This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different Show more
This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. Show less
Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclea Show more
Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclear. Here, we aimed to investigate the role of PRMT3 (protein arginine methyltransferase 3) in valvular calcification and calcific aortic valve disease progression. Both aortic valve leaflets and valvular interstitial cells from patients were used to evaluate the expression pattern and investigate the underlying mechanism of PRMT3 in calcific aortic valve disease pathogenesis. High-cholesterol diet-fed Apoe (apolipoprotein E)-deficient ( We found that PRMT3 expression was significantly upregulated during aortic valve calcification. RUNX2 (runt-related transcription factor 2) recruited P300 to promote PRMT3 expression through histone H3 lysine 27 acetylation. Moreover, We identify a previously unrecognized posttranslational mechanism regulating PCSK9 stability in valve interstitial cells during calcific aortic valve disease and establish a link between PRMT3-mediated arginine methylation and valve-specific lipid-osteogenic coupling. Show less
Atherosclerosis currently lacks effective therapeutic strategies specifically targeting and inhibiting foam cell formation. In this study, we engineered a macrophage nanoparticle composite drug delive Show more
Atherosclerosis currently lacks effective therapeutic strategies specifically targeting and inhibiting foam cell formation. In this study, we engineered a macrophage nanoparticle composite drug delivery system that utilizes macrophages for competitive lipid uptake, coupled with ROS-responsive statin nanoparticles aimed at inhibiting cholesterol synthesis. This integrated system embodies a "smart immunomodulatory" approach, leveraging the inherent activity and targeted capabilities of immune cells. Experimental results demonstrated that this system significantly reduced lipid accumulation within foam cells by inhibiting cholesterol uptake, promoting cholesterol efflux and inhibition of apoptosis. These effects were mediated through microenvironmental optimization and upregulation of ABCA-1 and SR-BI expression. In an APOE knockout mouse model of atherosclerosis, the system effectively lowered lipid levels, modulated inflammatory responses, and significantly reduced foam cell formation and atherosclerotic plaque development. The system enhanced Treg cell proliferation and TGF-β secretion. Moreover, the system demonstrated high biocompatibility and therapeutic efficacy, training macrophages to revert to a low-lipid and M2 phenotype. This targeted drug delivery system integrates multiple therapeutic mechanisms, including inhibition of cholesterol uptake, enhancement of cholesterol efflux, and immunomodulation, providing a promising new strategy for the treatment of atherosclerosis. Show less
Immune checkpoint blockade (ICB) has improved outcomes for patients with triple-negative breast cancer (TNBC), yet resistance remains widespread and its molecular basis is not fully understood. Throug Show more
Immune checkpoint blockade (ICB) has improved outcomes for patients with triple-negative breast cancer (TNBC), yet resistance remains widespread and its molecular basis is not fully understood. Through single-cell RNA sequencing (scRNA-seq) of paired pre- and post-treatment tumor samples from patients who failed to achieve pathological complete response (non-pCR) after neoadjuvant PD-1 therapy, we identified a marked upregulation of interleukin-27 receptor subunit alpha (IL27RA) in malignant epithelial cells within residual lesions. Integration with scRNA-seq profiles from an independent cohort of three pCR patients showed that this IL27RA upregulation in malignant epithelium is largely restricted to non-pCR residual tumors, and high IL27RA expression correlated with poor survival in TNBC cohorts. Mechanistically, IL27RA suppresses MHC-I expression by activating the PI3K/AKT pathway-rather than the classical IL-27/STAT axis-thereby impairing CD8⁺ T-cell cytotoxic function. Inhibition of AKT reversed this phenotype and restored antigen-specific killing. In orthotopic tumor models, mimicking systemic loss of Il27ra significantly reduced tumor growth and prolonged survival in immunocompetent mice, with single-cell profiling indicating enhanced intratumoral T-cell and NK-cell effector activity. Collectively, our findings identify an epithelial-intrinsic IL27RA-PI3K/AKT-MHC-I axis as a central driver of immune evasion and ICB resistance in TNBC and support IL27RA as a promising therapeutic target for overcoming immunotherapy resistance. Show less
Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 Show more
Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 (IRF6) is a transcription factor that regulates the inflammatory response following injury. In this work, the LSS-induced AS model was induced by the partial ligation of the left carotid artery in high-fat diet-fed ApoE 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
Xinjiang Province possesses several local sheep breeds which are well known for their tender meat, delicious taste, and lack of odor. At present, the microbial composition in the gastrointestinal trac Show more
Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF Show more
Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF-κB, but its role in POCD is unknown. Dendrobine, a sesquiterpenoid alkaloid from Dendrobium species, exhibits anti-inflammatory and neuroprotective activity. POCD was induced in aged C57BL/6 mice via sevoflurane anesthesia combined with exploratory laparotomy. Dendrobine (10 or 20 mg/kg) was administered, and cognitive outcomes were evaluated by Morris Water Maze and Novel Object Recognition. RNA sequencing, Western blotting, immunofluorescence, and in vitro microglia-neuron co-culture systems were employed to investigate inflammatory responses, apoptosis, synaptic plasticity, and signaling pathway activation. Functional roles of Runx1 were validated via siRNA knockdown, pharmacological inhibition (Ro5-3335), and overexpression in BV2 cells. Dendrobine improved spatial and recognition memory in POCD mice, reduced hippocampal microglial activation, proinflammatory cytokine expression (TNF-α, IL-1β, IL-6), and neuronal apoptosis while enhancing synaptic protein levels (BDNF, PSD95, SYN1). Transcriptomic and KEGG analyses revealed suppression of NF-κB signaling by dendrobine, with Runx1 identified as an upstream modulator. Dendrobine downregulated Runx1 expression in vivo and in vitro. Runx1 inhibition enhanced dendrobine's anti-inflammatory effects, whereas RUNX1 overexpression abolished them. Dendrobine ameliorates POCD by inhibiting the Runx1/NF-κB signaling pathway, suppressing neuroinflammation, promoting synaptic resilience, and preventing neuronal apoptosis. Runx1 appears to act as a key upstream mediator of NF-κB signaling in POCD. Targeting the Runx1/NF-κB axis represents a promising strategy for perioperative neuroprotection. 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
We examined whether the excess cardiovascular disease (CVD) risk among adults with steatotic liver disease (SLD) subtypes could be reduced or eliminated through joint control of low-density lipoprotei Show more
We examined whether the excess cardiovascular disease (CVD) risk among adults with steatotic liver disease (SLD) subtypes could be reduced or eliminated through joint control of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (hs-CRP). This prospective cohort study included 291,995 participants from the UK Biobank, comprising 77,187 with metabolic dysfunction-associated steatotic liver disease (MASLD), 22,190 with metabolic dysfunction and alcohol-associated liver disease (MetALD), 5474 with alcohol-associated liver disease (ALD), and 187,144 without SLD. Cox proportional hazards models were used to assess CVD risk associated with numbers of LDL-C, Lp(a), and hs-CRP controlled within the target range. During 12 years of median follow-up, 24,251 CVD events were documented, with 19,661 coronary heart disease and 5600 stroke. Among individuals with various SLD subtypes, those with all three factors controlled had the lowest risks of CVD, with HRs (95% CIs) of 0.65 (0.58, 0.72) in MASLD, 0.61 (0.49, 0.76) in MetALD, and 0.57 (0.35, 0.93) in ALD when comparing to zero-factor control. In addition, among individuals with SLD subtypes achieving all three factors within target ranges, the HRs (95% CIs) of CVD were 0.97 (0.88, 1.07) in MASLD, 0.90 (0.75, 1.08) in MetALD, and 0.63 (0.42, 0.95) in ALD, as compared with non-SLD controls. Similar association patterns were observed for coronary heart disease and stroke. Participants with various SLD subtypes who had optimally controlled LDL-C, Lp(a), and hs-CRP showed no excess or even lower risk of CVD as compared with the general population. Not available. Show less
Premature ejaculation (PE) accompanied by anxiety or depression is a complex clinical condition at the intersection of male reproductive dysfunction and emotional disorders. Increasing evidence sugges Show more
Premature ejaculation (PE) accompanied by anxiety or depression is a complex clinical condition at the intersection of male reproductive dysfunction and emotional disorders. Increasing evidence suggests that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play central and interrelated roles in its pathogenesis. In this review we examine the bidirectional functions of 5-HT and BDNF in both the reproductive and nervous systems, highlighting their importance in regulating ejaculation, emotional stability, and synaptic plasticity. A comprehensive literature search (2010-2025) was conducted across multiple databases using relevant Medical Subject Headings (MeSH) terms, including pertinent original research and review articles, to synthesize the roles and regulatory pathways of 5-HT and BDNF in PE with comorbid anxiety or depression. We summarize the shared and distinct roles of 5-HT and BDNF in maintaining physiological balance across these systems and focus on their involvement in the major pathological processes underlying PE with anxiety or depression, including neurotransmitter imbalance, neuroendocrine dysregulation, inflammation, and oxidative stress. Furthermore, we outline the related signaling pathways through which 5-HT and BDNF exert their effects and