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NT2/D1 embryonal carcinoma cells represent a well-established in vitro model of human neurogenesis. Alginate fibers’ platform, a 3D cell culture system, is a biocompatible, structurally supportive environment for neurogenesis suitable for investigating the effects of bioactive compounds on neurodevelopment. Using manual extrusion NT2/D1 cells were immobilized in alginate microfibers and neural differentiation was induced by 48h of induction with retinoic acid (RA). Initiation of neural differentiation in the 3D model was evaluated by assessment of morphological features, cell viability, apoptosis and expression of pluripotency factors and early neural markers. Using the same methodology, we investigate potential effects of major components of energy drinks, caffeine and taurine, on the NT2/D1 early neural progenitors. We established the alginate microfibers as a 3D model system for in vitro neural differentiation of immobilized NT2/D1 cells and evaluated the effects of caffeine and taurine on the early stages of neural differentiation of NT2/D1 cells. Upon RA induction NT2/D1 neural progenitors retained viability and proliferative capacity and showed decreased expression of pluripotency markers SOX2, OCT4, and NANOG and increased expression of early neural markers SOX3, PAX6, and miR219. We also revealed the effects of caffeine and taurine on the viability, proliferation and expression of SOX2 and PAX6 of the NT2/D1 neural progenitors. Neural differentiation of NT2/D1 cells immobilized within alginate microfibers represents a promising 3D model for studying the effects of bioactive compounds on human neurogenesis.

Astrocytes are the main homeostatic cells in the central nervous system able to respond to pathological conditions by transforming from quiescent to reactive state throughout the process known as reactive astrogliosis. This is a compensatory response that mediates tissue damage and recovery. During this process mature astrocytes reacquire some of precursor properties, but the underlying molecular mechanisms are still not fully understood. We focused our research on the reactivation-related functional properties of astrocytes governed by transcription factors SOX2 and SOX9. These transcription factors have important roles during gliogenesis, they are downregulated in mature astrocytes and re-expressed in reactive astrocytes. Initial screening of SOX2 and SOX9 expression after sensorimotor cortex ablation injury in rat was performed using immunohistochemistry. Further gain-of-function studies were done in vitro using astrocytes derived from NT2/D1 cell line (NT2/A). SOX2 and SOX9 were overexpressed in mature NT2/A by lentiviral transduction. The proliferative capacity of NT2/A cells following SOX2 and SOX9 over-expression was analyzed by immunostaining of Ki67, a nuclear protein associated with cellular proliferation. Additionally, wound-scratch assay was conducted to investigate the migratory potential of NT2/A cells post-SOX2 and SOX9 over-expression. The initial screening of SOX2 and SOX9 expression after brain injury in rat sensorimotor cortex showed up-regulation of these transcription factors in reactive astrocytes in the vicinity of the lesion area. In vitro functional studies showed that SOX2 overexpression leads to an increase in NT2/A proliferation and SOX9 over-expression promotes migration of NT2/A. The study highlights the importance of SOX2 and SOX9 in regulating the functional properties of astrocytes during reactive astrogliosis. The results imply that modulation of SOX genes expression may change the functional properties of astrocytes that holds the

Nowadays, it is a great challenge to develop new medicines for treating various infectious diseases. The treatment of these diseases is of utmost interest to further prevent the development of multi-drug resistance in different pathogens. Carbon quantum dots, as a new member of the carbon nanomaterials family, can potentially be used as a highly promising visible-light-triggered antibacterial agent. In this work, the results of antibacterial and cytotoxic activities of gamma-rayirradiated carbon quantum dots are presented. Carbon quantum dots (CQDs) were synthesized from citric acid by a pyrolysis procedure and irradiated by gamma rays at different doses (25, 50, 100 and 200 kGy). Structure, chemical composition and optical properties were investigated by atomic force microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, UV-Vis spectrometry and photoluminescence. Structural analysis showed that CQDs have a spherical-like shape and dose-dependent average diameters and heights. Antibacterial tests showed that all irradiated dots had antibacterial activity but CQDs irradiated with dose of 100 kGy had antibacterial activity against all seven pathogenreference bacterial strains. Gamma-ray-modified CQDs did not show any cytotoxicity toward human fetal-originated MRC-5 cells. Moreover, fluorescence microscopy showed excellent cellular uptake of CQDs irradiated with doses of 25 and 200 kGy into MRC-5 cells.

