating AD pathogenesis. Show less

Puerarin is a flavonoid bioactive component extracted from the Chinese herb radix puerariae, which has been reported to have anti-inflammatory and neuroprotective effects and is a potential drug for the treatment of neuroinflammatory diseases. There is increasing evidence that the gut-liver-brain axis is closely related to neurological disorders. However, studies on the use of puerarin for the treatment of depression based on gut-liver-brain axis-mediated inflammatory injury have not been reported. In the present study, a 4-week chronic restraint stress (CRS) mouse depression model was established. Place the mice in 50 mL centrifuge tubes for restraint. The tubes should be perforated with 15-20 small holes to ensure adequate ventilation. The restraint period is from 9:00 a.m. to 1:00 p.m. daily, during which food and water are withheld. Based on the results of previous studies, the better antidepressant dose of puerarin, 100 mg/kg, was chosen, and fluoxetine was used as a positive control to investigate the intervention effect and potential mechanism of puerarin on depression. All of the aforementioned drugs were administered via oral gavage. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT), novelty suspended feeding test (NSFT) and forced swimming test (FST) were used to observe the behavioral changes in mice to assess the antidepressant effects. The microbial composition of the intestinal tract was analyzed using 16S rRNA gene sequencing. Histopathological changes in colon and liver were also observed by HE staining method. The levels of lipopolysaccharide (LPS) in colon, serum, liver and prefrontal cortex (PFC) and the levels of 5-hydroxytryptamine (5-HT) in prefrontal cortex were detected by enzyme-linked immunosorbent assay (ELISA). The method was developed for the detection of 5-HT in the prefrontal cortex. The serum levels of glutamate transaminase (AST) and alkaline phosphatase (ALP) were measured by microplate assay. Finally, the expression of brain-derived neurotrophic factor (BDNF), TLR4, MYD88, p-IκB-α, and p-p65 proteins were determined by immunoblotting assay (Western Blot, WB) in mice with PFC. Puerarin was effective in alleviating CRS-induced depression-like behaviors measured in SPT, TST, FST and NSFT in mice. Compared with the CRS model group, puerarin increased the rate of sugar-water preference in the SPT and shortened the cumulative immobility time in the TST and FST as well as the ingestion latency in the NSFT in depressed mice. In addition, puerarin administration ameliorated CRS-induced gut microbiota dysbiosis in mice, elevating the abundance of Lactobacillaceae, Lactobacillus spp. Decreased the relative abundance of Ruminococcaceae, Ruminococcus, Desulfovibrionaceae, and Prevotella spp. Puerarin also reduced LPS, AST and ALP levels, improved damaged colon and liver tissues, inhibited neuroinflammatory damage mediated by the TLR4/MYD88/NF-κB signaling pathway, and up-regulated the levels of 5-HT and BDNF in the prefrontal cortex of the mice, thereby reversing CRS-induced depressive-like behaviors in depressed mice. Puerarin can improve CRS-induced depression in mice by regulating the gut-liver-brain axis and its related molecules. For example, it can regulate CRS-induced intestinal flora disorders and intestinal permeability, thereby reducing systemic LPS levels and the relative levels of AST and ALP, inhibiting the activation of the TLR4/MYD88/NF-κB signaling pathway by LPS, thereby reducing neuroinflammatory damage, and ultimately improving the depressive symptoms of CRS mice. Show less

This study explored the molecular mechanisms by which T7 peptide-modified liposomal irisin (T7@Lipo@Irisin) alleviates perioperative neurocognitive disorders (PND) via regulation of the AMPK/PGC-1α metabolic pathway. T7@Lipo@Irisin nanoparticles were prepared by thin-film hydration and ultrasonic dispersion and showed favorable physicochemical performance, with an encapsulation efficiency of approximately 85%. Serum analysis of healthy donors (n = 10) and PND patients (n = 6) showed higher IL-6 and TNF-α and lower brain-derived neurotrophic factor (BDNF) in PND. In vitro, T7@Lipo@Irisin restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, enhanced Neuro-2a hippocampal neuron viability, and activated the AMPK/PGC-1α axis under oxidative stress. In a PND mouse model, it improved Garcia neurological scores, preserved neuronal morphology, and decreased apoptosis. Multi-omic integration of scATAC-seq/scRNA-seq and TMT-based proteomics demonstrated enhanced neuro-glial crosstalk, epigenetic activation of metabolic/antioxidant genes (e.g., Sirt1, Nfe2l2), and upregulated pathways (mitochondrial function, NAD-dependent metabolism, synaptic homeostasis). Proteomics confirmed upregulation of SIRT1, NDUFS2, and BDNF, forming a network linked to energy metabolism and neural repair. Collectively, T7@Lipo@Irisin mitigates PND by activating AMPK/PGC-1α to enhance mitochondrial function and stabilize the neuro-microenvironment. Show less

