Exp Cell Res
· 2026 May · PMID 41734849
·
Publisher ↗
BACKGROUND: Cylindromatosis (CYLD) has been found to mediate lung cancer (LC) progression as a tumor suppressor, but its related molecular mechanism remains to be further elucidated. METHODS: The expression of CYLD, Krup...BACKGROUND: Cylindromatosis (CYLD) has been found to mediate lung cancer (LC) progression as a tumor suppressor, but its related molecular mechanism remains to be further elucidated. METHODS: The expression of CYLD, Kruppel-like factor 4 (KLF4), and TEK receptor tyrosine kinase (TEK) was analyzed by qRT-PCR or Western blot. The interaction between CYLD and KLF4 or TEK was confirmed using ChIP assay, dual-luciferase reporter assay and Co-IP assay. Cell proliferation, migration, invasion and apoptosis were determined by EdU assay, colony formation assay, transwell assay and flow cytometry. The role of KLF4/CYLD/TEK axis in vivo was further confirmed by constructing mice xenograft models. RESULTS: CYLD expression was markedly reduced in LC cells and tissues. Transcription factor KLF4 could bind to the promoter region of CYLD to enhance its transcription and expression. KLF4 overexpression repressed LC cell proliferation, migration, invasion and promoted apoptosis, while these effects were abolished by CYLD knockdown. CYLD could increase TEK expression by deubiquitination. The inhibitory effect of CYLD upregulation on LC cell growth and metastasis was reversed by TEK silencing. Animal study showed that overexpression of KLF4 significantly reduced LC tumor growth through activating the CYLD/TEK axis. CONCLUSION: KLF4-activated CYLD repressed LC cell growth and metastasis by increasing TEK deubiquitination, providing a new regulatory axis for the development of LC potential molecular targets.
Esophageal cancer (EC) is a highly prevalent and life-threatening malignancy. Early diagnosis and timely intervention are critical for improving patient survival outcomes. This review outlines the mechanisms and function...Esophageal cancer (EC) is a highly prevalent and life-threatening malignancy. Early diagnosis and timely intervention are critical for improving patient survival outcomes. This review outlines the mechanisms and functional roles of small interfering RNA (siRNA), microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA), with a particular emphasis on their applications in nucleic acid therapy for EC. Nucleic acid therapy exhibits significant promise in the areas of early monitoring, targeted therapy, and diagnosis and prognostic assessment of EC. Liquid biopsy technology has demonstrated potential in enhancing diagnostic accuracy for early disease detection and enabling real-time monitoring of responses to nucleic acid-based therapies. However, several challenges, including limited delivery efficiency, off-target effect, and the complexity of the tumor microenvironment, currently impede the widespread clinical application of nucleic acid therapy. Future research should prioritize the optimization of delivery systems, enhancement of targeting precision, and improvement of immune compatibility to facilitate the clinical translation of nucleic acid-based therapeutic approaches.
In the quest to enhance diabetic wound healing, we synthesized FeO@SiO/Schiff-base complex of Cu(II) magnetic nanoparticles (MNPs) embedded in sodium alginate hydrogel. This study analyzed the effects of 1% and 10% Cu(II...In the quest to enhance diabetic wound healing, we synthesized FeO@SiO/Schiff-base complex of Cu(II) magnetic nanoparticles (MNPs) embedded in sodium alginate hydrogel. This study analyzed the effects of 1% and 10% Cu(II) nanoparticles (NPs) concentrations on wound closure and tissue regeneration in a diabetic rat model. Streptozotocin-induced diabetic Sprague-Dawley rats were used to evaluate the in vivo efficacy of NPs. Characterization involved digital photography for wound closure quantification, histopathological analysis for tissue repair assessment, and statistical methods for data interpretation. Our findings indicated that the 1% Cu nanoparticle (NP) -embedded hydrogel significantly improved wound healing, including enhanced reepithelialization, collagen deposition, neovascularization, granulation tissue formation, and fibroblast activation, while also reducing inflammation. The 10% Cu NP formulation did not demonstrate the same level of efficacy, suggesting a concentration-dependent therapeutic window for copper ion release. This novel NP hydrogel showcases the potential of copper-based NPs in diabetic wound management, offering a cost-effective and promising approach for treating a global health issue.
