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Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.
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Disfunción Cognitiva , ARN Mensajero , Encefalopatía Asociada a la Sepsis , Animales , Acetilación , Encefalopatía Asociada a la Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/genética , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Masculino , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Neuronas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Sepsis/metabolismo , Sepsis/complicaciones , Sepsis/genética , Microglía/metabolismo , Hipocampo/metabolismo , Giro Dentado/metabolismoRESUMEN
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.
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Lesión Pulmonar Aguda , Ferroptosis , Ratones Endogámicos C57BL , Proteínas Quinasas Asociadas a Fase-S , Sepsis , Ubiquitinación , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/etiología , Sepsis/metabolismo , Sepsis/complicaciones , Sepsis/patología , Animales , Ratones , Humanos , Masculino , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Pulmón/patología , Pulmón/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genéticaRESUMEN
PURPOSE: To identify factors and indicators that affect chronic pain and pain relief, and to develop predictive models using machine learning. METHODS: We analyzed the data of 67,028 outpatient cases and 11,310 valid samples with pain from a large retrospective cohort. We used decision tree, random forest, AdaBoost, neural network, and logistic regression to discover significant indicators and to predict pain and treatment relief. FINDINGS: The random forest model had the highest accuracy, F1 value, precision, and recall rates for predicting pain relief. The main factors affecting pain and treatment relief included body mass index, blood pressure, age, body temperature, heart rate, pulse, and neutrophil/lymphocyte × platelet ratio. The logistic regression model had high sensitivity and specificity for predicting pain occurrence. IMPLICATIONS: Machine learning models can be used to analyze the risk factors and predictors of chronic pain and pain relief, and to provide personalized and evidence-based pain management.
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Dolor Crónico , Aprendizaje Automático , Humanos , Estudios Retrospectivos , Dolor Crónico/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Anciano , Manejo del Dolor/métodos , Modelos Logísticos , Factores de Riesgo , Árboles de DecisiónRESUMEN
Energy stress, characterized by the reduction of intracellular ATP, has been implicated in various diseases, including cancer. Here, we show that energy stress promotes the formation of P-bodies in a ubiquitin-dependent manner. Upon ATP depletion, the E3 ubiquitin ligase TRIM23 catalyzes lysine-63 (K63)-linked polyubiquitination of HCLS1-associated protein X-1 (HAX1). HAX1 ubiquitination triggers its liquidâliquid phase separation (LLPS) and contributes to P-bodies assembly induced by energy stress. Ubiquitinated HAX1 also interacts with the essential P-body proteins, DDX6 and LSM14A, promoting their condensation. Moreover, we find that this TRIM23/HAX1 pathway is critical for the inhibition of global protein synthesis under energy stress conditions. Furthermore, high HAX1 ubiquitination, and increased cytoplasmic localization of TRIM23 along with elevated HAX1 levels, promotes colorectal cancer (CRC)-cell proliferation and correlates with poor prognosis in CRC patients. Our data not only elucidate a ubiquitination-dependent LLPS mechanism in RNP granules induced by energy stress but also propose a promising target for CRC therapy.
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Proteínas Adaptadoras Transductoras de Señales , Lisina , Ubiquitinación , Humanos , Lisina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Estrés Fisiológico , Células HEK293 , Proliferación Celular , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , Gránulos Citoplasmáticos/metabolismo , Proteínas de Unión al GTPRESUMEN
Gas signaling molecules, including carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), have been shown to have cancer therapeutic potential, pointing to a new direction for cancer treatment. In recent years, a series of studies have confirmed that hydrogen (H2), a weakly reductive gas, also has therapeutic effects on various cancers and can mitigate oxidative stress caused by radiation and chemotherapy, reducing tissue damage and immunosuppression to improve prognosis. Meanwhile, H2 also has immunomodulatory effects, inhibiting T cell exhaustion and enhancing T cell anti-tumor function. It is worth noting that human intestinal flora can produce large amounts of H2 daily, which becomes a natural barrier to maintaining the body's resistance to diseases such as tumors. Although the potential anti-tumor mechanisms of H2 are still to be investigated, previous studies have shown that H2 can selectively scavenge highly toxic reactive oxygen species (ROS) and inhibit various ROS-dependent signaling pathways in cancer cells, thus inhibiting cancer cell proliferation and metastasis. The ROS scavenging ability of H2 may also be the underlying mechanism of its immunomodulatory function. In this paper, we review the significance of H2 produced by intestinal flora on the immune homeostasis of the body, the role of H2 in cancer therapy and the underlying mechanisms, and the specific application of H2 to provide new ideas for the comprehensive treatment of cancer patients.
