Genes & genomics最新文献

Background: The eye is a sensory organ that receives light and generates visual information. Refractive errors, which are influenced by both genetic and environmental factors, are a major cause of visual impairment. In particular, the high prevalence of myopia in some East Asian countries has become an increasing public health concern.

Objective: To gain insights into the genetic basis of refractive error, this study aimed to identify genetic associations for axial length (AL) and central corneal thickness (CCT), two quantitative ocular traits that contribute to refractive error.

Methods: We conducted genome-wide association (GWA) analyses of 649 Korean individuals using the Korea Biobank Array (KBA) chip to identify genetic variants associated with AL and CCT. After SNP imputation, a total of 9,408,715 common SNPs were included in the association analysis. Additionally, 97,434 rare variants were analyzed using q.emmax test. Gene-based analyses were further performed to detect genes significantly associated with these ocular traits.

Results: The GWA analyses identified 10 common variants (minor allele frequency [MAF] ≥ 1%) significantly associated with AL and 2 with CCT (P < 5 × 10⁻⁸). Analyses of rare variants (MAF < 1%) further detected 7 associations with AL and 2 with CCT. In addition, gene-based analysis identified MROH1 as significantly associated with AL.

Conclusion: This study identified novel genetic associations influencing AL and CCT in the Korean population. These findings provide new insights into the genetic architecture of refractive error and may contribute to improving eye health through the prediction of genetic predisposition to refractive errors.

Background: Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. Despite treatment advances, CRC still requires novel strategies to overcome drug resistance and metastasis. Midline 1 Interacting Protein 1 (MID1IP1) is highly expressed in cancers and promotes tumor growth through c-Myc-mediated ribosomal protein regulation. We hypothesized that MID1IP1 contributes to CRC progression via c-Myc and ferroptosis.

Objective: To investigate how MID1IP1 affects metabolic reprogramming, ferroptosis, and migration in CRC.

Methods: MID1IP1 was silenced in HCT116 cells using siRNA. Colony formation assays evaluated growth. Western blotting assessed c-Myc, ferroptosis-related proteins, glycolytic enzymes, and EMT markers. Intracellular ROS was measured with a fluorescence probe, and a ferroptosis inhibitor confirmed ferroptotic cell death. Immunofluorescence detected c-Myc and PKM2, while wound healing assays evaluated migration.

Results: MID1IP1 knockdown reduced cell growth and c-Myc stability, lowering glycolysis-related protein expression. GPX4 and other ferroptosis-protective proteins decreased, resulting in ROS accumulation and ferroptosis. Migration was inhibited, with altered EMT marker expression.

Conclusion: MID1IP1 promotes CRC cell survival by stabilizing c-Myc and preventing ferroptosis, while also influencing migration. These findings suggest that MID1IP1 may serve as a novel biomarker and therapeutic target in CRC.

Background: Radish sprouts (Raphanus sativus L.) are rich in dietary fibers and phytochemicals with antioxidant and anti-inflammatory activities. However, their whole-food effects on the gut-brain axis remain poorly defined.

Objective: This study examined the preventive potential of whole-food red radish sprout (RS) powder against high-fat diet (HFD)-induced obesity and cognitive decline in mice, focusing on its effects on barrier integrity, inflammation, oxidative stress, and gut microbiota.

Methods: Male C57BL/6 mice were fed an HFD for 16 weeks with or without RS powder (low or high dose). Assessments included body and tissue indices, oral glucose tolerance, serum leptin, cognitive performance, oxidative stress in brain, gene expression of tight junction and inflammatory markers in colon and brain, and fecal microbiota profiling using 16S rRNA sequencing.

Results: RS supplementation attenuated HFD-induced weight gain, improved glucose tolerance, and reduced leptin levels, with stronger effects at the higher dose. Cognitive deficits were rescued by RS, accompanied by alleviation of brain oxidative stress and reduced expression of neuroinflammatory genes (Tnf, Il6, Il1b, Aif1, Gfap). RS restored tight-junction genes (Tjp1, Ocln, Cldn1, Jam2, Cdh5) while simultaneously decreasing Cldn2 and pro-inflammatory transcripts, and upregulating Il10. Although alpha diversity was unchanged, beta diversity differed significantly; RS reduced the Firmicutes/Bacteroidota ratio, enriched Akkermansia and Lactobacillus, and suppressed Oscillibacter and Desulfovibrio.

Conclusion: Whole-food RS powder prevents HFD-induced obesity and cognitive decline by reinforcing barrier integrity, reducing inflammation and oxidative stress, and reshaping gut microbiota. These findings support RS as a practical functional food for early obesity intervention via gut-brain axis regulation.

