TFR2 regulates ferroptosis and enhances temozolomide chemo-sensitization in gliomas.

Glioma is a common type of brain tumor with high incidence and mortality rates. Iron plays an important role in various physiological and pathological processes. Iron entry into the cell is promoted by binding the transferrin receptor 2 (TFR2) to the iron-transferrin complex. This study was designed to assess the association between TFR2 and ferroptosis in glioma. Lipid peroxidation levels in glioma cells were assessed by determination of lipid reactive oxygen species (ROS), glutathione content, and mitochondrial membrane potential. The effect of TFR2 on TMZ sensitivity was examined by cell viability assays, flow cytometry, and colony formation assays. We found that Low TFR2 expression predicted a better prognosis for glioma patients. And overexpression of TFR2 promoted the production of reactive oxygen species and lipid peroxidation in glioma cells, thereby further promoting ferroptosis. This could be reversed by the ferroptosis inhibitors Fer-1 and DFO (both inhibitors of ferroptosis). Moreover, TFR2 potentiated the cytotoxic effect of TMZ (temozolomide) via activating ferroptosis. In conclusion, we found that TFR2 induced ferroptosis and enhanced TMZ sensitivity in gliomas. Our findings might provide a new treatment strategy for glioma patients and improve their prognosis.

Identification and validation of a novel prognostic signature based on mitochondria and oxidative stress related genes for glioblastoma.

BACKGROUND: Mitochondria represent a major source of reactive oxygen species (ROS) in cells, and the direct increase in ROS content is the primary cause of oxidative stress, which plays an important role in tumor proliferation, invasion, angiogenesis, and treatment. However, the relationship between mitochondrial oxidative stress-related genes and glioblastoma (GBM) remains unclear. This study aimed to investigate the value of mitochondria and oxidative stress-related genes in the prognosis and therapeutic targets of GBM. METHODS: We retrieved mitochondria and oxidative stress-related genes from several public databases. The LASSO regression and Cox analyses were utilized to build a risk model and the ROC curve was used to assess its performance. Then, we analyzed the correlation between the model and immunity and mutation. Furthermore, CCK8 and EdU assays were utilized to verify the proliferative capacity of GBM cells and flow cytometry was used to analyze apoptosis rates. Finally, the JC-1 assay and ATP levels were utilized to detect mitochondrial function, and the intracellular ROS levels were determined using MitoSOX and BODIPY 581/591 C11. RESULTS: 5 mitochondrial oxidative stress-related genes (CTSL, TXNRD2, NUDT1, STOX1, CYP2E1) were screened by differential expression analysis and Cox analysis and incorporated in a risk model which yielded a strong prediction accuracy (AUC value = 0.967). Furthermore, this model was strongly related to immune cell infiltration and mutation status and could identify potential targeted therapeutic drugs for GBM. Finally, we selected NUDT1 for further validation in vitro. The results showed that NUDT1 was elevated in GBM, and knockdown of NUDT1 inhibited the proliferation and induced apoptosis of GBM cells, while knockdown of NUDT1 damaged mitochondrial homeostasis and induced oxidative stress in GBM cells. CONCLUSION: Our study was the first to propose a prognostic model of mitochondria and oxidative stress-related genes, which provided potential therapeutic strategies for GBM patients.

Facile Electrochemical Synthesis of Bifunctional Needle-like Co-P Nanoarray for Efficient Overall Water Splitting.

The development of low-cost and high-performance bifunctional electrocatalysts for overall water splitting is still challenging. Herein, we employed a facile electrodeposition method to prepare bifunctional cobalt phosphide for overall water splitting. The needle-like cobalt phosphide (Co-P-1) nanoarray is uniformly distributed on nickel foam. Co-P-1 exhibits excellent electrocatalytic activity for hydrogen evolution reaction (HER, 85 mV at 10 mA/cm2, 60 mV/dec) and oxygen evolution reaction (OER, 294 mV at 50 mA/cm2, 60 mV/dec). The cell-voltage of 1.60 V is found to achieve the current density of 10 mA/cm2 for overall water splitting in the two-electrode system, comparable to that of previously reported Pt/C/NF||RuO2/NF. The excellent electrocatalytic performance can be attributed to the needle-like structure with more active sites, accelerated charge transfer and evolved bubbles' release. This work can provide new approach to the development of a bifunctional electrocatalyst for overall water splitting.

Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood-brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment. METHODS: Betulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models. RESULTS: BA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice. CONCLUSIONS: We successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM.

Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment.

Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood-brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.

Enzyme Tunnel Dynamics and Catalytic Mechanism of Norcoclaurine Synthase: Insights from a Combined LiGaMD and DFT Study.

