Search Results (163)

Ubiquitin-like proteins (UBLs) such as SUMO, NEDD8, ISG15, FAT10, and UFM1 are proteins that share structural similarities to ubiquitin. Like ubiquitin, they function as protein modifiers, catalyzing modifications through a conserved enzymatic cascade of E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. In doing so, UBLs regulate a diverse set of cellular processes, including stress response, antiviral activity, nuclear transport, cancer development, and autophagy. In recent years, the roles of UBLs during pathogenic bacteria infection have gained attention, although much still remains elusive. This review describes current findings related to UBL systems in the context of pathogenic bacteria infection, focusing on NEDD8, ISG15, FAT10, and UFM1. Specifically, we look at how the host UBL system responds to bacterial infection by inducing the host’s defense system, and how pathogenic bacteria manipulate the host UBL system to ensure successful infection. Full article

Myocardial fibrosis is a common pathological feature of multiple cardiovascular diseases, including heart failure, hypertension, and myocardial infarction, and is associated with poor prognosis. Despite extensive research, clinically validated molecular biomarkers for early diagnosis and reliable therapeutic targets for myocardial fibrosis remain limited. Post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, SUMOylation, and glycosylation, are critical regulators of fibrosis-related signaling pathways, yet a systematic bioinformatics-driven identification of PTM-related hub genes has not been performed. Three publicly available GEO datasets (GSE57345, GSE133054, GSE76314) comprising cardiac tissue from heart failure and control patients were integrated. Differentially expressed genes (DEGs) were identified using the limma package, then intersected with a curated PTM gene set derived from PhosphoSitePlus and UniProt databases. Weighted gene co-expression network analysis (WGCNA) identified fibrosis-associated modules, and protein–protein interaction (PPI) network analysis via STRING and CytoHubba pinpointed hub genes. Diagnostic performance was assessed by receiver operating characteristic (ROC) analysis across independent validation cohorts. Immune cell infiltration was estimated using CIBERSORT.Molecular docking with AutoDock Vina (version 1.2.3) was performed to evaluate binding affinity of FDA-approved cardiovascular drugs against identified hub protein targets. A total of 863 DEGs were identified in the training cohort (|log₂FC| > 1.0, adjusted p < 0.05), of which 138 overlapped with the PTM gene set. WGCNA revealed a turquoise module (r = 0.79, p < 0.001) most significantly correlated with fibrosis severity. PPI analysis identified five hub genes: SIRT3, SMAD3, NEDD4L, UBC9, and CAMK2D. ROC analysis demonstrated strong diagnostic performance (AUC range: 0.82–0.92) validated in independent cohorts. Hub genes showed significant correlations with M2 macrophage infiltration. Molecular docking identified spironolactone and finerenone as top-ranked ligands with binding energies of −8.7 and −8.4 kcal/mol against SMAD3 and SIRT3, respectively. This study, which is entirely in silico and based on publicly available transcriptomic datasets, systematically identifies five PTM-related hub genes as candidate diagnostic biomarkers and prioritised drug-repurposing targets in myocardial fibrosis. These findings are hypothesis-generating and require experimental validation (protein-level confirmation, cell- and animal-based functional assays, and biophysical binding studies) before any diagnostic or therapeutic claim can be made. Full article

