According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of th Show more
According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of the femoral head. As the exact biological mechanism among the three is still unclear, Mendelian randomization, computer-aided drug design, and transcriptomics sequencing were used to explore the specific mechanism of action. The study validated the specific signaling pathways through which dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head using animal experiments and transcriptomics sequencing. Data were obtained from public databases for Mendelian randomization analysis, and a two-sample Mendelian randomization was used to determine the intermediary role of core pathway-related targets. Computer-aided drug design was employed to assess the binding affinity between dihydroartemisinin and core targets. Transcriptome sequencing determined that dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head by regulating ferroptosis. We obtained 564 ferroptosis-related targets that met the analysis criteria and 1812 plasma proteins from the UK Biobank, and analyzed finngen_R11_OSTEON_DRUGS in the Finnish database as outcome. The results showed that there were two quantitative trait loci that had a causal relationship with ferroptosis targets. There were 110 protein quantitative trait loci causally associated with plasma proteins from the UK Biobank, and none of these loci had an inverse causal relationship with SONFH. Through mediation analysis, 7 mediating pathways were identified, yielding eight targets including ZP3, CCL17, APOE, C7ORF50, SPINK4, SPINK2, FTMT, and PRDX6. Computer-aided drug design revealed that CCL17 and PRDX6 exhibited the best docking effects. The study determined that CCL17 and PRDX6 have a significant causal relationship with SONFH. It also clarified the specific mechanism by which DHA may regulate ferroptosis to treat SONFH, which will provide a reference for the discussion of the prevention and treatment mechanisms of SONFH. Show less
Portulaca oleracea L. (purslane) is a widely cultivated herb with edible and medicinal value. Modern pharmacological studies have shown that purslane has potent anti-inflammatory effects. However, its Show more
Portulaca oleracea L. (purslane) is a widely cultivated herb with edible and medicinal value. Modern pharmacological studies have shown that purslane has potent anti-inflammatory effects. However, its potential role in ameliorating atherosclerosis remains unclear. This study aimed to investigate the efficacy of purslane extract in ameliorating atherosclerosis in apolipoprotein E(ApoE) knock-out (ApoE Show less
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the ef Show more
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less
Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress th Show more
Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2's function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology. Show less
Gliomas comprise a heterogeneous group of central nervous system tumors in which gene fusions (GFs) are significant oncogenic drivers and emerging diagnostic and therapeutic biomarkers. In cancer diag Show more
Gliomas comprise a heterogeneous group of central nervous system tumors in which gene fusions (GFs) are significant oncogenic drivers and emerging diagnostic and therapeutic biomarkers. In cancer diagnosis, GF detection largely relies on targeted short-read sequencing fusion panels, such as the Children's Hospital of Philadelphia (CHOP) Fusion Panel (FUSIP). While these panels are effective for detecting recurrent, well-characterized GFs, they are limited to predefined gene sets and cannot identify full-length transcripts. Here, we analyzed 49 high- and low-grade gliomas previously classified as fusion-negative by FUSIP using an untargeted whole-transcriptome RNA sequencing approach with Oxford Nanopore Technologies (ONT) long-read sequencing. This enabled transcriptome-wide fusion discovery of additional known and potentially novel oncogenic GFs beyond panel constraints. Long-read sequencing further allowed direct resolution of full-length fusion transcripts and their associated isoform structures. By integrating GF detection with isoform-level transcript analysis, we identified fusion-associated transcript isoforms with alternative splicing patterns that aligned near reported GF breakpoints, including Show less