Background: Osteoarthritis (OA) is a multifactorial joint disease involving both cartilage and subchondral bone. The molecular mechanism of subchondral bone in OA is still unclear.

Objective: This study aimed to identify key molecular targets and transcription factors (TFs) in subchondral bone that drive OA progression, with a focus on their diagnostic and therapeutic potential.

Methods: Differentially expressed genes (DEGs) from human OA patients and rat OA models were analyzed using RNA-seq data from GEO database. Then functional enrichment analysis, including GSEA, GO and KEGG revealed high conservation. The iRegulon analysis was applied to identify common TFs. Bingo analysis linked TF target genes to OA-relevant biological functions, and single-cell RNA sequencing (sc-RNA seq) identified the primary cell types expressing these TFs. Finally, the expression of identified TFs was validated in human OA and animal OA samples using immunofluorescence (IF) and qPCR.

Results: We identified 77 common DEGs in OA patients and rat models, including genes associated with bone development or remodeling. Functional enrichment analysis identified common biological processes, such as skeletal system development, and shared pathways, including calcium signaling, across both species. Moreover, iRegulon analysis identified three conserved TFs-Transcription Factor 12 (TCF12), E2F Transcription Factor 1 (E2F1), and TEA domain transcription factor 4 (TEAD4) in both humans and rats. Single-cell analysis revealed that TFs mainly originate from bone-related cell populations. Finally, experimental validation confirmed that TCF12 was up-regulated, while E2F1 and TEAD4 were down-regulated in human OA subchondral bone and mouse DMM model.

Conclusions: This study highlights TCF12, E2F1, and TEAD4 as key regulators of subchondral bone remodeling in OA. Their conserved expression patterns across species and strong correlation with OA progression suggest their potential as novel diagnostic markers and therapeutic targets for OA intervention.

Background: NVP-BEZ235 is a dual PI3K/mTOR inhibitor with promising antitumor activity in clear cell renal cell carcinoma (ccRCC). However, the mechanisms underlying acquired drug resistance remain incompletely defined.

Objective: To investigate whether epitranscriptomic regulation-specifically N6-methyladenosine (m6A) modification and its reader YTHDF3-drives reversible, non-genetic resistance to NVP-BEZ235 in ccRCC, and to identify key downstream effector genes.

Methods: NVP-BEZ235-resistant models were established from 786-O and PTEN-deficient Caki-1ko ccRCC cells via chronic drug exposure. Drug withdrawal assays were performed to evaluate the reversibility of resistance. Expression of m6A regulators was assessed by qRT-PCR and Western blotting. YTHDF3 was silenced using lentiviral shRNA, and changes in NVP-BEZ235 sensitivity were evaluated by CCK-8 and cell-cycle assays. Genome-wide m6A-RIP-seq and RNA-seq were integrated to define transcripts with coordinated changes in m6A methylation and expression, and core causal genes for ccRCC were prioritized by summary-based Mendelian randomization (SMR). YTHDF3-RNA interactions and dynamic m6A changes were validated by RIP-qPCR and MeRIP-qPCR, and the functional role of SYNM was tested by loss-of-function studies.

Results: NVP-BEZ235-resistant cells displayed a reversible, nonheritable phenotype, partially regaining drug sensitivity after short-term drug withdrawal. YTHDF3 was selectively upregulated in resistant cells, and its knockdown significantly lowered the IC50 of NVP-BEZ235 and suppressed proliferation. Integrated m6A-RIP-seq/RNA-seq analyses revealed extensive reprogramming of m6A methylation, and SMR identified SYNM as a core m6A-regulated gene associated with increased ccRCC risk. SYNM was overexpressed in ccRCC tissues and positively correlated with YTHDF3 expression. YTHDF3 bound SYNM mRNA in resistant cells, while m6A levels and expression of both YTHDF3 and SYNM were dynamically reversible upon drug withdrawal. Silencing SYNM robustly resensitized resistant cells to NVP-BEZ235.

Conclusions: Reversible resistance to NVP-BEZ235 in ccRCC is driven, at least in part, by an m6A-dependent YTHDF3-SYNM axis. Targeting YTHDF3 or SYNM may provide a rational strategy to overcome PI3K/mTOR inhibitor resistance in ccRCC.

Background: Intracerebral hemorrhage (ICH) is a primary non-traumatic parenchymal hemorrhage of the brain with a high mortality and disability rate. Acupuncture has been proved to alleviate neurological deficits after ICH.

