Dongfeng Wei

Background: Global aging has led to a rise in neurodegenerative diseases. Neuroinflammation constitutes a core pathological mechanism in these disorders. The Kongsheng Zhenzhong Pill (KSZZP), a modern preparation derived from a classical Chinese herbal formula, are reputed for their sedative and cognition-enhancing effects. However, the molecular mechanism underlying its modulation of microglia-mediated neuroinflammation remains unclear. The present study was designed to assess the intervention effects of KSZZP on LPS-induced neuroinflammation in BV-2 microglial cells and to preliminarily explore the potential molecular mechanisms involved. Methods: An in vitro neuroinflammation model was established in LPS-induced BV-2 microglial cells. The chemical components of KSZZP were identified using UPLC-Q-Exactive HFX technology. The pharmacological effects of KSZZP were evaluated by assessing cell activation, inflammatory response, oxidative stress, and apoptosis. Molecular docking and Western blotting were used to explore the specific mechanism of its action on the cGAS-STING pathway. Results: Chemical analysis identified 67 components in KSZZP, primarily flavonoids, prenyl lipids, and isoflavones. KSZZP treatment dose-dependently inhibited LPS-induced BV-2 microglial activation and significantly reduced pro-inflammatory factor release. Furthermore, it alleviated oxidative stress, mitigated mitochondrial ultrastructural damage, and inhibited apoptosis induced by LPS. Molecular docking revealed that key active components of KSZZP exhibit strong binding potential to cGAS and STING proteins. Western blotting further confirmed that KSZZP dose-dependently suppressed the expression of key cGAS-STING pathway proteins (cGAS, STING) and downstream proteins associated with M1 polarization (iNOS, TNF-α, COX-2). Conclusions: This study indicates that KSZZP alleviates LPS-induced microglial activation, neuroinflammation, oxidative stress, mitochondrial damage, and apoptosis, and these effects may involve the modulation of the cGAS-STING signaling pathway. Collectively, these findings provide a preliminary experimental basis for understanding the anti-neuroinflammatory mechanism of KSZZP and support its potential application in the prevention and treatment of neurodegenerative diseases.

Background: Elderly patients aged ≥ 65 years remain disproportionately vulnerable to severe COVID-19, with 30-day mortality rates ranging from 32% to 59% during the Omicron wave despite the variant’s reduced overall virulence. While blood pressure abnormalities are common in critically ill COVID-19 patients, the prognostic significance of admission diastolic blood pressure (DBP) as an independent predictor of short-term mortality in this population has not been systematically evaluated. Objective: To investigate the association between DBP and clinical outcomes in this vulnerable population. Methods: This retrospective cohort study included 240 consecutive elderly patients (aged ≥ 65 years) with severe/critical COVID-19 admitted to the Hospital from December 24, 2022 to January 24, 2023. Patients were categorized by admission DBP into three groups: hypotension (< 70 mmHg), optimal range (70– 89 mmHg), and poor control (≥ 90 mmHg). The primary outcome was 30-day mortality. Multivariable logistic regression analysis was performed to identify independent predictors of mortality. Results: The full predictive model incorporating admission DBP category, age, chronic kidney disease, secondary infection, and oxygen saturation demonstrated good discrimination (AUC 0.880, 95% CI: 0.832– 0.926). The Hosmer-Lemeshow goodness-of-fit test yielded χ²=19.077 (P=0.015), and the optimal discrimination threshold determined by Youden’s index yielded a sensitivity of 85.7% and a specificity of 84.6%. Conclusion: In elderly patients with severe/critical COVID-19, admission hypotension was a strong independent predictor of 30-day mortality. These findings suggest that careful blood pressure monitoring and avoidance of excessive DBP reduction may improve outcomes in this vulnerable population.

Tumor necrosis factor receptor‐associated factor interacting protein (TRAIP) has emerged as a critical regulator of multiple oncogenic processes across various malignancies. However, its specific functional role and underlying mechanisms in breast cancer pathogenesis remain to be fully elucidated. Integrated bioinformatics analysis of TCGA and GTEx datasets was performed to assess TRAIP expression patterns. Complementary experimental validation was conducted using immunohistochemistry, qRT‐PCR, and western blot in clinical specimens. Functional characterization of TRAIP in breast cancer cells was achieved through CCK‐8 proliferation assays, colony formation analysis, transwell migration/invasion tests, wound healing experiments, and flow cytometric apoptosis detection. Mechanistic investigations employed co‐immunoprecipitation and ubiquitination assays to delineate the TRAIP‐PLSCR4 interaction, supplemented by rescue experiments to confirm functional interdependence. Consistent overexpression of TRAIP was observed in breast cancer tissues compared to normal controls. Genetic knockdown of TRAIP significantly attenuated malignant phenotypes, including: (1) reduction in cellular proliferation, (2) decrease in colony‐forming capacity, (3) reduction in migratory/invasive potential, and (4) increase in apoptosis rates (Annexin V staining). Mechanistically, TRAIP functioned as an E3 ubiquitin ligase mediating proteasomal degradation of PLSCR4 through K48‐linked polyubiquitination (co‐IP validation). Notably, PLSCR4 silencing effectively rescued the tumor‐suppressive effects of TRAIP knockdown. This study identifies a novel TRAIP/PLSCR4 regulatory axis in breast cancer pathogenesis, wherein TRAIP exerts its oncogenic function via ubiquitination‐dependent degradation of tumor‐suppressive PLSCR4. These findings position TRAIP as a promising therapeutic target for precision breast cancer interventions.