Background/Objectives: Yes-associated protein 1 (YAP1) is a transcriptional cofactor that coordinates the complex interplay between cell proliferation, survival, differentiation, metabolism, biomechanics, and tissue regeneration. Previous studies have shown that YAP1 activity is reduced during aging, and replacing YAP1 function has been shown to rejuvenate old cells by mitigating senescence and its associated inflammation. Methods: As YAP1 is now confirmed to exert a profound regenerative influence on multiple organs, we wanted to gain more insight into the molecular signature of YAP1 expression relevant to brain cells. Since proteomics is a very powerful tool for discoveries, we generated SH-SY5Y cells stably expressing GFP-YAP1 and screened 8000 human proteins using multiplex arrays that utilize biotin-label-based antibody arrays. Results: We found YAP1 expression in astrocytes, microglia, neuronal and neuroblastoma cell lines, as well as human neurons. Importantly, YAP1 protein levels were significantly reduced selectively in the nuclear fractions of the brains of patients with Alzheimer’s disease (AD) relative to normal control (NC) subjects. The screen resulted in the identification of 283 differentially expressed proteins. In line with YAP1’s known role in the regulation of actin and cytoskeleton, we found a 2.53-fold upregulated level of Rho guanine nucleotide exchange factor 1 (ARHGEF1), a guanine nucleotide exchange factor (GEF) for the RhoA GTPase, which is crucial for dendritic spine regulation. A 6.19-fold upregulated level of NECAP endocytosis-associated 2 (NECAP2), the highest known increase for any protein in this screen, plays an essential role in clathrin-mediated endocytosis. Most importantly, another upregulated protein was Neudesin Neurotrophic Factor (NENF) (3.07-fold increase), also known as Neudesin, which primarily acts as a neurotrophic factor, and it promotes neuronal survival, enhances cell proliferation, and neurogenesis in neural progenitor cells. Neural Precursor Cell Expressed, Developmentally Down-Regulated 9(NEDD9) levels were also upregulated by 2.46-fold, and it affects neuronal cell number and synaptic connections through its role in neurite formation. However, it should be noted that these proteomic results are preliminary in nature as they are derived from single-sample data. The upregulated levels of ARHGEF1 and NEDD9 were confirmed by immunoblots. We also found a drastic reduction in the levels of p16INK4a, a marker of senescence. Conclusions: Thus, the anti-senescence effect of YAP1 may be mediated through p16INK4a, which in turn may be crucial for YAP1’s regenerative functions through NENF and NEDD9. Full article

Neurodevelopmental disorders (NDDs) are characterized by remarkable phenotypic heterogeneity, in which individuals harboring mutations in the same gene display divergent clinical manifestations, ranging from mild cognitive impairment to severe neurodevelopmental deficits. Advances in neurogenetics and neurogenomics have rapidly expanded the catalog of genes associated with NDDs and have provided unprecedented insight into the genetic architecture of these conditions. However, how identical or similar genetic variants give rise to such diverse phenotypic outcomes remains largely unknown. Ubiquitin-mediated protein regulation is a central mechanism controlling diverse processes essential for neural development, including chromatin regulation, transcriptional dynamics, protein turnover, and synaptic function. Importantly, ubiquitination is a multilayered regulatory process governed by multiple determinants, including the availability of ubiquitination sites on substrates, the activity of ubiquitin ligases, the opposing actions of deubiquitinases, and priming post-translational modifications such as phosphorylation or acetylation. These regulatory layers create a dynamic ubiquitination landscape that may vary across individuals, cell types, developmental stages, and environmental contexts. In this review, we discuss how insights from neurogenetics and neurogenomics can be integrated with knowledge of ubiquitin signaling to better understand the molecular basis of phenotypic heterogeneity in NDDs. We propose that differential ubiquitination represents an important mechanistic framework through which genetic variation is translated into diverse molecular and cellular outcomes. Understanding the interplay between neurogenetic variation and ubiquitin-dependent regulatory networks may provide new perspectives on disease mechanisms and inform future therapeutic strategies for neurodevelopmental disorders. Full article

Artemisia indica Willd. is widely used in traditional medicine and dietary practices. Phytochemical analysis of Artemisia indica Willd. aqueous extract (AAE) by HPLC–ESI–MS/MS identified isochlorogenic acid C (ICAC) as a major constituent. Angiotensin II (Ang II) disrupts renal tubular epithelial cell homeostasis and contributes to renal injury. In this study, we evaluated the protective effects of AAE and ICAC in Ang II-stimulated NRK52E cells. Both AAE and ICAC significantly reduced reactive oxygen species (ROS) production, mitochondrial dysfunction, and proinflammatory cytokine release. Mechanistic analyses showed that AAE inhibited Ang II type 1 receptor (AT1R)-mediated NF-κB activation and suppressed NLRP3 inflammasome signaling, thereby alleviating inflammatory responses and pyroptosis. In addition, AAE and ICAC restored sodium homeostasis by reactivating neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2), promoting epithelial sodium channel (ENaC) ubiquitination and reducing its apical membrane accumulation. Molecular docking suggested that ICAC interacts with the extracellular domain of α-ENaC, supporting its regulatory role. Overall, AAE and ICAC protect renal tubular epithelial cells against Ang II-induced injury by reducing oxidative stress, inflammation, and dysregulated sodium transport, highlighting their potential as plant-derived therapeutic agents for hypertension-associated renal dysfunction. Full article

