Search Results (42)

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

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

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

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

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

To investigate the genetic regulatory mechanism of supplementary feeding on muscle development in Oula sheep, we employed transcriptomic analysis to explore the differentially expressed genes (DEGs) in the longissimus dorsi muscle of Oula sheep at different ages under conditions of supplementary feeding and non-supplementary feeding, as well as the significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways of DEGs. Moreover, by combining with the method of weighted gene co-expression network analysis, we screened for the potential hub genes that might play crucial roles. The results demonstrated that the CD4 and ICAM1 genes and the PI3K-Akt signaling pathway might exert important functions during the lamb stage. At the growth stage, the AGL, PGM2L1, PRKAA2, NEDD4, and GBE1 genes might serve as core genes to regulate the growth of skeletal muscle in Oula sheep after supplementary feeding through signaling pathways such as starch and sucrose metabolism and insulin signaling pathway. This outcome provides a molecular-level interpretation of the regulatory mechanism of supplementary feeding on muscle growth and development in Oula sheep at different ages, offering a theoretical basis for the further improvement of the meat quality of Oula sheep and the enhancement of the quality of livestock products in the Qinghai–Tibet Plateau region. Full article

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC. Full article

Background: Sepsis is a life-threatening condition characterized by organ dysfunction due to an imbalanced immune response to infection, with high mortality. Ferroptosis, an iron-dependent cell death process, and cellular senescence, which exacerbates inflammation, have recently been implicated in sepsis pathophysiology. Methods: Weighted gene co-expression network analysis (WGCNA) was used to identify ferroptosis- and senescence-related gene modules in sepsis. Differentially expressed genes (DEGs) were analyzed using public datasets (GSE57065, GSE65682, and GSE26378). Receiver operating characteristic (ROC) analysis was performed to evaluate their diagnostic potential, while single-cell RNA sequencing (scRNA-seq) was used to assess their immune-cell-specific expression. Molecular docking was conducted to predict drug interactions with key proteins. Results: Five key genes (CD82, MAPK14, NEDD4, TXN, and WIPI1) were significantly upregulated in sepsis patients and highly correlated with immune cell infiltration. MAPK14 and TXN exhibited strong diagnostic potential (AUC = 0.983, 0.978). Molecular docking suggested potential therapeutic interactions with diclofenac, flurbiprofen, and N-acetyl-L-cysteine. Conclusions: This study highlights ferroptosis and senescence as critical mechanisms in sepsis and identifies promising biomarkers for diagnosis and targeted therapy. Future studies should focus on clinical validation and precision medicine applications. Full article

Alveolar active sodium transport is essential for clearing edema from airspaces, in a process known as alveolar fluid clearance (AFC). Although it has been reported that atrial natriuretic peptide (ANP) attenuates AFC, little is known about the underlying molecular effects of natriuretic peptides (NPs). Therefore, we examined the contribution of NPs to AFC and their effects as mediators of active sodium transport. By using the isolated liquid-filled lungs model, we investigated the effects of NPs on AFC. The expression of NPs, Na⁺, K⁺-ATPase, and Na⁺ channels was assessed in alveolar epithelial cells. Congestive heart failure (CHF) was induced by using the aortocaval fistula model. ANP and brain NP (BNP) significantly reduced AFC rate from 0.49 ± 0.02 mL/h in sham rats to 0.26 ± 0.013 and 0.19 ± 0.005 in ANP and BNP-treated groups, respectively. These effects were mediated by downregulating the active Na⁺ transport components in the alveolar epithelium while enhancing the ubiquitination and degradation of αENaC in the lungs, as reflected by increased levels of Nedd4-2. In addition, AFC was reduced in compensated CHF rats treated with ANP, while in decompensated CHF, ANP partially restored AFC. In conclusion, NPs regulate AFC in health and CHF. This research could help optimize pharmacological treatments for severe CHF. Full article

