The role of RUNX1/NF-κB in regulating PVAT inflammation in aortic dissection.

The pathogenesis of aortic dissection (AD), an aortic disease associated with high mortality, involves significant vascular inflammatory infiltration. However, the precise relationship between perivascular adipose tissue (PVAT) and aortic dissection remains incompletely understood. The objective of this study is to investigate the role of PVAT inflammation in the pathogenesis of aortic dissection and identify novel therapeutic targets for this disease. The mouse model of aortic dissection was established in this study through intraperitoneal injection of Ang II and administration of BAPN in drinking water. Additionally, control groups were established at different time points including the 2-week group, 3-week group, and 4-week group. qPCR and immunohistochemistry techniques were employed to detect the expression of inflammatory markers and RUNX1 in PVAT surrounding the thoracic aorta in mice. Additionally, an aortic dissection model was established using RUNX1 knockout mice, and the aforementioned indicators were assessed. The 3T3-L1 cells were induced to differentiate into mature adipocytes in vitro, followed by lentivirus transfection for the knockdown or overexpression of RUNX1. The study aimed to investigate the potential cell-to-cell interactions by co-culturing 3T3-L1 cells with A7r5 or RAW264.7 cells. Subsequently, human aortic PVAT samples were obtained through clinical surgery and the aforementioned indicators were detected. In comparison to the control group, the aortic dissection model group exhibited decreased expression of MMP-2 and NF-κB in PVAT, while TNF-α and RUNX1 expression increased. Suppression of RUNX1 expression resulted in increased MMP-2 and NF-κB expression in PVAT, along with decreased TNF-α expression. Overexpression of RUNX1 upregulated the expression levels of NF-Κb, MMP-2, and TNF-α in adipocytes, whereas knockdown of RUNX1 exerted an opposite effect. Macrophages co-cultured with adipocytes overexpressing RUNX1 exhibited enhanced CD86 expression, while vascular smooth muscle cells co-cultured with these adipocytes showed reduced α-SMA expression. In human samples, there was an increase in both RUNX1 and MMP-2 expression levels, accompanied by a decrease in TNF-α and NF-Κb expression. The presence of aortic dissection is accompanied by evident inflammatory alterations in the PVAT, and this phenomenon appears to be associated with the involvement of RUNX1. It is plausible that the regulation of PVAT's inflammatory changes by RUNX1/NF-κB signaling pathway plays a role in the pathogenesis of aortic dissection.

Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma.

OBJECTIVE: Circulating tumor cell (CTC) detection is a promising noninvasive technique that can be used to diagnose cancer, monitor progression, and predict prognosis. In this study, the authors aimed to investigate the clinical utility of CTCs in the management of diffuse glioma. METHODS: Sixty-three patients with newly diagnosed diffuse glioma were included in this multicenter clinical cohort. The authors used a platform based on isolation by size of epithelial tumor cells (ISET) to detect and analyze CTCs and circulating tumor microemboli (CTMs) in the peripheral blood of patients both before and after surgery. Least absolute shrinkage and selector operation (LASSO) and Cox regression analyses were used to verify whether CTCs and CTMs are independent prognostic factors for diffuse glioma. RESULTS: CTC levels were closely related to the degree of malignancy, WHO grade, and pathological subtypes. Receiver operating characteristic curve analysis revealed that a high CTC level was a predictor for glioblastoma. The results also showed that CTMs originate from the parental tumor rather than from the circulation and are an independent prognostic factor for diffuse glioma. The postoperative CTC level is related to the peripheral immune system and patient survival. Cox regression analysis showed that postoperative CTC levels and CTM status are independent prognostic factors for diffuse glioma, and CTC- and CTM-based survival models had high accuracy in internal validation. CONCLUSIONS: The authors revealed a correlation between CTCs and clinical characteristics and demonstrated that CTCs and CTMs are independent predictors for the diagnosis and prognosis of diffuse glioma. Their CTC- and CTM-based survival models can enable clinicians to evaluate patients' response to surgery as well as their outcomes.

RND1 inhibits epithelial-mesenchymal transition and temozolomide resistance of glioblastoma via AKT/GSK3-ß pathway.