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Microbioma Gastrointestinal , Neoplasias , Humanos , Especies Reactivas de Oxígeno , Hidrógeno/farmacología , Hidrógeno/uso terapéutico , Proliferación Celular , Inmunomodulación , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & controlRESUMEN
Regulatory T cells (Tregs) are a key determinant for the immunosuppressive and premetastatic niche for cancer progression after surgery resection. However, the precise mechanisms regulating Tregs function during surgical stress-facilitated cancer metastasis remain unknown. This study aims to unravel the mechanisms and explore potential strategies for preventing surgical stress-induced metastasis by targeting NEDD8. Using a surgical stress mouse model, we found that surgical stress results in the increased expression of NEDD8 in Tregs. NEDD8 depletion abrogates postoperative lung metastasis of colon cancer cells by inhibiting Treg immunosuppression and thereby partially recovering CD8+T cell and NK cell-mediated anti-tumor immunity. Furthermore, Treg mitophagy and mitochondrial respiration exacerbated in surgically stressed mice were attenuated by NEDD8 depletion. Our observations suggest that cancer progression may result from surgery-induced enhancement of NEDD8 expression and the subsequent immunosuppressive function of Tregs. More importantly, depleting or inhibiting NEDD8 can be an efficient strategy to reduce cancer metastasis after surgery resection by regulating the function of Tregs.
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Neoplasias del Colon , Linfocitos T Reguladores , Animales , Ratones , Terapia de Inmunosupresión , Linfocitos T CD8-positivos , Tolerancia Inmunológica , Inmunosupresores/metabolismo , Neoplasias del Colon/metabolismoRESUMEN
Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of sepsis and one of the leading causes of patient death. Pyroptosis is a specific programmed cell death characterized by the release of inflammatory cytokines. Appropriate pyroptosis can reduce tissue damage and exert a protective effect against infection during sepsis. However, overactivated pyroptosis results in massive cell death, leading to septic shock, multiple organ dysfunction syndrome, and even an increased risk of secondary infection. Recent studies suggest that pyroptosis can interact with and cross-regulate other types of cell death programs to establish a complex network of cell death, which participates in the occurrence and development of septic lung injury. This review will focus on the interactions between pyroptosis and other types of cell death, including apoptosis, necroptosis, PANoptosis, NETosis, autophagy, and ferroptosis, to summarize the role of pyroptosis in sepsis-induced lung injury, and will discuss the potential therapeutic strategies of targeting pyroptosis during sepsis treatment.
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Lesión Pulmonar , Sepsis , Humanos , Piroptosis , Lesión Pulmonar/complicaciones , Muerte Celular , Apoptosis , Sepsis/complicaciones , Sepsis/metabolismoRESUMEN
As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA+ B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA+ B cells overcame the suppression of CD8+ T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA+ B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating Cα gene transcription and IgA class switching. IgA+ B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA+ B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA+ B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy. SIGNIFICANCE: Metabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth. See related commentary by Bush and Perry, p. 3493.
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Neoplasias Colorrectales , Ayuno , Humanos , Animales , Ratones , Ayuno/fisiología , Dieta , Biomarcadores , Neoplasias Colorrectales/genética , Inmunoglobulina ARESUMEN
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis that manifests as a range of brain dysfunctions from delirium to coma. It is a relatively common complication of sepsis associated with poor patient prognosis and mortality. The pathogenesis of SAE involves neuroinflammatory responses, neurotransmitter dysfunction, blood-brain barrier (BBB) disruption, abnormal blood flow regulation, etc. Neuroinflammation caused by hyperactivation of microglia is considered to be a key factor in disease development, which can cause a series of chain reactions, including BBB disruption and oxidative stress. Metabolic reprogramming has been found to play a central role in microglial activation and executive functions. In this review, we describe the pivotal role of energy metabolism in microglial activation and functional execution and demonstrate that the regulation of microglial metabolic reprogramming might be crucial in the development of clinical therapeutics for neuroinflammatory diseases like SAE.
