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This study aims to elucidate the role of FGFR1 in activating the Wnt/β-catenin signaling pathway and the underlying mechanisms by which it promotes malignant progression in lung squamous cell carcinoma (LUSC). By integrating multi-omics analysis with functional experiments, the clinical heterogeneity of FGFR1 amplification, signaling crosstalk, and their regulatory networks governing tumor phenotypes were revealed. Using TCGA data (n = 490), we analyzed the relationship between FGFR1 copy number variation (CNV) and mRNA expression in LUSC, and validated the correlation with protein expression in a clinical cohort (n = 38). GSEA and single-gene GSEA were performed to identify signaling pathways associated with high FGFR1 expression. The interaction between FGFR1 and the Wnt/β-catenin pathway was investigated by immunohistochemistry, immunofluorescence, stable cell lines, Western blot, qPCR, and functional assays. FGFR1 amplification correlated with increased mRNA and protein expression. The top 25% FGFR1 high-expression group enriched Wnt/β-catenin, PI3K-Akt, and cAMP pathways. Mechanistically, FGFR1 promoted β-catenin nuclear accumulation and enhanced β-catenin signaling through PKA-associated phosphorylation and Akt/GSK3β-related regulation of β-catenin stability, and these effects were attenuated by AKT inhibition. CTNNB1 knockdown significantly inhibited proliferation, migration, invasion, and tumor growth of LUSC cells. Our findings indicate that FGFR1 activates Wnt/β-catenin signaling through coordinated regulation of β-catenin phosphorylation, stability, and subcellular localization, thereby promoting malignant progression in LUSC. These results provide a rationale for targeting the FGFR1-Wnt/β-catenin axis as a potential therapeutic strategy. Show less

This study aims to investigate the radioprotective effects of melatonin (MEL) against oxidative damage that may be caused by flattening filter (FF) and flattening filter-free (FFF) beam in the cerebrum and cerebellum of rat using various genetic markers. Forty female Wistar albino rats were randomly assigned to five groups. The control group received no intervention. The FF group received a single 16 Gy fraction at 600 MU/min. The FF+MEL group received the same FF protocol, preceded by melatonin (50 mg/kg, intraperitoneal) administered 15 min before irradiation. The FFF group received a single dose of 16 Gy at 2,400 MU/min. The FFF+MEL group received the same FFF protocol with melatonin administered as above. After treatment, cerebrum and cerebellum tissues were harvested, and mRNA expression levels of BDNF, CREB, BAX, BCL2 and IL6 were measured. Both FF and FFF radiotherapy treatments significantly increased BDNF, CREB, IL6, and BAX gene expression in cerebrum and cerebellum tissues, while decreasing BCL2 levels (P < 0.05). Melatonin treatment increased BDNF and CREB expression, significantly attenuated radiation-induced increases in IL6 and BAX, and partially reversed the decrease in BCL2 (P < 0.05). The increase in the BAX/BCL2 ratio after radiotherapy was significantly attenuated by melatonin treatment. Overall, FFF irradiation induced a stronger oxidative, inflammatory, and pro-apoptotic response than FF, whereas melatonin exhibited potent neuroprotective and anti-apoptotic effects. In conclusion, MEL demonstrates potential as a protective agent for healthy tissues during irradiations, owing to its antiapoptotic, anti-inflammatory, and neurotrophic properties. Show less

The APOE gene, which encodes Apolipoprotein E (ApoE), is the strongest genetic risk locus for Alzheimer's disease (AD). A substantial fraction of AD risk genes converges on pathways controlling lipid metabolism and immune regulation, in which microglia serve as a central integrative hub in the brain. Although microglial phenotypes linked to different APOE genotypes have been extensively characterised, the fundamental question of how ApoE shapes the core functions of human microglia remains unresolved. Here, we generated APOE knockout (KO) microglia from AD patient-derived induced pluripotent stem cells (iPSCs) and characterised their cellular and molecular phenotypes. Ablation of APOE resulted in marked lipid droplet accumulation and increased NLRP3 inflammasome activation. Transcriptomic analysis further revealed downregulation of cell cycle-related pathways, accompanied by enrichment of an oxidative stress-associated pathway. Consistent with these transcriptomic signatures, APOE KO microglia exhibited elevated intracellular reactive oxygen species (ROS) levels and a marked reduction in proliferative capacity. Given the importance of microglial proliferation for maintaining immune homeostasis in the brain, our findings highlight ApoE as being an important regulator of this process, with potential consequences for the pathogenesis of neurodegenerative disorders. Show less

