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Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of the RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we find that two structurally similar substrate-recognizing components of Cullin-RING E3 ligases, WSB1 and WSB2, can recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. We showed that WSB1/2 negatively regulated a subset of NF-κB target genes via associating with chromatin where they targeted methylated RelA for ubiquitination, facilitating the termination of NF-κB-dependent transcription. WSB1/2 specifically interacted with methylated lysines (K) 314 and 315 of RelA via their N-terminal WD-40 repeat (WDR) domains, thereby promoting ubiquitination of RelA. Computational modeling further revealed that a conserved aspartic acid (D) at position 158 within the WDR domain of WSB2 coordinates K314/K315 of RelA, with a higher affinity when either of the lysines is methylated. Mutation of D158 abolished WSB2's ability to bind to and promote ubiquitination of methylated RelA. Together, our study identifies a novel function and the underlying mechanism for WSB1/2 in degrading chromatin-bound methylated RelA and preventing sustained NF-κB activation, providing potential new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.
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Cromatina , Complexo de Endopeptidases do Proteassoma , Fator de Transcrição RelA , Ubiquitinação , Humanos , Cromatina/metabolismo , Células HEK293 , Lisina/metabolismo , Metilação , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteólise , Fator de Transcrição RelA/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
PURPOSE: This study compares the results of Artificial Intelligence (AI) diagnosis of rib fractures using initial CT and follow-up CT as the final diagnostic criteria, and studies AI-assisted diagnosis in improving the detection rate of rib fractures. METHODS: A retrospective study was conducted on 113 patients who underwent initial and follow-up CT scans due to trauma. The initial and follow-up CT were used as diagnostic criteria, respectively. All images were transmitted to the AI software (V2.1.0, Huiying Medical Technology Co., Beijing, China) for rib fracture detection. The radiologist group (Group 1), AI group (Group 2), and Radiologist with AI group (Group 3) reviewed CT images at an interval of one month, recorded and compared the differences in the sensitivity and specificity for diagnosing rib fractures. RESULTS: 589 and 712 rib fractures were diagnosed by the initial and follow-up CT, respectively. The initial CT diagnosis failed to detect 127 rib fractures, resulting in a missed rate of 17.84%. In addition, four normal ribs were mistakenly identified as being fractured. The follow-up CT was regarded as the diagnostic standard for rib fractures. The sensitivity and specificity were 82.16% and 99.80% for Group 1, 79.35% and 84.90% for Group 2, and 91.57% and 99.70% for Group 3. The sensitivity of Group 3 was higher than that of Group 1 and Group 2 (p < 0.05). The specificity was lower for Group 2 compared with Group 1 and Group 3 (p < 0.05). CONCLUSION: AI-assisted diagnosis improved the detection rate of rib fractures, the follow-up CT should be used for the diagnosis standard of rib fractures, and AI misdiagnoses can be greatly reduced when a radiologist reviews the diagnosis.
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Fraturas das Costelas , Humanos , Fraturas das Costelas/diagnóstico por imagem , Inteligência Artificial , Estudos Retrospectivos , Seguimentos , Tomografia Computadorizada por Raios X/métodos , Sensibilidade e EspecificidadeRESUMO
On account of incurable castration-resistant prostate cancer (CRPC) inevitably developing after treating with androgen deprivation therapy, it is an urgent need to find new therapeutic strategies. Flubendazole is a well-known anti-malarial drug that is recently reported to be a potential anti-tumor agent in various types of human cancer cells. However, whether flubendazole could inhibit the castration-resistant prostate cancer has not been well charified. Thus, the aim of the present study was to characterize the precise mechanism of action of flubendazole on the CRPC. In this study, we investigated the potential effect of flubendazole on cell proliferation, cell cycle and cell death in CRPC cells (PC3 and DU145). We found that flubendazole inhibited cell proliferation, caused cell cycle arrest in G2/M phase and promoted cell death in vitro, and suppressed growth of CRPC tumor in xenograft models. In addition, we reported that flubendazole induced the expression of P53, which partly accounted for the G2/M phase arrest and led to inhibition of the transcription of SLC7A11, and then downregulated the GPX4, which is a major ferroptosis-related gene. Furthermore, flubendazole exhibited synergistic effect with 5-fluorouracil (5-Fu) in chemotherapy of CRPC. This study provides biological evidence that flubendazole is a novel P53 inducer which exerts anti-proliferation and pro-apoptosis effects in CRPC through hindering the cell cycle and activating the ferroptosis, and indicates that a novel utilization of flubendazole in neoadjuvant chemotherapy of CRPC.