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Encefalopatías , Encefalopatía Asociada a la Sepsis , Sepsis , Humanos , Encefalopatía Asociada a la Sepsis/complicaciones , Encefalopatía Asociada a la Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/patología , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Sepsis/complicaciones , Barrera Hematoencefálica/metabolismo , Encefalopatías/etiología , Encefalopatías/patologíaRESUMEN
Emerging evidence suggests that pyroptosis is involved in sepsis. However, the role of neutrophil pyroptosis in sepsis and the mechanisms remains elusive. We find that N-acetyltransferase 10 (NAT10), an acetyltransferase responsible for the N4-acetylation of Cytidine (ac4C) in mRNA, is significantly downregulated in neutrophils from septic mice. Neutrophil-specific over-expression of NAT10 improves the survival and ameliorates lung injury in septic mice by inhibiting neutrophil pyroptosis. Notably, UNC-52-like kinase 1 (ULK1) is identified as the target of NAT10 in neutrophils. The decreased expression of NAT10 resultes in the decay of ULK1 transcripts and therefore the reduced expression of ULK1. As a regulator of STING phosphorylation, the loss of ULK1 enhances the activation of STING-IRF3 signaling and subsequently the elevated pyroptosis-inducing NLRP3 inflammasome in neutrophils. While over-expression of NAT10 restrains pyroptosis in neutrophils as well as septic lethality in mice by reversing the ULK1-STING-NLRP3 axis. The decreased expression of NAT10 are also observed in sepsis patients and its correlation with clinical severity is found. Collectively, our findings disclose that NAT10 is a negative regulator of neutrophil pyroptosis and its downregulation contributes to the progress of sepsis by exacerbating pyroptosis via the ULK1-STING-NLRP3 axis, therefore revealing a potential therapeutic target for sepsis.
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Piroptosis , Sepsis , Acetiltransferasas , Animales , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neutrófilos/metabolismo , ARN , Sepsis/genética , Sepsis/metabolismoRESUMEN
Neutrophil extracellular traps (NETs) assist pathogen clearance, while excessive NETs formation is associated with exacerbated inflammatory responses and tissue injury in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Autophagy is generally considered to be a protective process, but autophagy dysfunction is harmful. Whether and how NETs affect autophagic flux during sepsis-induced ALI are currently unknown. Here, we confirmed that the level of NETs was increased in ARDS patients and mice models, which led to impairment of autophagic flux and deterioration of the disease. Mechanistically, NETs activated METTL3 mediated m6A methylation of Sirt1 mRNA in alveolar epithelial cells, resulting in abnormal autophagy. These findings provide new insights into how NETs contribute to the development of sepsis-associated ALI/ARDS.
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Glioma is one of the most threatening tumors and the survival rate of the infected patient is low. The automatic segmentation of the tumors by reliable algorithms can reduce diagnosis time. In this paper, a novel 3D multi-threading dilated convolutional network (MTDC-Net) is proposed for the automatic brain tumor segmentation. First of all, a multi-threading dilated convolution (MTDC) strategy is introduced in the encoder part, so that the low dimensional structural features can be extracted and integrated better. At the same time, the pyramid matrix fusion (PMF) algorithm is used to integrate the characteristic structural information better. Secondly, in order to make the better use of context semantical information, this paper proposed a spatial pyramid convolution (SPC) operation. By using convolution with different kernel sizes, the model can aggregate more semantic information. Finally, the multi-threading adaptive pooling up-sampling (MTAU) strategy is used to increase the weight of semantic information, and improve the recognition ability of the model. And a pixel-based post-processing method is used to prevent the effects of error prediction. On the brain tumors segmentation challenge 2018 (BraTS2018) public validation dataset, the dice scores of MTDC-Net are 0.832, 0.892 and 0.809 for core, whole and enhanced of the tumor, respectively. On the BraTS2020 public validation dataset, the dice scores of MTDC-Net are 0.833, 0.896 and 0.797 for the core tumor, whole tumor and enhancing tumor, respectively. Mass numerical experiments show that MTDC-Net is a state-of-the-art network for automatic brain tumor segmentation.