BackgroundHabitual daytime napping is a significant aspect of many older adults' sleep-wake cycle. Growing evidence links napping and cognition in the context of Alzheimer's disease (AD), yet little is known about how genetic risk influences this relationship.ObjectiveThis study investigates interactions between genetic risk for AD and napping on cognition in 1655 cognitively healthy middle-aged to older adults.MethodsCognition was assessed using a self-administered online battery and reduced to three variables: memory, visuospatial abilities and executive functions. Genetic risk was assessed with the presence of Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with plasma levels largely unaffected by lifestyle modification or conventional lipid-lowering therapy. Although international guidelines increasingly recognize Lp(a) as a risk-enhancing factor, in many Asian populations thresholds for high Lp(a) and treatment strategies remain undefined. This Korean position paper, developed by the Lp(a) Task Force of the Korean Society of Lipid and Atherosclerosis, presents an evidence-based summary of the pathophysiology, clinical relevance, and therapeutic landscape surrounding Lp(a), with a focus on Korean-specific data. It reviews the genetic architecture of Lp(a), ethnic variability in concentrations, and its mechanistic roles in inflammation, thrombosis, and calcification. Based on large Korean cohorts, a 3-tiered classification is proposed of normal (<30 mg/dL), borderline high (30-49 mg/dL), and high (≥50 mg/dL), harmonizing global thresholds with local data. The document also highlights the limitations of current Lp(a) assays in Korea, and calls for standardized, isoform-insensitive testing. Novel therapeutics, including antisense oligonucleotides, small interfering RNAs, and small molecular inhibitors, have shown promising Lp(a)-lowering effects, with multiple phase 3 trials currently ongoing, or in planning. Given the unmet clinical need, the paper recommends incorporating Lp(a) into cardiovascular risk assessment, and calls for Korean-specific longitudinal studies, national screening strategies, and participation in clinical trials. These efforts will help clarify Lp(a)-associated risk in Korean patients and guide the adoption of future targeted therapies. Show less

Human studies have reported inconsistent associations between early-life exposure to per- and polyfluoroalkyl substances (PFAS), particularly during critical windows of brain development, and neurodevelopmental outcomes. To address the lack of clarity regarding how PFAS affect neurodevelopment, this study developed the first unified adverse outcome pathway (AOP) network to explore the mechanisms involved in developmental neurotoxicity (DNT). Of 343 AOPs retrieved from AOP-Wiki, 19 linear AOPs associated with DNT satisfied the inclusion criteria. To pinpoint critical nodes and relationships, the constructed DNT-AOP network was examined using topological metrics. Through a combination of qualitative weight of evidence (WoE) assessment and network topology analysis, two critical paths were identified: one based on thyroid hormone disruption and the other on the intracellular calcium (Ca 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 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

Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor 7. The structures and purity of all target compounds were confirmed by Show less