interact. We also evaluate current pharmacological and non-pharmacological interventions targeting these molecules, demonstrating their potential to improve both ejaculatory control and emotional symptoms, and critically appraise selective serotonin reuptake inhibitor (SSRI)-related risks and highlighted the need for individualized dosing and monitoring. Emerging evidence suggests that Traditional Chinese Medicine formulations can extend intravaginal ejaculatory latency and mitigate mood symptoms and may serve as stand-alone or adjunctive options to reduce reliance on selective serotonin reuptake inhibitors (SSRIs). Overall, 5-HT and BDNF are not only deeply involved in the biological mechanisms of PE with comorbid psychological disorders, but also represent promising biomarkers and therapeutic targets, and their integrative neuro-reproductive regulatory functions provide new insights into the diagnosis and treatment of this multifaceted condition. 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
Guoan Zhang, Baoguo Song, Xiaoyan Huang+1 more · 2026 · Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Springer · added 2026-04-24
In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. Howev Show more
In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. However, the regulation mode of its expression and the specific approaches by which it functions in lipid oxidative stress are still unclear. HUVECs and macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to induce endothelial cell injury. First, the effects of the RNA binding proteins IGF2BP1 and poly (A) binding protein cytoplasmic 1 (PABPC1) on the stability of NPC1L1 mRNA was evaluated. The interaction between NPC1L1 and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) was analyzed using Co-IP, and the co-localization of the two was detected using immunofluorescence. Combined with qPCR, Western blotting, CCK8, ferroptosis-related index and mitophagy-related index determination were performed to evaluate the expression of CYP11A1 in ox-LDL-treated HUVECs and its role of ferroptosis and mitophagy. Subsequently, pcDNA-NPC1L1 or CYP11A1 siRNA were individually or altogether transfected into ox-LDL-treated HUVECs to verify the involvement of CYP11A1 in NPC1L1-mediated ferroptosis and mitochondrial oxidative stress. Finally, ApoE-/- mice were fed with high-fat diet to establish an AS model in vivo and sh-NPC1L1 and/or Ad-CYP11A1 were injected via tail vein to verify the therapeutic effect of NPC1L1 knockdown on AS and reversal effect of CYP11A1. Either knockdown of IGF2BP1 or PABPC1 reduced NPC1L1 mRNA stability. Mechanistically, NPC1L1 interacted with CYP11A1 and promoted CYP11A1 protein expression. CYP11A1 was upregulated in ox-LDL-treated HUVECs and overexpression of CYP11A1 induced ferroptosis by activating excessive mitophagy, and knockdown of CYP11A1 reversed the promotion of NPC1L1 on mitophagy and ferroptosis in ox-LDL treated HUVECs. In vivo, injection of the sh-NPC1L1 lentiviral vector inhibited AS progression, while injection of the LV-CYP11A1 lentiviral vector attenuated the protective effect of sh-NPC1L1 on AS. PABPC1 and IGF2BP1 synergistically stabilized NPC1L1 mRNA, and NPC1L1 interacted with CYP11A1 to induce endothelial mitophagy and ferroptosis during AS. Show less
Recent evidence has shown that bone marrow mesenchymal stem cells (BMSCs) have multiple biological applications and play an important role in improving cognitive dysfunction. However, it is still uncl Show more
Recent evidence has shown that bone marrow mesenchymal stem cells (BMSCs) have multiple biological applications and play an important role in improving cognitive dysfunction. However, it is still unclear whether BMSCs play a role in cognitive impairment induced by chronic pain. This study aimed to evaluate the therapeutic effect of BMSCs on neuropathic pain-induced cognitive dysfunction and explore its potential mechanisms. A mouse chronic constriction injury (CCI) model was established, and the new object recognition task and fear conditioning were used to detect cognitive function; the expression of CXCL12/CXCR4 in blood and hippocampus was detected. After intravenous injection of BMSCs, changes in cognitive function and expression of the CXCL12/CXCR4 pathway, dentate gyrus neurogenesis, and excitability of hippocampal neurons were detected. In addition, induction of cognitive impairment in normal mice by CXCL12 recombinant protein was used to clarify whether the CXCL12/CXCR4 pathway mediates the cognitive function improvement effect of BMSCs. Our results found CCI mice showed significant cognitive impairment 21 days after surgery, with significantly increased expression of CXCL12/CXCR4 in blood and hippocampus. Intravenous injection of BMSCs significantly improved cognitive function, inhibited expression of CXCL12/CXCR4 in blood and hippocampus, promoted neurogenesis in dentate gyrus of CCI mice, and increased expression of BDNF and c-Fos in the hippocampus. In addition, BMSCs alleviate cognitive impairment induced by intravenous injection of CXCL12 recombinant protein in mice. In summary, BMSCs improve chronic neuropathic pain-induced cognitive dysfunction through peripheral blood CXCL12/CXCR4, and BMSCs may develop into therapeutic targets for chronic pain induced cognitive impairment. Show less