Cardiovascular diseases are the primary cause of mortality worldwide. In this scenario, atherosclerotic cardiovascular outcomes dominate since their incidence increases as populations grow and age. Atherosclerosis is a chronic inflammatory disease that affects arteries. Although its pathophysiology is heterogeneous, some genes are indissociably associated with its occurrence, and understanding their effects on the disease’s occurrence could undoubtedly define effective screening and treatment strategies. One such gene is NEDD4L. The NEDD4L gene is related to ubiquitin ligase enzyme activities. It is essential to regulate vascular inflammation, atherosclerosis plaque stability, endothelial and vascular smooth cell function, and lipid metabolism, particularly in controlling cholesterol levels. However, the evidence is dubious, and no review has yet synthesized the effects of targeting NEDD4L on atherosclerosis. Therefore, our review aims to fill this gap by analyzing the literature on NEDD4L concerning atherosclerosis occurrence. To achieve this goal, we performed a systematic literature search of reputable databases, including PubMed, Google Scholar, Web of Science, Scopus, and Embase. The inclusion criteria comprised peer-reviewed original studies using in vitro and animal models due to the unavailability of relevant clinical studies. Systematic reviews, meta-analyses, and articles that did not focus on the relationship between NEDD4L and atherosclerosis and those unrelated to this health condition were excluded. Studies not written in the English language were also excluded. The search strategy included studies from January 2000 to January 2025 in the final analysis to capture recent advancements. Following screening, five studies were included. Most of the included studies underscored NEDD4L’s role in increasing atherosclerosis plaque formation, but other studies indicated that stimulating NEDD4L may positively counter atherosclerosis plaque formation. Therefore, future research endeavors must address several limitations, which have been tentatively highlighted throughout the manuscript, for more informative research based on preclinical studies and to successfully translate the findings into clinical trials. Full article

Background and Objectives: Hypertension (HTN) constitutes a significant global health burden, yet the specific genetic variant responsible for blood pressure regulation remains elusive. This study investigates the genetic basis of hypertension in the Jordanian population, focusing on gene variants related to ion channels and transporters, including KCNJ1, WNK1, NPPA, STK39, LUC7L2, NEDD4L, NPHS1, BDKRB2, and CACNA1C. Materials and Methods: This research involved 200 hypertensive patients and 224 healthy controls. Whole blood samples were collected from each participant, and genomic DNA was extracted. The genetic distribution of the polymorphisms was analyzed. The haplotype frequencies were investigated using the SNPStats web tool, and the genotype and allele frequencies of the studied variants were assessed using the χ² test. Results: Sixteen single nucleotide polymorphisms (SNPs) from nine genes were evaluated. A significant association was observed between the rs880054 variant of the WNK1 gene and hypertension susceptibility, with the T allele elevating the risk of hypertension. This association remained important in the codominant model (p = 0.049) and the dominant model (p = 0.029). In addition, rs880054 was associated with clinical characteristics such as triglyceride levels and cerebrovascular accidents (p-value > 0.05). Conclusions: Our findings reveal a significant link between the rs880054 SNP and an increased hypertension risk, suggesting that variations in WNK1 may be crucial in regulating blood pressure. This study provides new insights into the genetic factors contributing to hypertension and highlights the potential of WNK1 as a target for future therapeutic interventions. Full article

Neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is an HECT (homologous to E6AP C terminus)-type E3 ubiquitin ligase. As previously documented, bioinformatics analysis revealed NEDD4L is downregulated in clear cell renal cell carcinoma (ccRCC). However, the target substrate regulated by NEDD4L in ccRCC remains unknown. Here, we assessed whether NEDD4L regulates Ras-related C3 botulinum toxin substrate 2 (RAC2) expression in ccRCC. In our study, integrated bioinformatics analysis indicated that low expression of NEDD4L and high expression of RAC2 were both associated with poor prognosis of ccRCC, pro-tumorigenic immunity, and multiple tumor-associated pathways. Our data confirmed the hypothesis indicated in the previous studies related to the downregulation of NEDD4L in ccRCC. NEDD4L was identified to target the RAC2 threonine 108–proline motif, and RAC2 overexpression rescued NEDD4L-mediated cell apoptosis and inhibition of cell growth and migration. Therefore, RAC2 is a novel and first identified target of NEDD4L in ccRCC, and the aberrant less expression of NEDD4L and consequent RAC2 upregulation may contribute to renal carcinogenesis. Our study offers insight into NEDD4L as a potential future therapeutic target for renal cell carcinoma or as a novel prognostic biomarker. Full article

The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis. However, much remains unknown about its role in adipogenesis. Here, we demonstrated that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Inhibition of neddylation by MLN4924 significantly reduced adipogenesis of 3T3-L1 and human stromal vascular cells. Deletion of NAE1, a subunit of the only NEDD8 E1 enzyme, suppressed neddylation and impaired adipogenesis. Neddylation deficiency did not affect mitotic cell expansion. Instead, it disrupted CREB/CEBPβ/PPARγ signaling, essential for adipogenesis. Interestingly, among the neddylation-targeted CUL family members, deletion of CUL3, but not CUL1, CUL2, or CUL4A, largely replicated the adipogenic defects observed with neddylation deficiency. A PPARγ agonist minimally rescued the adipogenic defects caused by the deletion of NAE1 and CUL3. In conclusion, our study demonstrates that neddylation and its targeted CUL3 are crucial for adipogenesis. These findings provide potential targets for therapeutic intervention in obesity and metabolic disorders. Full article