Lysophosphatidic acid (LPA) and its receptor LPA1 have been implicated in tissue inflammation and fibrosis; however, their role in mucus overproduction remains unclear. Pulmonary neuroendocrine cells (PNECs), which are rare airway epithelial cells, contribute to mucus overproduction and immune modulation. In this study, we investigated the role of the LPA/LPA1 receptor axis in goblet cell hyperplasia and mucus overproduction, as well as the contribution of PNECs, using a chronic mouse model of bronchial asthma. A chronic mouse model of asthma was established by sensitization and challenge with the house dust mite antigen Dermatophagoides pteronyssinus (Dp), with or without treatment using the LPA1 antagonist AM095. Airway hyperresponsiveness, histopathology, mediator concentrations, and molecular expression in lung homogenate supernatants were evaluated. Lysophospholipid levels and low-molecular-weight metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lung LPA 22:5 levels were elevated in Dp-challenged mice. LPA1 receptors were co-localized with PNECs in the lung. Treatment with AM095 reduced goblet cell hyperplasia by inhibiting the production of gamma-aminobutyric acid (GABA) and calcitonin gene-related peptide (CGRP) by PNECs. It also suppressed arginase 1 and polyamine production in CGRP-stimulated M2 macrophages. AM095 did not affect eosinophil extracellular trap (EET) formation in bronchoalveolar lavage fluid, which activates PNECs. The LPA/LPA1 axis promotes goblet cell hyperplasia through PNEC activation and downstream GABA and CGRP signaling in a chronic asthma model. LPA1 antagonism may represent a potential therapeutic strategy for controlling mucus overproduction in asthma. Show less

Lymphoplasmacytic lymphoma / Waldenström macroglobulinemia (LPL/WM) is a rare and indolent low-grade B-cell lymphoproliferative neoplasm that often presents with vague symptoms or asymptomatically. While it most commonly involves the bone marrow, LPL/WM can sometimes involve the lymph nodes and spleen, and rarely the central nervous system, skin, and pleural cavities. We report a rare case of lymphoplasmacytic lymphoma/ Waldenström macroglobulinaemia presenting with predominant myometrial and cervical involvement. A 57-year-old G2P2 postmenopausal female with a history of HPV + HSIL presented following a single episode of abnormal uterine bleeding with associated urinary urgency and pelvic pressure. Transvaginal ultrasound examination was unremarkable and endometrial biopsy via hysteroscopy was unsuccessful due to stenotic cervical os. The patient subsequently underwent a total robotic hysterectomy with bilateral salpingo-oophorectomy. Examination of histologic sections showed atypical perivascular lymphoid aggregates consistent with involvement by a low-grade B-cell lymphoma with predominant myometrial and cervical involvement. Differential diagnosis at the time included marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). Additional testing identified an IgM kappa paraproteinemia with MYD88 p.L265P mutation. Bone marrow biopsy and aspirate confirmed the diagnosis of lymphoplasmacytic lymphoma / Waldenström macroglobulinaemia (LPL/WM). To our knowledge, there have been only two cases previously described in the literature of LPL/WM involvement in the female genital tract; both of which had prominent involvement of the ovaries. Although exceedingly rare, LPL/WM involvement of the female genital tract should be considered on the differential diagnosis if atypical lymphoid cells or dense lymphoid aggregates are observed. 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 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

