Search Results (8,463)

Tau is classically defined as a microtubule-associated protein whose dysfunction underpins neurodegenerative disorders. However, its role in cardiac pathophysiology remains elusive despite recent evidence of its cardiac expression. Here, we report that a ~55 kDa Tau-immunoreactive species, which is commonly found in the nervous system, is markedly upregulated in isoproterenol-induced hypertrophic murine hearts, suggesting that this stress-inducible species is associated with maladaptive cardiac remodeling. Forced Tau expression was sufficient to induce hypertrophic growth in cultured cardiomyocytes. Cardiomyocyte-restricted Tau overexpression in transgenic mice recapitulated the progressive trajectory from hypertrophy to overt heart failure. Mechanistically, Tau overexpression triggered excessive mitochondrial fission, leading to mitochondrial dysfunction evidenced by reduced mitochondrial membrane potential, elevated reactive oxygen species, diminished activity of respiratory chain complexes I and IV, and decreased intracellular ATP. Pharmacological inhibition of mitochondrial fission with Mdivi-1 attenuated Tau overexpression-induced cardiomyocyte hypertrophy; taken together, our gain-of-function evidence identifies the ~55 kDa Tau-immunoreactive species as a stress-associated factor that disrupts mitochondrial dynamics to promote cardiac remodeling, and suggests Tau as a potential therapeutic target for cardiac diseases. Full article

NF-κB p65 (RelA) is a key regulator of inflammation, immunity, and stress responses. Recent evidence indicates that alternative p65 isoforms may diversify NF-κB signaling, but their functions remain largely unexplored. We previously identified a novel splice variant, p65 iso5, which contains an additional upstream exon and displays distinct molecular properties, including the ability to interact with dexamethasone in a glucocorticoid receptor-dependent manner. Here, we define the transcriptional programs regulated by p65 iso5 using RNA-seq analysis of HeLa cells expressing either p65 iso5 or canonical p65, with or without dexamethasone treatment. Under basal conditions, p65 iso5 expression was associated with reduced expression of genes involved in type I interferon and antiviral pathways as compared to the effects of canonical p65, while genes involved in translation, ribosome biogenesis, and metabolic activity were not reduced as with p65. Upon dexamethasone stimulation, p65 iso5 expression was associated with extensive transcriptome remodeling characterized by suppression of biosynthetic and proliferative programs and activation of metabolic and stress-adaptive pathways. Comparative analyses reveal that glucocorticoid responses are strongly isoform-dependent, with p65 iso5 expression being associated with distinct gene expression networks supported by distinct protein–protein interaction hubs. p65 iso5 is overexpressed in cirrhotic and hepatocellular carcinoma tissues as well as in high-grade colon tumors, suggesting clinical relevance. Our findings identify p65 iso5 as a context-dependent NF-κB modulator with unique transcriptional and metabolic functions and potential relevance in inflammation-associated diseases and cancer. Full article