BackgroundInterpreting blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) in a multicultural cohort is complicated by inconsistent evidence on racial differences. Kidney functi Show more
BackgroundInterpreting blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) in a multicultural cohort is complicated by inconsistent evidence on racial differences. Kidney function, which varies by race and influences biomarker levels, is often overlooked, potentially contributing to these inconsistencies.ObjectiveTo characterize racial differences in plasma levels of ADRD biomarkers after adjusting for comorbidities and assessed the impact of estimated glomerular filtration rate (eGFR) adjustment using either race-specific or race-neutral equations.MethodsData from the Einstein Aging Study, a multicultural cohort of older adults, included plasma biomarkers (Aβ Show less
Yiqi Huoxue Granule (YQHX), a traditional Chinese medicine (TCM) formulation, is extensively utilized for the treatment of atherosclerotic diseases. However, its active constituents and molecular mech Show more
Yiqi Huoxue Granule (YQHX), a traditional Chinese medicine (TCM) formulation, is extensively utilized for the treatment of atherosclerotic diseases. However, its active constituents and molecular mechanisms remain unclear. We utilized a systematic methodology to identify bioavailable compounds in vivo and predict and validate the principal targets and pathways responsible for their anti-atherosclerotic actions. Serum pharmacochemistry utilizing UPLC-Q-Exactive Orbitrap-MS was employed to identify the bioavailable compounds of YQHX. An integrated methodology combining network pharmacology and molecular docking was implemented to predict its potential targets and mechanisms against atherosclerosis, which were subsequently verified experimentally in apolipoprotein E-deficient (ApoE We identified 36 absorbable compounds in the serum of rats following YQHX administration, and 252 potential therapeutic targets were predicted. Protein-protein interaction analysis identified 10 hub targets, which are IL-6, TNF, EGFR, TP53, AKT, STAT3, SRC, CTNNB1, TLR4, and MMP-9. Enrichment analyses indicated that these targets are primarily involved in lipid metabolism and inflammatory responses, with significant enrichment in the PI3K-Akt and SRC signaling pathways. Molecular docking revealed strong binding affinities between the proteins EGFR, SRC, and AKT and their respective compounds. In ApoE This study systematically identified the bioactive compounds of YQHX and demonstrated its multi-target anti-atherosclerotic effect, which involved the enhancement of lipid metabolism and suppression of inflammation, mediated, at least in part, by the inhibition of the SRC/AKT signaling pathway. Show less
Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta Show more
Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Show less
Dietary protocatechuic acid (PCA) inhibits atherosclerosis development in male ApoE-/- mice. However, its anti-atherosclerotic property in genetically unmodified (wild-type) male or female mice remain Show more
Dietary protocatechuic acid (PCA) inhibits atherosclerosis development in male ApoE-/- mice. However, its anti-atherosclerotic property in genetically unmodified (wild-type) male or female mice remains unknown.Five-week-old C57BL/6J mice (half males and females) were divided into negative (fed a chow diet), positive (fed an atherogenic diet), or 5, 25, 50, 100, or 200 mg/kg BW/d of PCA (fed an atherogenic diet) groups. Oral gavage with PCA between 25-100 mg/kg BW/d for 25 weeks significantly attenuated atherogenic diet-induced plaque formation in a dose-dependent manner, whereas the anti-atherosclerotic efficiency of 200 mg/kg BW/d of PCA was comparable with that of 50 mg/kg BW/d. PCA did not affect serum lipids (total triglyceride, total cholesterol, HDL cholesterol), pro-inflammatory cytokines (tumor necrosis factor alpha, IL-1b, IL-6), oxidized LDL, and total antioxidant capacity, and acetylcholine or sodium nitroprusside-induced aortic relaxation. Instead, PCA (≥25 mg/kg BW/d) reduced macrophage accumulation and content of tumor necrosis factor alpha, superoxide, and 4-hydroxynonenal within plaques, and inhibited monocyte adhesion to aortic endothelium in both male and female mice.PCA inhibits early atherosclerosis formation in both male and female C57BL/6J mice with a "U-shaped" dose-response relationship, possibly by reducing inflammation burden and oxidative stress within atherosclerotic plaques. Show less
