Search Results (53)

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p < 5 × 10⁻⁸) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 × 10⁻²⁴) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10⁻³), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up. Full article

Rice sheath blight caused by Rhizoctonia solani is one of the most destructive diseases of rice. Bixafen has been proposed as a promising control agent with moderate resistance risk; however, its cellular mode of action remains unclear. Therefore, this study investigated the antifungal mechanism of bixafen from the perspective of programmed cell death (PCD). Bioassays showed that bixafen strongly inhibited R. solani, with a median effective concentration (EC₅₀) of 1.16 μg/mL. Morphologically, bixafen induced hyphae collapse, vacuolization, chromatin aggregation, and mitochondrial disruption. Transcriptome analysis further revealed that bixafen significantly altered the expression of genes involved in the tricarboxylic acid cycle and PCD pathways. In addition, bixafen, at the concentration of EC₅₀, triggered ROS accumulation accompanied by increased malondialdehyde (MDA) levels. These oxidative effects led to mitochondrial damage, characterized by loss of membrane potential, reduced Tomm20 expression, and decreased Aco-2 activity. Subsequently, bixafen activated apoptosis, as evidenced by induction of the mitochondria-associated inducer of death (AMID), down-regulation of Bcl-2, and DNA fragmentation. Moreover, bixafen also induced autophagy by reducing p62 and increasing Beclin-1 expression, which suggests the clearance of damaged mitochondria. Collectively, these results demonstrated that bixafen induced mitochondrial-dependent apoptosis and autophagy in R. solani, which provided novel insights into its cellular antifungal mechanism and supported its potential as a PCD-targeted fungicide. Full article

Mitophagy serves as an essential quality control mechanism that maintains mitochondrial homeostasis through selective autophagic clearance of damaged organelles. Vascular dementia (VD) has been increasingly associated with mitophagy dysregulation in recent studies. However, the precise molecular mechanisms underlying mitophagy’s involvement in VD pathogenesis remain poorly characterized. To elucidate the role of mitophagy in VD, we systematically examined the expression of key mitophagy pathways in hippocampal neurons of bilateral common carotid artery occlusion (BCCAO) rats and in oxygen–glucose deprivation (OGD)-treated HT22 cells. Intriguingly, under autophagy-deficient conditions, both BNIP3 and BNIP3L were markedly downregulated, whereas FUNDC1 expression increased; PINK1/Parkin levels remained unaltered. To further dissect the functional contributions of BNIP3 and BNIP3L, we administered the mitochondrial fission inhibitor Mdivi-1 to BCCAO model rats. Histopathological analysis revealed pronounced neuronal damage and apoptosis in the hippocampal region, which was further exacerbated upon Mdivi-1 treatment. In vitro, BNIP3 silencing significantly compromised cell viability, elevated reactive oxygen species (ROS) accumulation, disrupted mitochondrial membrane potential (ΔΨm), suppressed mitophagy, and increased apoptotic rates. Conversely, BNIP3 overexpression reversed these detrimental effects. Notably, treatment with the autophagy inhibitor 3-methyladenine (3-MA) diminished LC3B-Tomm20 colocalization and intensified apoptosis, reinforcing the critical role of BNIP3-mediated mitophagy in neuronal survival. Similarly, BNIP3L overexpression enhanced cell viability, attenuated ROS production, restored ΔΨm, and mitigated apoptosis, while 3-MA treatment again impaired mitophagic flux and worsened cell death. Collectively, these findings underscore the critical and distinct roles of BNIP3 and BNIP3L in maintaining mitochondrial homeostasis and neuronal survival under ischemic conditions. Full article