Fu S, Yan C, Liu B
… +6 more, Yan G, Li Y, Tang K, Wang H, Cui R, He Y
Exp Cell Res
· 2026 May · PMID 41720447
·
Publisher ↗
Secondary spinal cord injury (SCI) is characterized by sustained neuroinflammation and microglial activation. Agarotetrol (AH1), a principal bioactive component of agarwood, has demonstrated neuroprotective potential, ye...Secondary spinal cord injury (SCI) is characterized by sustained neuroinflammation and microglial activation. Agarotetrol (AH1), a principal bioactive component of agarwood, has demonstrated neuroprotective potential, yet its precise mechanism in SCI remains incompletely understood. A rat SCI model was established using vascular clip compression. AH1 was administered orally for 28 days. Behavioral tests, histology, immunofluorescence, Western blot, and ELISA were used to evaluate functional recovery, neuroinflammation, and microglial activation. In vitro, BV-2 cells were treated with AH1 and LPS to assess inflammatory responses and PPARγ involvement. AH1 treatment significantly improved motor function, reduced neuronal loss, and suppressed pro-inflammatory cytokine levels in SCI rats. In vitro, AH1 inhibited LPS-induced microglial activation and cytokine release. Mechanistically, AH1 directly bound to the PPARγ ligand-binding domain, enhanced PPARγ/PGC-1α/SRC-1 interaction, and promoted anti-inflammatory transcription. PPARγ knockdown abolished AH1's effects both in vivo and in vitro. AH1 attenuates neuroinflammation and promotes functional recovery after SCI by targeting PPARγ to modulate microglial polarization. These findings highlight AH1 as a potential therapeutic agent for SCI.
PURPOSE: To investigate whether the combination of KPT-8602 and interferon-γ (IFN-γ) can inhibit the progression of primary central nervous system lymphoma (PCNSL) by activating ZBP1-mediated PANoptosis. METHODS: Human l...PURPOSE: To investigate whether the combination of KPT-8602 and interferon-γ (IFN-γ) can inhibit the progression of primary central nervous system lymphoma (PCNSL) by activating ZBP1-mediated PANoptosis. METHODS: Human lymphoma cell lines including Raji (Burkitt's lymphoma) and U-2932 (Diffuse large B-cell lymphoma, DLBCL) were employed. The synergistic induction of PANoptosis by KPT-8602 and IFN-γ was evaluated using CCK8 assay, flow cytometry, YO-PRO/PI staining, and Western blot analysis. A mouse model of PCNSL was established through stereotaxic brain implantation. The efficacy and molecular mechanisms of the combined therapy were evaluated using HE staining, TUNEL staining, ELISA, multiplex immunofluorescence, and Western blot analysis. RESULTS: The combination therapy of KPT-8602 and IFN-γ exhibited synergistic inhibitory effects on lymphoma cell growth (CI < 1). The combination therapy group significantly enhanced apoptosis and PANoptosis, as well as upregulated the mRNA levels of PANoptosis-related inflammatory factors (IL-18, IL-1β) and the expression of PANoptosis-associated proteins. In the nude mouse model, the tumor volume was significantly smaller in the combination therapy group compared to the single-drug group. Additionally, there was a notable increase of TUNEL staining positivity in tumor tissue and elevated levels of the inflammatory factors IL-6 and CXCL13 in the cerebrospinal fluid. The Western blot analysis of tumor tissue was consistent with in vitro experiments, demonstrating significant activation of the PANoptosis pathway. CONCLUSIONS: The combination of KPT-8602 and IFN-γ can activate the pan-apoptotic pathway by upregulating ZBP1, thereby effectively inhibiting the growth of PCNSL. This study presented a promising new combination treatment strategy for PCNSL.