Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular ...mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear.
The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo.
The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo.
Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current studies on tumor progression focus on the roles of cytokines in the tumor microenvironment (TME), and recent research shows that transforming growth factor-
1 (TGF-
1) released from TME plays ...a pivotal role in tumor development and malignant transformation. The alteration in cellular metabolism is a hallmark of cancer, which not only provides cancer cells with ATP for fuel cellular reactions, but also generates metabolic intermediates for the synthesis of essential cellular ingredients, to support cell proliferation, migration, and invasion. Interestingly, we found a distinct metabolic change during TGF-
1-induced epithelial-mesenchymal transition (EMT) in glioblastoma cells. Indeed, TGF-
1 participates in metabolic reprogramming, and the molecular basis is still not well understood. NADPH oxidases 4 (NOX4), a member of the Nox family, also plays a key role in the biological effects of glioblastoma. However, the relationship between NOX4, TGF-
1, and cellular metabolic changes during EMT in glioblastoma remains obscure. Here, our findings demonstrated that TGF-
1 upregulated NOX4 expression accompanied by reactive oxygen species (ROS) through Smad-dependent signaling and then induced hypoxia-inducible factor 1
(HIF-1
) overexpression and nuclear accumulation resulting in metabolic reprogramming and promoting EMT. Besides, inhibition of glycolysis reversed EMT suggesting a causal relationship between TGF-
1-induced metabolic changes and tumorigenesis. Moreover, TGF-
1-induced metabolic reprogramming and EMT which modulated by NOX4/ROS were blocked when the phosphoinositide3-kinase (PI3K)/AKT/HIF-1
signaling pathways were inhibited. In conclusion, these suggest that NOX4/ROS induction by TGF-
1 can be one of the main mechanisms mediating the metabolic reprogramming during EMT of glioblastoma cells and provide promising strategies for cancer therapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This study aimed to investigate the incidence of adjacent segment degeneration (ASD) and its associated risk factors in adults after anterior cervical discectomy and fusion (ACDF) surgery.
An ...exhaustive search across multiple databases was conducted, including Embase, PubMed, Cochrane Library, and the Web of Science, to identify pertinent studies. We collected such patient data as demographic variables (including age, gender, body mass index), cervical spondylosis type (such as radiculopathy and myelopathy), diabetes status, smoking and drinking history, and radiological risk factors (such as preoperative ASD status, developmental spinal stenosis, T1 slope, and postoperative less cervical lordosis). Incidence estimates were calculated based on relevant data. Risk factors were assessed using odds ratios and weighted mean differences with 95% confidence intervals (CIs).
Our analysis incorporated a total of 21 studies for incidence analysis. The overall incidence of CASD following ACDF was found to be 11% and radiographical ASD was 30%. Old age (weighted mean difference = 3.21; 95% CI: 0.06, 6.36; P = 0.05), preoperative ASD status (odds ratio = 2.65; 95% CI: 1.53, 4.60; P < 0.01), developmental spinal stenosis (odds ratio = 2.46; 95% CI: 1.61, 3.77; P < 0.01), and postoperative reduction in cervical lordosis were identified as significant risk factors for the occurrence of CASD.
The incidence of CASD following ACDF was 11%. Risk factors for CASD included old age, preoperative adjacent segment degeneration, developmental spinal stenosis, and postoperative reduction in cervical lordosis. These findings provide valuable insights for the assessment of adjacent segment disease risk after ACDF, aiding surgeons in diagnosis and treatment decisions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BackgroundLow-grade glioma (LGG) is a common malignant tumor of the central nervous system. The clinical prognosis of different patients varies greatly, so exploring appropriate markers that affect ...the prognosis and treatment of LGG is important. The purpose of this study was to identify the potential effect of autophagy-related DNA methylation on the prognosis and immune microenvironment in LGG. MethodsThe methylation profile, transcription data and corresponding clinical information of 451 patients with LGG were obtained from The Cancer Genome Atlas (TCGA). Another methylation data and clinical information of 110 patients with LGG from Chinese Glioma Genome Atlas (CGGA) were used as the validation set. Through univariate and multivariate COX regression analysis, we identified the autophagy-related genes (ARGs) associated with methylation levels and prognosis, and established a risk assessment signature. The receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival curve were used to verify the model's effectiveness in predicting prognosis. Patients were divided into low- and high-risk groups based on risk scores. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore the differences in biological functions between the two groups. ESTIMATE and CIBERSORT algorithms were used to explore differences in immune infiltration and immunotherapy sites. Pearson correlation analysis was used to analyze the relative relationship between methylated cg sites and corresponding genes. ResultsA total of 6 ARGs (ARSB, CFLAR, WIPI2, RB1, ERN1, RAB24) were selected that were associated with methylation levels and prognosis. The area under the curve (AUC) =0.96, and the KM survival curve P<0.0001, which proves that the risk assessment model has a good effect in predicting the prognosis of LGG. GO and KEGG enrichment analysis showed that the model mainly involved major histocompatibility complex (MHC) II receptors, antigen processing and presentation, and immune cell differentiation. In addition, we also found differences in immune infiltration and immune checkpoints between high- and low-risk groups. ConclusionsThe methylation levels of these 6 ARGs have a strong predictive potential for LGG, and the methylation regulation of ARGs has an important impact on the immune microenvironment of LGGs.