Cheliped regeneration in the E. sinensis is a tightly regulated physiological process, yet the molecular regulatory mechanisms underlying sexual dimorphism during regeneration remain unclear. In this study, we combined morphological observation with transcriptomic analysis to systematically investigate the regenerative stage characteristics and sex-related differences. The papilla stage 4 dpa was identified as a pivotal transitional stage, bridging initial wound healing and cellular dedifferentiation (2 dpa) with subsequent redifferentiation and morphogenesis (7 dpa). Morphological sex-based differences characterized by larger regenerating chelipeds in males became prominent by the late stage (28 dpa). Notably, the molecular foundation of sexual dimorphism was found to be established at 4 dpa, significantly preceding the emergence of phenotypic differences. This early divergence was driven by sex-dimorphic endocrine networks: males exhibited preferential expression of genes such as Fem-1c-like, Cyp2L1-like, CpAMP1A-like and Nedd4-like, while females showed enrichment in elevated aromatase activity. Weighted gene co-expression network analysis (WGCNA) identified the Hox gene Antp as a core hub regulator, exhibiting high co-expression with key epidermal-related genes such as Cht6, Cht2-like and more. Its suppressed expression at 2 dpa aligned with the requirements for dedifferentiation, whereas its peak at 4 dpa indicated a crucial role in orchestrating appendage patterning and exoskeleton assembly. RNA interference (RNAi) knockdown of Antp resulted in obscured differentiation between the propodus and carpus in both sexes and confirmed its regulatory control over downstream targets including Ubx, Bmp2-like, and CpAMP1A-like. This study suggests a putative hierarchical regulatory model in which systemic hormonal signals may integrate Antp and other sex-biased regulators to potentially facilitate structured limb regeneration. These findings offer tentative novel insights into the interplay between developmental plasticity and sex-based regulatory divergence in decapod crustaceans. Full article

Background: Keloid scarring is a fibroproliferative disorder driven by a complex interplay of genetic, epigenetic, and environmental factors, resulting in significant cosmetic and functional impairment. Despite its high prevalence in African, Asian, and Hispanic populations, the molecular mechanisms underlying ancestry-dependent susceptibility remain incompletely understood. Methods: This narrative review synthesizes current genomic, epigenetic, and multi-omic evidence related to keloid scarring. Relevant literature was identified through a targeted, structured, non-systematic search of PubMed, Scopus, Web of Science, SciELO, and Google Scholar up to August 2025, focusing on genetic susceptibility loci, epigenetic regulation, and ancestry-related differences. PRISMA-ScR guidelines were used as a reporting framework to enhance transparency, without implying a formal systematic review methodology. Results: This synthesis identifies recurrent susceptibility loci at 1q41, 3q22.3, and 15q21.3 across multiple populations. Variants in NEDD4 and regulatory regions near BMP2 emerge as key modulators of profibrotic signaling pathways, including TGF-β/SMAD and NF-κB. Additionally, epigenetic reprogramming and long non-coding RNA networks, such as CACNA1G-AS1, appear to sustain fibroblast hyperactivation. A persistent limitation is the marked underrepresentation of Latin American populations in current genomic studies. Conclusions: Integrating ancestry-specific genomic variation with epigenetic markers is essential for advancing precision diagnostic and therapeutic strategies in keloid scarring. Future research should prioritize diverse, multicenter cohorts and integrative multi-omics approaches to improve risk stratification and enable targeted interventions for this disfiguring condition. Full article