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need to clarify its molecular drivers. Here, we identify DSN1 as a key promoter of CRC invasion and metastasis. Anal...Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need to clarify its molecular drivers. Here, we identify DSN1 as a key promoter of CRC invasion and metastasis. Analysis of clinical samples and public datasets revealed that DSN1 is significantly upregulated in CRC tissues and associated with poor overall survival. Functional assays demonstrated that DSN1 knockdown markedly suppressed CRC cell migration and invasion in vitro and reduced metastases in vivo. Mechanistically, DSN1 knockdown accelerated c-MYC protein degradation without affecting its mRNA levels. Cycloheximide chase and proteasome inhibition assays confirmed that DSN1 stabilizes c-MYC by preventing its ubiquitin-proteasome-mediated degradation. We further identified FZR1 as a c-MYC targeting E3 ligase and showed that DSN1 competes with c-MYC for FZR1 binding, thereby attenuating c-MYC ubiquitination. Rescue experiments confirmed that c-MYC overexpression reversed the anti-metastatic effects of DSN1 silencing. Collectively, our findings uncover a DSN1-FZR1-c-MYC regulatory axis that sustains c-MYC stability and drives CRC progression, highlighting DSN1 as a potential therapeutic target.
Renal fibrosis is a key pathological process in the progression of chronic kidney disease to end-stage renal disease. However, its underlying mechanisms remain unclear, and there is a lack of effective, early, non-invasi...Renal fibrosis is a key pathological process in the progression of chronic kidney disease to end-stage renal disease. However, its underlying mechanisms remain unclear, and there is a lack of effective, early, non-invasive diagnostic markers and specific therapeutic targets. In this study, we constructed a cross-species, multi-model research system to systematically analyze the dynamic expression characteristics of miR-30e-5p and its molecular regulatory mechanism in the different pathological stages of renal fibrosis. We also assessed its clinical translational value. Additionally, the study examined the expression of miR-30e-5p in organs affected by fibrosis. The following was found: 1) miR-30e-5p exhibited distinct expression patterns across injury and fibrosis models. Its expression was upregulated in acute kidney injury but significantly downregulated in various cellular and animal models of renal fibrosis, showing a negative correlation with fibrosis severity. 2) Mechanistic studies indicated that miR-30e-5p inhibits epithelial-mesenchymal transition by targeting Vimentin, thereby attenuating renal fibrosis. 3) Administration of miR-30e-5p agomir ameliorated renal fibrosis in vivo, suggesting its potential as a therapeutic target. 4) In different drug intervention models, the expression level of miR-30e-5p significantly increased after renal fibrosis remission. 5) In different mechanistically induced mouse models of renal fibrosis, the changes in expression of miR-30e-5p in blood, urine, and renal tissues were consistent and significantly decreased. Following pharmacological treatment and agonist intervention, the expression of miR-30e-5p was significantly increased in these body fluids and tissues. This result was also validated in the blood and urine of patients with renal fibrosis. 6) In models of pulmonary, hepatic and myocardial fibrosis, miR-30e-5p expression was significantly down-regulated in tissues and blood, while it was significantly up-regulated in urine. Our results demonstrate that miR-30e-5p attenuates renal fibrosis by targeting Vimentin and may serve as a candidate biomarker for diagnosis and non-invasive monitoring. Its conserved dysregulation in multiple organs also suggests a broader role in fibrotic diseases.