Astrocytes are the main homeostatic cells in the brain with important roles both in physiological and pathological conditions. They have a unique ability to become reactivated in response to different types of brain pathologies, which serves as a compensatory response that modulates tissue damage and recovery. Also, senescent astrocytes have profound implications in age-related neurodegenerative disorders. The molecular mechanisms underlying astrocyte reactivation and senescence are still not well understood. To investigate the roles of SOX2 and SOX9 transcription factors and miR-21 in these phenotypic alternations of astroglia, astrocytes derived from NT2/D1 cell line (NT2/A) were used as a model system. Western blot analyses showed that the expression of both SOX2 and SOX9 decreases during the maturation of NT2/A and they are re-expressed upon in vitro induced injury. Further modulation of the SOX2 and SOX9 expression will reveal their roles in the regulation of astrocytes reactivation. Down-regulation of mir-21 in both immature and mature NT2/A by using the antisense technology, induced the decline in cell proliferation revealed by Ki67 proliferation marker. Also the premature cellular senescence was induced as indicated by increase in SA-ß-gal activity and the expression of p21 and p53. Additionally, in silico analysis predicted many of the genes, previously shown to be upregulated in senescent astrocytes, as miR-21 targets. Clarifying the roles of SOX genes and miRNAs in astrocyte reactivation and senescence would contribute to better understanding of the functions of these cells at the molecular level, which holds promise for development of new therapeutic strategies.

Introduction: The NT2/D1 embryonal carcinoma cell line represents a well-established in vitro model of human neurogenesis. It’s widely used for studying neurodevelopmental processes, neurotoxicity, and neurodegenerative disorders. The utilization of alginate fibers as a 3D cell culture system offers a biocompatible and structurally supportive environment for neural differentiation and maturation of cells, making it a suitable tool for investigating neurodevelopmental processes. Methods: In thisstudy, we evaluated the alginate microfibers as a 3D modelsystem for in vitro neural differentiation of NT2/D1 cells.We described the immobilization of NT2/D1 cellsin alginate microfibers and the effect of propagation in this 3D model on morphological features, viability, and proliferation of immobilized cells. We also assessed the RA-induced initiation of neural differentiation of NT2/D1 cellsin alginate microfibers by comparison with the initiation of neural differentiation in adherent 2D cell culture. Results: Our results showed that immobilized NT2/D1 acquired morphological features characteristic of cells propagated in 3D model systems and retain viability, proliferative capacity, and ability to attach to adherent surfaces. In addition, immobilized NT2/D1 cells preserved neural differentiation capacity. Upon RA induction we detected a marked decrease in the expression of specific pluripotency-maintaining markers, SOX2, OCT4, and NANOG. Consecutively, the expression of early neural markers, SOX3, PAX6, and miR219 was significantly increased. Conclusion: Neural differentiation of NT2/D1 cellsimmobilized within alginate fibersrepresents a highly promising 3D modelsystem forstudying human neurogenesis and offers a valuable platform forscreening the effect of drugs and bioactive compounds on human neural differentiation.

Figure S1. TEM micrographs a) CQD_25, b) CQD_50,c) CQD_100, and d) CQD_200 samples, respectively.

Nowadays, it is a great challenge to develop new medicines for treating various infectious diseases. The treatment of these diseases is of utmost interest to further prevent the development of multi-drug resistance in different pathogens. Carbon quantum dots, as a new member of the carbon nanomaterials family, can potentially be used as a highly promising visible-light-triggered antibacterial agent. In this work, the results of antibacterial and cytotoxic activities of gamma-ray-irradiated carbon quantum dots are presented. Carbon quantum dots (CQDs) were synthesized from citric acid by a pyrolysis procedure and irradiated by gamma rays at different doses (25, 50, 100 and 200 kGy). Structure, chemical composition and optical properties were investigated by atomic force microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, UV-Vis spectrometry and photoluminescence. Structural analysis showed that CQDs have a spherical-like shape and dose-dependent average diameters and heights. Antibacterial tests showed that all irradiated dots had antibacterial activity but CQDs irradiated with dose of 100 kGy had antibacterial activity against all seven pathogen-reference bacterial strains. Gamma-ray-modified CQDs did not show any cytotoxicity toward human fetal-originated MRC-5 cells. Moreover, fluorescence microscopy showed excellent cellular uptake of CQDs irradiated with doses of 25 and 200 kGy into MRC-5 cells.