The apolipoprotein E (APOE) ε4 allele increases Alzheimer disease risk. Understanding genotype-specific dietary needs could inform more personalized prevention strategies. To test the hypothesis that higher meat consumption may be associated with cognitive health benefits in individuals with APOE genotypes ε3/ε4 and ε4/ε4 (APOE34/44) and to examine whether this association differs from that in other genotypes. This population-based cohort study used panel data analyses conducted in January 2025 to January 2026 over 15 years of follow-up in the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), using strategies aligned with causal inference principles. Recruitment was done in 2001 to 2004 among adults without dementia aged 60 years or older. The primary exposure was total meat consumption in grams per total kilocalories assessed via validated food frequency questionnaires. The secondary exposure was the ratio of processed to total meat. Global cognitive trajectory, measured as change in z score per 10 years, was analyzed by linear regression. Incident dementia was analyzed using Fine and Gray subdistribution hazard ratios (sHRs), treating nondementia death as a competing risk. Among 2157 older adults without dementia (mean [SD] age 71.2 [9.2] years; 1337 female [62.0%]), 1680 participants had longitudinal cognition data and 569 participants (26.4%) had APOE34/44 genotypes. During follow-up, 296 participants developed dementia and 690 died without dementia. Among participants with APOE34/44 genotypes, higher total meat consumption (top vs bottom quintile) was associated with better cognitive trajectories (β = 0.32; 95% CI, 0.07 to 0.56; P = .01) and reduced dementia risk (sHR, 0.45; 95% CI, 0.21 to 0.95; P = .04). No associations were found in participants with APOE22/23/24/33 genotypes (cognitive trajectory: β = -0.11; 95% CI, -0.27 to 0.06; P = .20; dementia: sHR, 0.95; 95% CI, 0.57 to 1.61; P = .86). P values for APOE interaction were .004 for cognition and .10 for dementia. In the top quintile of meat consumption, dementia risk and cognitive decline were similar between APOE strata. A higher ratio of processed to total meat was unfavorably associated with dementia (sHR, 1.14; 95% CI, 1.01 to 1.29; P = .04), showing no APOE interaction and no substantial difference between unprocessed red meat and poultry. Post hoc analyses suggested concordant APOE interaction for all-cause mortality (unprocessed meat exposure, APOE34/44: HR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04; P for interaction = .03). In this study, higher meat consumption was associated with better cognitive trajectories and lower dementia risk among individuals with APOE34/44 genotypes. The expected cognitive disadvantage among individuals with APOE34/44 genotypes was not observed at high meat consumption, suggesting clinical and public health relevance. Show less

Intermediate monocytes (IM) exhibit proinflammatory properties and contribute to atherosclerosis. Elevated lipoprotein(a) [Lp(a)] levels modulate monocyte behavior, while proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated in inflammatory pathways beyond lipid metabolism. The effects of PCSK9 inhibition on monocyte subset distribution in high-risk coronary artery disease patients remain unclear. To assess the effects of lipoprotein fractions and PCSK9 inhibitor (PCSK9i) therapy on monocyte subset distribution in patients with stable coronary artery disease and highly elevated Lp(a) levels. We followed 100 statin-treated patients in the stable phase after myocardial infarction with highly elevated Lp(a), randomized to PCSK9i or placebo for six months. Biochemical, genetic, and cellular analyses were performed at baseline and follow-up. At baseline, IM levels correlated with total cholesterol (ρ = -0.202, In high-risk patients, PCSK9 inhibition modulates monocyte-lipoprotein interactions without affecting the monocyte subset distribution. PCSK9 may promote vascular inflammation through CCL2 regulation, which appears more closely related to Lp(a) composition than its circulating concentration. NCT04613167; https://www.clinicaltrials.gov/study/NCT04613167, date of registration: 6th of October 2020. Show less

This study aimed to assess the prevalence of genetic variants responsible for extreme levels of high-density lipoprotein cholesterol (HDL-C) and evaluate the adequacy of current thresholds for genetic testing of HDL-related dyslipidemia. Using data from the Tromsø Study, a population-based cohort in Northern Norway, we identified 210 individuals with HDL-C levels ≤ 0.5 mmol/L or ≥ 3.0 mmol/L. Six HDL-related genes (ABCA1, APOA1, CETP, LCAT, PLTP, SCARB1) were sequenced in these participants. We classified variants according to ACMG guidelines, incorporating functional assays and UK Biobank data for additional phenotype-genotype associations. We identified 38 variants of interest across six HDL-related genes, of which 10 were considered potentially causative, found in 14 individuals. Genetic causes were detected in 33.3% of individuals with low HDL-C and 5.05% of those with high HDL-C. Sex-specific analyses showed that using HDL-C thresholds aligned with population distributions improved detection of individuals with pathogenic variants, particularly among women with high HDL-C and men with low HDL-C. These findings suggest that current uniform thresholds may overlook clinically relevant cases and that incorporating sex-specific HDL-C distributions could enhance the identification of individuals with suspected genetic HDL disorders. Genetic testing for HDL-related dyslipidemia is underutilized, with many individuals not meeting the current extreme HDL-C threshold criteria. Revised sex-specific thresholds for genetic testing will improve the identification of pathogenic variants and provide more accurate diagnoses of HDL-related disorders. Continued research is essential to refine our understanding of HDL genetics and its clinical implications. Show less