Non-POU domain containing octamer binding protein (NONO) is a multifunctional nuclear protein which plays important roles in regulating nuclear processes such as transcription and splicing. However, the role of NONO play...Non-POU domain containing octamer binding protein (NONO) is a multifunctional nuclear protein which plays important roles in regulating nuclear processes such as transcription and splicing. However, the role of NONO played in regulating airway smooth muscle (ASM) contraction remains largely unknown. In this study, we aimed to delineate the effects and the underlying mechanisms of NONO on ASM contraction. By deploying NONO gene knockout (NONO K.O.) mice, we examined tracheal contractility using a mechanical recording system. The expression of PDE4 was quantified by real-time PCR, the contents of IP, calmodulin, cAMP, myosin light chain kinase (MLCK) and phosphorylated MLC (p-MLC) were determined through ELISA. The results showed a significant decline of ASM contractility in NONO K.O. mice compared with wild type (W.T.), PDE inhibitor IBMX and PDE4 inhibitor rolipram largely attenuated the decreased ASM contraction of NONO K.O. mice. PDE4A-C mRNA expression were up-regulated while basal level of cAMP, calmodulin and IP declined in NONO K.O. mice. Furthermore, two important components of the contractile apparatus, MLCK and p-MLC, were also decreased after carbachol (CCh) stimulation. These data demonstrated that NONO was capable of regulating ASM contraction through, at least partially, PDE4/cAMP signaling pathways and provided a novel regulatory target of ASM contractility.
Enzalutamide resistance remains a critical obstacle in the treatment of castration-resistant prostate cancer (CRPC), with potassium calcium-activated channel subfamily N member 4 (KCNN4) emerging as a key mediator of the...Enzalutamide resistance remains a critical obstacle in the treatment of castration-resistant prostate cancer (CRPC), with potassium calcium-activated channel subfamily N member 4 (KCNN4) emerging as a key mediator of therapeutic failure. Here, we demonstrate that KCNN4 is significantly upregulated in enzalutamide-resistant PCa cells and clinical tissues, correlating with poor prognosis. Mechanistically, p300, a histone acetyltransferase, directly binds to KCNN4 and mediates its acetylation at lysine 16, which competitively inhibits ubiquitination-mediated degradation, thereby stabilizing KCNN4 protein. Notably, p300 inhibition disrupts KCNN4 acetylation, restores its proteasomal degradation, and resensitizes resistant cells to enzalutamide both in vitro and in vivo. Moreover, KCNN4 knockdown suppresses tumor growth and synergizes with enzalutamide in xenograft models, underscoring the therapeutic potential of targeting the p300-KCNN4 axis. Collectively, our findings reveal a previously unrecognized epigenetic regulatory mechanism coupling p300-mediated acetylation to potassium channel stability, providing a promising therapeutic strategy to overcome chemoresistance in advanced prostate cancer.
Glioma represents the most aggressive form of primary brain tumor, characterized by restricted therapeutic strategies and unfavorable survival rates. Accumulating studies indicate that ferroptosis is critically involved...Glioma represents the most aggressive form of primary brain tumor, characterized by restricted therapeutic strategies and unfavorable survival rates. Accumulating studies indicate that ferroptosis is critically involved in the advancement of glioma. Although cold-inducible RNA-binding protein (CIRP), an RNA chaperone protein, upregulated in various malignancies, has not been thoroughly investigated in glioma. This research revealed that CIRP is a significantly upregulated gene in glioma patients, with high expression correlating with worse prognosis. Through functional experiments, we demonstrated that CIRP enhances proliferative, migratory, and invasive capacities of glioma cells. Notably, we discovered that CIRP enhanced GBM cell resistance to ferroptosis, as evidenced by reduced intracellular iron levels, decreased lipid peroxidation, and elevated antioxidant capacity. Mechanistic studies revealed that CIRP facilitated the interaction between the E3 ubiquitin ligase UBR5 and ACSL4, leading to increased ubiquitination and subsequent proteasomal degradation of ACSL4. In summary, our findings indicate that CIRP advances glioma progression via inhibiting ferroptosis through the promotion of UBR5-mediated ACSL4 degradation.
