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N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment.
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Proliferación Celular , Neoplasias Pulmonares , Ratones Desnudos , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas , Serina-Treonina Quinasas TOR , Proteínas Supresoras de Tumor , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Línea Celular Tumoral , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ratones , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A remarkable cancer-related role of zinc finger protein 367 (ZNF367) has been demonstrated in multiple malignancies. However, whether ZNF367 has a role in small-cell lung cancer (SCLC) remains unexplored. The purpose of this work was to explore the potential role and mechanism of ZNF367 in SCLC. In silico analysis using the Gene Expression Omnibus (GEO) dataset revealed high levels of the ZNF367 transcript in SCLC. Examination of clinical tissues confirmed the significant abundance of ZNF367 in SCLC tissues compared with adjacent non-malignant tissues. The genetic depletion of ZNF367 in SCLC cells led to remarkable alterations in cell proliferation, the cell cycle, colony formation and chemosensitivity. Mechanistically, ZNF367 was shown to regulate the activation of yes-associated protein (YAP) associated with the up-regulation of phosphorylated large tumour suppressor kinase 2 (LATS2). Further investigation revealed that ZNF367 affected the LATS2-YAP cascade by regulating the expression of citron kinase (CIT). Re-expression of constitutively active YAP diminished the tumour-inhibiting function of ZNF367 depletion. Xenograft experiments confirmed the tumour-inhibiting effect of ZNF367 depletion in vivo. In summary, our results demonstrate that the inhibition of ZNF367 displays anticancer effects in SCLC by inhibiting YAP activation, suggesting it as a potential druggable oncogenic target.
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Neoplasias Pulmonares , Ratones Desnudos , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas , Factores de Transcripción , Proteínas Supresoras de Tumor , Proteínas Señalizadoras YAP , Animales , Femenino , Humanos , Masculino , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Esophageal cancer (EC) is a familiar digestive tract tumor with highly lethal. The hypoxic environment has been demonstrated to be a significant factor in modulating malignant tumor progression and is strongly associated with the abnormal energy metabolism of tumor cells. Serine hydroxymethyl transferase 2 (SHMT2) is one of the most frequently expressed metabolic enzymes in human malignancies. The study was designed to investigate the biological functions and regulation mechanisms of SHMT2 in EC under hypoxia. We conducted RT-qPCR to assess SHMT2 levels in EC tissues and cells (TE-1 and EC109). EC cells were incubated under normoxia and hypoxia, respectively, and altered SHMT2 expression was evaluated through RT-qPCR, western blot, and immunofluorescence. The biological functions of SHMT2 on EC cells were monitored by performing CCK-8, EdU, transwell, sphere formation, glucose uptake, and lactate production assays. The SHMT2 protein lactylation was measured by immunoprecipitation and western blot. In addition, SHMT2-interacting proteins were analyzed by bioinformatics and validated by rescue experiments. SHMT2 was notably upregulated in EC tissues and cells. Hypoxia elevated SHMT2 protein expression, augmenting EC cell proliferation, migration, invasion, stemness, and glycolysis. In addition, hypoxia triggered lactylation of the SHMT2 protein and enhanced its stability. SHMT2 knockdown impeded the malignant phenotype of EC cells. Further mechanistic studies disclosed that SHMT2 is involved in EC progression by interacting with MTHFD1L. Hypoxia-induced SHMT2 protein lactylation and upregulated its protein level, which in turn enhanced MTHFD1L expression and accelerated the malignant progression of EC cells.
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Previous studies have linked the lactate/albumin (L/A) ratio to poor outcomes in various conditions, but its connection to mortality in patients with both heart failure (HF) and chronic kidney disease (CKD) remains unclear. Using data from 1537 patients in MIMIC-IV, this study examined the relationship between L/A ratio and in-hospital and one-year mortality, employing Cox models, Kaplan-Meier (KM) analysis, and restricted cubic splines (RCS). The non-survivor group showed higher L/A ratios than survivors (1.04 ± 0.78 vs. 0.58 ± 0.29, p < 0.001), indicating a significant link between higher L/A ratios and mortality. Cox analysis identified the L/A ratio was significantly related to all-cause mortality both in-hospital (HR 2.033; 95% CI 1.576-2.624; p < 0.001) and one-year (HR 1.723; 95% CI 1.428-2.078; p < 0.001). The association between L/A ratio and mortality was non-linear and increasing. The KM survival curves demonstrated significantly poorer survival outcomes for the high L/A group compared to the low L/A group, a difference that was statistically validated by a significant log-rank test (log-rank p < 0.001). L/A ratio has a significant association with poor prognosis in patients with HF and CKD patients in a critical condition. This finding demonstrates that L/A ratio might be useful in identifying patients with HF and CKD at high risk of all-cause death. Further large-scale prospective studies are needed to verify these results and inform clinical decisions.