Background/Objectives: Alzheimer’s disease (AD) involves amyloid and tau pathology with neuroimmune dysregulation, and Yixin Yangshen Granules (YXYS) shows neuroprotective promise, though mechanisms remain unclear. This study aimed to elucidate the multi-target mechanisms of YXYS in AD. Methods: The study began by analyzing a public human AD hippocampal snRNA-seq dataset to identify cell-type-specific pathological pathways and profiled YXYS constituents by UPLC-QTOF-MS. In vitro, YXYS cytoprotection against mitochondrial dysfunction and oxidative stress was tested in Aβ_25–35-challenged HT22 cells; in vivo efficacy was assessed in Aβ_1–42-induced mice via behavioral and histopathological analyses. Integrated transcriptomic and proteomic profiling of brain tissue, with ELISA, qRT-PCR, and Western blot validation, confirmed pathway targets. Using the intersection of transcriptomic and proteomic targets as biological input, the DTIAM deep learning framework was employed to prioritize active YXYS constituents. Finally, molecular docking and 100-ns dynamics simulations demonstrated direct binding of Ganosporelactone A to HIF−1α. Results: AD snRNA-seq analysis highlighted HIF−1 and AGE-RAGE signaling as prominent pathways in the AD hippocampus, particularly enriched in brain microvascular endothelial cells, implicating neurovascular hypoxic and inflammatory stress. In Aβ-induced mice, YXYS improved cognition, reduced Aβ pathology, suppressed neuroinflammation, and promoted neuronal survival, consistent with in vitro evidence of restored mitochondrial function. Multi-omics confirmed convergence on HIF−1 and AGE-RAGE pathways, with YXYS rebalancing the neuroimmune microenvironment by reducing pro-inflammatory M0 macrophages. Screening against these consensus signaling hubs, deep learning analysis prioritized Ganosporelactone A as the top-ranked modulator, and molecular further demonstrated the stable binding of Ganosporelactone A to HIF−1α, linking YXYS to mitigation of hypoxic stress. Conclusions: Guided by multi-omics and deep learning, our findings suggest that YXYS may alleviate AD-related phenotypes through multi-target modulation of the HIF−1 and AGE-RAGE pathways, with associated improvements in neuro-immune homeostasis and reductions in oxidative stress, neuroinflammation, and hypoxia.

Stroke, which leads to death and disability in high proportions globally, is one of the most deleterious neurological diseases. Ischemic stroke (IS) is the major cause of disease attack and accounts for ~70% of all incident stroke cases in China. Up to now, only two therapies for IS were officially approved, which are intravenous administration of recombinant tissue-plasminogen activator (rt-PA) and endovascular mechanical thrombectomy to rapidly recanalize the occluded artery, which both recanalize the occluded artery rapidly to reduce disability, but are limited in a fixed time window. In this study, the therapeutic effect of a traditional Chinese medicine, DengZhanXiXin injection (DZXI), was evaluated on middle cerebral artery occlusion (MCAO) rats at the neurobehavioral and pathophysiological levels through neurological tests, neurohistological staining, proteomic assay, and biological information analysis. We found that DZXI significantly ameliorated the neurological deficit, prevented infarct volume evolution, and protected cortical neural cells from death in ischemia penumbra on MCAO rats. Furthermore, corresponding therapeutic molecular targets were investigated through proteomic analysis of ischemic hemispheres of MCAO rats. One hundred ninety-one differentially expressed proteins involved in response to metal ions, neurofilament bundle assembly, and modulation of chemical synaptic transmission were identified between the MCAO model and DZXI groups after 7 days. DZXI influenced the expression levels of proteins in 13 specific biological functions, with cell signaling and chemical synaptic transmission-associated proteins being most affected. Subsequent molecular docking analysis predicted binding potential between key target proteins and DZXI compounds. The results suggested that DZXI ameliorates neurological deficits by potentially affecting cellular signaling and chemical synaptic transmission physiological processes.