Background: Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) primarily participates in protein synthesis by binding aminoacyl-tRNA complexes to facilitate peptide chain elongation on ribosomes. Its expression and functional roles exhibit significant heterogeneity across various malignancies, exerting dual regulatory effects as both an oncogene and a tumor suppressor. This study aims to investigate the potential prognostic value and tumor-suppressive role of EEF1A1 in kidney renal clear cell carcinoma (KIRC). Methods: We analyzed the differential expression of EEF1A1 in KIRC and its correlation with patient prognosis based on the TCGA, GEO, and HPA databases. The STRING and GEPIA databases were utilized to perform functional enrichment analysis of its interacting proteins and co-expressed genes. The xCell algorithm was employed to assess the correlation between EEF1A1 and immune cell infiltration, immune checkpoints, and immunomodulatory molecules. Furthermore, drug sensitivity analysis was conducted to evaluate its clinical application potential. Finally, the expression of EEF1A1 in 786-0 and A498 cell lines was validated via qRT-PCR and Western blotting. Furthermore, CCK-8, wound healing, and Transwell migration/invasion assays were performed to evaluate cell proliferation, migration, and invasion, respectively. Results: EEF1A1 may function as a negative regulator of malignant behaviors in KIRC tissues and cell lines, and its expression level was closely associated with clinicopathological features and prognosis of patients. GO, KEGG, and GSEA enrichment analyses revealed that low EEF1A1 expression is closely linked to immunosuppressive pathways. Further immunological analysis confirmed significant correlations between EEF1A1 and various immune cell infiltrates, immune checkpoints, tumor-infiltrating lymphocytes, and immunomodulatory molecules. Moreover, cells with high EEF1A1 expression exhibited increased sensitivity to anti-tumor drugs, with expression levels negatively correlated with inhibitory activity (IC50). Finally, overexpression of EEF1A1 significantly inhibited the proliferation, migration, and invasion of clear cell renal cell carcinoma cells. Conclusions: EEF1A1 serves as a potential prognostic biomarker in KIRC and is associated with clinical progression, immune-related characteristics, metabolic pathways, and drug sensitivity. Functional validation further supports its role in regulating malignant phenotypes of KIRC cells. Full article

Background/Objectives: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory bladder disorder that lacks an effective treatment agent. Fucoidan (FUC), isolated from Fucus vesiculosus, is a sulfated polysaccharide that exhibits potent anti-inflammatory and anti-fibrotic activities. This study investigated the protective effects and underlying mechanisms of FUC in IC/BPS. Methods: NLRP3 inflammasome activation and AKT signaling were evaluated by Western blotting, qRT-PCR, immunofluorescence, pharmacological inhibition, gene silencing, and overexpression. Molecular docking assessed potential FUC–protein interactions. In vivo mouse model evaluated the protective effects and toxicity of FUC. Results: In SV-HUC-1 cells, FUC significantly attenuated TNF-α-induced expression of NLRP3 and cleaved caspase-1 and c-IL-1β expression at both the transcriptional and protein levels. Residual inflammasome activity after FUC treatment remained further suppressible by MCC950 or siNLRP3. FUC also reduced TNFα-induced AKT phosphorylation, whereas AKT silencing and overexpression enhanced and partially reversed the inhibitory effect of FUC on inflammasome signaling, respectively. The molecular docking results suggested potential interactions between FUC and key inflammasome-related proteins, including NLRP3, caspase-1, IL-1β, and AKT. In interstitial cystitis mice, FUC mitigated cyclophosphamide (CYP)-induced bladder injury, reduced bladder expression of inflammasome-associated markers, and exhibited no significant toxicity in major organs. Conclusions: These findings indicate that FUC alleviates urothelial inflammatory injury and experimental cystitis, at least in part, by suppressing the AKT/NLRP3 inflammasome axis, supporting its potential as a therapeutic candidate for IC/BPS. Full article

Background: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland. Although most patients have favorable outcomes, a subset of patients develop aggressive disease characterized by lymph node metastasis and recurrence. Increasing evidence indicates that inflammatory factors participate in tumor progression. However, the expression pattern and functional role of interleukin-1 beta (IL1β) in PTC remain unclear. This study aimed to investigate the expression, biological function, and underlying molecular mechanisms of IL1β in PTC progression. Methods: IL1β expression and its clinical relevance were evaluated using public databases, 152 paired PTC and adjacent non-cancerous tissue samples, and PTC cell lines. Functional assays, including cell proliferation, colony formation, wound-healing, transwell invasion, and flow cytometry assays, were performed to investigate the effects of IL1β on malignant phenotypes. RNA sequencing, proteomic analysis, co-immunoprecipitation assays, rescue experiments, and a xenograft mouse model were conducted to identify and validate the downstream molecular mechanisms of IL1β. Results: IL1β expression was significantly reduced in PTC tissues and cell lines and was negatively associated with lymph node metastasis. Overexpression or recombinant protein treatment of IL1β inhibited PTC cell proliferation, migration, invasion, epithelial–mesenchymal transition, and tumor growth, while promoting apoptosis. Mechanistically, IL1β increased the expression of SMDT1 gene and suppressed MAPK signaling activity by reducing MEK/ERK phosphorylation. Knockdown of SMDT1 gene partially reversed the inhibitory effects of IL1β on PTC cell progression and MAPK pathway activation. Conclusions: This study demonstrates that IL1β functions as a tumor suppressor in PTC through regulation of the SMDT1-MAPK signaling axis. These findings provide new insights into the role of inflammatory regulation in thyroid cancer (THCA) progression and suggest that IL1β-related molecular pathways may represent potential biomarkers or therapeutic targets for aggressive PTC. Full article