Apolipoprotein E (APOE) and Galectin-3 (Gal-3) are markers of activated microglia in neurodegenerative diseases of the central nervous system, whose targeting is protective in mouse models of glaucoma Show more
Apolipoprotein E (APOE) and Galectin-3 (Gal-3) are markers of activated microglia in neurodegenerative diseases of the central nervous system, whose targeting is protective in mouse models of glaucoma. In this study, we examined levels of APOE and Gal-3 in human aqueous humor (AH) and serum samples. Single-center, cross-sectional study. A total of 100 glaucoma and 110 control patients at Massachusetts Eye and Ear. We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. At the start of ophthalmic surgery, we collected AH and serum from 100 glaucoma and 110 control patients. APOE and Gal-3 levels were quantified by enzyme-linked immunosorbent assays. APOE and Gal-3 levels in AH and serum. APOE and Gal-3 levels were significantly elevated in the AH of glaucoma patients compared to controls (2.72 vs. 0.85 µg/ml, P < 0.0001 for APOE, and 2.89 vs. 1.45 ng/ml, P < 0.001 for Gal-3). A positive correlation was observed between AH APOE and Gal-3 levels in the glaucoma cohort (R = 0.44, P < 0.0001). While serum Gal-3 levels were similar between groups (25.5 vs. 25.7 ng/ml, P = 0.92), APOE levels were significantly elevated in the serum of glaucoma patients compared to controls (58.7 vs. 30.2 µg/ml, P < 0.0001). Serum APOE levels were not correlated with AH APOE levels in either the glaucoma or the control groups (both R ~ 0, P > 0.05) or dependent on APOE genotype. Our findings demonstrate that AH Gal-3 and APOE are elevated in patients with glaucoma. In contrast, only serum APOE was elevated in our glaucoma cohort, possibly reflecting the known dysregulation of lipid metabolism that occurs in this disease. Show less
Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is critical for early intervention. Many existing models lack the ability to capture the nonlinear n Show more
Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is critical for early intervention. Many existing models lack the ability to capture the nonlinear nature of cognitive decline and individual heterogeneity. This study employed a semi‑parametric joint model to analyze longitudinal cognitive trajectories and identify robust predictors of conversion. Data from 596 participants (184 AD converters, 412 stable MCI) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal assessments included ADAS‑Cog13, ADAS‑Cog11, CDR‑SB, FAQ, RAVLT‑IR, RAVLT‑L, and MMSE. A semi‑parametric joint model combining B‑splines for the longitudinal process with a Cox survival submodel was fitted for each cognitive measure. Model performance was evaluated using AIC, BIC, intraclass correlation coefficient (ICC), time‑dependent C‑index, dynamic AUC, and calibration curves. Subgroup analyses were conducted by APOE‑ε4 carrier status. In multivariable joint models, APOE‑ε4 carriage was a consistent risk factor (HR range: 1.38-1.77). Higher scores on ADAS‑Cog13 (HR = 3.71 per SD), ADAS‑Cog11 (HR = 2.71), CDR‑SB (HR = 3.79), and FAQ (HR = 2.85) increased the hazard of conversion, whereas higher scores on RAVLT‑IR (HR = 0.23), RAVLT‑L (HR = 0.14), and MMSE (HR = 0.53) were protective. All models showed high ICCs (0.94-0.98) and moderate‑to‑good predictive accuracy over 2, 5, and 8 year horizons (C‑index: 0.585-0.668). CDR‑SB and FAQ exhibited the strongest effect sizes and clearest dose‑dependent trajectories across APOE‑ε4 subgroups. Calibration curves demonstrated good agreement between predicted and observed survival. The semi‑parametric joint model effectively captures nonlinear cognitive‑functional decline and provides validated predictions of AD risk. APOE‑ε4 genotype combined with longitudinal monitoring of CDR‑SB and FAQ offers a robust framework for stratifying progression risk in clinical MCI management. Show less
Atherosclerosis is a chronic inflammatory condition marked by the deposition of lipids within the arterial wall and the infiltration of inflammatory cells, culminating in the development of atheroscle Show more