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Anti-Helmínticos/uso terapêutico , Antineoplásicos/uso terapêutico , Ferroptose/efeitos dos fármacos , Mebendazol/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Anti-Helmínticos/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Camundongos Nus , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
The integration of multiple functions with organic polymers-based nanoagent holds great potential to potentiate its therapeutic efficacy, but still remains challenges. In the present study, we design and prepare an organic nanoagent with oxygen-evolved and targeted ability for improved phototherapeutic efficacy. The iron ions doped poly diaminopyridine (FeD) is prepared by oxidize polymerization and modified with hyaluronic acid (HA). The obtained FeDH appears uniform morphology and size. Its excellent colloidal stability and biocompatibility are demonstrated. Specifically, the FeDH exhibits catalase-like activity in the presence of hydrogen peroxide. After loading of photosensitizer indocyanine green (ICG), the ICG@FeDH not only demonstrates favorable photothermal effect, but also shows improved generation ability of reactive oxygen species (ROS) under near-infrared laser irradiation. Moreover, the targeted uptake of ICG@FeDH in tumor cells is directly observed. As consequence, the superior phototherapeutic efficacy of the targeted ICG@FeDH over non-targeted counterparts is also confirmed in vitro and in vivo. Hence, the results demonstrate that the developed nanoagent rationally integrates the targeted ability, oxygen-evolved capacity and combined therapy in one system, offering a new paradigm of polymer-based nanomedicine for tumor therapy.
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Ácido Hialurônico/farmacologia , Oxigênio/farmacologia , Fototerapia/métodos , Polímeros/farmacologia , Animais , Humanos , Verde de Indocianina , Raios Infravermelhos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular , Células PC-3 , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Purpose: To explore the clinical and imaging features of rare site Kimura's disease (KD). Methods: Retrospective analysis was conducted on the clinical manifestations, laboratory examinations, and imaging features of five patients with rare site KD. All imaging data, including the location, quantity, size, uniformity, boundary, and enhanced appearance of the lesion were evaluated by two independent radiologists. Results: Of the five patients, four were asymptomatic, and one experienced localized skin itching. Four cases involved subcutaneous nodules in the upper arm, while one was in the inguinal region. The main manifestations were single (three cases) or multiple (two cases) subcutaneous nodules/masses, with three patients accompanied by local lymph node enlargement. Four patients exhibited elevated eosinophil counts in their peripheral blood. Four patients had lesions with vascular flow voids; in three of these, the lesions also showed prominent enhancement. Notably, the lesion in a 5-year-old did not show vascular flow voids but displayed significant enhancement. Additionally, two patients showed edema around the lesions. Conclusion: The presence of solitary or multiple subcutaneous nodules/masses in the upper arm or inguinal area, accompanied by lymph node enlargement, elevated eosinophils in the peripheral blood, and the observation of internal vascular within the lesion, can aid in the diagnosis of KD occurring in uncommon anatomical locations.
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Microplastics (MPs) exists widely in the environment, and the resulting pollution of MPs has become a global environmental problem. Plants can absorb MPs through their roots. However, studies on the mechanism of the effect of root exposure to different size MPs on vegetables are limited. Here, we use Polystyrene (PS) MPs with different particle sizes to investigate the internalization, physiological response and molecular mechanism of lettuce to MPs. MPs may accumulate in large amounts in lettuce roots and migrate to the aboveground part through the vascular bundle, while small particle size MPs (SMPs, 100 nm) have stronger translocation ability than large particle size MPs (LMPs, 500 nm). MPs can cause physiological and biochemical responses and transcriptome changes in lettuce. SMPs and LMPs resulted in reduced biomass (38.27 % and 48.22 % reduction in fresh weight); caused oxidative stress (59.33 % and 47.74 % upregulation of SOD activity in roots) and differential gene expression (605 and 907 DEGs). Signal transduction, membrane transport and alteration of synthetic and metabolic pathways may be the main causes of physiological toxicity of lettuce. Our study provides important information for understanding the behavior and fate of MPs in edible vegetables, especially the physiological toxicity of MPs to edible vegetables, in order to assess the potential threat of MPs to food safety and agricultural sustainable development.