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Neoplasias Encefálicas , Procesamiento de Imagen Asistido por Computador , Algoritmos , Neoplasias Encefálicas/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Redes Neurales de la Computación , Programas InformáticosRESUMEN
Background: Opioids are widely used during primary debulking surgery (PDS) for ovarian cancers, and a high mu-opioid receptor (MOR) expression predicts worse cancer outcomes. However, the impact of MOR expression on survival outcomes in ovarian cancers is still not clear. Methods: A retrospective cohort study was conducted in patients who underwent PDS in ovarian cancer patients. MOR expression was measured in tumor and normal tissue. Primary outcomes were overall survival (OS) and disease-free survival (DFS). Secondary outcomes included perineural invasion (PNI), intraoperative sufentanil consumption, length of stay (LOS), and verbal numerical rating scale (VNRS) on postoperative day 1 (POD1), POD3, and POD5. Results: After propensity score matching, a total of 366 patients were finally enrolled in this study. There were no significant differences in OS rates in patients with high versus low levels of MOR (1-year OS: 82.9% versus 83.3%, 3-year: 57.8% versus 59.1%, 5-year: 22.4% versus 23.1%,respectively) in the ovarian cancers. There were no significant differences in DFS between the groups. Intraoperative sufentanil consumption was higher in the MOR high-expression group compared with the MOR low-expression group. Tumors expressing high levels of MOR showed higher rates of PNI. VNRS in the MOR high-expression group was higher on POD1. Conclusion: MOR is not an independent predictor of worse survival in ovarian cancers but is associated with high rates of perineural invasion.
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BACKGROUND: Intravenous lidocaine has been postulated to improve long-term survival after surgery for pancreatic cancer through anti-inflammatory effects, anti-tumour effects, or both. We investigated whether intraoperative lidocaine improves survival after pancreatectomy for pancreatic cancer and whether lidocaine modified the formation of neutrophil extracellular traps (NETs), high levels of which are associated with poor prognosis. METHODS: Patients undergoing pancreatectomy were randomly assigned to i.v. lidocaine (continuous intraoperative infusion of 2 mg kg-1 h-1, after 1.5 mg kg-1 bolus at induction of anaesthesia) or saline placebo. The co-primary outcomes were survival/disease-free survival 3 yr after surgery. Secondary outcomes (masked to treatment allocation) included intraoperative opioid (sufentanil) dose, postoperative complications, and circulating and tumour-associated NETs (immunofluorescence assay, enzyme-linked immune assay, or both). RESULTS: A total of 563 participants (34.6% female; median age, 64 yr) completed 3 yr of clinical follow-up. Overall, 283 participants were randomised to lidocaine infusion, and 280 participants were randomised to placebo. Infusion of lidocaine did not alter overall (hazard ratio [HR]=0.98; 95% confidence interval [CI], 0.81-1.17; P=0.79) or disease-free survival (HR=0.91; 95% CI, 0.71-1.17; P=0.44). Mean intraoperative sufentanil dose was reduced by lidocaine infusion (47.6 µg [4.6]) compared with placebo (68.4 µg [4.8]; P<0.001), but postoperative complications and length of hospital stay were similar between groups. Circulating NETs were lower after lidocaine infusion up to 3 days after surgery, but tumour-associated NETs were not altered by intraoperative treatment. CONCLUSION: In patients undergoing pancreatectomy for pancreatic cancer, intraoperative infusion of lidocaine did not improve overall or disease-free survival. Reduced formation of circulating NETs was absent in pancreatic tumour tissue. CLINICAL TRIAL REGISTRATION: NCT03245346; updated in Chi-CTR-2000035469.
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Lidocaína , Neoplasias Pancreáticas , Anestésicos Locales , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/tratamiento farmacológico , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Complicaciones Posoperatorias/inducido químicamente , Sufentanilo , Neoplasias PancreáticasRESUMEN
ABSTRACT: As a global major health problem and a leading cause of death, sepsis is defined as a failure of homeostasis, which is mainly initiated by an infection and followed by sustained excessive inflammation until immune suppression. Despite advances in the identification and management of clinical sepsis, morbidity, and mortality remain high. In addition, clinical trials have failed to yield promising results. In recent years, the mechanism of regulated cell death (RCD) in sepsis has attracted more and more attention, because these dying cells could release a large number of danger signals which contribute to inflammatory responses and exacerbation of sepsis, providing a new direction for us to make treatment strategy. Here we summarize mechanisms of several forms of RCD in sepsis including necroptosis, pyroptosis, ferroptosis. In conclusion, targeting RCD is considered a promising approach to treat sepsis.
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Ferroptosis , Sepsis , Humanos , Inflamación , Necroptosis , Piroptosis , Sepsis/terapiaRESUMEN
PURPOSE OF REVIEW: The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. RECENT FINDINGS: Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.