Atherosclerosis is a chronic inflammatory condition marked by the deposition of lipids within the arterial wall and the infiltration of inflammatory cells, culminating in the development of atherosclerotic plaques. Ubiquitin-specific protease 18, USP18, a specific deubiquitinating enzyme, has been demonstrated to exert protective effects on the cardiovascular system. Pathological studies were performed utilizing human coronary arteries obtained from the Forensic Medical Examination Center of Guizhou Medical University, in conjunction with the aorta from experimental ApoE knockout mice. The ApoE knockout mice underwent intervention with adenovirus carrying USP18-RNAi and a control adenovirus containing hU6-MCS-CMV-EGFP, after which pathological analyses were conducted. In vitro, THP-1 cells, induced with phorbol ester, were subjected to treatment with si-USP18 or si-NC, followed by exposure to oxidized low-density lipoprotein. The expression levels of USP18 and proteins associated with the TAK1/NF-κB signaling pathway, as well as the interaction between USP18 and TAK1, were assessed using Western blotting, RT-PCR, and immunofluorescence techniques.The interaction between USP18 and TAK1 was confirmed using molecular docking techniques, co-immunoprecipitation assays, and immunofluorescence analysis. The purpose of this study is to explore the role of USP18 on atherosclerosis and the underlying mechanism. The expression of USP18 is elevated in early-stage human coronary atherosclerotic plaques but decreases in advanced lesions. Treatment of macrophages derived from THP-1 cells and bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS) results in reduced USP18 expression. In ApoE USP18 modulates TAK1 to suppress the activation of the NF-κB signaling pathway in macrophages, consequently exerting an anti-atherosclerotic effect and offering a potential therapeutic strategy for atherosclerosis treatment. Show less
Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We ana Show more
Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We analysed the expression of deubiquitinating enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an ApoE USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in ApoE This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease. This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.). 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
Aortic dissection is a life-threatening cardiovascular disease whose complex cellular pathophysiology is studied using various mouse models. To systematically evaluate their fidelity, we performed cro Show more
Aortic dissection is a life-threatening cardiovascular disease whose complex cellular pathophysiology is studied using various mouse models. To systematically evaluate their fidelity, we performed cross-species single-cell RNA sequencing, integrating data from human aortic dissection with five mouse models (BAPN, Ang-II, Ang-II apoE Show less
Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phen Show more
Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phenotype of ECs. Recent studies have revealed that cell phenotype-specific alternative splicing of FGFR2 premRNA (precursor mRNA) results in the mutually exclusive inclusion of either exon IIIb or IIIc, leading to critical differences in receptor function. This study aimed to investigate the role of FGFR2 alternative splicing in EC senescence and atherosclerosis development, and to elucidate the underlying mechanisms. Clinical samples and animal models were used to assess the association between FGFR2-IIIc isoform expression and EC senescence as well as atherosclerotic plaque formation. The mechanisms underlying FGFR2-IIIc-induced EC senescence were elucidated through a combination of in vivo and in vitro investigations. In addition, genetically engineered mice with endothelial-specific overexpression or knockdown of FGFR2-IIIc were utilized to investigate the impact of FGFR2-IIIc on vascular endothelial senescence and the progression of atherosclerosis. Elevated expression of the FGFR2-IIIc isoform was detected in clinical samples and animal models of aging and atherosclerosis, where it correlated with both EC senescence and atherosclerotic plaque formation. Mechanistically, the alternative splicing-mediated switch from FGFR2-IIIb to FGFR2-IIIc established an FGF2-FGFR2-IIIc autocrine feedback loop, which drove ECs toward a senescence-associated secretory phenotype via the PKC (protein kinase C) ε/STAT3 (signal transducer and activator of transcription) pathway. Senescence-inducing stimuli promoted the binding of the splicing factor hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) to exon IIIb of the This study reveals that FGFR2 splicing mediated by hnRNP H1 promotes EC senescence and atherosclerosis via an FGF2-FGFR2-IIIc autocrine loop. These findings identify FGFR2-IIIc as a potential therapeutic target for age-related atherosclerosis. Show less