BACKGROUND: Metabolic reprogramming is a hallmark of cancer and offers promising therapeutic targets. Disrupting core metabolic pathways may impair energy supply and biosynthetic processes in tumor cells, providing new s...BACKGROUND: Metabolic reprogramming is a hallmark of cancer and offers promising therapeutic targets. Disrupting core metabolic pathways may impair energy supply and biosynthetic processes in tumor cells, providing new strategic insights for colorectal cancer (CRC) treatment. METHODS: We integrated metabolism-associated genes and applied LASSO regression to identify core prognostic genes. A metabolic risk model was developed and validated using public datasets. Analyses included survival, functional enrichment, immune infiltration, and drug sensitivity. Lentivirus-mediated DLAT overexpression was used for in vitro validation to assess migration, invasion, proliferation, drug response, cell cycle, and apoptosis. RESULTS: The risk model stratified CRC patients into high- and low-risk groups, with significantly worse overall survival in the high-risk group. Functional analysis revealed enrichment in cell cycle, immune response, inflammation, and metabolic pathways. The high-risk group showed reduced infiltration of B cells, T cells, NK cells, and dendritic cells. Drug-sensitivity analysis indicated higher IC50 values for chemotherapy and targeted agents in high-risk patients, suggesting broad resistance. In vitro, DLAT overexpression suppressed migration, invasion, and proliferation, enhanced chemosensitivity, induced cell cycle arrest, and promoted apoptosis. CONCLUSIONS: DLAT plays a critical role in CRC progression and treatment response, demonstrating potential as a prognostic biomarker and therapeutic target.
Volatile anesthetics that reversibly render humans immobile and unconscious have analogous reversible effects on the motility of non-neural organisms including plants and single cells. The molecular mechanisms by which t...Volatile anesthetics that reversibly render humans immobile and unconscious have analogous reversible effects on the motility of non-neural organisms including plants and single cells. The molecular mechanisms by which they do this remain unclear, but are difficult to study in mammals because of complex interactions among diverse tissues and cell types. Here we use freely available software to study cell swimming speeds in the single-celled ciliate species Tetrahymena pyriformis. We first extend previous findings with other volatile anesthetics, to show that isoflurane also reversibly slows swimming speed in Tetrahymena. We then show that prior exposure to the microtubule (MT) stabilizing drug epothilone B (10 nM) confers resistance to isoflurane's anesthetic effect on swimming speed. This result suggests that isoflurane slows swimming in part by interacting with MTs. This conclusion is consistent with our previous experiments supporting that binding to MTs contributes to isoflurane-induced unconsciousness in rats and mice. Our present results are thus consistent with the hypothesis that all ciliates are sensitive to volatile anesthetics, and support conserved molecular mechanisms of anesthetic action in single-celled organisms and mammals. Moreover, our preparation enables inexpensive high-throughput testing of the functional roles played by specific candidate molecular targets of volatile anesthetics in ciliates.
BACKGROUND: Tendon-bone healing refers to the repair process at the tendon-bone interface following injury, during which the osteogenic differentiation of tendon stem cells (TSCs) plays a critical role. The present resea...BACKGROUND: Tendon-bone healing refers to the repair process at the tendon-bone interface following injury, during which the osteogenic differentiation of tendon stem cells (TSCs) plays a critical role. The present research aims to elucidate the role of ADAM8 in regulating the osteogenic differentiation of rat TSCs. METHODS: Rat TSCs were isolated and cultured. ADAM8 overexpression plasmids were constructed to transfect rat TSCs. Cell viability, apoptosis, osteogenic differentiation, and Runx2/OCN mRNA expression were assessed using the CCK-8 assay, flow cytometry, Alizarin Red staining, and quantitative real-time PCR, respectively. Protein expression of Runx2, OCN, as well as the phosphorylation levels of PI3K and Akt were detected using Western blot. RESULTS: ADAM8 overexpression led to inhibited TSC viability and increased apoptosis. Simultaneously, ADAM8 overexpression also inhibited the osteogenic differentiation capacity of TSCs, evidenced by reduced ALP activity, fewer mineralized nodules, and decreased the expression of the osteogenesis-related genes Runx2 and OCN. Further mechanistic studies demonstrated that ADAM8 overexpression significantly inhibited the phosphorylation levels of PI3K and AKT after osteogenic induction, but these changes were reversed by adding the PI3K agonist 740Y-P. Additionally, 740Y-P was also able to rescue the inhibitory effects of ADAM8 overexpression on TSC proliferation and osteogenic differentiation. CONCLUSION: ADAM8 regulates the proliferation and osteogenic differentiation of rat TSCs through the PI3K/AKT signaling.