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Show less

Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression. Show less

Insomnia and anxiety are highly comorbid, severely compromising quality of life. Efficacy of current pharmacological interventions for this dual condition remains limited. Zhi-Gan Formula (ZG), consisting of Zhi-Zi-Chi Decoction and Ganmai Dazao Decoction, two classic Traditional Chinese Medicine (TCM) formulae clinically widely used for insomnia or anxiety, holds promise as a therapeutic option for insomnia-anxiety comorbidity. This study aimed to assess ZG's sleep-promoting and anxiolytic efficacy, and investigate the novel mechanism through which pituitary adenylate cyclase-activating polypeptide (PACAP) in the medial prefrontal cortex (mPFC) modulates comorbid sleep and anxiety conditions. Mice received 4-chloro-DL-phenylalanine (PCPA) injections and were subsequently administered ZG or diazepam. Behaviors were assessed using the pentobarbital-induced sleep test, open-field test (OFT), and elevated plus-maze test (EPM). Key pathways were identified via network pharmacology analysis and validated using long-term potentiation (LTP) recordings and protein quantification. Viral-mediated PACAP knockdown vectors were transfected into the mPFC. PCPA administration induced insomnia and anxiety-like behaviors. ZG administered for 3 days significantly shortened sleep latency, prolonged sleep duration, and alleviated anxiety-like behaviors, whereas diazepam only partially improved anxiety-like behaviors. Network pharmacology analysis suggested ZG's engagement in neuropeptide-receptor interactions and synaptic transmission pathways. Assessments of synaptic plasticity showed that ZG improved mPFC LTP and the expression of synaptic proteins (PSD95, synapsin-1, BDNF) impaired in the model mice. Moreover, the expression of the neuropeptide PACAP and downstream eEF2 signaling for synaptic protein synthesis were all improved by ZG. Crucially, perfusion of a PACAP agonist in the mPFC brain slices from sleep-deprived mice rescued LTP deficits. Finally, mPFC PACAP knockdown abolished the therapeutic effects and the enhanced expressions of the synaptic proteins by ZG. ZG alleviated insomnia-anxiety comorbidity by restoring synaptic plasticity in the mPFC via the PACAP-eEF2-BDNF pathway, which may also shed light on the development of a novel therapeutic approach for the treatment of sleep-anxiety comorbidity. Show less

To observe the effect of acupuncture on astrocyte activation following cerebral ischemia-reperfusion injury (CIRI) Transcriptome and single-cell sequencing were used to analyse gene expression in middle cerebral artery occlusion (MCAO)-induced rats. Acupuncture was applied at Baihui (GV20) and Dazhui (GV14) for 7 d. The infarct volume was assessed CIRI activated p38 MAPK signaling, increased the expression of A1 markers (GFAP and C3), and proinflammatory cytokines, and decreased the expression of the A2 marker S100A10. Acupuncture inhibited p38 phosphorylation, upregulated MSK1, reduced C3 and inflammatory cytokines, increased S100A10 expression, decreased infarct volume, and improved neurological function. Acupuncture protects against ischemic stroke by targeting the p38 MAPK/MSK1 pathway. It inhibits p38 MAPK phosphorylation and activates MSK1, thereby promoting a shift in astrocyte polarization from the pro-inflammatory A1 to the reparative A2 type, as reflected by decreased C3 and increased S100A10 expression. This shift reduces pro-inflammatory cytokines, alleviates cerebral inflammation, and promotes neural repair, ultimately diminishing infarct volume, restoring neurons, and improving behavior. These findings elucidate the mechanism of acupuncture and support its clinical use. Show less

Osteoporosis (OP) is a metabolic bone disease characterized by low bone mineral density (BMD), and its pathogenesis involves endoplasmic reticulum (ER) stress-related cell death. This study aimed to identify diagnostic biomarkers associated with ER stress-related cell death in OP and explore their underlying mechanisms. The training dataset (GSE56815), validation dataset (GSE56814), and single-cell RNA sequencing (scRNA-seq) dataset (GSE147287) were downloaded. Differentially expressed genes (DEGs) between OP patients and controls were identified. Candidate genes were obtained by intersecting DEGs with ER stress-related genes and programmed cell death (PCD)-related genes. Machine learning was used to screen intersection genes, and biomarkers were determined via expression level analysis. Gene set enrichment analysis (GSEA), immune cell infiltration analysis, drug prediction and molecular docking, scRNA-seq analysis, key cell screening, cell communication analysis, and pseudotime analysis were performed. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) were further conducted. A total of 28 candidate genes were obtained by intersection. CAMKK2 and DAPK3 were confirmed as biomarkers, and were consistently down-regulated in both datasets and verified by RT-qPCR. GSEA analysis revealed that biomarkers were enriched in cytokine-cytokine receptor interaction. Correlations between biomarkers and activated dendritic cells were found via immune cell infiltration analysis. Preliminary computational analyses indicated that drugs including calcitriol and danazol may potentially interact with the biomarkers in a stable manner. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were identified as potential key cells via scRNA-seq analysis. Complex interactions involving BM-MSCs, such as ANGPTL4-CDH11 mediating BM-MSC self-communication, were revealed by cell communication analysis. Dynamic expression of biomarkers during BM-MSC differentiation was shown by pseudotime analysis: CAMKK2 fluctuated with differentiation stages, while DAPK3 shifted from high to low then high expression. CAMKK2 and DAPK3 were confirmed as diagnostic biomarkers for OP, providing insights into OP diagnosis and potential therapeutic targets. Show less