To investigate the correlation between thyroid hormone levels and cognitive dysfunction in older patients with subclinical hypothyroidism (SCH). A retrospective matched case-control study (1:2 ratio) Show more
To investigate the correlation between thyroid hormone levels and cognitive dysfunction in older patients with subclinical hypothyroidism (SCH). A retrospective matched case-control study (1:2 ratio) was conducted, enrolling 420 participants aged ≥ 60 years (140 SCH cases, 280 euthyroid controls) matched by gender, age (± 5 years) and education level. Thyroid function parameters, including thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb), and cognitive performance assessed via the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Auditory Verbal Learning Test (AVLT), Trail Making Test (TMT), and Stroop Color and Word Test (Stroop Test) were measured. The SCH patients had TSH levels consistent with the grouping criteria (TSH > 4.2 mIU/L), higher thyroid autoantibody positivity, and poorer cognitive performance across all domains (all P < 0.001). A dose-response relationship was observed between increasing TSH levels and worsening cognitive function. Multivariate logistic regression identified TSH (odds ratio, OR = 1.19), FT3 (OR = 0.68), age, education and APOE ε4 carrier status as independent predictors of cognitive impairment (ROC AUC = 0.786). Stratified analyses showed stronger associations in females and those aged < 75 years, whereas the significance of the correlation between TSH and cognitive impairment was lost in patients aged ≥ 75 years. Sensitivity analyses confirmed the robustness of the findings. The SCH is independently associated with cognitive dysfunction in older people, with thyroid hormones playing a critical role. The findings suggest potential clinical implications for thyroid function monitoring and cognitive protection in this population. Show less
Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) has been implicated in cell death, glucose homeostasis, and tumor progression, yet its role in atherosclerosis (AS) remains unclear. In this Show more
Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) has been implicated in cell death, glucose homeostasis, and tumor progression, yet its role in atherosclerosis (AS) remains unclear. In this study, SNHG5 expression was markedly elevated in aortic tissues of high-fat diet-fed apoE Show less
Emerging evidence establishes hepatic dysfunction as a critical modulator of breast cancer (BC) progression through metabolic, endocrine, and inflammatory crosstalk, yet the molecular mediators remain Show more
Emerging evidence establishes hepatic dysfunction as a critical modulator of breast cancer (BC) progression through metabolic, endocrine, and inflammatory crosstalk, yet the molecular mediators remain incompletely characterized. This review systematically examines the liver-BC axis to identify mechanistic drivers and therapeutic opportunities for patients with comorbid conditions. We conducted an integrated analysis combining a comprehensive literature review with computational biology approaches, including protein-protein interaction network analysis, functional pathway enrichment (KEGG/GO), and multi-omics data mining from GEO, TCGA, and CPTAC databases, supplemented by experimental validations from preclinical models. Our analysis revealed hepatic dysfunction promotes BC progression through five interconnected pathways: insulin resistance-driven IGF1-PI3K/AKT activation, estrogen metabolism imbalance via CYP19A1/ESR1, IL6-STAT3/NLRP3-mediated inflammation, HMOX1/APOE-dependent metabolic rewiring, and FAK-Src/MMP9-regulated ECM remodeling. Key molecular mediators include nuclear receptors (ESR1), cytokines (IL-1β), growth factors (HGF), and receptor tyrosine kinases, with SPP1 and PTPN2 emerging as potential circulating biomarkers linking hepatic dysfunction to aggressive BC phenotypes. The crosstalk between hepatic dysfunction and BC is mediated by a network of proteins and pathways, offering potential targets for therapeutic intervention. Future research should focus on translational validation and personalized strategies for BC patients with comorbid liver conditions. This mechanistic insight may advance early diagnosis and precision treatment paradigms. Show less