The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships. We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication. We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes. Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings. Show less

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children. Long Mu Ning Xin Decoction (LMNXD) shows established clinical efficacy against ADHD, yet its mechanistic basis is not fully elucidated. This study investigates the therapeutic potential of LMNXD for ADHD and explores its underlying mechanisms of action. Thirty spontaneously hypertensive rats (SHRs/NCrl) were randomly divided into five groups: a model (SHR) group, low-, medium-, and high-dose LMNXD (LMNXD-LD, LMNXD-MD, LMNXD-HD)groups, and a methylphenidate hydrochloride (MPH) group. Additionally, six Wistar Kyoto (WKY/NCrl) rats were designated as the control group.Behavioral performance was assessed using the open field test and Morris water maze. The expression levels of glial fibrillary acidic protein (GFAP), dopamine deceptor D1 (DRD1), and brain-derived neurotrophic factor (BDNF) in the rat hippocampus, prefrontal cortex (PFC), and striatum were evaluated by immunofluorescence, immunohistochemistry, and Western blot. Potential targets and mechanisms were explored through transcriptomic sequencing and network pharmacology, with subsequent validation by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Compared to the SHR group, LMNXD ameliorated hyperactivity, impulsivity, deficits in spatial memory and learning ability in SHR/NCrl rats. It also effectively reduced GFAP expression in the hippocampus while increasing DRD1 expression in the PFC and BDNF levels in the striatum. Network pharmacology predicted that LMNXD might alleviate ADHD by acting on pathways including phosphatidylinositide 3-kinase-Akt (PI3K-Akt), calcium signaling, and cyclic adenosine monophosphate (cAMP) signaling. Consistent with this prediction, transcriptomic analysis of rat hippocampi showed that LMNXD influences the cAMP and PI3K-Akt signaling pathways, as well as serotonergic and cholinergic synapses. RT-qPCR further confirmed that LMNXD likely exerts its therapeutic effect by regulating the mRNA expression of ATPase Plasma Membrane Ca LMNXD may ameliorates hyperactive-impulsive behaviors and improves spatial memory and learning in SHRs/NCrl rats by modulating ATP2B4, GRIN3A, OXTR, COL6A2, and ITGA1 within the cAMP and PI3K-Akt signaling pathways. This intervention also upregulates DRD1 and BDNF expression while downregulating GFAP levels. Show less

Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer's disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association between DM and AD risk while others have not. Therefore, this meta-analysis aimed to systematically evaluate the association between DM and AD risk. Comprehensive searches were conducted in PubMed, Web of Science, and Embase databases to identify cohort or case-control studies investigating the association between DM and AD risk. All eligible studies published before October 2025 were included. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. Hazard ratio (HR) and 95% confidence interval (CI) were pooled as the effect size for meta-analysis. Heterogeneity among studies was evaluated using Cochran's A total of 11 studies involving 3,393,545 participants were included. A meta-analysis revealed that DM was significantly associated with an increased risk of AD (HR = 1.36, 95% CI (1.19, 1.55), This meta-analysis provides compelling evidence that DM is an independent risk factor for AD, offering important implications for clinical practice and future research. However, due to the methodological limitations of this study, the results should be interpreted with caution. Large-scale, high-quality prospective cohort studies are needed to fully investigate the relationship between DM and AD risk. https://www.crd.york.ac.uk/prospero/, identifier CRD420251159844. Show less