Alzheimer disease (AD) is a primary neurodegenerative disorder of the brain with an unknown cause and complex pathogenesis. It is the most common form of dementia and poses a significant threat to the Show more
Alzheimer disease (AD) is a primary neurodegenerative disorder of the brain with an unknown cause and complex pathogenesis. It is the most common form of dementia and poses a significant threat to the health of the aging population worldwide. However, effective pharmacological treatments remain limited. This study employed publicly available genome-wide association study summary statistics, which included 4907 plasma proteins as exposures and AD as the outcome. To explore the causal relationship between plasma proteins and AD, 5 Mendelian randomization (MR) analyses were applied. Heterogeneity in the results was assessed using the Cochrane Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test. Sensitivity analysis was conducted using a leave-one-out approach. Plasma proteins exhibiting significant associations with AD were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses to elucidate their biological functions and pathways. The protein-protein interaction network was constructed via the STRING database, and hub genes were identified based on node degree and visualized with Cytoscape. Potential drug candidates targeting these hub genes were predicted via the Drug Signatures Database. The binding affinities of the candidate drugs to the hub gene-encoded proteins were subsequently validated through molecular docking via the CB-Dock2 platform. Finally, the expression patterns of the hub genes across various cell types were explored via single-cell sequencing analysis, and an external GEO validation dataset was established for verification. MR analysis revealed that 39 plasma proteins were significantly associated with AD. Functional and pathway enrichment analyses revealed that these proteins were predominantly enriched in the nuclear factor-κB signaling pathway. Further screening identified 10 hub genes: APOE, CSF3, TNFAIP3, PHGDH, PEBP1, MICB, LGMN, TGM1, CD55, and CCL21. The Drug Signatures Database predicted 5 potential drug candidates. Molecular docking analysis demonstrated strong binding affinities between these drug candidates and the hub genes. Single-cell sequencing analysis revealed that most hub genes presented elevated expression levels in oligodendrocytes. The results of the MR analysis were consistent with those of the external validation set, underscoring the reliability of this study. Through MR analysis, this study systematically identified 10 hub genes associated with AD and predicted 5 potential drug candidates. These findings offer novel insights into the molecular mechanisms underlying AD and may contribute to improved strategies for clinical diagnosis and targeted therapy. Show less
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-ce Show more
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-centered approaches fail to capture how distinct affective temperaments co-occur within individuals. This study aimed to identify latent profiles of affective temperaments and examine their association with NSSI, exploring the statistical mediating role of cognitive emotion regulation (CER). A cross-sectional study was conducted from February 2025 to September 2025 at the First Hospital of Hebei Medical University. A total of 290 adolescents (aged 10–19) diagnosed with Major Depressive Disorder were recruited, with 282 valid responses included in the final analysis. Participants completed the TEMPS-A, CERQ, and ASHS. Latent Profile Analysis (LPA) was utilized to identify temperament subgroups. Mediation analysis with bootstrapping was performed to test the indirect effects of CER strategies. LPA identified three distinct profiles: Resilient/Low-risk (Class 1, 32.6%), Anxious-Depressive (Class 2, 46.1%), and Mixed-Dysregulated (Class 3, 21.3%). The Mixed-Dysregulated group, characterized by simultaneous elevations in depressive, anxious, irritable, and cyclothymic temperaments, exhibited the highest frequency (45.2 ± 21.3 times/year) and prevalence (98.8%) of NSSI compared to other groups ( The findings delineate a specific “Mixed-Dysregulated” risk phenotype within adolescent depression that is associated with severe NSSI. Interventions should move beyond standard depression care to target cognitive flexibility and emotional regulation skills. Statistical mediation analysis suggests that this risk is mediated by maladaptive cognitive emotion regulation strategies. Not applicable. Show less
The selective cholesteryl ester transfer protein (CETP) inhibitor obicetrapib is in clinical evaluation for dyslipidemia and cardiovascular risk reduction. This study investigated how obicetrapib alon Show more
