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The metastasis of hepatocellular carcinoma (HCC) poses a significant threat to the survival of patients. G protein-coupled receptor 56 (GPR56) has garnered extensive attention within malignant tumor research and plays a crucial role in cellular surface signal transmission. Nonetheless, its precise function in HCC remains ambiguous. Our investigation reveals a notable rise in GPR56 expression levels in human HCC cases, with heightened GPR56 levels correlating with unfavorable prognoses. GPR56 regulates TGF-ß pathway by interacting with TGFBR1, thereby promoting HCC metastasis. At the same time, GPR56 is subject to regulation by the canonical cascade of TGF-ß signaling, thereby establishing a positive feedback loop. Furthermore, the combination application of TGFBR1 inhibitor galunisertib (GAL) and GPR56 inhibitor Dihydromunduletone (DHM), significantly inhibits HCC metastasis. Interventions towards this signaling pathway could offer a promising therapeutic approach to effectively impede the metastasis of GPR56-mediated HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Metástase Neoplásica , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores Acoplados a Proteínas G , Transdução de Sinais , Fator de Crescimento Transformador beta , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Fator de Crescimento Transformador beta/metabolismo , Animais , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Quinolinas/farmacologia , Regulação Neoplásica da Expressão Gênica , Masculino , PirazóisRESUMO
Large language models (LLMs) hold great promise in summarizing medical evidence. Most recent studies focus on the application of proprietary LLMs. Using proprietary LLMs introduces multiple risk factors, including a lack of transparency and vendor dependency. While open-source LLMs allow better transparency and customization, their performance falls short compared to the proprietary ones. In this study, we investigated to what extent fine-tuning open-source LLMs can further improve their performance. Utilizing a benchmark dataset, MedReview, consisting of 8161 pairs of systematic reviews and summaries, we fine-tuned three broadly-used, open-sourced LLMs, namely PRIMERA, LongT5, and Llama-2. Overall, the performance of open-source models was all improved after fine-tuning. The performance of fine-tuned LongT5 is close to GPT-3.5 with zero-shot settings. Furthermore, smaller fine-tuned models sometimes even demonstrated superior performance compared to larger zero-shot models. The above trends of improvement were manifested in both a human evaluation and a larger-scale GPT4-simulated evaluation.
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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Thus, it is essential to investigate potential druggable targets to improve IPF treatment outcomes. By screening a curated library of 201 small molecules, we have identified chlorquinaldol, a known antimicrobial drug, as a potential antifibrotic agent. Functional analyses have demonstrated that chlorquinaldol effectively inhibits the transition of fibroblasts to myofibroblasts in vitro and mitigates bleomycin-induced pulmonary fibrosis in mice. Using a mass spectrometry-based drug affinity responsive target stability strategy, we revealed that chlorquinaldol inhibited fibroblast activation by directly targeting methionine synthase reductase (MTRR). Decreased MTRR expression was associated with IPF patients, and its reduced expression in vitro promoted extracellular matrix deposition. Mechanistically, chlorquinaldol bound to the valine residue (Val-467) in MTRR, activating the MTRR-mediated methionine cycle. This led to increased production of methionine and s-adenosylmethionine, counteracting the fibrotic effect. In conclusion, our findings suggest that chlorquinaldol may serve as a novel antifibrotic medication, with MTRR-mediated methionine metabolism playing a critical role in IPF development. Therefore, targeting MTRR holds promise as a therapeutic strategy for pulmonary fibrosis.
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The cell death field has profited from the increasing attention of the scientific community and has been shown to lie at the very basis of cancer initiation and progression. Cuproptosis is a recently proposed method of cell death in 2022, and it is different from any previously reported method. The principle is that copper ions lead to aggregation and instability of intracellular proteins. An increasing number of researchers are dedicated to enriching the mechanism of cuproptosis and exploring its relationship with cancer. Studies have found that intracellular copper levels have an impact on the occurrence and development of lymphoma. The complexity of lymphoma and the limitations of treatment necessitate in-depth studies of the disease. We will review the mechanism of cuproptosis and its potential in lymphoma therapy.
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Objective: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis. Methods: We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci. Results: We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10-6). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10-8). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3, and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function. Conclusion: Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.
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Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively.
