Bo Yan

Alzheimer’s disease (AD), the leading cause of dementia, is characterized by amyloid beta accumulation and tau pathology propagation. Nanomedicine, a discipline enabling targeted drug delivery with precision, holds significant promise in the treatment of neurodegenerative diseases. This review explores the diagnostic and therapeutic applications of nanomaterials in neurodegenerative diseases, particularly AD, emphasizing their properties and their role in modulating pathogenic proteins. Advances in the development of novel anti-AD nanomedicines and their clinical progress are also highlighted. Despite the growing potential of nanotechnology in AD therapy, a definitive cure remains elusive. The review further addresses the current challenges in the field of AD nanomedicines and outlines future research directions to propel their development.

Background: In recent decades, the widespread use of polyethylene terephthalate (PET) has led to the proliferation of PET microplastics (PET-MPs) in the environment, posing potential threats to human health, including ulcerative colitis (UC). However, the underlying molecular mechanisms remain unclear. Methods: Data sourced from public databases were harnessed to predict the targets of PET-MPs and identify UC-related differentially expressed genes. Functional enrichment analyses were conducted to uncover relevant biological pathways. Three machine learning (ML) algorithms were utilized to screen for hub genes associated with PET-MPs-induced UC, followed by the evaluation of these hub genes using eight ML algorithms via SHapley Additive exPlanations (SHAP) analysis. Subsequently, a nomogram was constructed and validated based on a risk prediction model, and single-cell sequencing analysis and molecular docking were performed. An animal model was established via coadministration of 3% dextran sulfate sodium (DSS) and PET-MPs. Western blot analysis was employed to verify the protein expression levels in intestinal tissues. Results: Eleven potential targets related to PET-MPs-induced UC toxicity were identified. Four hub genes (CTSK, NAAA, PDE4B, and PFKFB3) were successfully screened out, exhibiting significant expression disparities in UC samples. The constructed risk prediction model demonstrated high prediction accuracy. Single-cell analysis revealed distinct expression patterns of the hub genes across different cell types, and molecular docking confirmed strong binding affinities between PET-MPs and these genes. Animal experiments revealed that the expression levels of CTSK, PDE4B, and PFKFB3 in the DSS + PET-MPs group were significantly upregulated, while the expression level of NAAA was significantly downregulated, compared with the DSS group. Conclusion: This study offers valuable insights into the molecular mechanisms by which PET-MPs may induce UC, providing a theoretical foundation for understanding the potential health risks associated with PET-MPs exposure.

Aging leads to neurodegenerative diseases, such as cognitive decline, which are induced by persistent chronic low‐grade inflammation in the brain driven by microglial activation. However, whether and how brain‐derived exosomes from aged mice (A‐exo) induce a pro‐inflammatory state and cellular senescence in microglia within the aging brain is poorly understood. Here, we report that brain‐derived exosomes from aged mice (A‐exo) cause cognitive decline in normal young mice, inducing microglial overactivation, lipid droplet accumulation, and senescence‐associated secretory phenotype (SASP) secretion. This abnormal microglial activity arises from the elevated expression of PTGDS in A‐exo due to mouse aging, resulting in increased central and peripheral D‐prostanoid receptor 1 (DP1) ligand PGD2 levels, which subsequently leads to sustained DP1 signaling activation. Consequently, this process promotes myeloid cell infiltration, cellular senescence, and cognitive decline by generating a senescent, pro‐inflammatory microglial phenotype. Blocking the DP1 receptor ameliorates A‐exo‐mediated microglial overactivation, myeloid cell infiltration, and cellular senescence. Strikingly, DP1 receptor blockade improves cellular senescence, neuroinflammation, and cognitive decline in aged mice. Our findings reveal a systemic mechanism underlying the sustained activation of microglia following brain aging, paving the way for improving chronic neuroinflammation, cellular senescence, and cognitive decline associated with aging.