Background: The Xinjiang Black pig is an excellent breed developed by the Xinjiang Production and Construction Corps in the 1990s; however, it has been endangered by the impact of commercial breeds. Methods: Whole genomes of 224 individuals from the Xinjiang Black pig conservation population were resequenced. Results: Genetic structure and diversity analyses revealed that Xinjiang Black pigs underwent severe inbreeding and were genetically closely linked to Landrace pigs. The genetic diversity of the F₂ generation was well preserved in the existing breeding scheme. A total of 686 significant selection regions and 406 candidate genes were identified using F_ST and θπ complementary methods, with Xinjiang Black pigs, Min pigs, and Laiwu pigs as ancestral populations, and F₂. Based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and quantitative trait loci annotations, potential germplasm candidate genes were identified. Among these, SOX5, HMG20A, and NEDD4 are associated with fat deposition; SPRY1, MNS1, DMXL2, and ALB are closely associated with male reproductive ability; ARPP19 and TLN2 are strongly associated with oestrous cycle regulation and oocyte maturation; and SLC4A4 and SLC12A1 are extremely important for osmotic regulation and foetal survival. Conclusions: These findings deepen our understanding of the genetic mechanisms of artificial selection in Xinjiang Black pigs and provide a theoretical basis for subsequent breeding and genetic research on this breed. Full article

With the rapid development of genomic big data and genome-wide association study technologies, massive genomic data are available for the genetic dissection, development and utilization of important economic traits. Various GWAS algorithms have become increasingly efficient, enabling high-performance processing of these massive datasets. This has made it possible to conduct genetic dissection of economic traits based on big data and advanced statistical methods, which will provide accurate target loci for future trait improvement and genetic manipulation, greatly accelerating the process of genetic breeding. In this study, genotyping of 426 fish was performed using the T7 sequencing platform and 555,242 SNPs distributed across all the chromosomes were screened by data cleaning. We compared the performance of two GWAS methods, GCTA and GEMMA, in both single-trait and multi-trait frameworks. Twenty-nine SNPs significantly associated with seven traits were identified through single and multi-trait combined GWAS. Single-trait GWAS analysis using GCTA identified 1047 and 1452 significant loci for six growth traits and one sex trait (phenotypic sex, male or female) respectively, ultimately revealing 10 candidate genes, including slc48a1a, filip1L, nedd9, Crebbpa, LOC134024622, zbtb18, LOC117378376, LOC131530706, syde2, and col24a1. Similarly, 671 and 642 significant SNPs were detected with GEMMA for single-trait GWAS associated with six growth traits and the sex trait, respectively. In total, 16 candidate genes were mapped for these seven traits. Multi-trait GWAS was also performed using GEMMA for the six growth traits (sex was included as a covariate). The traits were grouped into five combinations based on their genetic correlations. A total of 37 SNPs were identified, corresponding to 10 candidate genes: LOC131530706, LOC134022516, abat, maml3, cica, LOC124013321, slc25a12, dnah10, syt9a, and LOC136932979. Notably, five overlapping candidate genes (LOC131530706, LOC134022516, abat, slc25a12 and dnah10) were also identified in both single- and multi-trait GWAS methods of GEMMA, highlighting their genetic stability and significance. The two GWAS methods, GCTA and GEMMA, identified two genes that were the same. The results of this study provide molecular markers and genetic resources for the improvement of growth traits in Plecoglossus altivelis. Full article

Background: Long INterspersed Element-1 (LINE-1) retrotransposons comprise 17–20% of the human genome. These retroelements are normally silenced early in embryonic development through epigenetic mechanisms and reawakened during oncogenesis, leading to transcriptional dysregulation, genomic instability, and immune evasion. Methods: In the present study, we categorized LINE-1 transcripts across 121 non-small cell lung cancer (NSCLC) cell lines from the Cancer Cell Line Encyclopedia (CCLE) by subfamily, length, orientation, chromosomal origin, and distribution. In addition, high-prevalence insertions were mapped to nearby genes to assess potential functional interactions. Results: LINE-1 transcript abundance and length in NSCLC were dominated by evolutionarily young subfamilies, particularly L1HS and L1PA2 through L1PA5. Chromosomal patterns were conserved across NSCLC subtypes, with modest enrichment of L1HS activity on Chromosome 4 and the X Chromosome. The lung squamous cell carcinoma (LSQCC) subtype exhibited the highest total levels of L1HS expression relative to other NSCLC subtypes. Race modestly influenced LINE-1 transcript abundance, with cell lines derived from self-identified African American individuals showing elevated overall LINE-1 and L1HS expression. Age showed a weak positive correlation with total LINE-1 abundance. Integrative analysis revealed recurrent hotspots at 22q12.1 and 20p11.21 that were transcriptionally active across subtypes and coincided with previously reported intact LINE-1 elements active in epithelial cancers. Recurrent insertions were located near cancer-associated genes, including RB1, NEDD4, FTO, LAMA2, NOD1, and KCNB2, implicating LINE-1 activity in cis-regulatory remodeling of oncogenic pathways. Conclusions: Together, these findings indicate that LINE-1 transcript heterogeneity in NSCLC is shaped by host genomic architecture and conserved functional hotspots, providing new insights into the mechanisms of genetic and epigenetic dysregulation associated with LINE-1 retroelements. Full article