Successful wound healing requires remodeling of the extracellular matrix and efficient cell proliferation and migration. In recent years, antimicrobial peptides such as the marine-derived epinecidin-1 (Epi-1) have gained...Successful wound healing requires remodeling of the extracellular matrix and efficient cell proliferation and migration. In recent years, antimicrobial peptides such as the marine-derived epinecidin-1 (Epi-1) have gained attention for their potential contributions in tissue regeneration in addition to their antimicrobial properties. This study investigated the proliferative and regenerative effects of Epi-1 on the A375 cell line, an in vitro human skin model, and explored the underlying mechanisms by which Epi-1 promotes wound healing. We hypothesized that Epi-1 would enhance cell migration and proliferation through the upregulation of vimentin (VIM) and nuclear factor kappa b-1 (NFκB1), genes encoding for proteins and signaling molecules involved in cell motility and cytoskeletal reorganization. We determined that an optimal dose for Epi-1 treatment, 50 μg/ml, increased cell viability, proliferation, and horizontal and vertical migration. Moreover, RT-qPCR analysis revealed a significant increase in NFκB1 expression, with no change in VIM. Gelatin zymography revealed MMP2 activity remained unaffected by treatment, while MMP9 activity was significantly decreased. Taken together, these results suggest that Epi-1 promotes migration through NFκB-linked, non-proteolytic mechanisms in human skin cells. These findings highlight the novel regenerative potential of Epi-1 and support its future development as an alternative to traditional antibiotic therapies in wound healing.
BACKGROUND: Atherosclerotic lesions commonly develop in curved or bifurcated arteries, where blood flow exhibits characteristics of low shear stress (LSS). Subjected to LSS continually, endothelial cells (ECs) adopt a pr...BACKGROUND: Atherosclerotic lesions commonly develop in curved or bifurcated arteries, where blood flow exhibits characteristics of low shear stress (LSS). Subjected to LSS continually, endothelial cells (ECs) adopt a pro-atherosclerotic phenotype. Ferroptosis is a recently identified form of controlled cell demise prompted by iron-dependent buildup of cellular reactive oxygen species (ROS), which has been associated with diverse cardiovascular diseases, particularly atherosclerosis (AS). P53 is a broadly acting tumor suppressor that can be activated by diverse stimuli and mediates multiple biological outcomes, including cell cycle arrest, DNA repair, apoptosis, and ferroptosis. However, it remains unknown whether LSS promotes the development of AS by inducing P53-dependent ferroptosis in endothelial cells. METHODS: In our experiments, we induced LSS by partial ligation of the right common carotid artery in high-fat diet-fed (HFD) male ApoE mice. The application of LSS applied on human umbilical vein endothelial cells (HUVECs) in vitro was through a parallel plate flow chamber configuration. RESULTS: Our findings demonstrated that LSS induced endothelial ferroptosis, which in turn accelerated AS development both in vivo and in vitro. This effect was partially counteracted by both the ferroptosis inhibitor Fer-1 and endothelium-specific glutathione peroxidase 4 (GPX4) overexpression in ApoE mice. Mechanistically, LSS was found to promote ferroptosis by driving the upregulation and nuclear translocation of P53 in HUVECs, which transcriptionally repressed xCT. Conversely, silencing or inhibiting P53 mitigated LSS-induced ferroptosis. These findings were corroborated in vivo, where endothelial-specific P53 knockout or inhibition effectively suppressed atherosclerotic plaque formation in mice. CONCLUSIONS: Our experiments suggested that LSS promotes atherosclerosis by inducing endothelial ferroptosis through the P53/xCT signaling pathway.