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Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.
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Permeabilidad Capilar , Síndrome Hepatopulmonar , Monocitos , Oncostatina M , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Transducción de Señal , Bazo , Animales , Humanos , Síndrome Hepatopulmonar/metabolismo , Masculino , Monocitos/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Bazo/metabolismo , Oncostatina M/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Ratas , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Esplenectomía , Ratas Sprague-Dawley , Pulmón/metabolismo , Pulmón/irrigación sanguínea , Femenino , Persona de Mediana Edad , Adulto , Glicocálix/metabolismoRESUMEN
Freeze-thaw cycles and compactness are two critical factors that significantly affect the engineering properties and safety of building foundations, especially in seasonally frozen regions. This paper investigated the effects of freeze-thaw cycles on the shear strength of naturally strongly chlorine saline soil with the compactness of 85%, 90% and 95%. Three soil samples with different compactness were made. Size and mass changes were measured and recorded during freeze-thaw cycles. Shear strength under different vertical pressures was determined by direct shear tests, and the cohesion and friction angle were measured and discussed. Microstructure characteristic changes of saline soil samples were observed using scanning electron microscopy under different freeze-thaw cycles. Furthermore, numerical software was used to calculate the subsoil-bearing capacity and settlement of the electric tower foundation in the Qarhan Salt Lake region under different freeze-thaw cycles. Results show that the low-density soil shows thaw settlement deformation, but the high-density soil shows frost-heaving deformation with the increase in freeze-thaw cycles. The shear strength of the soil samples first increases and then decreases with the increase in freeze-thaw cycles. After 30 freeze-thaw cycles, the friction angle of soil samples is 28.3%, 29.2% and 29.6% lower than the soil samples without freeze-thaw cycle, the cohesion of soil samples is 71.4%, 60.1% and 54.4% lower than the samples without freeze-thaw cycle, and the cohesion and friction angle of soil samples with different compactness are close to each other. Microstructural changes indicate that the freeze-thaw cycle leads to the breakage of coarse particles and the aggregation of fine particles. Correspondingly, the structure type of soil changes from a granular stacked structure to a cemented-aggregated system. Besides, the quality loss of soil samples is at about 2% during the freeze-thaw cycles. Results suggest that there may be an optimal compactness between 90 and 95%, on the premise of meeting the design requirements and economic benefits. This study can provide theoretical guidance for foundation engineering constructions in seasonally frozen regions.
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BACKGROUND: The triglyceride-glucose (TyG) index has demonstrated correlations with adverse clinical outcomes in patients with ischaemic stroke, coronary heart disease and cardiac failure. However, its association with overall mortality in individuals concurrently experiencing heart failure (HF) and chronic kidney disease (CKD) remains inadequately explored. METHODS: Utilizing the Medical Information Mart for Intensive Care IV (Version 2.2) repository, subjects underwent quartile stratification based on the TyG index. The primary endpoint was all-cause mortality during hospitalization. Cox proportional hazard models were employed to examine the correlation between TyG and all-cause mortality in HF patients with CKD. Evaluation involved Kaplan-Meier (KM) analysis and restricted cubic splines (RCSs) to compare mortality rates during hospitalization and 1 year after admission across cohorts with varying TyG index levels. RESULTS: A cohort of 1537 HF and CKD patients participated. Cox regression analysis revealed elevated TyG levels as an independent risk factor for both in-hospital and 1 year mortality. RCS analysis indicated a rising, non-linear association between TyG levels and all-cause mortality (P value for non-linear <0.001). KM survival curves demonstrated a statistically significant reduction in survival rates within the high TyG index group compared with the low one (log-rank P < 0.001). CONCLUSIONS: The TyG index exhibited substantial independent prognostic value for elevated in-hospital and 1 year all-cause mortality among the cohort with HF and CKD. These findings suggest that assessing the TyG index could play a crucial role in developing novel therapeutic strategies to improve outcomes for this high-risk demographic.