Idiopathic pulmonary fibrosis is a chronic, progressive, interstitial lung disease for which specific and effective drug therapies are still lacking. Lathyrol is a diterpene compound with broad pharmacological activities that can be extracted from the traditional Chinese medicine Leptochloa chinensis (L.) Nees. To investigate the anti-pulmonary fibrosis effect of lathyrol and its underlying mechanism. In vivo, a mouse model of pulmonary fibrosis was induced by bleomycin, treated with intraperitoneal injections of lathyrol. In vitro, myofibroblast conversion was induced in three fibroblast cell lines by stimulating them with TGF-β1, followed by treatment with lathyrol. Transcriptomic analysis was performed to assess the regulation of signaling pathways and gene expression patterns modulated by lathyrol. The effects of lathyrol on PPARγ activation, as well as on the nuclear translocation and ubiquitination of phosphorylated Smad3, were examined. The interaction among Nedd4, PPARγ, and phosphorylated Smad3 was detected. In vivo, lathyrol ameliorated pathological fibrosis in the lungs of mice with pulmonary fibrosis and this effect was blocked by a PPARγ inhibitor. In vitro, lathyrol inhibited the transdifferentiation of fibroblasts into myofibroblasts, and these effects were suppressed by either inhibiting PPARγ activation or specifically silencing the PPARγ gene. Lathyrol inhibited the nuclear translocation of phosphorylated Smad3 and promoted its ubiquitination, while also enhancing the interaction among Nedd4, PPARγ, and phosphorylated Smad3. These effects were abolished following the specific silencing of either PPARγ or Nedd4. In conclusion, Lathyrol inhibits myofibroblast transformation by suppressing TGF-β/Smad pathway activation through PPARγ activation, thereby exerting its anti-pulmonary fibrosis effects. Full article

Atrial fibrillation (AF) is the most common sustained arrhythmia, and its initiation and progression involve multiple mechanisms, including electrical remodeling, structural remodeling, inflammatory responses, and oxidative stress. In recent years, the ubiquitin–proteasome system (UPS), a central pathway for maintaining intracellular protein homeostasis, has attracted increasing attention in the pathogenesis of AF. By regulating the degradation and expression of ion channel proteins, Ca²⁺-handling molecules, and pro-fibrotic signaling factors, the UPS plays a pivotal role in key pathological processes such as electrical and structural remodeling. Several E3 ubiquitin ligases (e.g., NEDD4-1/2, MuRF1, WWP1/2, TRAF6), deubiquitinating enzymes (e.g., JOSD2), and immunoproteasome subunits (e.g., β5i) have been shown to exert critical regulatory effects on atrial electrophysiological disturbances, interstitial remodeling, and inflammation. This review provides a comprehensive summary of the regulatory mechanisms of the UPS in AF-associated pathological processes, outlines potential therapeutic targets, and highlights current intervention strategies, including proteasome inhibitors, selective E3 ligase modulators, and natural compounds. Moreover, we discuss the latest advances and future perspectives regarding the application of UPS-based interventions in AF, aiming to provide theoretical foundations and research insights for the mechanistic exploration and innovative therapeutic development of AF. Full article