Social connectedness promotes healthy aging and is associated with lower risk for psychological disorders and cognitive decline. However, little is known about the mechanisms underlying these relationships, and whether different network features are associated with unique health benefits. We used comprehensive data from 386 community-dwelling older adults with and without cognitive impairment to test the relationship between psychological and cognitive function and their personal social networks. Data were collected using a multisite sampling strategy, and included detailed social network interviews and comprehensive measures of episodic memory, executive function, and language. Longitudinal effects were evaluated using a subsample at high-risk for decline, having either at least one copy of APOE ε4 or a current diagnosis of impairment ( The online version contains supplementary material available at 10.1038/s41598-026-44571-9. Show less

Atherosclerosis, a chronic inflammatory disease, is the most relevant cause of ischaemic stroke or myocardial infarction. Vascular endothelial cells (ECs) play a significant role in the development of atherosclerosis. In this chronic inflammatory environment, we aimed to investigate whether a Evolocumab (Evb) could mitigate atherosclerosis progression by inhibiting EC activation via in vivo and in vitro assays. In vivo, we investigated the ability of Evb to prevent atherosclerotic lesion formation in ApoE Show less

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less

The neural precursor cell expressed developmentally down-regulated protein 1 (NEDD1) is implicated in tumorigenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to explore the oncogenic role, regulatory mechanisms, and tumor microenvironment interactions of NEDD1 in HCC. Multi-omics analyses were performed using public datasets (TCGA, GEO) and in-house clinical samples. These included expression and survival analysis, epigenetic (DNA methylation) and post-translational (phosphorylation) profiling, functional pathway enrichment, and drug sensitivity prediction. Functional validation was conducted via NEDD1 knockdown in HCC cells and a subcutaneous xenograft model. The co-expression and spatial distribution of NEDD1 and its predicted partner MZT2B were investigated using single-cell (GSE140228) and spatial transcriptomic (HRA000437) datasets. NEDD1 was significantly overexpressed in HCC tissues and correlated with poor prognosis. Its overexpression was potentially linked to promoter hypomethylation and aberrant phosphorylation. NEDD1 knockdown suppressed HCC cell proliferation, migration, and tumor growth in vivo. Notably, NEDD1 expression positively correlated with immune checkpoint molecules (PD-1, CTLA-4), and low NEDD1 expression was associated with better predicted response to immunotherapy. Single-cell and spatial transcriptomics revealed that NEDD1 and MZT2B co-expression was highly enriched in specific macrophage subsets (e.g., APOE+) and exhibited cell context-dependent heterogeneity, suggesting they may constitute a dynamic functional module within the HCC microenvironment. This multi-omics study suggests NEDD1 as a potential prognostic biomarker and therapeutic target in HCC. We propose a novel model wherein the NEDD1-MZT2B module may operate in both tumor cells and immunosuppressive macrophages, potentially influencing disease progression and immunotherapy response. Show less

Coronary heart disease (CHD) is driven by endothelial dysfunction and chronic vascular inflammation. hsa-miR-2110 (miR-2110) has been associated with adverse cardiovascular outcomes, but its mechanistic role in CHD remains unclear. In this study, miR-2110 expression was quantified in peripheral blood from CHD patients and healthy controls. Functional effects were assessed in EA.hy926 endothelial cells following lentiviral overexpression of miR-2110. The target gene Show less

Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the CNS and plays an important role in brain metabolism and lipid homeostasis. In the CNS, ApoE is primarily secreted by astrocytes under homeostatic conditions and by microglia in certain disease-related conditions. APOE has three major alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and APOE2 results in decreased risk relative to APOE3. ApoE derived from astrocytes and microglia have been hypothesized to play different roles in the disease pathogenesis of AD. In this study, we profiled the lipidome and proteome of ApoE lipoproteins secreted by astrocytes or microglia and found that they differed according to the cellular source of ApoE and the ApoE isoform. Lipidomics revealed that microglia-derived ApoE lipoproteins were enriched in cholesteryl esters, whereas astrocyte ApoE lipoproteins were enriched in SM. Proteomics revealed that astrocyte ApoE lipoproteins were enriched in proteins involved in glucose metabolism and acute phase response. Microglia-secreted lipoproteins were enriched in proteins involved in complement activation, synapse pruning, proteolysis, and the innate immune response. Further comparison of ApoE lipoproteins from APOE4 microglia revealed that ApoE4 lipoproteins were enriched in complement component 1q and Lpl compared with ApoE2 and ApoE3 microglial lipoproteins, which were enriched in Ankk1 (ankyrin repeat and kinase domain containing 1) and apolipoprotein C1. These results provide the molecular foundation for better understanding of how ApoE functions as an apolipoprotein with the lipoprotein cargo being dependent on the cellular source and ApoE isoform, ultimately contributing to CNS homeostasis and disease pathogenesis. Show less

Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events. Show less

Aniridia, driven by PAX6 mutations, causes aniridia-associated keratopathy (AAK), a progressive condition linked to limbal stem cell deficiency. A major hurdle to developing targeted therapies for AAK is the incomplete understanding of the molecular abnormalities in affected corneas. To address this, we leveraged Pax6± (Pax6 het) mice, a model of AAK, and applied single-cell RNA sequencing (scRNA-seq) to profile the transcriptomic changes at a single-cell resolution. ScRNA-seq of corneal/limbal tissues of wild type (WT) and Pax6 het mice were conducted. Immunostaining was performed to examine the expression of specific markers for stem cells. ScRNA-seq identified a quiescent limbal epithelial stem cell (LESC)-like cell cluster and an early transient amplifying cell (eTAC)-like cluster. An increase in the cell numbers in these two clusters in the Pax6 het mouse corneas was observed. Immunostaining detected a marked increase in markers for these two clusters including Tmem176b, Apoe, and Krt15 in the corneal epithelium of Pax6 het mice, suggesting an increase of these LESC/eTA-like cells into the corneal epithelium. The Pax6 deficiency inhibited the expression of genes involved in cell proliferation in the eTAC-like cluster as well as the expression of genes related to corneal epithelial cell fate and differentiation compared with WT mice. Our single cell transcriptome of the limbus and cornea of Pax6 het mice indicates that AAK may be due to the increase of dysfunctional stem/eTACs with defects in committing to a corneal epithelial cell fate and differentiation. Show less

Atherosclerosis (AS), the primary pathophysiological foundation of coronary artery disease (CAD), initiates through endothelial dysfunction that facilitates lipid deposition and plaque formation. Emerging evidence implicates dipeptidyl peptidase IV (DPP4) in vascular pathologies, yet its mechanistic role in AS-associated endothelial ferroptosis remains undefined. Multidisciplinary approaches were employed: 1) Bioinformatic analysis of public databases identified DPP4-ferroptosis-AS associations; 2) Clinical samples measured plasma DPP4 levels across CAD severity strata; 3) Atherogenic progression was compared between DPP4 Clinical samples analysis revealed a significant increase in plasma DPP4 levels in patients with severe coronary artery stenosis, with DPP4 enrichment observed at plaque. Animal studies demonstrated that DPP4 deficiency attenuated progression of AS and ferroptosis in murine models. Cellular experiments revealed ox-LDL upregulated DPP4 expression, concomitant with increased ferroptosis susceptibility and endothelial dysfunction. DPP4 inhibition preserved endothelial viability by blocking lipid peroxide accumulation. Mechanistically, mouse proteomics revealed that ferroptosis and autophagy pathways were associated with DPP4 in AS. DPP4 destabilized FTH1 via NCOA4-mediated ferritinophagy, proven by concordant rescue effects of chloroquine (autophagy inhibition) and saxagliptin (DPP4 inhibition) on FTH1 preservation. This study establishes endothelial DPP4 as a regulator of ferritinophagy-driven ferroptosis, inducing endothelial dysfunction in AS. Our findings propose targeting the DPP4-NCOA4-FTH1 axis as a promising strategy to preserve endothelial viability and halt early AS progression, with translational implications for repurposing DPP4 inhibitors in cardiovascular therapeutics. Show less

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E-deficient (ApoE Show less

Mild depression in women is a distinct disorder with unclear immune mechanisms. This study aims to identify peripheral inflammatory biomarkers and to explore acupuncture's immunomodulatory effects via Olink proteomics. Thirty female participants (18-45 years) were assigned to healthy controls (HC), mild depression (MD), and acupuncture treatment (ACU). Plasma samples were analyzed using the Olink https://www.chictr.org.cn/showprojEN.html?proj=189355, identifier ChiCTR2300068054. Show less