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The survival outcomes of patients with chest wall sarcomas (CWS) were evaluated after receiving wide excision and chest wall reconstruction by using three-dimensional printed (3DP) implants. The survival outcomes evaluating the effect of 3DP implants for chest wall reconstruction is lacking. Here, forty-nine patients with CWS underwent radical wide excision and chest wall reconstruction using 3DP implants. The surgical data and long-term survival outcomes were collected and analyzed. With a median follow-up of 36 months, the disease-free survival (DFS) and overall survival (OS) were 31.7% and 58.5%, respectively. In addition, the 3-year DFS and OS can be significantly differentiated using the classification criteria of tumor grade, tumor size tumor area. Hence, wide excision and chest wall reconstruction using three-dimensional printed implants are a safe and effective treatment for chest wall sarcoma. The novel classification criteria of tumor size and area have the potential to predict the prognosis of CWS.
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Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular cells during aging. Suppressing ferroptosis alleviates macrophage-mediated tubular partial epithelial-mesenchymal transition in vitro, thereby mitigating the expression of fibrosis-related genes. Using SCENIC analysis, we infer Stat1 as a key age-related transcription factor promoting iron dyshomeostasis and ferroptosis in macrophages by regulating the expression of Pcbp1, an iron chaperone protein that inhibits ferroptosis. Furthermore, through virtual screening and molecular docking from a library of anti-aging compounds, we construct a docking model targeting Pcbp1, which indicates that the natural small molecule compound Rutin can suppress macrophage senescence and ferroptosis by preserving Pcbp1. In summary, our study underscores the crucial role of macrophage iron dyshomeostasis and ferroptosis in renal aging. Our results also suggest Pcbp1 as an intervention target in aging-related renal fibrosis and highlight Rutin as a potential therapeutic agent in mitigating age-related renal chronic low-grade inflammation and fibrosis.
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Exudate management is of significant clinical value for the treatment of acute wound. Various wound dressings have been developed to restore the function of injured tissues and promote wound healing, but proper exploiting the healing factors inside exudate and achieving anti-adhesion wound care remains a challenge. Herein, we present a novel multi-functional composite dressing (MCD) by coupling supernatant lyophilized powder of mesenchymal stem cells (MSC-SLP) with a sandwich-structured wound dressing (SWD). The developed MCDs demonstrated unique unidirectional drainage capability, stable anti-adhesion characteristics, and improved wound healing performance. The designed SWD with both superhydrophobic inner surface and liquid-absorption ability of mid layer enables the dressings exhibit desired anti-adhesion property to neoformative granulation tissues, favorable shielding effect to exogenous bacteria, as well as appropriate exudate-retaining capability and unidirectional exudate-absorption property. The introduction of MSC-SLP in SWD was demonstrated to further improve wound healing quality. Compared to medical gauze, the synergic effect of SWD and MSC-SLP significantly accelerates wound healing rate by over 30%, avoids tissue avulsion when changing dressings, and produces a flat-smooth closure surface. More importantly, the wound treated with MCDs presents more skin accessory organs and blood vessels in regenerated tissues than other groups. In vivo/vitro biocompatibility evaluations indicated little toxicity, demonstrating the biosecurity of the developed dressings. The proposed method offers great potential in clinical applications particularly for chronic wound treatments.
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Alzheimer's disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia. Growing evidence suggests that Alzheimer's disease is associated with accumulating various amyloid-ß oligomers in the brain, influenced by complex genetic and environmental factors. The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer's disease are believed to primarily result from synaptic dysfunction. Throughout life, environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders. These changes, known as epigenetic modifications, also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity. In this context, we highlight recent advances in understanding the roles played by key components of the epigenetic machinery, specifically DNA methylation, histone modification, and microRNAs, in the development of Alzheimer's disease, synaptic function, and activity-dependent synaptic plasticity. Moreover, we explore various strategies, including enriched environments, exposure to non-invasive brain stimulation, and the use of pharmacological agents, aimed at improving synaptic function and enhancing long-term potentiation, a process integral to epigenetic mechanisms. Lastly, we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer's disease. We suggest that addressing Alzheimer's disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.