Carbon quantum dots as a novel type of carbon nanomaterials have attracted the attention of many researchers because of their unique optical, antibacterial, and anticancer properties as well as their biocompatibility. In this study, for the first time, carbon quantum dots were prepared from o-phenylenediamine dissolved in toluene by a solvothermal route. Subsequently, the prepared carbon quantum dots were encapsulated into polyurethane films by a swelling–encapsulation–shrink method. Analyses of the results obtained by different characterization methods (AFM, TEM, EDS, FTIR, photoluminescence, and EPR) indicate the significant influence of the precursor on structural, chemical, and optical properties. Antibacterial and cytotoxicity tests showed that these dots did not have any antibacterial potential, because of the low extent of reactive oxygen species production, and showed low dark cytotoxicity. By investigating the cellular uptake, it was established that these dots penetrated the HeLa cells and could be used as probes for bioimaging.

Figure S1: (a) TEM micrograph of CQDs, (b) top view AFM image of CQDs, (c) height profile of CQDs, and (d) particle size distribution of CQDs.

Glioblastoma (GBM) continues to be the most devastating primary brain malignancy. Despite significant advancements in understanding basic GBM biology and enormous efforts in developing new therapeutic approaches, the prognosis for most GBM patients remains poor with a median survival time of 15 months. Recently, the interplay between the SOX (SRY-related HMG-box) genes and lncRNAs (long non-coding RNAs) has become the focus of GBM research. Both classes of molecules have an aberrant expression in GBM and play essential roles in tumor initiation, progression, therapy resistance, and recurrence. In GBM, SOX and lncRNAs crosstalk through numerous functional axes, some of which are part of the complex transcriptional and epigenetic regulatory mechanisms. This review provides a systematic summary of current literature data on the complex interplay between SOX genes and lncRNAs and represents an effort to underscore the effects of SOX/lncRNA crosstalk on the malignant properties of GBM cells. Furthermore, we highlight the significance of this crosstalk in searching for new biomarkers and therapeutic approaches in GBM treatment.

Carbon quantum dots as a novel type of carbon nanomaterials have attracted the attention of many researchers because of their unique optical, antibacterial, and anticancer properties as well as their biocompatibility. In this study, for the first time, carbon quantum dots were prepared from o-phenylenediamine dissolved in toluene by a solvothermal route. Subsequently, the prepared carbon quantum dots were encapsulated into polyurethane films by a swelling–encapsulation–shrink method. Analyses of the results obtained by different characterization methods (AFM, TEM, EDS, FTIR, photoluminescence, and EPR) indicate the significant influence of the precursor on structural, chemical, and optical properties. Antibacterial and cytotoxicity tests showed that these dots did not have any antibacterial potential, because of the low extent of reactive oxygen species production, and showed low dark cytotoxicity. By investigating the cellular uptake, it was established that these dots penetrated the HeLa cells and could be used as probes for bioimaging.

The family of SOX genes encodes proteins that display properties of both classical transcription factors and architectural components of chromatin. During development of nervous system, as well as adult neurogenesis, SOX transcription factors govern diverse cellular processes such as maintaining the multipotency of neural stem cells, cell proliferation, cell fate decision, migration as well as terminal differentiation of neurons. Despite their well-known function in development and brain homeostasis, the expression and role of these genes in pathology- induced neural stem cell plasticity is poorly understood. Reduction in oxygen supply or ischemia are involved in various pathological conditions, such as stroke, traumatic brain injury and cardiac arrest, which promotes neurogenesis, angiogenesis, cell proliferation and other cell mechanisms for survival under the stress. The aim of the present study was to analyze the expression of SOX genes during in vitro neurogenesis following chemical hypoxia. Neuronal differentiation of human pluripotent embryonal carcinoma stem cell line NT2/D1 was used as an in vitro model system for studying the process of human neurogenesis. Depending on different concentration, RA directed the differentiation of NT2/D1 cells into neurons with a different phenotype. The effect of stress caused by hypoxia on the properties of pluripotent cells as well as the induction of neural differentiation was monitored in vitro by culturing NT2/D1 cells in the presence of cobalt chloride, a chemical inducer of hypoxia. The results of the analysis showed that the effect of hypoxia on the expression of SOX2 and OCT4 proteins involved in maintaining the pluripotency of cells depends on the duration of action of cobalt chloride. After short-term exposure of the cells, an increase in the levels of expression of SOX2 and OCT4 proteins was detected, while long-term treatment of the cells led to a decrease in the expression of these proteins. Furthermore, result