The ε4 allele of the apolipoprotein E (APOE) gene strongly increases Alzheimer’s disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes TOMM40 and APOC1, suggesting a complex cis-regulatory landscape. To investigate chromatin architecture and its impact on gene regulation across this region, we performed chromosome conformation capture in human cell lines and postmortem brain tissues, consistently identifying TOMM40–APOE and APOE–APOC1 interactions. We further developed a digital PCR assay to quantify APOE–APOC1 interaction strength and measured APOC1 mRNA via RT-qPCR. Enhanced chromatin interaction correlated with elevated APOC1 transcription in AD specimens. Genotypic analysis showed that ε3/ε4 carriers had strong chromatin interaction and transcriptional activation, whereas ε4/ε4 homozygotes exhibited minimal chromatin remodeling despite similar APOC1 expression, suggesting a decoupling of chromatin architecture and transcriptional output. These findings underscore the interplay of AD status, APOE genotype, and locus-specific chromatin dynamics in disease susceptibility. Integration of 3D genome topology with transcriptomic profiling offers a framework to study APOE-related disorders and supports broader application across neurodegenerative loci for genotype-guided therapy development. Full article

Objectives: Alzheimer’s disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia. Methods: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored. Results: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups. Conclusions: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer’s disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk. Full article

Background: Colorectal cancer (CRC) is a major contributor to cancer-related mortality globally. Despite significant advances in therapeutic strategies, CRC continues to exhibit high recurrence rates. This underscores the urgent need for reliable, non-invasive biomarkers to improve diagnostic precision, early detection, and clinical outcomes. Methods: Gene expression datasets from the GEO database were analyzed to identify differentially expressed genes between CRC and normal tissue samples. Hub genes were identified through an integrative approach combining module membership, gene significance, differential expression, and network centrality. Prognostic significance was assessed via overall survival analysis, and diagnostic utility through ROC curve and AUC. Further integrative analysis included immune cell infiltration, promoter methylation, genetic alterations, and regulatory network construction. Results: An integrated approach identified 989 candidate hub genes. Of these, 128 genes demonstrated significant prognostic potential: 67 were associated with poor overall survival and 61 with favorable outcomes. These genes exhibited patterns of co-expression and positive correlations with immune cell infiltration, particularly B cells, dendritic cells, macrophages, mast cells, and monocytes. Twenty-three hub genes, including MACC1, YEATS4, HMMR, TIGD2, CENPE, GNL3, GMPS, NCAPG, RRM1, DLGAP5, YARS2, CCT8, MET, ZWILCH, KPNA2, KIF15, TRUB1, AURKA, NUDT21, PBK, TOMM20, KIAA1549, and MCM4, showed high diagnostic accuracy in distinguishing CRC from normal tissues. Furthermore, 18 hub genes exhibited statistically significant differential promoter methylation and may serve as promising candidates for epigenetic biomarkers in CRC. Conclusions: Our findings provide a strong foundation for developing more accurate multi-gene prognostic and diagnostic panels and personalized therapies for CRC, with the goal of improving clinical outcomes and reducing the global burden of this disease. Full article

Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy. Full article

The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration. Full article

Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, has a notably high prevalence in Sweden (136/10⁵). Although monogenic forms represent only a small subset of PD cases, several genetic factors—including nucleotide repeat expansions (NREs) in ATXN2, ATXN3, C9ORF72, TBP, POLG, TOMM40, CACNA1A, and PRNP—have been implicated in neurodegenerative conditions with parkinsonian features. However, their contribution to PD pathogenesis in the Swedish population remains understudied. We analyzed DNA from 161 Swedish PD patients and 546 controls and evaluated clinical and CSF biomarkers (tau, phospho-tau, and β-amyloid). Intermediate ATXN2 CAG expansions were significantly associated with PD (3.40%, p = 0.0027), and novel promoter structural variations were identified. C9ORF72 G4C2 expansions were also linked to PD (2.48%, p = 0.0018), with distinct methylation patterns in PD cases. POLG Not-10/Not-11Q alleles were positively associated (9.62%, p = 0.014), while TOMM40 showed partial associations for rare genotypes (14.28%, p = 0.0014). Pathological expansions in TBP were marginally significant, while ATXN3, CACNA1A, and PRNP showed no associations. Two-way ANOVA identified significant interactions between APOE E3/E4 and POLG 10/11Q genotypes, affecting age at diagnosis (p = 0.025) and CSF β-amyloid levels. Regression highlighted tau as a key predictor of age at diagnosis (p = 0.02). Longitudinally, APOE E4 predicted cognitive decline (p = 0.015), and TOMM40 haplotypes correlated with motor deficits. In conclusion, ATXN2, C9ORF72, and POLG emerge as key genetic risk factors for PD in the Swedish population, with TOMM40 and TBP contributing partially. Altered CSF biomarker patterns support the existence of distinct molecular subtypes and warrant further investigation of novel ATXN2 variants as potential PD modifiers. Full article