Background and purpose: The role of PD-L1/PD-1 axis in IS remains controversial, with conflicting outcomes from systemic PD-1 or PD-L1 knockout models. These discrepancies underscore the complexity of PD-L1/PD-1 signaling and highlight the need to explore its cell-specific functions, particularly in neurons and microglia. Neurons, as the primary functional cells in the CNS, play a critical role in modulating local immune responses, yet their contribution to PD-L1/PD-1 signaling in IS is unknown. Furthermore, the mechanisms linking PD-L1/PD-1 to microglial polarization remain unclear. This study investigates whether targeted suppression of neuronal PD-L1 alleviates IS injury by modulating the PD-1/RFX1 axis and driving microglial polarization toward an anti-inflammatory phenotype. Methods: Middle cerebral artery occlusion (MCAO) was performed in mice to model IS. Neuronal PD-L1 was selectively suppressed using AAV. Microglial polarization, PD-1 and RFX1 expression, and neuroinflammation were assessed via flow cytometry, immunofluorescence, 4D-FastDIA proteomics, and qPCR/ELISA. In vitro, PD-1 knockdown BV2 cells and RFX1 overexpression models were established to validate mechanistic interactions. Results: Neuronal PD-L1 suppression reduced infarct volume, improved cerebral blood flow, and alleviated neurological deficits in ischemic stroke mice. Microglial PD-1 expression decreased significantly, accompanied by a phenotypic shift from pro-inflammatory to anti-inflammatory states. RFX1, exclusively expressed in microglia, was downregulated and identified as a key regulator of PD-1 and microglial polarization. In vitro, RFX1 overexpression reversed the anti-inflammatory effects of PD-1 knockdown, restoring pro-inflammatory cytokine levels. Critically, neuronal PD-L1 suppression spared peripheral immune cells, avoiding systemic immune disruption. These findings establish the PD-1/RFX1 axis as a central mediator of neuron-microglia crosstalk in IS neuroinflammation. Conclusion: Neuronal PD-L1 suppression attenuates IS injury by modulating the PD-1/RFX1 axis to promote anti-inflammatory microglial polarization. This study reveals a novel neuron-microglia crosstalk mechanism and highlights RFX1 as a therapeutic target for IS. The neuron-specific strategy overcomes limitations of systemic PD-L1/PD-1 inhibition, offering a precise and clinically translatable approach to mitigate neuroinflammation while preserving peripheral immune homeostasis.

Background: Ulcerative colitis (UC) is a challenging chronic intestinal inflammation. Anoikis, a type of programmed cell death triggered by detachment from the extracellular matrix, is crucial in various physiological and pathological contexts. This study aims to explore the biological and clinical implications of anoikis-related genes (ARGs) in UC. Methods: Gene expression microarrays from normal and UC mucosal tissues focused on ARGs. Differentially expressed genes (DEGs) related to anoikis in UC were identified. Weighted gene co-expression network analysis (WGCNA) screened UC-related module genes. GO, KEGG, GSEA, and GSVA analyses were used to uncover mechanisms. Machine learning identified hub ARG-DEGs highly correlated with UC, and diagnostic nomograms assessed their diagnostic potential. The CIBERSORT algorithm analyzed changes in the UC immune microenvironment related to hub UC-ARGs. Potential drugs, miRNAs, and transcription factors (TFs) interacting with these hub UC-ARGs were investigated, and animal experiments verified their expression. Results: 49 ARG-DEGs were identified, mainly linked to the PI3K-AKT signaling pathway, inflammatory signal regulation, and extracellular matrix (ECM)-receptor interactions. Notably, CDH3 and SERPINA1 showed significant diagnostic potential for UC, confirmed by the Wilcoxon rank-sum test, independent validation sets, Western blot, and immunohistochemical staining. Significant variations in immune cell infiltration and activation within UC samples correlated with hub UC-ARGs were observed using the CIBERSORT algorithm. Conclusion: Anoikis may drive UC progression by initiating an immune inflammatory response. CDH3 and SERPINA1 are promising biomarkers and therapeutic targets for UC.

Inflammatory age (iAge) is a vital concept for understanding the intricate interplay between chronic inflammation and aging in the context of cancer. However, the importance of iAge-clock-related genes (iAge-CRGs) across cancers remains unexplored. This study aimed to explore the mechanisms and applications of these genes across diverse cancer types. We analyzed profiling data from over 10,000 individuals, covering 33 cancer types, 750 small molecule drugs, and 24 immune cell types. We focused on DCBLD2’s function at the single-cell level and computed an iAge-CRG score using GSVA. This score was correlated with cancer pathways, immune infiltration, and survival. A signature was then derived using univariate Cox and LASSO regression, followed by ROC curve analysis, nomogram construction, decision curve analysis, and immunocytochemistry. Our comprehensive analysis revealed epigenetic, genomic, and immunogenomic alterations in iAge-CRGs, especially DCBLD2, leading to abnormal expression. Aberrant DCBLD2 expression strongly correlated with cancer-associated fibroblast infiltration and prognosis in multiple cancers. Based on GSVA results, we developed a risk model using five iAge-CRGs, which proved to be an independent prognostic index for uveal melanoma (UVM) patients. We also systematically evaluated the correlation between the iAge-related signature risk score and immune cell infiltration. iAge-CRGs, particularly DCBLD2, emerge as potential targets for enhancing immunotherapy outcomes. The strong correlation between abnormal DCBLD2 expression, cancer-associated fibroblast infiltration, and patient survival across various cancers underscores their significance. Our five-gene risk signature offers an independent prognostic tool for UVM patients, highlighting the crucial role of these genes in suppressing the immune response in UVM.Kindly check and confirm whether the corresponding affiliation is correctly identified.I identified the affiliation is correctly.thank you.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured Please check and confirm.I confirm the abstract is correctly ,thank you.