Development of new types of antimicrobial coatings is of utmost importance due to increasing problems with pathogen transmission from various infectious surfaces to human beings. In this study, new types of highly potent antimicrobial polyurethane composite films encapsulated by hydrophobic riboflavin-based carbon polymer dots are presented. Detailed structural, optical, antimicrobial, and cytotoxic investigations of these composites were conducted. Low-power blue light triggered the composites to eradicate Escherichia coli in 30 min, whereas the same effect toward Staphylococcus aureus was reached after 60 min. These composites also show low toxicity against MRC-5 cells. In this way, RF-CPD composites can be used for sterilization of highly touched objects in the healthcare industry.

Precise tuning of gene expression, accomplished by regulatory networks of transcription factors, epigenetic modifiers, and microRNAs, is crucial for the proper neural development and function of the brain cells. The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis, such as maintaining the cell stemness, cell proliferation, cell fate decisions, and terminal differentiation into neurons and glial cells. MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression. Together with other gene regulatory factors, microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment. The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain. Deregulated SOX/microRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies, including neurodegenerative disorders, traumatic brain injury, and cancer. Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neurorestoration. Numerous studies have confirmed complex interactions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma. Keeping in mind the crucial roles of SOX genes and microRNAs in neural development, we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions. Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies.

Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies.

ključne aktere u procesima održavanja pluripotentnosti, ćelijskog opredeljivanja i diferencijacije. Precizno koordinisana aktivnost ovih gena neophodna je za pravilan tok humane neuralne diferencijacije. U ovoj doktorskoj disertaciji analizirani su ekspresioni profili i epigenetički mehanizmi regulacije ekspresije pomenutih gena u ranim fazama neuralne diferencijacije NTeraT2/D1 ćelija indukovane retinoičnom kiselinom.U ovom model sistemu in vitro neuralne diferencijacije detektovane su dinamične izmene u ekspresionim profilima gena SOX1 i SOX3 i gena faktora pluripotentnosti (SOX2, OCT4 i NANOG) tokom ranih faza neuralne diferencijacije. Pokazano je da se ekspresija gena SOX1 i SOX3 aktivira odmah nakon indukcije neuralne diferencijacije ovih ćelija, čime je potvrđena njihova uloga ranih neuralnih markera. Ekspresija gena SOX2, OCT4 i NANOG, koji formiraju jezgro regulatorne mreže odgovorne za održavanje pluripotentnosti, smanjuje se tokom inicijacije neuralne diferencijacije i izlaska NTera2/D1 ćelija iz stanja pluripotentnosti na osnovu čega je zaključeno da signali koji indukuju neuralnu diferencijaciju već u početnim stadijumima dovode do intenzivnih promena u „molekularnom miljeu“ ćelije.U analizi epigenetičkih mehanizama uključenih u regulaciju ekspresije ispitivanih gena praćeni su metilacija DNK i dinamika izmene histonskih posttranslacionih modifikacija na njihovim regulatornim regionima, sa posebnim osvrtom na regulaciju ekspresije gena SOX3. Metodom metilacija-specifičnog PCR-a pokazano je da su promotori gena SOX1 i SOX3 hipometilovani kako u nediferenciranim NTera2/D1 ćelijama, tako i u ćelijama čija je neuralna diferencijacija indukovana retinoičnom kiselinom. Metodom bisulfitnog pirosekvenciranja DNK, koja predstavlja zlatni standard u merenju stepena metilacije, potvrđena je hipometilacija jednog od dva CpG ostrva u okviru promotora gena SOX3 čime je potvrđeno da metilacija DNK nije mehanizam regulacije ekspresije ovog gena u ranim fazama neuralne d, genes SOX1 and SOX3, together with pluripotency factors (SOX2, OCT4 and NANOG), have key roles in pluripotency maintenace, cell specification and differentiation and they act in a coordinate manner to regulate process of human neurogenesis. This doctoral disertation provides an insight into the expression profiles and epigenetic regulation of these genes during the early phases of retinoic acid-induced neural differentiation of NTera2/D1 cells.In this in vitro model system of human neurogenesis we have demontrated that expression profiles of SOX3 and SOX1 genes and pluripotency factors (SOX2, OCT4 i NANOG) are highly dynamic. It is shown that retinoic acid activates expression of SOX1 and SOX3, confirming their roles as early neural markers in vertebrates. Expression of SOX2, OCT4 and NANOG, which constitute core pluripotency regulatory circuitry, is reduced during the course of neural differentiation, suggesting that response to differentitation-inducing stimuli is followed by fast and intensive changes in cell transcriptome.For the analyses of epigenetic mechanisms acting on regulatory regions of SOX1 and SOX3 genes and pluripotency factors, DNA methylation and histone modifications profiles were examined, with special emphasis on SOX3 gene regulation. Using methylation-specific PCR it is shown that SOX1 and SOX3 gene promoters are hypomethylated in both undifferentiated NTera2/D1 cells and cells induced with retinoic acid. Bisulphite sequencing of the CpG island II in the promoter of SOX3 gene further confirmed that DNA methylation is not a mechanism governing regulation of SOX3 activity during the early stages of NTera2/D1 cell differentiation.Selected histone posttranslational modifications profiles on the regulatory regions of SOX1 and SOX3 genes and pluripotency factors were analyzed using chromatin immunoprecipitation. Changes in abundance of active H3K4me3 and H2B-acetyl marks on SOX3 regulatory regions are correlated with transcriptional activation of this