Zien Lin, Zhiye Wu, Lisha Li+9 more · 2026 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Atherosclerotic plaque rupture, driven by a vicious pathological cycle between endothelial-to-mesenchymal transition (EndMT) and chronic inflammation, represents a major therapeutic challenge in cardi Show more
Atherosclerotic plaque rupture, driven by a vicious pathological cycle between endothelial-to-mesenchymal transition (EndMT) and chronic inflammation, represents a major therapeutic challenge in cardiovascular disease. Current clinical strategies, including statins and antiplatelet agents, fail to disrupt the EndMT-inflammation axis, while conventional TGF-β pathway inhibitors-critical for EndMT regulation-exhibit narrow therapeutic windows and systemic toxicity owing to the pleiotropic nature of TGF-β signaling. Here, we reported VRBPC, a VCAM-1-targeting, reactive oxygen species (ROS)-responsive baicalin-peptide conjugate that undergoes in situ self-assembly within atherosclerotic plaques to form a "molecular latch" that breaks the EndMT-inflammation loop. Upon VCAM-1-mediated endocytosis into activated endothelial cells, VRBPC responds to elevated ROS levels in the plaque microenvironment, triggering localized self-assembly that enhances baicalin retention and promotes its competitive binding to HSP90-a critical chaperone for TGF-β receptor stabilization. This mechanism inhibits Smad2/3 phosphorylation, reverses EndMT, and simultaneously suppresses inflammatory responses in macrophages. In vitro, VRBPC effectively restored endothelial phenotype, reduced aberrant migration, and diminished foam cell formation alongside pro-inflammatory cytokine secretion. In ApoE Show less
Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation pla Show more
Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation plays a crucial role in multiple cardiovascular diseases. The objective of this study is to examine whether diabetic atherosclerotic calcification is regulated by S-nitrosylation of AMP-activated protein kinase (AMPK), a regulator of VSMC phenotype switching. The atherosclerotic plaque was induced by feeding Apoe In cultured VSMCs, high glucose (HG), but not high osmotic pressure, triggered nitrosative stress, reduced AMPKβ1 protein levels, increased AMPKβ1 S-nitrosylation and ubiquitination, and led to calcification. These effects were abolished by mutating AMPKβ1 at cysteine 173 or 223. Furthermore, mutations of AMPKβ1 at Cys173/223 to alanine restored AMPKβ1 protein levels and suppressed the AKT/Runx2 pathway in HG-treated VSMCs. In vivo, enforced expression of mutated AMPKβ1 (Cys173Ala plus Cys223Ala), but not overexpression of wild-type AMPKβ1, significantly prevented atherosclerotic calcification in diabetic Apoe Nitrosative stress contributes to atherosclerotic calcification in diabetes through AMPKβ S-nitrosylation. In perspective, it is advisable to consider inhibiting AMPKβ S-nitrosylation in diabetic patients with atherosclerosis. Show less
Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth m Show more
Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. Show less
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Show more
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less
Euphorbia Lathyris L. Seed (ELLS) is a Traditional Chinese Medicine (TCM), which has long been used in China. This study was designed to reveal the synergistic mechanism of ELLS in the treatment of co Show more