Background. Stem cell‐derived extracellular vesicles (SCEVs) have emerged as a potential therapy for hemorrhagic stroke. However, their effects are not fully understood. The aim of this study was to comprehensively evaluate the effects of SCEVs therapy in rodent models of hemorrhagic stroke, including subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Materials and Methods. We conducted a comprehensive search of PubMed, EMBASE, and Web of Science until May 2023 to identify studies investigating the effects of SCEVs therapy in rodent models of ICH. The functional outcomes were assessed using neurobehavioral scores. Standardized mean differences (SMDs) and confidence intervals (CIs) were calculated using a random‐effects model. Three authors independently screened the articles based on inclusion and exclusion criteria. All statistical analyses were performed using Revman 5.3 and Stata 17.0. Results. Twelve studies published between 2018 and 2023 met the inclusion criteria. Our results showed that SCEVs therapy improved neurobehavioral scores in the rodent SAH model (SMD = −3.49, 95% CI: −4.23 to −2.75; p < 0.001). Additionally, SCEVs therapy improved the chronic neurobehavioral scores of the rodent ICH model (SMD = 2.38, 95% CI: 0.36–4.40; p = 0.02) but did not have a significant impact on neurobehavioral scores in the acute and subacute phases. Significant heterogeneity was observed among the studies, and further stratification and sensitivity analyses failed to identify the source of heterogeneity. Conclusions. Our findings suggest that SCEVs therapy may improve neurofunctional behavior after hemorrhagic stroke and provide important insights into the design of preclinical trials.

Purpose: The aged microenvironment plays a crucial role in tumor onset and progression. However, it remains unclear whether and how the aging of the extracellular matrix (ECM) influences cancer onset and progression. Furthermore, the mechanisms and implications of extracellular matrix senescence-related genes (ECM-SRGs) in pan-cancer have not been investigated. Methods: We collected profiling data from over 10,000 individuals, covering 33 cancer types, 750 small molecule drugs, and 24 immune cell types, for a thorough and systematic analysis of ECM-SRGs in cancer. Results: We observed a significant correlation between immune cell infiltrates and Gene Set Variation Analysis enrichment scores of ECM-SRGs in 33 cancer types. Moreover, our results revealed significant differences in immune cell infiltration among patients with copy number variations (CNV) and single nucleotide variations (SNV) in ECM-SRGs across various malignancies. Aberrant hypomethylation led to increased ECM-SRGs expression, and in specific malignancies, a connection between ECM-SRGs hypomethylation and adverse patient survival was established. The frequency of CNV and SNV in ECM-SRGs was elevated. We observed a positive correlation between CNV, SNV, and ECM-SRGs expression. Furthermore, a correlation was found between the high frequency of CNV and SNV in ECM-SRGs and poor patient survival in several cancer types. Additionally, the results demonstrated that ECM-SRGs expression could serve as a predictor of patient survival in diverse cancers. Pathway analysis unveiled the role of ECM-SRGs in activating EMT, apoptosis, and the RAS/MAPK signaling pathway while suppressing the cell cycle, hormone AR, and the response to DNA damage signaling pathway. Finally, we conducted searches in the “Genomics of Drug Sensitivity in Cancer” and “Genomics of Therapeutics Response Portal” databases, identifying several drugs that target ECM-SRGs. Conclusions: We conducted a comprehensive evaluation of the genomes and immunogenomics of ECM-SRGs, along with their clinical features in 33 solid tumors. This may provide insights into the relationship between ECM-SRGs and tumorigenesis. Consequently, targeting these ECM-SRGs holds promise as a clinical approach for cancer treatment.

Background and Aims: Duodenal endoscopic submucosal dissection (ESD) has been considered to be the most challenging because of its high incidence of complications, which has hindered the development of duodenal ESD. The aim of this study is to discuss operation tips for duodenal ESD and to assess the efficacy and safety of duodenal ESD. Patients and Methods: Eighty-two patients who underwent ESD in the digestive endoscope center for superficial duodenal epithelial tumors (SDETs) from January 2017 to June 2021 were studied. Patients were divided into three groups according to the occurrence of complications, and the clinical characteristics and surgical efficacy of each group were compared. Results: SDETs in 82 patients were completely removed by ESD, with a 97.5% R0 resection rate. The average size of resected lesions was 23.8 ± 6.5 mm. There were significant differences in lesion size and operation time between the normal and intraprocedural complication groups ( P < .05). Similarly, between the normal and delayed complication groups, significant differences were noted in lesion location, size, operation time, occupied circumference, and postoperative hospitalization duration ( P < .05). Conclusion: Duodenal ESD is prone to complications that increase the complexity of the procedure. By improving the necessary technique and skills, duodenal ESD remains safe and effective.