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Microplásticos , Poliestirenos , Poliestirenos/toxicidade , Microplásticos/toxicidade , Plásticos/toxicidade , Lactuca , Estresse Oxidativo , VerdurasRESUMO
The carotid web is commonly found in the carotid bulb or the beginning of the internal carotid artery. It presents as a thin layer of proliferative intimal tissue originating from the arterial wall and extending into the vessel lumen. A large body of research has proven that the carotid web is a risk factor for ischemic stroke. This review summarizes the current research status of the carotid web and focuses on its imaging presentation.
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Tumor-derived exosomes and their contents promote cancer metastasis. Phosphoglycerate mutase 1 (PGAM1) is involved in various cancer-related processes. Nevertheless, the underlying mechanism of exosomal PGAM1 in prostate cancer (PCa) metastasis remains unclear. In this study, we performed in vitro and in vivo to determine the functions of exosomal PGAM1 in the angiogenesis of patients with metastatic PCa. We performed Glutathione-S-transferase pulldown, co-immunoprecipitation, western blotting and gelatin degradation assays to determine the pathway mediating the effect of exosomal PGAM1 in PCa. Our results revealed a significant increase in exosomal PGAM1 levels in the plasma of patients with metastatic PCa compared to patients with non-metastatic PCa. Furthermore, PGAM1 was a key factor initiating PCa cell metastasis by promoting invadopodia formation and could be conveyed by exosomes from PCa cells to human umbilical vein endothelial cells (HUVECs). In addition, exosomal PGAM1 could bind to γ-actin (ACTG1), which promotes podosome formation and neovascular sprouting in HUVECs. In vivo results revealed exosomal PGAM1 enhanced lung metastasis in nude mice injected with PCa cells via the tail vein. In summary, exosomal PGAM1 promotes angiogenesis and could be used as a liquid biopsy marker for PCa metastasis.
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Exossomos , MicroRNAs , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Actinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células Endoteliais/metabolismo , Exossomos/metabolismo , Camundongos Nus , MicroRNAs/metabolismo , Metástase Neoplásica/patologia , Fosfoglicerato Mutase/genética , Fosfoglicerato Mutase/metabolismo , Neoplasias da Próstata/patologiaRESUMO
Proliferating trichilemmal tumor is a very rare benign tumor that has the potential to transition into a malignant tumor. PTT most commonly affects the scalps of women above 60 years old and is frequently misdiagnosed due to its rarity. Herein, we present a case of a 68-year-old man with a malignant proliferating trichilemmal tumor on his right thumb. X-ray image showed a soft tissue mass on his thumb accompanied by bone destruction, while 18F-FDG PET revealed a hypermetabolic mass in the first index with axillary lymph node metastasis.
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The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.
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Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.
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The interaction between LncRNA and RNA-binding protein (RBPs) plays an essential role in the regulation over the malignant progression of tumors. Previous studies on the mechanism of SNHG1, an emerging lncRNA, have primarily focused on the competing endogenous RNA (ceRNA) mechanism. Nevertheless, the underlying mechanism between SNHG1 and RBPs in tumors remains to be explored, especially in prostate cancer (PCa). SNHG1 expression profiles in PCa were determined through the analysis of TCGA data and tissue microarray at the RNA level. Gain- and loss-of-function experiments were performed to investigate the biological role of SNHG1 in PCa initiation and progression. RNA-seq, immunoblotting, RNA pull-down and RNA immunoprecipitation analyses were utilized to clarify potential pathways with which SNHG1 might be involved. Finally, rescue experiments were carried out to further confirm this mechanism. We found that SNHG1 was dominantly expressed in the nuclei of PCa cells and significantly upregulated in PCa patients. The higher expression level of SNHG1 was dramatically correlated with tumor metastasis and patient survival. Functionally, overexpression of SNHG1 in PCa cells induced epithelial-mesenchymal transition (EMT), accompanied by down-regulation of the epithelial marker, E-cadherin, and up-regulation of the mesenchymal marker, vimentin. Increased proliferation and migration, as well as accelerated xenograft tumor growth, were observed in SNHG1-overexpressing PCa cells, while opposite effects were achieved in SNHG1-silenced cells. Mechanistically, SNHG1 competitively interacted with hnRNPL to impair the translation of protein E-cadherin, thus activating the effect of SNHG1 on the EMT pathway, eventually promoting the metastasis of PCa. Our findings demonstrate that SNHG1 is a positive regulator of EMT activation through the SNHG1-hnRNPL-CDH1 axis. SNHG1 may serve as a novel potential therapeutic target for PCa.