GBM is one of the most malignant tumor in central nervous system. The resistance to temozolomide (TMZ) is inevitable in GBM and the characterization of TMZ resistance seriously hinders clinical treatment. It is worthwhile exploring the underlying mechanism of aggressive invasion and TMZ resistance in GBM treatment. Bioinformatic analysis was used to analyze the association between RND1 and a series of EMT-related genes. Colony formation assay and cell viability assay were used to assess the growth of U87 and U251 cells. The cell invasion status was evaluated based on transwell and wound-healing assays. Western blot was used to detect the protein expression in GBM cells. Treatment targeted RND1 combined with TMZ therapy was conducted in nude mice to evaluate the potential application of RND1 as a clinical target for GBM. The overexpression of RND1 suppressed the progression and migration of U87 and U251 cells. RND1 knockdown facilitated the growth and invasion of GBM cells. RND1 regulated the EMT of GBM cells via inhibiting the phosphorylation of AKT and GSK3-ß. The promoted effects of RND1 on TMZ sensitivity was identified both in vitro and in vivo. This research demonstrated that the overexpression of RND1 suppressed the migration and EMT status by downregulating AKT/GSK3-ß pathway in GBM. RND1 enhanced the TMZ sensitivity of GBM cells both in vitro and in vivo. Our findings may contribute to the targeted therapy for GBM and the understanding of mechanisms of TMZ resistance in GBM.

RETINOBLASTOMA RELATED 1 switches mitosis to meiosis in rice.

The transition from mitosis to meiosis is a critical event in the reproductive development of all sexually reproducing species. However, the mechanisms that regulate this process in plants remain largely unknown. Here, we find that the rice (Oryza sativa L.) protein RETINOBLASTOMA RELATED 1 (RBR1) is essential to the transition from mitosis to meiosis. Loss of RBR1 function results in hyper-proliferative sporogenous-cell-like cells (SCLs) in the anther locules during early stages of reproductive development. These hyper-proliferative SCLs are unable to initiate meiosis, eventually stagnating and degrading at late developmental stages to form pollen-free anthers. These results suggest that RBR1 acts as a gatekeeper of entry into meiosis. Furthermore, cytokinin content is significantly increased in rbr1 mutants, whereas the expression of type-B response factors, particularly LEPTO1, is significantly reduced. Given the known close association of cytokinins with cell proliferation, these findings imply that hyper-proliferative germ cells in the anther locules may be attributed to elevated cytokinin concentrations and disruptions in the cytokinin pathway. Using a genetic strategy, the association between germ cell hyper-proliferation and disturbed cytokinin signaling in rbr1 has been confirmed. In summary, we reveal a unique role of RBR1 in the initiation of meiosis; our results clearly demonstrate that the RBR1 regulatory module is connected to the cytokinin signaling pathway and switches mitosis to meiosis in rice.

Self-Assembled nanoparticles of natural bioactive molecules enhance the delivery and efficacy of paclitaxel in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Paclitaxel (PTX) is a well-established and highly effective anti-cancer drug for peripheral solid tumors. However, the application of PTX in GBM is hindered by several limitations, including poor water solubility, restricted entry across the blood-brain barrier (BBB), and enhanced excretion by efflux transporters. P-glycoprotein (P-gp) is a crucial efflux transporter that is abundantly present in cerebral vascular endothelial cells and GBM cells. It plays a significant role in the exocytosis of PTX within tumor tissues. METHODS: Recently, we have developed a novel technique for creating self-assembled nanoparticles utilizing a range of natural bioactive molecules. These nanoparticles can encapsulate insoluble drugs and effectively cross the BBB. In additional, we revealed that certain nanoparticles have the potential to act as P-gp inhibitors, thereby reducing the excretion of PTX. In this study, we conducted a screening of bioactive molecular nanoparticles to identify those that effectively inhibit the function of P-gp transporters. RESULTS: Among the candidates, we identified ursolic acid nanoparticles (UA NPs) as the P-gp inhibitors. Furthermore, we prepared co-assembled UA NPs embedded with paclitaxel, referred to as UA-PTX NPs. Our results demonstrate that UA-PTX NPs can enhance the blood concentration of PTX, facilitate its entry into the BBB, and inhibit the function of P-gp, resulting in a decrease in the excretion of PTX. This discovery effectively addressed the above three issues associated with the use of PTX in glioma treatment. CONCLUSIONS: UA-PTX NPs demonstrate strong anti-tumor effects and show great potential for treating GBM.

Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis.

Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for recurrent GBM is lacking, necessitating the understanding of key mechanisms driving tumor recurrence and the identification of new targets for intervention. Here, we integrated single-cell RNA-sequencing data spanning 36 patient-matched primary and recurrent GBM (pGBM and rGBM) specimens, with 6 longitudinal GBM spatial transcriptomics to explore molecular alterations at recurrence, with each cell type characterized in parallel. Genes involved in extracellular matrix (ECM) organization are preferentially enriched in rGBM cells, and MAFK is highlighted as a potential regulator. Notably, we uncover a unique subpopulation of GBM cells that is much less detected in pGBM and highly expresses ECM and mesenchyme related genes, suggesting it may contribute to the molecular transition of rGBM. Further regulatory network analysis reveals that transcription factors, such as NFATC4 and activator protein 1 members, may function as hub regulators. All non-tumor cells alter their specific sets of genes as well and certain subgroups of myeloid cells appear to be physically associated with the mesenchyme-like GBM subpopulation. Altogether, our study provides new insights into the molecular understanding of GBM relapse and candidate targets for rGBM treatment.

Ursolic acid nanoparticles for glioblastoma therapy.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). The effect of chemotherapy of GBM is limited due to the existence of blood-brain barrier (BBB). The aim of this study is to develop self-assembled nanoparticles (NPs) of ursolic acid (UA) for GBM treatment. METHODS: UA NPs were synthesized by solvent volatilization method. Western blot analysis fluorescent staining and flow cytometry were launched to explore the anti-glioblastoma mechanism of UA NPs. The antitumor effects of UA NPs were further confirmed in vivo using intracranial xenograft models. RESULTS: UA were successfully prepared. In vitro, UA NPs could significantly increase the protein levels of cleaved-caspase 3 and LC3-II to strongly eliminate glioblastoma cells through autophagy and apoptosis. In the intracranial xenograft models, UA NPs could further effectively enter the BBB, and greatly improve the survival time of the mice. CONCLUSIONS: We successfully synthesized UA NPs which could effectively enter the BBB and show strong anti-tumor effect which may have great potential in the treatment of human glioblastoma.

BZW1 as an oncogene is associated with patient prognosis and the immune microenvironment in glioma.

BACKGROUND: Glioma is the most common primary tumor in the human central nervous system. This study was designed to explore the expression of BZW1 in glioma and its relevance to the clinicopathological features and outcome of glioma patients. METHODS: Glioma transcription profiling data were obtained from The Cancer Genome Atlas (TCGA). TIMER2, GEPIA2, GeneMANIA, and Metascape were searched in the present study. Cell and animal experiments were conducted to verify the effect of BZW1 on glioma cell migration in vitro and in vivo. Transwell assays, western blotting and immunofluorescence assays were performed. RESULTS: We found that BZW1 was highly expressed in gliomas and correlated with poor prognosis. BZW1 could promote glioma proliferation. GO/KEGG analysis revealed that BZW1 was involved in collagen-containing extracellular matrix and was correlated with ECM-receptor interactions, transcriptional misregulation in cancer and the IL-17 signaling pathway. In addition, BZW1 was also associated with the glioma tumor immune microenvironment. CONCLUSION: BZW1 can promote glioma proliferation and progression, and its high expression is correlated with a poor prognosis. BZW1 is also associated with the tumor immune microenvironment of glioma. This study may facilitate further understanding of the critical role of BZW1 in human tumors, including gliomas.

The RNA-binding protein CSTF2 regulates BAD to inhibit apoptosis in glioblastoma.

RNA-binding proteins (RBP) regulate several aspects of co- and post-transcriptional gene expression in cancer cells. CSTF2 is involved in the expression of many cellular mRNAs and involved in the 3'-end cleavage and polyadenylation of pre-mRNAs to terminate transcription. However, the role of CSTF2 in human glioblastoma (GBM) and the underlying mechanisms remain unclear. In the present study, CSTF2 was found to be upregulated in GBM, and its high expression predicted poor prognosis. Knockdown CSTF2 induced GBM cell apoptosis both in vitro and in vivo. Specific mechanism studies showed that CSTF2 unstabilized the mRNA of the BAD protein by shortening its 3' UTR. Additionally, an increase in the expression level of CSTF2 decreased the expression level of BAD. In conclusion, CSTF2 binds to the mRNA of the BAD protein to shorten its 3'UTR, which negatively affects the BAD mediated apoptosis and promotes GBM cell survival.

[Corrigendum] HHLA2 is a novel prognostic predictor and potential therapeutic target in malignant glioma.