Objective: Our previous study found that UBL4A is up-regulated in the ICH rat treated with acupuncture, and may be a potential molecular target for acupuncture treatment of ICH. However, the molecular mechanism behind UBL4A is unclear.

Methods: UBL4A knockdown was conducted in ICH rats with acupuncture treatment to explore its role in the therapeutic effects of acupuncture on ICH. In vitro, the effects of UBL4A on heme-induced neuronal injury were evaluated using E18 rat embryonic primary cortical neurons. Proteomic experiments were used to verify the regulatory relationship between UBL4A and MAPK14.

Results: UBL4A knockdown has opposite effects to the therapeutic effects of acupuncture on ICH, including increasing corner turn score, brain water content and the number of degenerated and apoptotic neuron in ICH rats. UBL4A knockdown increased the level of ROS, OPA1-S/L, p-MAPK14 and mitochondrial Drp1, and decreased mitochondrial membrane potential, ATP level and MFN2 level in rat brain tissue. In vitro, UBL4A overexpression reduced ROS level and mitochondrial membrane potential and inhibited the activation of the MAPK14/Drp1 signaling pathway. Co-IP verified the binding of UBL4A and MAPK14, and MAPK14 overexpression reversed the effect of UBL4A on hemin-induced neuronal apoptosis and ROS level.

Conclusion: Our study confirms that UBL4A is involved in the therapeutic effect of acupuncture on ICH, and affects mitochondrial damage and oxidative stress through MAPK14 ubiquitination.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder marked by heterogeneous symptoms and comorbidities, complicating diagnosis and obscuring its neurobiological basis.

Objective: To investigate molecular mechanisms underlying ADHD, particularly the inattentive subtype, by examining Ctnnβ1 (catenin beta 1) and Itgβ1 (integrin beta 1), key components of the Wnt/β-catenin signaling pathway implicated in neurodevelopmental disorders.

Methods: Spontaneously hypertensive rats (SHR/NCrl), a validated ADHD model, were assessed for attentional performance through behavioral testing. Hippocampal and peripheral blood expression of Ctnnβ1 and Itgβ1 were quantified. A subset received atomoxetine to evaluate pharmacological effects on behavioral and molecular outcomes.

Results: SHR/NCrl rats displayed attentional impairments compared with controls. These deficits were accompanied by elevated hippocampal and peripheral expression of Ctnnβ1 and Itgβ1. Atomoxetine treatment normalized gene expression and improved attentional performance, demonstrating amelioration at both molecular and behavioral levels.

Conclusion: Dysregulation of Wnt/β-catenin/integrin signaling may contribute to the ADHD pathophysiology. Concordant upregulation of Ctnnβ1 and Itgβ1 in brain and peripheral blood may support their potential as peripheral biomarkers of ADHD. Responsiveness of these genetic markers to atomoxetine treatment indicates potential value for treatment monitoring and supports targeting this pathway in future therapeutic strategies.

Background: Defensins, small cationic peptides with strong antimicrobial activity, are key effectors of innate immunity. α-defensins, human neutrophil peptides, are produced primarily by neutrophils and serve as an essential component of the airway defense system against invading pathogens. However, accumulating evidence indicates that α-defensins released from human neutrophils are markedly elevated in various lung diseases, where excessive α-defensins exert cytotoxic effects on epithelial and immune cells.

Objective: We investigated how α-defensins influence macrophage inflammatory responses and aimed to elucidate the molecular mechanisms underlying α-defensin-induced macrophage activation.

Methods: Through RNA-seq analysis, we identified key molecules potentially involved in α-defensin-induced inflammatory signaling and validated these candidates using qRT-PCR and western blotting.

Results: Our results show that α-defensins significantly upregulate both the gene expression and protein levels of RNF31 in macrophages, leading to enhanced phosphorylation of NF-κB p65 and increased production of pro-inflammatory cytokines. Furthermore, when co-cultured with lung epithelial cells, α-defensin-stimulated macrophages induced NLRP3 expression in epithelial cells, suggesting that macrophage-epithelial crosstalk contributes to α-defensin-driven airway inflammation.

Conclusion: Together, our results reveal that α-defensins promote macrophage-driven inflammation through RNF31-dependent NF-κB activation and subsequent macrophage-epithelial communication, providing new insight into the inflammatory mechanisms of lung injury. These findings uncover a previously unrecognized α-defensin-RNF31 signaling pathway that amplifies macrophage-mediated airway inflammation, highlighting RNF31 as a potential therapeutic target for inflammatory lung diseases.