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BACKGROUND: The treatment of myeloid sarcoma (MS) is challenging and has not markedly improved patient prognosis. The introduction of venetoclax (VEN) has changed the treatment of MS, and venetoclax-based therapy has been described as very promising in several case reports. METHODS: In this retrospective study, we analyzed the treatment outcomes of 14 patients with MS treated with venetoclax-based therapy at The First Affiliated Hospital of Xiamen University from January 2020 to October 2023 RESULTS: The cohort consisted of 7 (50%) women and 7 (50%) men with an average age of 37.5 years. Four patients (28.6%) had isolated MS de novo, 2 (14.2%) were diagnosed synchronously with AML, and 8 (57.2%) had isolated extramedullary relapse. The most common sites for MS in our cohort were the skin and lung, followed by the spinal canal, soft tissue, bone and kidney. Five patients were affected at more than three sites. Nine patients received VEN in combination with azacytidine, and 5 patients received VEN in combination with other agents. The median number of venetoclax therapies administered was 2 cycles (range: 1-10 cycles). A response was observed in all patients included in the study, with 8 patients (57.2%) achieving a CR and 3 patients (21.4%) achieving a PR, corresponding to an ORR (including CR and PR) of 78.6%. The median follow-up time for all patients was 13 months (range 1-44 months), and the 1 year OS for all patients was 67.7%. CONCLUSIONS: Venetoclax-based therapy shows excellent efficacy and safety in MS patients in the "real world" at a single institution, and a corresponding prospective study is needed to verify this conclusion.
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Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation-specific homologous factor (EHF), a member of the E26 transformation-specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma-associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor-associated macrophages (TAMs) through the C-C motif chemokine 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co-expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF-mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2-TAMs to inhibit EHF-driven CCA development.
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Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.
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Objective: Cold-induced transient myocardial ischemia has been described in patients with systemic sclerosis. The clinical impact of cold exposure in systemic sclerosis patients with acute cardiac conditions is unknown. We compared the seasonal variation of acute cardiac hospitalizations in patients with and without systemic sclerosis. Methods: We performed a retrospective cross-sectional study using the National Inpatient Sample from 2016 to 2019. The primary outcome was acute cardiac hospitalization primarily due to heart failure, acute myocardial infarction, or cardiac arrhythmias. We compared the proportion of acute cardiac hospitalizations in each season in patients with and without systemic sclerosis. We also performed a subgroup analysis by US geographic region (Northeast, Midwest, South, West). Results: There were a total of 10,118,002 acute cardiac hospitalizations over the 4-year study period. Compared to those without systemic sclerosis, patients with systemic sclerosis who were hospitalized for acute cardiac care were younger (mean age 67 ± 13 vs 70 ± 14 years, p < 0.01), a greater proportion were female (82% vs 45%, p < 0.01), and a smaller proportion were Caucasian (68% vs 71%, p < 0.01). There was a lesser proportion of traditional cardiovascular risk factors in systemic sclerosis compared to non-systemic sclerosis patients. There was no significant difference in the proportion of winter admissions between systemic sclerosis and non-systemic sclerosis patients for total acute cardiac hospitalizations (26.4% vs 25.9%, p = 0.51), heart failure (27.0% vs 26.5%, p = 0.64), acute myocardial infarction (26.9% vs 25.5%, p = 0.50), or arrhythmias (24.3% vs 25.0%, p = 0.68). The results were consistent across all four US geographic regions. Conclusion: Our study did not support that patients with systemic sclerosis had a disproportionally higher risk of acute cardiac hospitalization in winter compared to the general population. We found that systemic sclerosis patients hospitalized for acute cardiac care had a lower burden of traditional cardiovascular risk factors than their non-systemic sclerosis counterparts.
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The use of biochar for soil improvement and emission reduction has been widely recognized for its excellent performance. However, the choice of feedstock and pyrolysis temperature for biochar production significantly affects its surface parameters and interactions with soil substances. In this study, we retrieved 465 peer-reviewed papers on the application of biochar in reducing greenhouse gas emissions and nutrient losses in soil and analyzed the changes in biochar physicochemical parameters from different feedstock and pyrolytic temperatures. Molecular simulation computing technology was also used to explore the impacts of these changes on the interaction between biochar and soil substances. The statistical results from the peer-reviewed papers indicated that biochar derived from wood-based feedstock exhibits superior physical characteristics, such as increased porosity and specific surface area. Conversely, biochar derived from straw-based feedstock was found to contain excellent element content, such as O, N, and H, and biochar derived from straw and produced at low pyrolysis temperatures contains a significant number of functional groups that enhance the charge transfer potential and adsorption stability by increasing surface charge density, charge distribution and bonding orbitals. However, it should be noted that this enhancement may also activate certain recalcitrant C compounds and promote biochar decomposition. Taken together, these results have significant implications for biochar practitioners when selecting suitable feedstock and pyrolysis temperatures based on agricultural needs and increasing their understanding of the interaction mechanism between biochar and soil substances.