Based on previous investigations where bis-bibenzyls isolated from liverworts showed various biological activities (cytotoxic, antimicrobial, and antiviral), we investigated their cytotoxic activity in several human cancer cell lines. From the methylene-chloride/methanol extract of the liverwort Pellia endiviifolia, three bis-bibenzyls of the perrottetin type were isolated, namely perrottetin E, 10′-hydroxyperrottetin E, and 10,10′-dihydroxyperrottetin E. The last two were found for the first time in this species. Their structures were resolved using 1D and 2D NMR, as well as by comparison with data in the literature. Cytotoxic activity of the isolated compounds was tested on three human leukemia cell lines, HL-60 (acute promyelocytic leukemia cells), U-937 (acute monocytic leukemia cells), and K-562 (human chronic myelogenous leukemia cells), as well as on human embryonal teratocarcinoma cell line (NT2/D1) and human glioblastoma cell lines A-172 and U-251, and compared to the previously isolated bis-bibenzyls (perrottetins) of similar structure. The isolated compounds exhibited modest activity against leukemia cells and significant activity against NT2/D1 and A-172. Overall, the most active cytotoxic compounds in this investigation were perrottetin E (1), isolated in this work from Pellia endiviifolia, and perrottetin F phenanthrene derivative (7), previously isolated from Lunularia cruciata and added for a comparison of their cytotoxic activity.

Nowadays, a larger number of aggressive and corrosive chemical reagents as well as toxic solvents are used to achieve structural modification and cleaning of the final products. These lead to the production of residual, waste chemicals, which are often reactive, cancerogenic, and toxic to the environment. This study shows a new approach to the modification of graphene quantum dots (GQDs) using gamma irradiation where the usage of reagents was avoided. We achieved the incorporation of S and N atoms in the GQD structure by selecting an aqueous solution of L-cysteine as an irradiation medium. GQDs were exposed to gamma-irradiation at doses of 25, 50 and 200 kGy. After irradiation, the optical, structural, and morphological properties, as well as the possibility of their use as an agent in bioimaging and photodynamic therapy, were studied. We measured an enhanced quantum yield of photoluminescence with the highest dose of 25 kGy (21.60%). Both S- and N-functional groups were detected in all gamma-irradiated GQDs: amino, amide, thiol, and thione. Spin trap electron paramagnetic resonance showed that GQDs irradiated with 25 kGy can generate singlet oxygen upon illumination. Bioimaging on HeLa cells showed the best visibility for cells treated with GQDs irradiated with 25 kGy, while cytotoxicity was not detected after treatment of HeLa cells with gamma-irradiated GQDs.

The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodege

Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.