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Neoplasias , Humanos , Neoplasias/patología , Sistema InmunológicoRESUMEN
Neutrophil extracellular traps (NETs) production is a major strategy employed by polymorphonuclear neutrophils (PMNs) to fight against microbes. NETs have been implicated in the pathogenesis of various lung injuries, although few studies have explored NETs in sepsis-associated acute lung injury (SI-ALI). Here, we demonstrate a major contribution of NETs to the pathology of sepsis-associated ALI by inducing ferroptosis of alveolar epithelial cells. Using both in vitro and in vivo studies, our findings show enhanced NETs accumulation in sepsis-associated ALI patients and mice, as well as the closely related upregulation of ferroptosis, the induction of which depends on METTL3-induced m6A modification of GPX4. Using a CLP-induced sepsis-associated ALI mouse model established with METTL3-/- versus WT mice, in addition to METTL3 knockout and overexpression in vitro, we elucidated and confirmed the critical role of ferroptosis in NETs-induced ALI. These findings support a role for NETs-induced METTL3 modification and the subsequent induction of ferroptosis in the pathogenesis of sepsis-associated ALI.
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Lesión Pulmonar Aguda , Trampas Extracelulares , Ferroptosis , Sepsis , Lesión Pulmonar Aguda/patología , Células Epiteliales Alveolares , Animales , Humanos , Metiltransferasas , Ratones , Sepsis/complicaciones , Sepsis/patologíaRESUMEN
Sepsis is an acute life-threatening disorder associated with multiorgan dysfunction that remains the leading cause of death in intensive care units. As sepsis progresses, it causes prolonged immunosuppression, which results in sustained mortality, morbidity, and susceptibility to secondary infections. Using a mouse model of sepsis, we found that the long noncoding RNA HOTAIRM1 (HOXA transcript antisense RNA myeloid-specific 1) was highly expressed in mice during the late phase of sepsis. The upregulation of HOTAIRM1 was induced by Notch/Hes1 activation and, moreover, was critical for the formation of an immunosuppressive microenvironment. HOTAIRM1 induced T cell exhaustion by increasing the percentage of PD-1+ T cells and regulatory T cells, accompanied by elevated PD-L1. Blockade of either Notch/Hes1 signaling or HOTAIRM1 inhibited T cell exhaustion in late sepsis, having alleviated lung injury and improved survival of mice. Further mechanistic studies identified HOXA1 as a key transcription factor targeted by HOTAIRM1 to regulate PD-L1 expression in lung alveolar epithelial cells. These results implicated that the Notch/Hes1/HOTAIRM1/HOXA1/PD-L1 axis was critical for sepsis-induced immunosuppression and could be a potential target for sepsis therapies.
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Tolerancia Inmunológica/inmunología , MicroARNs/genética , Sepsis/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Sepsis/microbiología , Factor de Transcripción HES-1/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Background: Patients with sepsis may progress to acute respiratory distress syndrome (ARDS). Evidence of neutrophil extracellular traps (NETs) in sepsis-induced lung injury has been reported. However, the role of circulating NETs in the progression and thrombotic tendency of sepsis-induced lung injury remains elusive. The aim of this study was to investigate the role of tissue factor-enriched NETs in the progression and immunothrombosis of sepsis-induced lung injury. Methods: Human blood samples and an animal model of sepsis-induced lung injury were used to detect and evaluate NET formation in ARDS patients. Immunofluorescence imaging, ELISA, Western blotting, and qPCR were performed to evaluate in vitro NET formation and tissue factor (TF) delivery ability. DNase, an anti-TF antibody, and thrombin inhibitors were applied to evaluate the contribution of thrombin to TF-enriched NET formation and the contribution of TF-enriched NETs to immunothrombosis in ARDS patients. Results: Significantly increased levels of TF-enriched NETs were observed in ARDS patients and mice. Blockade of NETs in ARDS mice alleviated disease progression, indicating a reduced lung wet/dry ratio and PaO2 level. In vitro data demonstrated that thrombin-activated platelets were responsible for increased NET formation and related TF exposure and subsequent immunothrombosis in ARDS patients. Conclusion: The interaction of thrombin-activated platelets with PMNs in ARDS patients results in local NET formation and delivery of active TF. The notion that NETs represent a mechanism by which PMNs release thrombogenic signals during thrombosis may offer novel therapeutic targets.