Illyrian iris (Iris pallida subsp. illyrica (Tomm. ex Vis.) K.Richt.) is a rhizomatous geophyte, an endemic species (subspecies), occurring within a limited range along the eastern coast of the Adriatic Sea. The study presents the first in-depth chemical and functional investigation of its rhizome extracts using both conventional and greener solvents, as well as essential oil (EO) via hydrodistillation, employing gas chromatography-mass spectrometry (GC/MS) and ultra-high-performance liquid chromatography-diode array detector-tandem mass spectrometry (UHPLC-DAD-MS/MS) for metabolic fingerprinting, which was further interpreted through a chemosensory lens. High-performance thin-layer chromatography (HPTLC) bioautography (HPTLC-DPPH/ HPTLC-Tyrosinase) was applied for the first time to this species, revealing zones of bioactivity. HaCaT cell viability and spectrophotometric assays were employed to further evaluate the cosmetic potential. Results showed a distinctive volatile profile of EO, including, to the best of our knowledge, the first identification of a silphiperfol-type sesquiterpenoid in the Illyrian iris rhizome. UHPLC-DAD-MS/MS and HPTLC fingerprinting further supported solvent-dependent differences in metabolite composition. Notably, acetone, ethyl acetate, and ethanol extracts exhibited similar chemical profiles, while greener extracts showed more divergent patterns. The results provide a foundation for the future exploration of Illyrian iris in sustainable cosmetic applications, emphasizing the need for further in vitro and in vivo validation. Full article

Positron emission tomography (PET) has become a powerful tool in Alzheimer’s disease (AD) research by enabling in vivo visualization of pathological biomarkers. Recent efforts have aimed to integrate PET-derived imaging phenotypes with genome-wide association studies (GWASs) to better elucidate the genetic architecture underlying AD. This systematic review examines studies that leverage PET imaging in the context of GWASs (PET-GWASs) to identify genetic variants associated with disease risk, progression, and brain region-specific pathology. A comprehensive search of PubMed and Embase databases was performed on 18 February 2025, yielding 210 articles, of which 10 met pre-defined inclusion criteria and were included in the final synthesis. Studies were eligible if they included AD populations, employed PET imaging alongside GWASs, and reported original full-text findings in English. No formal protocol was registered, and the risk of bias was not independently assessed. The included studies consistently identified APOE as the strongest genetic determinant of amyloid burden, while revealing additional significant loci including ABCA7 (involved in lipid metabolism and amyloid clearance), FERMT2 (cell adhesion), CR1 (immune response), TOMM40 (mitochondrial function), and FGL2 (protective against amyloid deposition in Korean populations). The included studies suggest that PET-GWAS approaches can uncover genetic loci involved in processes such as lipid metabolism, immune response, and synaptic regulation. Despite limitations including modest cohort sizes and methodological variability, this integrated approach offers valuable insight into the biological pathways driving AD pathology. Expanding PET-genomic datasets, improving study power, and applying advanced computational tools may further clarify genetic mechanisms and contribute to precision medicine efforts in AD. Full article