Following the publication of this article, an interested reader drew to the authors' attention that, in Fig. 1F on p. 2311 showing a representative high­grade glioma specimen, the data were either duplicated or overlapping with the data featured in Fig. 1D, which showed a low­grade glioma specimen. After having consulted their original data, the authors have realized that the data for Fig. 1D were inadvertently selected incorrectly. The corrected version of Fig. 1, now showing the correct data for the high­magnification high­grade glioma specimen in Fig. 1F, is shown on the next page. The authors sincerely apologize for the error that was introduced during the preparation of this figure, thank the Editor of Oncology Reports for granting them the opportunity to publish a Corrigendum, and are grateful to the reader for alerting them to this issue. The authors also regret any inconvenience that this mistake may have caused. [Oncology Reports 42: 2309-2322, 2019; DOI: 10.3892/or.2019.7343].

GmTOC1b inhibits nodulation by repressing GmNIN2a and GmENOD40-1 in soybean.

Symbiotic nitrogen fixation is an important factor affecting the yield and quality of leguminous crops. Nodulation is regulated by a complex network comprising several transcription factors. Here, we functionally characterized the role of a TOC1 family member, GmTOC1b, in soybean (Glycine max) nodulation. RT-qPCR assays showed that GmTOC1b is constitutively expressed in soybean. However, GmTOC1b was also highly expressed in nodules, and GmTOC1 localized to the cell nucleus, based on transient transformation in Nicotiana benthamiana leaves. Homozygous Gmtoc1b mutant plants exhibited increased root hair curling and produced more infection threads, resulting in more nodules and greater nodule fresh weight. By contrast, GmTOC1b overexpression inhibited nodulation. Furthermore, we also showed that GmTOC1b represses the expression of nodulation-related genes including GmNIN2a and GmENOD40-1 by binding to their promoters. We conclude that GmTOC1b functions as a transcriptional repressor to inhibit nodulation by repressing the expression of key nodulation-related genes including GmNIN2a, GmNIN2b, and GmENOD40-1 in soybean.

BCAS3 accelerates glioblastoma tumorigenesis by restraining the P53/GADD45α signaling pathway.

As in many other cancers, highly malignant proliferation and disordered cell division play irreplaceable roles in the exceedingly easy recurrence and complex progression of glioblastoma multiforme (GBM); however, mechanistic studies of the numerous regulators involved in this process are still insufficiently thorough. The role of BCAS3 has been studied in other cancers, but its role in GBM is unclear. Here, our goal was to investigate the expression pattern of BCAS3 in GBM and its potential mechanism of action. Using TCGA database and human GBM samples, we found that BCAS3 expression was up-regulated in GBM, and its high expression predicted poor prognosis. To further investigate the relationship between BCAS3 and GBM characteristics, we up-regulated and down-regulated BCAS3 expression in GBM to detect its effect on cell proliferation and cell cycle. At the same time, we established U87 cells stably overexpressing BCAS3 and generated an intracranial xenograft model to investigate the Potential role of BCAS3 in vivo. Finally, based on in vitro cell experiments and in vivo GBM xenograft models, we observed that BCAS3 significantly regulates GBM cell proliferation and cell cycle and that this regulation is associated with p53/GADD45α Signaling pathway. Taken together, our findings suggest that BCAS3 is inextricably linked to the progression of GBM and that targeting BCAS3 may have therapeutic effects in GBM patients.

Rho family GTPase 1 (RND1), a novel regulator of p53, enhances ferroptosis in glioblastoma.

BACKGROUND: Ferroptosis is an iron dependent cell death closely associated with p53 signaling pathway and is aberrantly regulated in glioblastoma (GBM), yet the underlying mechanism needs more exploration. Identifying new factors which regulate p53 and ferroptosis in GBM is essential for treatment. METHODS: Glioma cell growth was evaluated by cell viability assays and colony formation assays. Lipid reactive oxygen species (ROS) assays, lipid peroxidation assays, glutathione assays, and transmission electron microscopy were used to assess the degree of cellular lipid peroxidation of GBM. The mechanisms of RND1 in regulation of p53 signaling were analyzed by RT-PCR, western blot, immunostaining, co-immunoprecipitation, ubiquitination assays and luciferase reporter assays. The GBM-xenografted animal model was constructed and the tumor was captured by an In Vivo Imaging System (IVIS). RESULTS: From the The Cancer Genome Atlas (TCGA) database, we summarized that Rho family GTPase 1 (RND1) expression was downregulated in GBM and predicted a better prognosis of patients with GBM. We observed that RND1 influenced the glioma cell growth in a ferroptosis-dependent manner when GBM cell lines U87 and A172 were treated with Ferrostatin-1 or Erastin. Mechanistically, we found that RND1 interacted with p53 and led to the de-ubiquitination of p53 protein. Furthermore, the overexpression of RND1 promoted the activity of p53-SLC7A11 signaling pathway, therefore inducing the lipid peroxidation and ferroptosis of GBM. CONCLUSIONS: We found that RND1, a novel controller of p53 protein and a positive regulator of p53 signaling pathway, enhanced the ferroptosis in GBM. This study may shed light on the understanding of ferroptosis in GBM cells and provide new therapeutic ideas for GBM.