Euphorbia Lathyris L. Seed (ELLS) is a Traditional Chinese Medicine (TCM), which has long been used in China. This study was designed to reveal the synergistic mechanism of ELLS in the treatment of colorectal cancer (CRC) by using network pharmacology method and molecular docking. In addition, related in vitro experiments will be conducted to verify the efficacy of ELLS. ELLS related compounds were obtained from TCMSP database. Then active compounds were screened by ADME (absorption, distribution, metabolism, and excretion). Additionally, TCMSP, BATMAN-TCM, STITCH, Swiss Target Prediction and literatures were used to capture the relationships between drugs and targets. A compound-target (C-T) network was established by Cytoscape. Target genes related to CRC were acquired from GeneCards, TTD and OMIM databases. Correlations about compound-target-pathway (C-T-P) were visualized by Cytoscape. The protein-protein interaction (PPI) network was constructed by STRING. Gene survival analysis came from the GEPIA2. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via metascape. Molecular docking analysis was constructed by the AutoDock Vina. And the efficacy of ELLS in combating CRC was verified using HCT116 and SW620 cells. A total of 12 active compounds and 173 associated targets of ELLS compounds were identified. Sixty-three common genes were obtained by matching 173 potential genes of ELLS with 1554 CRC related genes and PPI network screened out key targets, including AKT1, CASP3, ESR1, TNF, HSP90AA1. Five core compounds were beta-sitosterol, stigmasterol, euphol, Artemetin and lathyrol. Eight core targets were PRKACA, PRKCA, AR, BAX, GSK3B, NFKB1, RXRA and NCOA2 in the C-T-P network. KEGG pathway analysis indicated that ELLS effectively treated CRC through regulation of pathways in cancer, Epstein-Barr virus infection, thyroid hormone signaling pathway, bile secretion, and transcriptional misregulation in cancer. Gene survival analysis showed that 7 genes (APAF1, APOE, CASP3, HDAC2, NFKB1, PGR, and SNAI1) were significantly related in CRC patients’ survival and prognosis. Molecular docking results suggested that almost all of the core compound-targets had an excellent binding activity (affinity < − 5 kcal/mol). CCK8 results indicated that ELLS (20 µg/mL, 24-hour treatment) significantly inhibited the proliferation of HCT116 cells, while it had minimal impact on the viability of normal NCM460 cells under the same conditions (survival rate ≥ 80%). Key targets of ELLS could regulate multiple signaling pathways and biological process in treating CRC which provided a scientific basis for further elucidating the mechanism of molecules and screening drug targets. Show less
Alzheimer's disease (AD) is the leading cause of dementia worldwide, with substantial unmet clinical needs. The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late onset AD, Show more
Alzheimer's disease (AD) is the leading cause of dementia worldwide, with substantial unmet clinical needs. The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late onset AD, with each copy increasing risk approximately two- to three-fold, and homozygous carriers facing up to a 10- to 15-fold higher risk compared to APOE3 carriers. APOE4 contributes to diverse pathogenic mechanisms including lipid dysregulation, neuroinflammation, synaptic dysfunction, and vascular compromise. The precise, allele-specific correction of APOE4 therefore holds transformative therapeutic potential. CRISPR-based genome editing technologies, including nuclease disruption, base editing, and prime editing, offer unprecedented opportunities to directly modify APOE4 at its genomic source. Here, we review mechanistic underpinnings of APOE4 pathology, summarize current gene editing platforms for APOE4 correction, evaluate relevant in vitro and in vivo model systems, and assess delivery strategies with an emphasis on nanoparticle and exosome based approaches. We highlight recent breakthroughs in exosome mediated APOE4 editing while addressing ongoing technical hurdles in allele specificity and translational barriers such as Cas nuclease immunogenicity, limited delivery efficiency across the blood brain barrier (BBB), and concerns over long term genomic safety. This review concludes that overcoming BBB constraints remains the most significant challenge for clinical translation, and that innovations in exosome and nanoparticle based delivery platforms represent the most promising strategies for advancing CRISPR therapeutics for AD. Show less
Alzheimer's disease pathology (ADP) and Lewy body pathology (LBP) are traditionally associated with distinct cognitive profiles. However, growing evidence highlights the role of behavioral and psychol Show more