The selective cholesteryl ester transfer protein (CETP) inhibitor obicetrapib is in clinical evaluation for dyslipidemia and cardiovascular risk reduction. This study investigated how obicetrapib alone and with ezetimibe reduces non-HDL-C, affects atherosclerotic lesion progression, and regression when added to background atorvastatin intervention. APOE∗3-Leiden.CETP mice received a Western-type diet (WTD) or this diet supplemented with obicetrapib, ezetimibe, or both. After 8 weeks, all interventions reduced non-HDL-C levels (obicetrapib: -53%; ezetimibe: -19%; combination: -75%). Obicetrapib mono and combination treatment blocked CETP activity (-99% and -98%), thereby increasing HDL-C levels (+286% and +256%). Very low-density lipoprotein (VLDL) cholesterol production was not affected, while obicetrapib and the combination with ezetimibe increased VLDL clearance (plasma half-life [ Show less
Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclero Show more
Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE High-cholesterol diet-fed apoE Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia. Show less
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment co Show more
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment compromises therapeutic efficacy. We developed an innovation CE-SKP/CPH/P2G3 scaffold which effectively repairs focal cartilage defects and emulates native cartilage ontogeny: the superficial CE-SKP hydrogel layer recruits SMSCs and promotes chondrogenesis; the middle CPH hydrogel layer induces chondrocyte hypertrophic calcification, forming cartilage calcified layer; and the basal P2G3 nanofiber membrane isolates subchondral cells, enforcing a top-down developmental sequence and preserving a localized hypoxic niche. Show less
Press needle therapy, may alleviate depressive-like behaviors. Male rats were randomly allocated into four groups ( Press-needle ameliorated depressive-like behaviors in CUMS-exposed rats, restored bo Show more
Press needle therapy, may alleviate depressive-like behaviors. Male rats were randomly allocated into four groups ( Press-needle ameliorated depressive-like behaviors in CUMS-exposed rats, restored body weight gain and improved behavioral performance. The treatment upregulated the hippocampal BDNF/TrkB/CREB signaling pathway, increasing BDNF, TrkB, CREB, AKT, and PI3K in the hippocampus. The therapy modulated serotonergic neurotransmission by increasing hippocampal 5-HTT expression, while downregulating 5-HT1A and 5-HT2C receptors and PKA. Notably, press-needle exerted anti-neuroinflammatory effects, reducing hippocampal and serum levels of TNF-α and IL-6. Histopathological analysis confirmed its neuroprotective efficacy, demonstrating attenuated neuronal damage in hippocampal tissues. Show less
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a Show more
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don Show more
Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less
Ying Yang, Xiang Li, Dan-Li Tang+4 more · 2026 · Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica · added 2026-04-24
This study established a hyperlipidemia model by feeding Sprague-Dawley rats a high-fat diet for 8 weeks. The rats were randomly assigned to the following groups: model group, atorvastatin calcium gro Show more
This study established a hyperlipidemia model by feeding Sprague-Dawley rats a high-fat diet for 8 weeks. The rats were randomly assigned to the following groups: model group, atorvastatin calcium group(4.8 mg·kg~(-1)), low-, medium-, and high-dose Tanyu Tongzhi Optimization Decoction(TYTZD) groups(3.6, 7.2, and 14.4 g·kg~(-1)), and a normal diet control group. After 4 weeks of continuous administration, hematoxylin-eosin(HE) and oil red O staining were used to observe liver pathological changes and lipid infiltration. Automatic biochemical analyzer were performed to assess blood lipid profiles, coagulation function, and liver function. Transcriptomic and proteomic analyses were employed to identify differentially expressed genes(DEGs) and proteins(DEPs), followed by enrichment analysis. The MCODE algorithm was applied to classify DEGs and DEPs into modules, and network separation index(S₍AB)) was calculated to assess module separation, enabling construction of a gene-protein co-expression network for core target screening. The diagnostic accuracy of core targets was evaluated by area under the receiver operating characteristic(ROC) curve(AUC), and ELISA was used to measure core target expression. Western blot detected the expression of core pathway-related proteins in liver tissue. RESULTS:: demonstrated that TYTZD significantly improved dyslipidemia, coagulation dysfunction, liver injury, hepatic pathology, and lipid infiltration in hyperlipidemic rats. Transcriptomic analysis identified 571 DEGs significantly reversed by TYTZD, mainly enriched in inflammatory signaling pathways such as Toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB). Proteomic analysis identified 102 reversed DEPs, mainly involved in cholesterol metabolism pathways. Integrated analysis identified core targets including TLR4, tumor necrosis factor-α(TNF-α), integrin subunit alpha M(ITGAM), Toll-like receptor 2(TLR2), matrix metalloproteinase 9(MMP9), interleukin-1β(IL-1β), apolipoprotein E(APOE), and apolipoprotein C2(APOC2), all with AUC values greater than 0.70. ELISA showed that TYTZD intervention significantly downregulated MMP9, TNF-α, IL-1β, TLR2, ITGAM, and TLR4, and upregulated APOC2 and APOE. Western blot indicated that TYTZD reduced TLR4, p-NF-κB, and IL-1β protein expression in liver tissue. In conclusion, TYTZD may exert anti-hyperlipidemic effects through regulation of core targets such as ITGAM, TLR4, and APOC2, and by modulating the TLR4/NF-κB signaling pathway to intervene in inflammatory responses and cholesterol metabolism, thereby achieving multi-target, multi-pathway therapeutic effects against hyperlipidemia. Show less
Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as n Show more
Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as nutritional strategies in NDDs. We analyzed different polyphenol types across seven NDDs, 13 studies involving 849 participants were included. Prespecified outcomes comprised global cognition (Mini-Mental State Examination, MMSE), domain-specific cognition (Alzheimer's Disease Cooperative Study-Cognitive Subscale, ADCS-Cog), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living, ADCS-ADL), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), and selected biomarkers (plasma amyloid-β40 and brain-derived neurotrophic factor, BDNF). Reporting followed PRISMA 2020 guidelines, methods conformed to the Cochrane Handbook, and certainty of evidence was assessed using GRADE. Overall, polyphenol supplementation was associated with improved global cognition (pooled MD in MMSE = 2.06; 95% CI 0.62-3.49). In subgroup analyses, flavonoids were associated with a modest but significant improvement in MMSE scores, whereas stilbenes produced a significant benefit in daily functioning (ADCS-ADL) without clear gains in MMSE or ADCS-Cog and no consistent effects on NPI. Anthocyanidins, phenolic acids, and lignans did not significantly affect cognitive outcomes (MMSE or ADCS-Cog), and polyphenol subclasses did not yield robust or consistent changes in NPI or biomarker endpoints (Aβ40 and BDNF). Specific polyphenol subclasses therefore appear to confer selective cognitive and functional benefits, with stilbenes primarily supporting functional outcomes and flavonoids potentially enhancing global cognition. Show less
Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adv Show more
Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance. PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes. GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement. Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine. The online version contains supplementary material available at 10.1186/s11658-026-00867-2. Show less
Previous research has suggested that high levels of internet use are associated with lower levels of physical activity. However, recent studies have yielded mixed findings. First, we aim to explore th Show more
Previous research has suggested that high levels of internet use are associated with lower levels of physical activity. However, recent studies have yielded mixed findings. First, we aim to explore the prevalence of internet addiction and sedentary behavior among college students. Second, we examine the relationship between sedentary behavior and body composition. Additionally, we employ latent profile analysis (LPA) to identify subgroups of internet addiction profiles and to explore the associations between these latent profiles and sedentary behavior. This cross-sectional study examined the relationship between sedentary behavior, internet addiction, and body composition among 369 Chinese college students. Sedentary behavior was assessed via self-reported sitting time, internet addiction was measured using a standardized questionnaire, and body composition was evaluated with the InBody 120 device. LPA, an individual-centered method, was used to identify homogeneous subgroups of internet addiction. 42.3 % of students exhibited internet addiction and 72.6 % reported ≥6 h of daily sitting. LPA revealed two distinct profiles of internet addiction-"Regular" (57.2 %) and "Internet addiction" (42.8 %)-highlighting its heterogeneous nature. The findings suggest that age (p = 0.296), gender (p = 0.304), and sedentary time (p = 0.954) may not be the primary factors contributing to these profiles. Policymakers and campus health programs should tailor interventions to distinct internet addiction subgroups. Further research is needed to examine psychological, behavioral, and social contributors, as well as long-term effects. Show less
To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained Show more
To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR < 0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies. Show less
Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant a Show more
Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of bloodbased biomarkers for Alzheimer's disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer's disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer's disease progression. Additionally, bloodbased biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer's disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of bloodbased biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer's disease. This review provides a comprehensive and updated evaluation of the translational potential of bloodbased biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer's disease using these biomarkers. Show less