With the improvement of living standards, people’s awareness of health care is becoming stronger and stronger. Rabbit meat is a very high-quality and healthy meat, but its consumption is low due to its poor flavor. To explore the regulatory mechanism of nutrition on the meat quality of rabbits, twenty-four rabbits were fed a control diet or a high-fat (5 percent lard) diet over 15 days. The contents and tissues of the jejunum were subjected to 16S sequencing and mRNA transcriptome sequencing, respectively. The results indicated that there were significant differences in species diversity through beta diversity analysis (p < 0.05). The diversity of alpha in the experimental group was also significantly reduced (p < 0.05). Based on gene function annotation, 8 bacteria at the phylum level and 11 bacteria at the genus level that are related to the metabolism of adipose tissue showed significant differences between the two groups (p < 0.05). The transcriptome results of the jejunum showed significant differences in 135 genes between the experimental group and control group (p < 0.05). Gene annotation revealed 10 differentially expressed genes related to fat metabolism, which regulate 36 signaling pathways. We speculated that Alloprevotella may influence drip loss and cooked meat rate by changing the expression of PHGDH through correlation analysis. In addition, Coprococcus may influence IMF by changing the expression of NEDD4, ANGPTL3, and CYP8B1. These results indicated that a high-fat diet changed the species and composition of bacteria in the rabbit jejunum. Alloprevotella and Coprococcus may influence rabbit meat quality and flavor by changing PHGDH, NEDD4, ANGPTL3, and CYP8B1 gene expression in the host. This study laid a molecular foundation for the improvement of rabbit meat quality through nutritional diets. Full article

The allelopathic compound coumarin inhibits root growth across numerous species, but its mechanism is unknown. Through a genetic screen in Arabidopsis mutants, we identified the mutants for AXR1 (AUXIN RESISTANT 1) and ECR1 (E1 C-TERMINAL RELATED 1), two subunits of the NEDD8-activating enzyme (NAE), that are resistant to coumarin. Conversely, overexpression of the NEDD8-encoding gene RUB1 (RELATED TO UBIQUITIN 1) caused hypersensitivity, while the NAE inhibitor MLN4924 blocked coumarin’s effect. Since neddylation regulates auxin signaling, we analyzed downstream AUX/IAA proteins and found that the loss-of-function mutant of AUXIN RESISTANT 2 (AXR2) (also known as IAA7) was resistant to coumarin. We further showed that coumarin treatment leads to the accumulation of the AXR2 protein. Taken together, these results demonstrate that coumarin inhibits primary root growth by modulating auxin signaling via neddylation. Full article

Background: Gastric cancer (GC) remains a leading cause of cancer mortality. E3 ubiquitin ligases, as central regulators of protein stability and signaling within the ubiquitin–proteasome system, have been implicated in tumor progression, but their functional roles in GC are not well established. Methods: We integrated bioinformatics analysis of TCGA and GEO datasets, in vitro experiments (including cell proliferation, migration, and apoptosis assays), and computational modeling to identify key prognostic factors in GC. Results: We established two molecular subtypes (E3GC1/E3GC2) with distinct clinical outcomes and developed a 10-gene prognostic signature. The model showed moderate predictive accuracy (AUC: 0.61–0.71) and was validated externally. MMRN1 was upregulated in GC cells and its knockdown significantly inhibited malignant phenotypes. Critically, drug sensitivity analysis revealed high-risk patients were more sensitive to proteasome inhibitors (bortezomib), while low-risk patients responded better to taxane-based chemotherapy (docetaxel). Molecular docking predicted a high-confidence interaction between MMRN1 and NEDD4L, suggesting potential ubiquitination regulation. Conclusions: MMRN1 drives GC cell proliferation and migration in vitro and may be regulated by NEDD4L-mediated ubiquitination. Our study provides a foundation for E3 ligase-based patient stratification and personalized therapy selection in GC. While this study provides comprehensive multi-omics evidence supporting the role of MMRN1 in GC progression, its clinical translation is limited by the lack of in vivo validation and direct experimental evidence of NEDD4L-MMRN1 physical interaction. Further studies using animal models and clinical specimens are warranted to confirm these findings. Full article