Experimental autoimmune uveoretinitis (EAU) shows degeneration of retinal neurons, including retinal ganglion cells (RGCs), already in its early phase. Based on our previous study demonstrating the attenuation of EAU by brain-derived neurotrophic factor (BDNF), whose retinal levels were increased by visual stimulation (VS), this study evaluated the effect of VS on BDNF protein expression in brain visual centers, its retrograde transport to the retina, and RGC survival in healthy and EAU mice. 14-day VS increased BDNF expression in the superior colliculus (SC) but not in the lateral geniculate nucleus and primary visual cortex in healthy and EAU mice compared to their unstimulated groups. Furthermore, VS increased numbers of BDNF-positive neurons and astrocytes in the retinorecipient superficial SC (sSC) in healthy and EAU mice, although stimulated EAU mice showed a modest reduction in BDNF-positive neurons compared to stimulated healthy mice. In contrast, unstimulated EAU mice exhibited a marked loss of sSC BDNF-positive neurons and astrocytes compared to unstimulated healthy mice. Additionally, VS promoted retrograde axonal transport of fluorescently labeled BDNF from the sSC to the retina, where it was detected in RGCs, inner retinal neurons, and Müller cells (MCs). These results suggest that VS-induced increases in BDNF expression in the sSC and its retrograde transport to the retina may directly affect multiple types of retinal neurons and MCs, on which BDNF can exert neurotrophic and protective effects. The overall attenuation of EAU histopathology and retinal inflammation, along with improved survival of RGCs in VS-treated EAU mice, is consistent with this suggestion. Show less

We evaluated the accuracy of standard machine learning (ML) algorithms in predicting 1-year cognitive decline in Alzheimer's disease patients with mild cognitive impairment (ADMCI) using resting-state electroencephalographic (rsEEG) biomarkers enriched with APOE genotype, sex, age, and educational attainment data. The study analyzed datasets from 63 ADMCI patients obtained from an international archive. The ML algorithms included Simple Logistic Regression, Model Trees, Logistic Regression, K-nearest neighbor, and Support Vector Machine. Input features comprised lobar rsEEG source activities across delta (<4 Hz) to alpha (≈10-12 Hz) bands, cerebrospinal fluid (CSF Aβ1-42/p-tau), and structural magnetic resonance imaging (sMRI) biomarkers. Cognitive decline was assessed over a 1-year follow-up ("stable" vs. "decliner") based on Mini-Mental State Examination (MMSE) scores. The four independent ML algorithms accurately predicted changes in the MMSE score over a 1-year follow-up, with accuracies of 77-78% in ADMCI participants aged ≥ 70 years and 74-77% in those aged < 70 years. These findings suggest that rsEEG biomarkers in ADMCI patients may not only reveal underlying pathophysiological mechanisms affecting cortical arousal and vigilance but also hold predictive value for cognitive outcomes. 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) 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

Atherosclerosis is respectively correlated with interleukin-6/interleukin-6 receptor (IL6/IL6R) mediated inflammation signaling and macrophages ferroptosis. Nonetheless, the underlying mechanism of IL6/IL6R signaling mediated macrophages ferroptosis in atherosclerosis remains unknown. This study aims to investigate whether IL6/IL6R signaling mediated macrophages ferroptosis through mitochondrial fragmentation and mitophagy impairment. Two human atherosclerotic transcriptomic datasets were used to conduct bioinformatic analysis. In vitro, counting kit-8 (CCK-8) assays, flow cytometry, immunofluorescence staining, malondialdehyde (MDA) and glutathione (GSH) assay kits were employed to evaluate reactive oxygen species (ROS) levels and macrophages ferroptosis. Transmission electron microscopy (TEM), laser confocal microscope and seahorse experiments were used to evaluate changes of mitochondrial morphology and mitochondrial function. Western blotting (WB) was used to quantify key markers of mitophagy and ferroptosis. In vivo, histological stainings and WB were used to determine the effects of IL6R deficiency on atherosclerosis, mitophagy and ferroptosis. Integrated bioinformatic analysis revealed that the IL6 expression could stratify early and advanced plaques. IL6 induced macrophages ferroptosis by increasing ROS and MDA levels, depleting GSH level, promoting lipid peroxidation and suppressing glutathione peroxidase 4 (GPX4) expression. Dynamin-related protein 1 (Drp1) mediated excessive mitochondrial fragmentation in IL6-induced macrophages, resulting in more shortened mitochondria, impaired oxidative phosphorylation (OXPHOS) and ROS accumulation. Activation of mitophagy, the process of mitochondrial fragmentation clearance, could increase GPX4 expression and attenuate the lipid peroxidation level in IL6 induced macrophages. Aggravation of ferroptosis further compromised mitophagy-related proteins expression. Targeting IL6R signaling attenuated atherosclerotic burden in ApoE [Image: see text] The online version contains supplementary material available at 10.1007/s10753-025-02359-5. Show less