CALCIUM-DEPENDENT PROTEIN KINASE38 regulates flowering time and common cutworm resistance in soybean.

Photoperiod-sensitive plants such as soybean (Glycine max) often face threats from herbivorous insects throughout their whole growth period and especially during flowering; however, little is known about the relationship between plant flowering and insect resistance. Here, we used gene editing, multiple omics, genetic diversity and evolutionary analyses to confirm that the calcium-dependent protein kinase GmCDPK38 plays a dual role in coordinating flowering time regulation and insect resistance of soybean. Haplotype 2 (Hap2)-containing soybeans flowered later and were more resistant to the common cutworm (Spodoptera litura Fabricius) than those of Hap3. gmcdpk38 mutants with Hap3 knocked out exhibited similar flowering and resistance phenotypes as Hap2. Knocking out GmCDPK38 altered numerous flowering- and resistance-related phosphorylated proteins, genes, and metabolites. For example, the S-adenosylmethionine synthase GmSAMS1 was post-translationally upregulated in the gmcdpk38 mutants. GmCDPK38 has abundant genetic diversity in wild soybeans and was likely selected during soybean domestication. We found that Hap2 was mostly distributed at low latitudes and had a higher frequency in cultivars than in wild soybeans, while Hap3 was widely selected at high latitudes. Overall, our results elucidated that the two distinct traits (flowering time and insect resistance) are mediated by GmCDPK38.

TGF-ß induces GBM mesenchymal transition through upregulation of CLDN4 and nuclear translocation to activate TNF-α/NF-κB signal pathway.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. The unregulated expression of Claudin-4 (CLDN4) plays an important role in tumor progression. However, the biological role of CLDN4 in GBM is still unknown. This study aimed to determine whether CLDN4 mediates glioma malignant progression, if so, it would further explore the molecular mechanisms of carcinogenesis. Our results revealed that CLDN4 was significantly upregulated in glioma specimens and cells. The inhibition of CLND4 expression could inhibit mesenchymal transformation, cell invasion, cell migration and tumor growth in vitro and in vivo. Moreover, combined with in vitro analysis, we found that CLDN4 can modulate tumor necrosis factor-α (TNF-α) signal pathway. Meanwhile, we also validated that the transforming growth factor-ß (TGF-ß) signal pathway can upregulate the expression of CLDN4, and promote the invasion ability of GBM cells. Conversely, TGF-ß signal pathway inhibitor ITD-1 can downregulate the expression of CLDN4, and inhibit the invasion ability of GBM cells. Furthermore, we found that TGF-ß can promote the nuclear translocation of CLDN4. In summary, our findings indicated that the TGF-ß/CLDN4/TNF-α/NF-κB signal axis plays a key role in the biological progression of glioma. Disrupting the function of this signal axis may represent a new treatment strategy for patients with GBM.

Hsa_circ_0072309 enhances autophagy and TMZ sensitivity in glioblastoma.

AIMS: Circular RNAs have been reported to play key roles in the progression of various cancers, including gliomas. The present study was designed to investigate the role of hsa_circ_0072309 in autophagy and temozolomide (TMZ) sensitivity in glioblastoma (GBM). METHODS: The effect of hsa_circ_0072309 on autophagy and TMZ sensitivity were examined by GFP-RFP-LC3, transmission electron microscopy(TEM), flow cytometry, Western blot, and immunofluorescence. The mechanism of hsa_circ_0072309 regulating p53 signaling pathway was analyzed using Western blot, IP, and rescue experiments. RESULTS: Low hsa_circ_0072309 expression predicts poor prognosis for glioma patients. The regulation of hsa_circ_0072309 on autophagy and TMZ sensitivity depends on the status of p53. Hsa_circ_0072309 promoted autophagy by p53 signaling pathway and enhanced sensitivity of glioblastoma to temozolomide (TMZ) in p53 wild-type GBM, but not in p53 mutant GBM. Hsa_circ_0072309 inhibits p53 ubiquitination and increases the stability of p53 protein in the context of p53 wild-type. MiR-100 mediates hsa_circ_0072309 regulating p53. P53 inhibitor or autophagy inhibitor could reverse the effect of hsa_circ_0072309 on TMZ sensitivity in p53 wild-type GBM. CONCLUSIONS: This study revealed a function of hsa_circ_0072309 promoting autophagy by p53 signaling pathway and enhancing TMZ sensitivity. These findings demonstrated that hsa_circ_0072309 may be a potential and promising target in designing the treatment strategy for GBM.