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Pirólise , Solo , Solo/química , Temperatura , Teoria da Densidade Funcional , Carvão Vegetal/químicaRESUMO
Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and offer high design flexibility, excellent biocompatibility, adjustable morphology, and biodegradability, making them promising candidates for drug delivery. This paper reviews peptide-mediated drug delivery systems, focusing on self-assembled peptides and peptide-drug conjugates. It discusses the mechanisms and structural control of self-assembled peptides, the varieties and roles of peptide-drug conjugates, and strategies to augment peptide stability. The review concludes by addressing challenges and future directions.
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Currently, a significant proportion of inflammatory bowel disease (IBD) patients fail to respond to conventional drug therapy such as immunosuppressants and biologic agents. Interference with the JAK/STAT pathway and blocking of IL-1 signaling are two promising therapeutic strategies for these unresponsive IBD patients. This work describes the discovery of an inhibitor 10v that not only blocks NLRP3 and AIM-2 inflammasome-mediated IL-1ß signaling, but also reduces the expression of STAT1 and STAT5 in the JAK/STAT pathway. Importantly, 10v exhibits a significant anti-IL-1ß effect and decreases the levels of STAT1 and STAT5 in a mouse model of colitis. As a result, a novel small molecule is identified with a dual inhibitory capacity towards both inflammasomes/IL-1ß and STAT pathways, which supports further exploration of the therapeutic potential for IBD patients that do not respond to current drug therapy.
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Deterioration of neurovascular conditions can be rapid in patients with spontaneous subarachnoid haemorrhage (SAH) and often lead to poor clinical outcomes. Therefore, it is crucial to promptly assess and continually track the progression of the disease. This study incorporated baseline clinical conditions, repeatedly measured neurological grades and haematological biomarkers for dynamic outcome prediction in patients with spontaneous SAH. Neurological intervention, mainly aneurysm clipping and endovascular embolisation, was also incorporated as an intermediate event in developing a neurological intervention transition (NIT) joint model. A retrospective cohort study was performed on 701 patients in spontaneous SAH with a study period of 14 days from the MIMIC-IV dataset. A dynamic prognostic model predicting outcome of patients was developed based on combination of Cox model and piecewise linear mixed-effect models to incorporate different types of prognostic information. Clinical baseline covariates, including cerebral oedema, cerebral infarction, respiratory failure, hydrocephalus and vasospasm, as well as repeated measured Glasgow Coma Scale (GCS), glucose and white blood cell (WBC) levels were covariates contributing to the optimal model. Incorporation of neurological intervention as an intermediate event increases the prediction performance compared with baseline joint modelling approach. The average AUC of the optimal model proposed in this study is 0.7783 across different starting points of prediction and prediction intervals. The model proposed in this study can provide dynamic prognosis for spontaneous SAH patients and significant potential benefits in critical care management.
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Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/terapia , Estudos Retrospectivos , Prognóstico , Biomarcadores , Escala de Coma de Glasgow , Resultado do TratamentoRESUMO
ABCC1 belongs to the ATP-binding cassette (ABC) superfamily, which encompasses a total of 48 constituent members. ABCC1 has been shown to be associated with the growth, progression, and drug resistance of various types of cancer. However, the impact of ABCC1 on cancer immune infiltration and pan-cancer prognosis has been rarely studied. Our comprehensive pan-cancer analysis unveiled elevated ABCC1 expression across various cancers. ABCC1 overexpression consistently predicted unfavorable outcomes based on TCGA data. Moreover, ABCC1 expression exhibited intricate associations with diverse immune-related genes and demonstrated a close correlation with immune scores across multiple tumor types. Analysis of scRNA-seq data from the GEO database revealed that the expression of ABCC1 in hepatocellular carcinoma (HCC) cells is significant positively correlated with macrophage infiltration. Furthermore, various in vitro and in vivo experiments substantiated the role of ABCC1 in promoting the progression of HCC, along with increased macrophage recruitment. Based on the results, we propose ABCC1 as a potentially valuable prognostic indicator and a prospective target for immune-based cancer therapies.