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder driven by metabolic dysregulation and chronic inflammation, for which targeted pharmacotherapies remain limited. Rutin, a bioactive flavonoid from Sophora japonica and Fagopyrum esculentum, possesses notable anti-inflammatory and antioxidant properties. This study explored its pharmacological effects and underlying mechanism in NAFLD using a combination of in vivo and in vitro approaches. We found that rutin administration markedly attenuated hepatic steatosis, reduced oxidative stress, restored mitochondrial function, and improved liver injury markers, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), in both high-fat diet (HFD)-fed ApoE Show less

Fibrillary glomerulonephritis is a rare cause of proteinuric kidney disease characterized by Congo red-negative fibrillary deposits and typically shows DNAJB9 positivity on immunohistochemistry. Amyloidosis is defined by Congo red positivity and can be typed by laser microdissection-tandem mass spectrometry when routine studies are inconclusive. We report the case of a 64-year-old man with proteinuria and declining kidney function whose kidney biopsy showed DNAJB9-positive fibrillary glomerulonephritis in glomeruli, but Congo red-positive deposits confined to the medulla were DNAJB9 negative. Laser microdissection-tandem mass spectrometry of the medullary deposits identified apolipoprotein A-IV amyloidosis, establishing concurrent fibrillary glomerulonephritis and apolipoprotein A-IV amyloidosis in the same biopsy. Apolipoprotein A-IV amyloidosis is often medullary predominant and, in rare hereditary forms related to autosomal dominant Show less

Atherosclerosis (AS) is a cardiovascular disorder accompanied by endothelial dysfunction and vascular inflammation. We aim to investigate the effects of Ras guanine nucleotide-releasing protein 3 (RasGRP3), a guanine nucleotide exchange factor in AS. Decreased RasGRP3 protein expression was observed in the endothelium of high-fat diet-fed ApoE The online version contains supplementary material available at 10.1007/s10753-026-02473-y. Show less

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

To elucidate the molecular basis of intramuscular fat (IMF) variation in yellow-feathered broilers, we selected 10 high-IMF (HF) and 10 low-IMF (LF) breast muscle samples from a total of 214 samples, after z-score filtering for LC-MS lipidomics and RNA-seq analyses. Lipidomics identified 94 differentially expressed lipids (DELs; 83 upregulated, 11 downregulated in HF), predominantly triglycerides (TGs, 20.2%), phosphatidylethanolamines (PEs, 15.3%), phosphatidylcholines (PCs, 12.1%), and sphingomyelins (SMs, 8.4%). LION/web enrichment indicated an unsaturated lipid-rich phenotype, characterized by fatty acids containing ≥ 2 double bonds and membrane structural components. RNA-seq revealed 423 differentially expressed genes (DEGs; 312 upregulated, 111 downregulated in HF), enriched in plasma membrane, cell periphery, retinol metabolism, and steroid hormone biosynthesis pathways. RT-qPCR validation of nine lipid metabolism-related DEGs confirmed the RNA-seq trends. Cross-omics Pearson correlation between these DEGs and the top 20 DELs identified PLIN1, SCD, and APOB as central regulatory hubs strongly associated with multiple polyunsaturated TGs and PCs. Functional overlap across omics layers suggests coordinated membrane remodeling and unsaturated lipid deposition in HF breast muscle, providing a data-driven framework for future mechanistic validation and breeding strategies. Show less