The dual role of p62 in ferroptosis of glioblastoma according to p53 status.

BACKGROUND: Ferroptosis plays a key role in human cancer, but its function and mechanism in glioma is not clear. P62/SQSTM1 was reported to inhibit ferroptosis via the activation of NRF2 signaling pathway. In this study we reveal a dual role of p62 in ferroptosis of glioblastoma (GBM) according to p53 status. METHOD: Lipid peroxidation analysis, transmission electron microscopy (TEM), GSH assay were performed to determine the level of ferroptosis. Western blot and qPCR were obtained to detect the expression of ferroptosis markers. Construction of mutant plasmids, immunoprecipitation, luciferase assay and rescue-experiments were performed to explore the regulatory mechanism. RESULTS: P62 overexpression facilitates ferroptosis and inhibits SLC7A11 expression in p53 mutant GBM, while attenuates ferroptosis and promotes SLC7A11 expression in p53 wild-type GBM. P62 associates with p53 and inhibits its ubiquitination. The p53-NRF2 association and p53-mediated suppression of NRF2 antioxidant activity are diversely regulated by p62 according to p53 status. P53 mutation status is required for the dual regulation of p62 on ferroptosis. In wild-type p53 GBM, the classical p62-mediated NRF2 activation pathway plays a major regulatory role of ferroptosis, leading to increased SLC7A11 expression, resulting in a anti-ferroptosis role. In mutant p53 GBM, stronger interaction of mutant-p53/NRF2 by p62 enhance the inhibitory effect of mutant p53 on NRF2 signaling, which reversing the classical p62-mediated NRF2 activation pathway, together with increased p53's transcriptional suppression on SLC7A11 by p62, leading to a decrease of SLC7A11, resulting in a pro-ferroptosis role. CONCLUSION: Together, this study shows novel molecular mechanisms of ferroptosis regulated by p62; the mutation status of p53 is an important factor that determines the therapeutic response to p62-mediated ferroptosis-targeted therapies in GBM.

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.

HSP27 protects against ferroptosis of glioblastoma cells.

Ferroptosis, as an new form of non-apoptotic regulated cell death, plays an important role in human cancers. Although it is reported that HSP27 is an novel regulator of ferroptosis in cancer, it remains unknown how HSP27 affects ferroptosis in glioma. In this study, we examined the effect of HSP27 on the ferroptosis of glioblasotma. HSP27 overexpression protects glioblastoma cells from erastin-induced ferroptosis while HSP27 depletion promotes erastin-induced ferroptosis of glioblastoma. Notably, HSP27 phosphorylation is required for the protective function of HSP27 in erastin-induced ferroptosis. Overall, our study reveal novel molecular mechanisms of ferroptosis in glioma and also identify HSP27 as a negative regulator of ferroptosis and a potential target for the treatment of glioma.

MICAL2 Promotes Proliferation and Migration of Glioblastoma Cells Through TGF-ß/p-Smad2/EMT-Like Signaling Pathway.

Recent studies showed that molecule interacting with CasL2 (MICAL2) could be a novel tumor growth factor, and it is closely associated with tumor growth and invasion. However, the role it plays in glioblastoma (GBM) and its potential mechanisms are currently unknown. Our study is designed to identify the effect of MICAL2 on GBM cells and the potential mechanisms behind it. Here, we found that MICAL2 interacts with TGF receptor-type I (TGFRI) and promotes the proliferation and migration of glioblastoma through the TGF-ß/p-Smad2/EMT-like signaling pathway. MICAL2-knockdown inhibited the proliferation of glioblastoma cells, which was related to cell cycle arrest and downregulation of DNA replication. The invasion abilities of U87 and U251 cells were reduced after the knockdown of MICAL2. MICAL2 promoted the growth of GBM in nude mice. High MICAL2 predicts poor outcome of GBM patients. MICAL2 could be identified as a novel promising therapeutic target for human GBM.