Microglia, the resident immune cells of the central nervous system (CNS), play essential roles in maintaining brain homeostasis. While transient activation is protective, chronic microglial reactivity contributes to neuroinflammatory damage and neurodegeneration. The mitochondrial mechanisms underlying this shift remain poorly understood. Here, we investigated whether lipopolysaccharide (LPS) induces coordinated mitochondrial and metabolic alterations in BV-2 microglial cells. LPS stimulation (100 ng/mL, 24 h) induced a reactive phenotype, with increased Iba1 (+82%), F4/80 (+132%), and Cd68 (+44%), alongside elevated hydrogen peroxide (~6-fold) and nitrite (~45-fold). Cytotoxicity increased by 40% (LDH assay), and cell viability dropped to ~80% of the control (MTT). Extracellular lactate increased, indicating glycolytic reprogramming. However, LPS-primed cells showed greater ATP depletion under antimycin A challenge, reflecting impaired metabolic flexibility. Hoechst staining revealed a ~4-fold increase in pyknotic nuclei, indicating apoptosis. Mitochondrial dysfunction was confirmed by a 30–40% reduction in membrane potential (TMRE, JC-1), a ~30% loss of Tomm20, and changes in dynamics: phospho-Drp1 increased (+23%), while Mfn1/2 decreased (33%). Despite a ~70% rise in Lamp2 signal, Tomm20–Lamp2 colocalization decreased, suggesting impaired mitophagy. High-resolution respirometry revealed decreased basal (−22%), ATP-linked (24%), and spare respiratory capacity (41%), with increased non-mitochondrial oxygen consumption. These findings demonstrate that LPS induces mitochondrial dysfunction, loss of metabolic adaptability, and increased apoptotic susceptibility in microglia. Mitochondrial quality control and energy flexibility emerge as relevant targets to better understand and potentially modulate microglial responses in neuroinflammatory and neurodegenerative conditions. Full article

The objective of this study was to elucidate the proteomic and transcriptomic alterations within the cartilage in Kashin–Beck disease (KBD) compared to a normal control. We conducted a comparison of the expression profiles of proteins, mRNAs, and lncRNAs via data-independent acquisition (DIA) proteomics and transcriptome sequencing in six KBD individuals and six normal individuals. To facilitate the functional annotation enrichment analysis of the differentially expressed (DE) proteins, DE mRNAs, and DE lncRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we conducted integration analysis of multi-omics datasets using mixOmics. We revealed a distinct proteomic signature, highlighting 53 DE proteins, with notable alterations in the pathways related to tryptophan metabolism and microbial metabolism. Additionally, we identified 160 DE mRNAs, with the functional enrichment analysis uncovering pathways related to RNA metabolism and protein splicing. Furthermore, our analysis of the lncRNAs demonstrated biological processes involved in protein metabolism and cellular nitrogen compound metabolic processes. The integrative analysis uncovered significant correlations, including the positive correlation between superoxide dismutase 1 (SOD1) and mitochondrial import receptor subunit TOM6 homolog (TOMM6), and the negative correlation between C-X9-C motif-containing 1 (CMC1) and succinate–CoA ligase [GDP-forming] subunit beta, mitochondrial (SUCLG2). Our results provide novel insights into the molecular mechanisms underlying KBD. Full article

Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening complication of sepsis, characterized by high mortality and prolonged hospitalization. Early diagnosis and effective therapy remain difficult despite extensive investigation. To address this, we developed an AI-driven integrative framework that combines a Transformer-based deep learning model with established machine learning techniques (LASSO, SVM-RFE, Random Forest and neural networks) to uncover complex, nonlinear interactions among gene-expression biomarkers. Analysis of normalized microarray data from GEO (GSE95233 and GSE69063) identified differentially expressed genes (DEGs), and KEGG/GO enrichment via clusterProfiler revealed key pathways in immune response, protein synthesis, and antigen presentation. By integrating multiple transcriptomic cohorts, we pinpointed 617 SA-AKI-associated DEGs—21 of which overlapped between sepsis and AKI datasets. Our Transformer-based classifier ranked five genes (MYL12B, RPL10, PTBP1, PPIA, and TOMM7) as top diagnostic markers, with AUC values ranging from 0.9395 to 0.9996 (MYL12B yielding 0.9996). Drug–gene interaction mining using DGIdb (FDR < 0.05) nominated 19 candidate therapeutics for SA-AKI. Together, these findings demonstrate that melding deep learning with classical machine learning not only sharpens early SA-AKI detection but also systematically uncovers actionable drug targets, laying groundwork for precision intervention in critical care settings. Full article

Background/Objectives: Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships of vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—with Alzheimer’s disease (AD), and five cognitive traits. Methods: We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Results: Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2, and APOC1. Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5, and FOCAD. Conclusions: Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the APOE region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given APOE’s roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation. Full article