Soil salinization acts as a major abiotic stress and severely hampers global agricultural productivity. Elucidating the molecular mechanisms underlying plant salt tolerance is of great significance for crop improvement. Remorin (REM) proteins are plant-specific membrane marker proteins that play a key role in stress signaling; however, their function in the salt tolerance response of sugar beet remains unclear. In this study, 14 BvREM gene family members were identified. Phylogenetic analysis revealed that this family can be divided into five subgroups and exhibits significant interspecies collinearity with Arabidopsis. Transcriptomic analysis showed that several BvREM genes were up-regulated under salt stress, with BvREM12 displaying greater expression fold change than most other family members. Using sugar beet line M14 as the gene resource material, we explored the potential function and proposed a working regulatory model for candidate gene BvREM12 in salt stress response. Subcellular localization results indicated that the BvREM12 protein is localized to the cell membrane and nucleus. Overexpression of BvREM12 significantly increased biomass accumulation in Arabidopsis, elevated antioxidant enzyme activities, decreased MDA levels, and increased proline content; a high K⁺/Na⁺ ratio was maintained, whilst Ca²⁺ levels were significantly higher than in the Col-0. Furthermore, qRT-PCR analysis revealed that several key salt-responsive genes were significantly up-regulated under salt stress. In summary, BvREM12 integrates the ‘Ca²⁺-SOS3-SOS2-SOS1’ signaling pathway with the ‘H⁺-ATPase-AKT1’ ion transport system to synergistically regulate Na⁺ efflux and K⁺ influx, thereby maintaining cellular ion homeostasis and redox balance, and significantly enhancing the plant salt tolerance. This study systematically characterized the sugar beet BvREM gene family and functionally dissected BvREM12. Different from previous studies on REM proteins mainly focusing on ROS scavenging at plasma membrane nanodomains, our work reveals that BvREM12, which is dual-localized to the plasma membrane and nucleus, coordinates the Ca²⁺-dependent SOS signaling cascade and H⁺-ATPase-AKT1 ion transport system to jointly maintain ion homeostasis and redox balance under salt stress. This work provides candidate genes and a mechanistic reference for molecular breeding of salt-tolerant sugar beet. Full article

Aptamer-functionalized liposomes are a promising strategy to improve the selectivity of anticancer therapies. AT11-L2 is a G-quadruplex (G4)-forming aptamer with high affinity for nucleolin (NCL), which is overexpressed at the surface of non-small cell lung cancer (NSCLC) cells. Here, we developed AT11-L2-functionalized liposomes loaded with doxorubicin (DOX) or BRACO-19 for targeted delivery to NSCLC cells. The effects of both compounds on AT11-L2 stability and the ability of the aptamer to retain G4 folding after liposome conjugation were evaluated. Liposomes were characterized for size, polydispersity, surface charge, stability, encapsulation efficiency, and release profile. Biological activity was assessed in A549 and MRC-5 cells. Liposomes had an average size of approximately 110 nm, with a slight size increase and reduced surface charge after AT11-L2 functionalization. The aptamer retained G4 folding in 100 mM KCl after conjugation. Encapsulation efficiency was approximately 90%. DOX showed substantial release within 72 h, whereas BRACO-19 exhibited a more sustained profile. AT11-L2-DOX liposomes showed preferential effects in A549 cells, while BRACO-19 formulations displayed lower selectivity and cytotoxicity. Additionally, the NCL-dependent internalization of AT11-L2-functionalized liposomes was supported by a protein-blocking assay using an anti-NCL antibody. These results support AT11-L2-functionalized liposomes as a versatile NCL-targeted delivery system for NSCLC. Full article