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Antígenos CD/metabolismo , Caderinas/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/metabolismo , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/patologiaRESUMO
The circRNAs, a new subclass of non-coding RNAs that are catalyzed by RNA-binding proteins (RBPs), have been reported to be associated with the progression of multiple types of cancer. We previously discovered that heterogeneous nuclear ribonucleoprotein L (HnRNP-L), a multi-functional RBP, is associated with pro-proliferation and anti-apoptosis activities in prostate tumor cells. In this study, we aim to establish the biological relevance of circCSPP1 (a newly discovered signature circRNA in prostate cancer [PCa]) and HnRNP-L to prostate cancer progression. First, we demonstrated that circCSPP1 expression was higher in prostate cancer tissues than in benign tissues and higher in prostate cancer cells than in benign cells. Then, the in vitro gain- and loss-of-function experiments showed that the circCSPP1 expression in prostate cancer cells was regulated by HnRNP-L, and the increased circCSPP1 significantly induced autophagy, which led to an enhanced potential in proliferation, migration, and invasion of prostate cancer cells. These results were consistent with the in vivo experiment where increased or decreased circCSPP1 was associated with higher or slower growth rate in grafted tumors. Finally, we demonstrated the potential competing endogenous RNA network, involving circCSPP1, miR-520h, and early growth response factor 1 (EGR1), in prostate cancer cells, which may play an important role in prostate cancer progression. Our study indicated that the increase in circCSPP1 in prostate cancer, which may be catalyzed by HnRNP-L, can induce cellular autophagy through the circCSPP1-miR-520h-EGR1 axis, leading to the progression of prostate tumor. This newly discovered circRNA biomarker may be used for clinical prognosis of prostate cancer as well as for development of novel therapy plans.
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BACKGROUND: CircRNAs recently have shown critical roles in tumor biology. However, their roles in prostate cancer (PCa) remains largely unclear. METHODS: CircRNA microarrays were performed in immortal prostate cell line RWPE1 and PCa cell lines as DU145, PC3, LNCaP, C4-2, and 22RV1. Combined with upregulated circRNAs in PCa tissues, circNOLC1 expression was validated in PCa cells and tissues via qRT-PCR and FISH. Sanger sequencing, actinomycin D, gDNA, and cDNA, RNase R assays were used to assess the circular characteristics of circNOLC1. CCK-8, colony formation, transwell migration assays, and mice xenograft models were conducted to evaluate the functions of PCa cells after circNOLC1 knockdown and overexpression. RNA pulldown, luciferase reporter assay, FISH (fluorescence in situ hybridization), and CHIP were utilized to illustrate the further mechanisms of circNOLC1. RESULTS: Our research indicated that circNOLC1 was overexpressed in PCa cells and tissues, and circNOLC1 was more stable than linear NOLC1 mRNA. CircNOLC1 promoted PCa cells proliferation and migration in vitro and vivo. Additionally, we found that circNOLC1 could upregulate PAQR4 expression by sponging miR-647, leading to the activation of PI3K/Akt pathway. Moreover, NF-kappaB was identified to bind to the NOLC1 promoter sites and upregulated both NOLC1 and circNOLC1 expression. CONCLUSION: CircNOLC1, elevated by transcription factor NF-kappaB, promotes PCa progression via a miR-647/PAQR4 axis, and circNOLC1 is a potential biomarker and target for PCa treatment.