Alzheimer's disease pathology (ADP) and Lewy body pathology (LBP) are traditionally associated with distinct cognitive profiles. However, growing evidence highlights the role of behavioral and psychological symptoms of dementia (BPSD) in shaping clinical presentations. The combined influence of cognitive and behavioral symptoms across neuropathologically confirmed ADP, LBP, and mixed AD-LBP has not been systematically examined. This study aimed to identify clinically meaningful subtypes by jointly analyzing cognitive performance and BPSD profiles in individuals with autopsy-confirmed dementia pathology. This retrospective longitudinal cohort study used data from the National Alzheimer Coordinating Center (NACC), collected across multiple U.S. Alzheimer's Disease Research Centers. Participants had a Clinical Dementia Rating (CDR) Global score ≤1 at baseline and autopsy-confirmed ADP, LBP, or mixed AD-LBP. Cognitive outcomes included standardized tests of memory, executive function, and language. BPSD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), which captures ten symptom domains: agitation, apathy, depression, delusions, disinhibition, auditory and visual hallucinations, irritability, personality change, and REM sleep behavior disorder. Cluster analysis was applied to identify subtypes based on combined cognitive and BPSD data. The study included 1,028 participants (mean age at baseline 76.4 years; 47.6% female): 521 with ADP, 96 with LBP, and 411 with mixed AD-LBP. A three-cluster clinical subtype (CS) solution best fit the data. The most symptomatic group (CS-3) had the youngest age at first visit (mean 72.1 years), the highest BPSD burden, and the fastest cognitive and functional decline across ADP and AD-LBP groups. CS-1 and CS-2 exhibited milder early cognitive impairment and lower BPSD burden. Within ADP and AD-LBP, CS-2 showed slower progression than CS-1, fewer APOE ε4 carriers (41% vs. 58%), and better memory scores, despite reporting a higher frequency of agitation. These findings reveal distinct clinical subtypes that cut across traditional pathological boundaries, emphasizing the need to incorporate both cognitive and behavioral features into early dementia characterization. This multidimensional approach can improve guide personalized prognosis and care planning and enhance clinical trial design by considering disease heterogeneity. The study supports integrated clinical profiling as important factor in robust evaluation of dementia outcomes. Show less
Antihypertensive medications (AHMs) may modulate Alzheimer's disease (AD) pathogenesis via cerebrovascular or neuroinflammatory pathways, yet evidence remains conflicting. This study investigated caus Show more
Antihypertensive medications (AHMs) may modulate Alzheimer's disease (AD) pathogenesis via cerebrovascular or neuroinflammatory pathways, yet evidence remains conflicting. This study investigated causal associations between AHM use and AD risk, focusing on drug classes, blood pressure status, and apolipoprotein E epsilon 4 (APOE ε4) effects. We integrated genetic causal inference with longitudinal survival analyses in a dual-evidence framework. Mendelian randomization (MR) was used to estimate class-specific causal effects at the population level. To examine effect modification by genetic and clinical factors, we analyzed 532 cognitively normal or mildly impaired older adults in ADNI with baseline assessments, with time-to-AD conversion modeled using Cox regression stratified by hypertension history and APOE ε4 status. Overall antihypertensive use showed no significant association with AD risk in hypertensive individuals (HR = 0.71) or APOE ε4 carriers (HR = 0.72). However, ARBs demonstrated protective associations in APOE ε4 carriers (HR = 0.32, 95% CI: 0.12-0.86). MR analysis supported causal protective effects for angiotensin II receptor blockers (ARBs, OR = 0.94, 95% CI: 0.89-0.98), calcium channel blockers (CCBs, OR = 0.93, 95% CI: 0.90-0.97), and beta-blockers (BBs, OR = 0.92, 95% CI: 0.86-0.98), whereas ACEIs lacked MR support and thiazide diuretics showed no benefit. Our findings reveal class-specific antihypertensive effects on AD risk. ARBs demonstrated the strongest protection, particularly in APOE ε4 carriers, while BBs and CCBs showed neuroprotective benefits. Results suggest AD prevention involves mechanisms beyond blood pressure reduction alone, supporting precision medicine with genotype-guided antihypertensive selection for genetically vulnerable individuals. Show less