This study conducts a systematic investigation into the catalytic mechanism of norcoclaurine synthase (NCS), a key enzyme in the biosynthesis of tetrahydroisoquinolines (THIQs) with therapeutic applications. By integration of LiGaMD and DFT calculations, the reaction pathway of NCS is mapped, providing detailed insights into its catalytic activity and selectivity. Our findings underscore the critical role of E103 in substrate capture and reveal the hitherto unappreciated influence of nonpolar residues M183 and L76 on tunnel dynamics. A prominent discovery is the identification of a high-energy barrier (44.2 kcal/mol) associated with the aromatic electrophilic attack, which pinpoints the rate-limiting step. Moreover, we disclose the existence of dual transition states leading to different products with the energetically favored six-membered ring formation consistent with experimental evidence. These mechanistic revelations not only refine our understanding of NCS but also advocate for a renewed emphasis on enzyme tunnel engineering for optimizing THIQs biosynthesis. The research sets the stage for translating these findings into practical enzyme modifications. Our results highlight the potential of NCS as a biocatalyst to overcome the limitations of current synthetic methodologies, such as low yields and environmental impacts, and provide a theoretical contribution to the efficient, eco-friendly production of THIQs-based pharmaceuticals.

Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-ß in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a significantly malignant and lethal brain tumor with an average survival time of less than 12 months. Several researches had shown that Claudin-3 (CLDN3) is overexpressed in various cancers and might be important in their growth and spread. In this study, we used qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence staining assays to investigate the expression levels of various proteins. To explore the proliferation abilities of GBM cells, we conducted the CCK-8 and EdU-DNA formation assays. Wound healing and transwell assays were used to investigate the capacities of invasion and migration of GBM cells. Additionally, we constructed an intracranial xenograft model of GBM to study the in vivo role of CLDN3. Our study devoted to investigate the function of CLDN3 in the pathogenesis and progression of GBM. Our study revealed that CLDN3 was upregulated in GBM and could stimulate tumor cell growth and epithelial-mesenchymal transition (EMT) in both laboratory and animal models. We also discovered that CLDN3 expression could be triggered by transforming growth factor-ß (TGF-ß) and reduced by specific inhibitors of the TGF-ß signaling pathway, such as ITD-1. Further analysis revealed that increased CLDN3 levels enhanced TGF-ß-induced growth and EMT in GBM cells, while reducing CLDN3 levels weakened these effects. Our study demonstrated the function of CLDN3 in facilitating GBM growth and metastasis and indicated its involvement in the tumorigenic effects of TGF-ß. Developing specific inhibitors of CLDN3 might, therefore, represent a promising new approach for treating this devastating disease.

3D Porous VOx/N-Doped Carbon Nanosheet Hybrids Derived from Cross-Linked Dicyandiamide-Chitosan Hydrogels for Superior Supercapacitor Electrode Materials.

Three-dimensional porous carbon materials with moderate heteroatom-doping have been extensively investigated as promising electrode materials for energy storage. In this study, we fabricated a 3D cross-linked chitosan-dicyandiamide-VOSO4 hydrogel using a polymerization process. After pyrolysis at high temperature, 3D porous VOx/N-doped carbon nanosheet hybrids (3D VNCN) were obtained. The unique 3D porous skeleton, abundant doping elements, and presence of VOx 3D VNCN pyrolyzed at 800 °C (3D VNCN-800) ensured excellent electrochemical performance. The 3D VNCN-800 electrode exhibits a maximum specific capacitance of 408.1 F·g-1 at 1 A·g-1 current density and an admirable cycling stability with 96.8% capacitance retention after 5000 cycles. Moreover, an assembled symmetrical supercapacitor based on the 3D VNCN-800 electrode delivers a maximum energy density of 15.6 Wh·Kg-1 at a power density of 600 W·Kg-1. Our study demonstrates a potential guideline for the fabrication of porous carbon materials with 3D structure and abundant heteroatom-doping.

TMEM2 induces epithelial-mesenchymal transition and promotes resistance to temozolomide in GBM cells.

Glioblastoma multiforme (GBM) is the most common intracranial malignant tumor and is notorious for its poor prognosis. An important element in the short overall survival of GBM patients is the lack of understanding the pathogenesis and progression of tumor and deficiency biomarkers that can be used for early diagnosis and therapeutic sensitivity monitoring. Studies have shown that transmembrane protein 2 (TMEM2) is participated in tumorigenesis of various human tumors, including rectal and breast cancers. Although Qiuyi Jiang et al. have reported that TMEM2 combined with IDH1/2 and 1p19q can predict the survival time of glioma patients based on bioinformatics, its expression and biological role of glioma remain unclear. In our study, we investigated the effect of TMEM2 expression level on glioma malignancy in public datasets and an independent internal dataset. We revealed TEMM2 expression was higher in GBM tissues than in non-tumor brain tissues (NBT). Moreover, the increase in TMEM2 expression level was closely related to tumor malignancy. The survival analysis showed that TMEM2 high expression reduces survival time in all glioma patients, including GBM and LGG patients. Subsequent experiments demonstrated that knockdown TMEM2 inhibited proliferation of GBM cells. In addition, we analyzed TMEM2 mRNA levels in different GBM subtypes, and demonstrated that TMEM2 expression was upregulated in mesenchymal subtype. Meanwhile, bioinformatics analysis and transwell assay indicated that knockdown TMEM2 suppressed epithelial-mesenchymal transition (EMT) in GBM. Importantly, Kaplan-Meier analysis demonstrated that TMEM2 high expression reduced the treatment response to TMZ in GBM patients. Knockdown of TMEM2 alone did not reduce apoptosis GBM cells, but significant apoptotic cells were observed in the group treated with additional TMZ. These studies may contribute to improving the accuracy of early diagnosis and evaluating the effectiveness of TMZ treatment in GBM patients.

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma.

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.