Protein tyrosine phosphatases (PTPs) are key regulators of intracellular signaling cascades involved in cell growth, proliferation, differentiation, inflammation, and cancer. PTPN23, a non-receptor PTP, is involved in endosomal sorting and thereby regulates the internalization of growth factor receptors, such as the epidermal growth factor receptor (EGFR). PTPN23 has been proposed to exert tumor-suppressive effects in several epithelial cancers, including breast and lung cancer. PTPN23 is ubiquitously expressed in the body; however, it is particularly highly expressed in the intestine, where it plays an essential role in maintaining intestinal homeostasis. Despite these observations, its involvement in colorectal carcinoma (CRC) remains largely unexplored. To investigate the function of PTPN23 in CRC, we generated PTPN23-overexpressing CRC cell lines and evaluated their effects in vitro and in subcutaneous tumor models. Our in-vitro findings demonstrate that PTPN23 overexpression resulted in reduced proliferation levels and follow-up experiments showed suppression of colorectal cancer growth and proliferation in experimental CRC models. These effects were accompanied by changes in EGFR-associated signaling; however, the underlying mechanism, including a potential role of EGFR trafficking, remains to be established through direct experimental validation. Together, these findings expand current knowledge of PTPN23 in colorectal cancer and provide a basis for future studies addressing its biological function and therapeutic relevance. Full article

Non-coding RNAs have emerged as gene-regulatory molecules acting at epigenetic, transcriptional, and post-transcriptional levels. Among them, microRNAs are short RNA molecules consisting of approximately 22 nucleotides. Increased microRNA expression suppresses target protein expression, whereas decreased microRNA expression relieves this repression and can induce overexpression of target proteins. microRNAs integratively regulate highly complex biological processes, including cell proliferation, differentiation, apoptosis, morphogenesis, and immune responses. Therefore, alterations in microRNA expression profiles may be directly linked to the fundamental pathogenesis of systemic sclerosis (SSc), an autoimmune and fibrotic disease involving multiple organs. This focused narrative review examines microRNAs involved in SSc fibrosis, vasculopathy, and immune dysregulation; extracellular-particle-associated microRNAs; and circulating and hair-derived microRNAs as candidate biomarkers. It also summarizes evidence on long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), yRNAs, and PIWI-interacting RNAs (piRNAs). Finally, therapeutic perspectives, including microRNA mimics, antisense inhibitors, and broader RNA-targeted strategies, are discussed together with key challenges in validation and clinical translation. Full article

Stem diameter is an important agronomic trait determining plant architecture, lodging resistance and yield formation, yet its cytological and molecular mechanisms in the major cucurbit crop Luffa remain largely unclear. Herein, two Luffa inbred lines, S1174 (Luffa acutangula, thin stem) and P93075 (Luffa cylindrica, thick stem), were analyzed. Dynamic phenotyping uncovered a sigmoidal growth pattern with three key developmental stages: initiation (0 d), rapid growth (6 d), and maturation (20 d), during which P93075 consistently exhibited a significantly larger stem diameter than S1174 from 6 d onward. Anatomical analysis showed that P93075 displayed greater parenchyma cell size and vascular bundle area than S1174, suggesting that stem diameter variation is closely associated with parenchyma cell expansion and vascular bundle enlargement. Transcriptome profiling further identified 2611 differentially expressed genes (DEGs), mainly enriched in cell wall organization, phenylpropanoid biosynthesis, and hormone signaling pathways. Through temporal expression patterns of shared DEGs across developmental phases and co-expression network analysis, LacEXT3, encoding a cell wall extensin protein, was prioritized as a promising candidate gene associated with stem radial growth. Consistent with its markedly higher expression in P93075, heterologous overexpression of LacEXT3 in Arabidopsis resulted in increased stem diameter accompanied by reduced plant height. Overall, this study provides new insights into the developmental, cytological, and transcriptomic landscape underlying stem diameter variation in Luffa and offers a valuable resource for future investigation of the molecular mechanisms of stem thickening. Full article