Background: Lipid metabolism changes occur in early Alzheimer's disease (AD) patients. Yet little is known about metabolic gene changes in early AD cortex. Methods: The lipid metabolic genes selected from two datasets (GSE39420 and GSE118553) were analyzed with enrichment analysis. Protein–protein interaction network construction and correlation analyses were used to screen core genes. Literature analysis and molecular docking were applied to explore potential therapeutic drugs. Results: 60 lipid metabolic genes differentially expressed in early AD patients’ cortex were screened. Bioinformatics analyses revealed that up-regulated genes were mainly focused on mitochondrial fatty acid oxidation and mediating the activation of long-chain fatty acids, phosphoproteins, and cholesterol metabolism. Down-regulated genes were mainly focused on lipid transport, carboxylic acid metabolic process, and neuron apoptotic process. Literature reviews and molecular docking results indicated that ACSL1, ACSBG2, ACAA2, FABP3, ALDH5A1, and FFAR4 were core targets for lipid metabolism disorder and had a high binding affinity with compounds including adenosine phosphate, oxidized Photinus luciferin, BMS-488043, and candidate therapeutic drugs especially bisphenol A, benzo(a)pyrene, ethinyl estradiol. Conclusions: AD cortical lipid metabolism disorder was associated with the dysregulation of the PPAR signaling pathway, glycerophospholipid metabolism, adipocytokine signaling pathway, fatty acid biosynthesis, fatty acid degradation, ferroptosis, biosynthesis of unsaturated fatty acids, and fatty acid elongation. Candidate drugs including bisphenol A, benzo(a)pyrene, ethinyl estradiol, and active compounds including adenosine phosphate, oxidized Photinus luciferin, and BMS-488043 have potential therapeutic effects on cortical lipid metabolism disorder of early AD.

Exploration and utilization of exosome biomarkers and their related functions provide the possibility for the diagnosis and treatment of post-stroke cognitive impairment (PSCI). To identify the new diagnostic and prognostic biomarkers of plasma exosome were uzed label-free quantitative proteomics and biological information analysis in PSCI patients. Behavioral assessments were performed, including the Mini-Mental Status Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Barthel index, the Morse Fall Seale (MFS) between control group (n = 10) and PSCI group (n = 10). The blood samples were collected to analyse the biomarker and differentially expressed proteins of plasma exosome using label-free quantitative proteomics and biological information. The exosomes marker proteins were determined by Western blot. The exosome morphology was observed by transmission electron microscopy. The scores of MMSE and MoCA were significantly decreased in the PSCI group. The PT% and high-density lipoprotein decreased and the INR ratio increased in PSCI group. The mean size of exosome was approximately 71.6 nm and the concentration was approximately 6.8E+7 particles/mL. Exosome proteomics identified 259 differentially expressed proteins. The mechanisms of cognitive impairment are related to regulate the degradation of ubiquitinated proteins, calcium dependent protein binding, cell adhesive protein binding, formation of fibrin clot, lipid metabolism and ATP-dependent degradation of ubiquitinated proteins in plasma exosome of PSCI patients. Plasma levels of YWHAZ and BAIAP2 were significantly increased while that of IGHD, ABCB6 and HSPD1 were significantly decreased in PSCI patients. These proteins might be target-related proteins and provide global insights into pathogenesis mechanisms of PSCI at plasma exosome proteins level.

Background Recently, the plasma exosome biomarkers of post-stroke cognitive impairment (PSCI) have been brought into focus. Exploration and utilization of exosome biomarkers and their related functions provided the possibility for the diagnosis and treatment of PSCI. Aims To identify for new diagnostic and prognostic biomarkers of plasma exosome using label-free quantitative proteomics and biological information analysis in PSCI patients. Methods A series of behavioral assessments were performed, including the Mini-Mental Status Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Barthel index, the Morse Fall Seale (MFS) beteen control group (n = 10) and PSCI group (n = 10). The blood samples were collected to analyse the biomarker and differentially expressed proteins of plasma exosome using label-free quantitative proteomics and biological information. The exosomes marker proteins were determined by Western blot. The exosome morphology was observed by transmission electron microscopy. Results The scores of MMSE and MoCA were significantly decreasd in the PSCI group. The PT% and high-density lipoprotein decreasd and the INR ratio increasd in PSCI group. The mean size of exosome was approximately 71.6 nm and the concentration was approximately 6.8E + 7 particles/mL. Exosome proteomics identificated 259 differentially expressed proteins, including 131 up-regulated proteins and 128 down-regulated proteins. The mechanisms of cognitive impairment are related to up-regulation of degradation of ubiquitinated proteins, calcium dependent protein binding, cytoskeleton reorganization, platelet aggregation and down-regulation of cell adhesive protein binding, formation of fibrin clot, complement activation, lipid metabolism and ATP-dependent degradation of ubiquitinated proteins in plasma exosome of PSCI patients. Plasma levels of YWHAZ and BAIAP2 were significantly increased while that of IGHD, ABCB6 and HSPD1 were significantly decreased in PSCI patients. Conclusion These proteins might be target-related proteins and provide global insights into pathogenesis mechanisms of PSCI at plasma exosome proteins level.