Current studies on tumor progression focus on the roles of cytokines in the tumor microenvironment (TME), and recent research shows that transforming growth factor-β1 (TGF-β1) released from TME plays ...a pivotal role in tumor development and malignant transformation. The alteration in cellular metabolism is a hallmark of cancer, which not only provides cancer cells with ATP for fuel cellular reactions, but also generates metabolic intermediates for the synthesis of essential cellular ingredients, to support cell proliferation, migration, and invasion. Interestingly, we found a distinct metabolic change during TGF-β1-induced epithelial-mesenchymal transition (EMT) in glioblastoma cells. Indeed, TGF-β1 participates in metabolic reprogramming, and the molecular basis is still not well understood. NADPH oxidases 4 (NOX4), a member of the Nox family, also plays a key role in the biological effects of glioblastoma. However, the relationship between NOX4, TGF-β1, and cellular metabolic changes during EMT in glioblastoma remains obscure. Here, our findings demonstrated that TGF-β1 upregulated NOX4 expression accompanied by reactive oxygen species (ROS) through Smad-dependent signaling and then induced hypoxia-inducible factor 1α (HIF-1α) overexpression and nuclear accumulation resulting in metabolic reprogramming and promoting EMT. Besides, inhibition of glycolysis reversed EMT suggesting a causal relationship between TGF-β1-induced metabolic changes and tumorigenesis. Moreover, TGF-β1-induced metabolic reprogramming and EMT which modulated by NOX4/ROS were blocked when the phosphoinositide3-kinase (PI3K)/AKT/HIF-1α signaling pathways were inhibited. In conclusion, these suggest that NOX4/ROS induction by TGF-β1 can be one of the main mechanisms mediating the metabolic reprogramming during EMT of glioblastoma cells and provide promising strategies for cancer therapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The hazard of ice accretion on overhead power circuits is significant, yet predicting it is very difficult. The key reason lies in the shortage of sufficient observational data on ice thickness, and ...previous studies have also rarely taken into account micro-terrain and micro-meteorological conditions. In response to the challenge of simulating overhead line icing, this study introduces a new icing simulation technique that fully considers the effects of micro-terrain and micro-meteorology. For this technique, typical micro-terrains of overhead line areas are first identified by using high-resolution elevation data, and the icing thickness characteristics in different micro-terrains are analyzed. Subsequently, icing thickness simulations for different micro-terrains are conducted. The results indicate that during the icing process, the icing thickness ranges from 5 mm to 8 mm under three types of micro-terrain, namely, “uplift type”, “alpine drainage divide type” and “canyon wind channel type”, whereas the icing thickness is less than 5 mm in the “flat type” of micro-terrain. This finding suggests that the first three micro-terrain types facilitate icing on overhead transmission lines due to the condensation and uplifting effects of water vapor caused by terrain. However, flat terrain lacks the conditions necessary for water vapor accumulation and thus is not easy to form icing. The results are advantageous for the deployment of overhead power lines in intricate terrain. It is advisable to steer clear of regions susceptible to icing, and endeavor to install circuits in level territories whenever feasible. In addition, the simulated icing thickness under different terrains is in good agreement with the observations. Specifically, the correlation coefficient between simulated and observed icing thickness is significant at the 0.99 confidence level, and the deviations between them are within 0.5 mm. This signifies that the forecasting methodologies employed are dependable and possess significant implications as a reference for disaster prevention and mitigation efforts.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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