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OBJECTIVE: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP. METHODS: We performed a case-control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth's logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA. RESULTS: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10-7). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p<0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB, RELA and REL using higher criticism test weighted by eigenvector centrality. CONCLUSIONS: This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments.
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Variação Genética , Policondrite Recidivante , Humanos , Predisposição Genética para Doença , Sequenciamento do Exoma , Policondrite Recidivante/genética , Exoma/genéticaRESUMO
OBJECTIVE: Ruxolitinib was recently approved to treat corticosteroid-resistant acute graft-versus-host disease (GvHD). However, it is unknown as to whether starting ruxolitinib at a lower versus higher acute GvHD grade or earlier versus later affected outcomes. This study identified the impact of starting acute GvHD grade and start time after declaring corticosteroid resistance and the effect on complete and overall response rates to ruxolitinib therapy. METHODS: Retrospective, observational multi-center study. We divided cohorts into starting ruxolitinib ≤ 7 days (N = 45) versus at > 7 days after declaring corticosteroid resistance (N = 24). RESULTS: In ≤ 7 days cohort complete response (CR) rates at day 28 were 69% (54, 81%) versus 25% (11, 47%; p = .001) in > 7 days cohort, and overall response (OR) rates were 91% (78, 96%) versus 80% (48, 92%; p = .25). CONCLUSIONS: Our data suggest that starting ruxolitinib in ≤ 7 days of declaring corticosteroid failure regardless of G vHD grade improves complete response rate but not OR rates. Starting ruxolitinib at grade I and within 7 days may get a more significant response.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Nitrilas , Pirazóis , Pirimidinas , Humanos , Estudos Retrospectivos , Corticosteroides/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologiaRESUMO
To investigate the conversion of carbon and nitrogen organic matter to humus mediated by mineral material additives through biotic and abiotic pathways, three chicken manure composting experiments were conducted using calcium superphosphate (CS) and fly ash (FA). Results showed that CS and FA promoted carbon and nitrogen organic degradation and improved compost maturity. The ratio of humic acid-like to fulvic acid-like substances for FA (30) was significantly higher than for control (18) and CS (13). Excitation-emission-matrix spectra and parallel factor analysis identified a higher transformation of protein-like components into humic-like components in FA. Network analysis showed that CS improved compost maturity by promoting the rapid conversion of humus precursors to humus, while FA increased the richness and diversity of the microbial community, such as Chloroflexi, the unique phylum in FA. Overall, CS and FA facilitated the humification process through abiotic and biotic pathways, and FA had better humification performance.
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Compostagem , Solo , Nitrogênio/análise , Carbono , Substâncias Húmicas/análise , Esterco , MineraisRESUMO
Aim: To elucidate the clinicopathological and prognostic values of interferon regulatory factor (IRF) family genes in acute myeloid leukemia (AML). Patients & methods: Differential expression analysis and survival analysis from several reliable databases were conducted and further validated using patients with AML. Results: The expression level of IRF1/2/4/5/7/8/9 in patients with AML was upregulated, while IRF3/6 expression was downregulated. High IRF1/7/9 expression indicated a worse overall survival rate. Conclusion: Overexpression of IRF1/7/9 may be associated with poor survival in patients with AML, suggesting that the IRF family may be a promising therapeutic target.
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Fatores Reguladores de Interferon , Leucemia Mieloide Aguda , Humanos , Prognóstico , Fatores Reguladores de Interferon/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Análise de SobrevidaRESUMO
Sepsis-associated acute kidney injury (SA-AKI) has a high mortality rate and lacks effective targeted treatment. We applied lipopolysaccharides-induced injury models in human and mouse renal tubular epithelial cells, and at the same time, we selected a commonly used sedative drug, dexmedetomidine, to investigate its potential for renal protection. We found a significant increase in the expression level of HSP90, and the interaction with glutathione peroxidase 4 (GPX4) led to autophagic degradation of GPX4, triggering ferroptosis. Dexmedetomidine reduced the degradation of GPX4 by increasing the binding of KEAP1 and HSP90 in the cytoplasm. Therefore, lipid peroxidation and ferroptosis were reduced. Similarly, dexmedetomidine showed renal protective effects in C57BL/6J male mice with SA-AKI induced by cecal ligation. Our study reveals a new mechanism of renal tubular epithelial cell ferroptosis in SA-AKI treated with dexmedetomidine.