Neuroblastoma (NB) is a prevalent pediatric tumor, accounting for over 15% of cancer-related fatalities in children. Super-enhancers (SEs), as pivotal cis-regulatory elements known for driving oncogene expression across...Neuroblastoma (NB) is a prevalent pediatric tumor, accounting for over 15% of cancer-related fatalities in children. Super-enhancers (SEs), as pivotal cis-regulatory elements known for driving oncogene expression across various tumors, may serve as an innovative strategy for deciphering NB pathogenesis. Here, we meticulously analyzed epigenomic and transcriptomic data to delineate the distinct SE landscape in NB. Our study identified a NB-specific and NB-common SE at the MAB21L2 locus. Functional analyses further underlined MAB21L2's oncogenic role in NB, linking its high expression to poor patient outcomes. MAB21L2 knockdown strikingly inhibited the growth of NB tumor cells in vitro and reduced their proliferation in vivo. Notably, through RNA-seq analysis and experimental verification, we demonstrated that MAB21L2 substantially enhanced the migratory capacity of NB cells. Collectively, these findings underscore the indispensable role of the super-enhancer-MAB21L2 axis in the pathogenesis of NB and provide mechanistic insights into NB progression.
Graphene nanoparticles are increasingly used in materials manufacturing, pollutant treatment, energy storage, and electronic devices, and the potential risk of occupational and environmental exposure is a concern. The me...Graphene nanoparticles are increasingly used in materials manufacturing, pollutant treatment, energy storage, and electronic devices, and the potential risk of occupational and environmental exposure is a concern. The mechanisms of lung fibrosis induced by nano-graphene with different properties are complex. In addition, multiple modes of programmed cell death (PCD) occur during lung fibrosis, and whether cuproptosis and autophagy exert regulatory effects during the progression of lung fibrosis induced by nano-graphene remains undocumented. In this study, we constructed mouse models with varying doses of graphene and exposure durations. We observed the dynamics of pathological changes in lung histology and the time-series expression of biomarkers. We discovered that graphene could deposit in lung tissue, leading to the pathological manifestations of pulmonary fibrosis; this was coincident with elevated copper ion concentration, cellular cuproptosis, and excessive autophagy. In short, our results may contribute to further elucidation of the potential respiratory toxic effects and mechanisms of graphene, and to the early development of targeted preventive and control measures by providing new ideas and reference points.
Proliferative diabetic retinopathy (PDR) is characterized by pathological angiogenesis and endothelial dysfunction driven by hyperglycemia. Ribosome biogenesis plays a crucial role in endothelial proliferation, yet its i...Proliferative diabetic retinopathy (PDR) is characterized by pathological angiogenesis and endothelial dysfunction driven by hyperglycemia. Ribosome biogenesis plays a crucial role in endothelial proliferation, yet its involvement in PDR remains unexplored. This study investigates the role of NOP14, a key regulator of ribosome biogenesis, in PDR progression and its interplay with Wnt/β-catenin signaling. NOP14 expression was elevated in PDR models and HG-treated human retinal endothelial cells (HRECs). Knockdown of NOP14 ameliorated retinal damage in PDR mice, decreased angiogenesis-related proteins (CD31, VEGFA, PDGF, ANG2). In vitro, NOP14 knockdown suppressed HG-induced endothelial proliferation, DNA synthesis, mitochondrial activity, and tube formation, accompanied by reduced ribosome biogenesis and promoted cell apoptosis. While overexpression of NOP14 exhibited the opposite effect to NOP14 knockdown on HG-induced HRECs. Mechanistically, NOP14 activated Wnt/β-catenin signaling, as evidenced by increased p-GSK-3β, β-catenin and Cyclin D1 levels and Wnt/β-catenin activity. Activation of Wnt/β-catenin signaling partially rescued the effects of NOP14 knockdown on endothelial dysfunction and ribosome biogenesis. NOP14 promotes PDR progression by driving ribosome biogenesis and endothelial dysfunction through Wnt/β-catenin signaling activation. Targeting the NOP14/Wnt/β-catenin axis offers a promising therapeutic strategy for mitigating pathological angiogenesis in PDR.