Ochratoxin A (OTA) accumulation by Penicillium nordicum is enhanced at high salt concentrations. The genes involved in OTA biosynthesis include a polyketide synthase (PKS), although other PKSs outside the cluster could influence OTA production. This study aimed to evaluate a potential new PKS involved in OTA biosynthesis and the metabolites related to this mycotoxin. Optimised protocols were designed for the gene expression analysis of five genes that encoded the previously reported PKS to be overexpressed in dry-cured meat products (n2, n3, n4, n5 and n6). Their expression was tested in two P. nordicum strains (Pn15 and Pn856) grown in CYA medium with different salt concentrations. Fungal mycelia were used for gene expression analyses and metabolomics. Three genes (n3, n4 and n6) seem to be related to OTA biosynthesis in Pn856. However, n2 might be involved in OTA degradation. The lack of correlations between the genes studied and OTA in Pn15 could be due to the low OTA levels quantified. The metabolites coniferyl alcohol and 6-hydroxy-8-methoxy-3-methylisochroman were positively correlated to OTA, and 3-methylbutanoic acid and cephalosporolide E might be used as indicators to predict OTA. These results show the complex regulation and influence of PKS proteins on OTA levels. Full article

How individual diguanylate cyclases generate specific outputs within bacterial c-di-GMP networks remains unclear. Here, we characterized PA0290, a PAS-PAC-GGDEF protein of Pseudomonas aeruginosa, and examined its relationship with the c-di-GMP receptor PelD. Deletion or overexpression of PA0290 alone did not significantly affect biofilm formation. A bacterial adenylate cyclase two-hybrid screen identified PelD as a candidate PA0290-interacting protein, and co-expression of PA0290 and PelD markedly enhanced static and flow-cell biofilm formation. Purified PA0290 generated an HPLC product peak with a retention time closely matching that of the authentic c-di-GMP standard, whereas substitution of the conserved GGEEF motif with GGAAF reduced product formation and weakened the biofilm-enhancing phenotype observed upon PA0290–PelD co-expression. PA0290–PelD co-expression did not produce sustained activation of the bulk c-di-GMP-responsive cdrA-lux reporter. Clinical isolates also displayed heterogeneous biofilm-forming capacity and variable PA0290 and pelD transcript abundance. Together, these findings support a functional association between PA0290 and PelD in biofilm regulation. The absence of sustained bulk c-di-GMP-responsive reporter activation suggests that this phenotype is not accompanied by a generalized increase in c-di-GMP-responsive transcription. Full article

Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is an inducible NAD-consuming enzyme and execution factor in axon degeneration. Rapid ATP collapse after SARM1 activation, however, is not fully explained by NAD depletion alone. We used SARM1-overexpressing HEK293 cells and the cell-permeant activator CZ-48 to examine SARM1-induced non-apoptotic cell death, termed sarmoptosis. CZ-48 induced cell death that was suppressed by HSP90/70-annotated ATP-competitive compounds, especially geldanamycin and VER-155008 (VER), without reducing SARM1 abundance. VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48/SARM1-driven cytotoxicity from generic NAD depletion. In cell-free assays, purified SARM1 reduced ATP levels; this effect was enhanced by SARM1’s activator NMN and attenuated by its pharmacological inhibitors, although the in vitro activity was modest and the reaction products remain to be identified. ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure. Full article

Background/Objectives: Sjögren’s Syndrome (SS) is an autoimmune disorder with impaired exocrine gland function. Its pathogenesis remains elusive, but aberrant innate/adaptive immunity and dysregulated interferon signaling are core features. Current SS research lacks exploration of innate immune mechanisms and therapeutic targets. Phloretin, a natural dihydrochalcone derivative, inhibits excessive innate immune activation, yet its role and mechanism in SS remain unreported. Methods: This study aimed to explore the therapeutic efficacy of phloretin against Sjögren’s syndrome (SS) and elucidate the regulatory mechanism underlying its effects on dendritic cells (DCs) and the Stimulator of Interferon Genes (STING)-driven innate immune cascade. Clinical specimens were utilized to analyze DC infiltration and STING expression in the labial glands of SS patients. In vivo experiments were conducted on NOD/Ltj SS mice with phloretin treatment, using hydroxychloroquine as a positive control. For in vitro studies, DCs were stimulated with poly I:C to verify the functional effects of phloretin and its regulatory role in the STING/TANK-binding kinase 1 (TBK1)/Interferon Regulatory Factor 3 (IRF3) signaling. Salivary secretion, glandular inflammatory responses, and systemic immune overactivation were evaluated in SS mice. In poly I:C-stimulated DCs, cell activation, migration, and co-stimulatory molecule expression were measured. The regulatory effects of phloretin on the STING signaling cascade and STING ubiquitin-mediated degradation were examined by Western blotting. Phloretin, initially identified as a candidate compound via virtual screening, was subjected to thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulation (MD) for direct binding verification with STING. The STING overexpression rescue experiment further corroborates that phloretin modulates innate immune responses in a STING-dependent manner. Results: Clinical results revealed obvious infiltration of CD11c⁺STING⁺ DCs and CD11c⁺p-TBK1⁺ DCs in labial gland lesions of SS patients. In NOD/Ltj SS mice, phloretin treatment recovered salivary secretion, relieved glandular inflammatory injury, and restrained excessive activation of innate and adaptive immune responses, showing comparable therapeutic effects compared with hydroxychloroquine. In vitro experiments confirmed that phloretin could alleviate poly I:C-induced abnormal activation and migration of DCs, as well as reduce the expression of co-stimulatory molecules. Mechanistically, phloretin was found to interfere with the STING signaling cascade, alter the ubiquitination level of STING protein, and further inhibit the abnormal activation of DCs, which may contribute to its protective effects against Sjögren’s syndrome. Notably, results from MD, CETSA and DARTS collectively validate the interaction between phloretin and STING protein, providing solid molecular-level evidence for its regulatory effect on STING signaling transduction. Conclusions: DCs and STING-driven innate immunity critically contribute to SS progression. Phloretin effectively ameliorates SS-related immune disorders by restraining DC overactivation and STING signaling, supporting it as a promising candidate agent for SS treatment. Full article

Stem development determines plant architecture and mechanical support, directly affecting yield, lodging resistance, and ornamental quality. Microtubules are essential components of the plant cytoskeleton, but their role in stem development in herbaceous peony (Paeonia lactiflora Pall.) remains largely unexplored. Here, a β-tubulin gene, PlTUB1, was identified from P. lactiflora. Its coding sequence was 1353 bp in length, encoding a 450-amino-acid protein that localized to microtubules, and its transcript levels declined progressively during stem development. Transient virus-induced gene silencing of PlTUB1 in P. lactiflora, with a silencing efficiency of approximately 55%, enhanced stem development, with increased stem diameter, elevated cellulose accumulation, and thickened secondary walls. Given that cellulose deposition and secondary wall thickening were closely associated with cortical microtubule organization, the role of PlTUB1 in microtubule regulation was further examined. Heterologous overexpression of PlTUB1 in Arabidopsis thaliana disrupted transverse microtubule alignment, reduced cellulose deposition, and impaired secondary wall and xylem development, thereby confirming the mechanistic link between PlTUB1 and microtubule organization. Collectively, these findings demonstrated that PlTUB1 negatively regulates stem development by modulating microtubule organization and secondary wall deposition, providing new insights into the cytoskeletal regulation of stem development in P. lactiflora. Full article