U937 Cells Research Articles

Carbon ion irradiation conquers the radioresistance by inducing complex DNA damage and apoptosis in U251 human glioblastomas cells.

Glioblastoma multiforme (GBM) is the most malignant brain tumor, with radiotherapy frequently employed following surgical resection. However, conventional radiation therapies often yield suboptimal results. This study investigated the effects of X-ray and carbon ion irradiation on the glioblastoma cell line U251 to assess the distinctive advantages of carbon ion treatment and explore mechanisms for overcoming radiation resistance. The findings indicated that carbon ion irradiation more effectively inhibited colony formation and induced more severe apoptosis and cell cycle disorder in U251 cells. Immunofluorescence assays revealed larger and more abundant ϒ-H2AX and 53BP1 foci in the carbon ion irradiation group. Western blot analysis demonstrated that carbon ion-induced DNA damage repair involved a complex array of pathways, with the RAD51-mediated homologous recombination (HR) pathway being predominant, while the Rad23B-mediated nucleotide excision repair (NER) pathway and XRCC1-mediated base excision repair (BER) were more relevant in response to X-ray irradiation. These results suggest that carbon ion irradiation may overcome radioresistance by inducing more complex DNA damage and apoptosis, thus providing insights for targeting new strategies in combining gene therapy with radiotherapy.

Exploratory Study on Nanoparticle Co-Delivery of Temozolomide and Ligustilide for Enhanced Brain Tumor Therapy

Background: Temozolomide (TMZ) is the first-line therapy for glioblastoma (GBM), but its clinical efficacy is limited by its short half-life, poor brain targeting, adverse side effects, and the development of drug resistance. Ligustilide (LIG) has been shown to enhance blood-brain barrier permeability and reduce P-glycoprotein activity, thereby potentiating the synergistic effect of TMZ against GBM. Methods: The dual-drug-loaded nanoparticles encapsulating both TMZ and LIG (TMZ/LIG-NPs) were prepared using Poly (d,l-lactic-co-glycolide)-monomethoxy poly (ethylene glycol) (PLGA-mPEG). The physicochemical properties of the NPs, including particle size and zeta potential, were characterized. Cellular uptake of NPs was evaluated using flow cytometry and fluorescence staining. The pharmacokinetic profile and cytotoxicity of TMZ/LIG-NPs were compared to those of free TMZ and a mixture of TMZ and LIG in rat and glioma cells, respectively. Results: The mean particle size of TMZ/LIG-NPs was 117.6 ± 0.7 nm, with a zeta potential of −26.5 ± 0.4 mV. Cellular uptake of NPs was significantly higher than that of free drug in U251 cells. Encapsulation of TMZ in NPs significantly increased its half-life by 1.62-fold compared to free TMZ and significantly improved its pharmacokinetic profile. Moreover, the storage stability of the TMZ/LIG-NPs solution was extended to one month. The toxicity of TMZ/LIG-NPs to glioma cells C6 and U251 was markedly enhanced compared to the mixture of TMZ and LIG. Conclusions: The development of TMZ/LIG-NPs using PLGA-mPEG effectively enhanced the stability and efficacy of both TMZ and LIG. This dual drug-loaded nanoparticle system represents a promising strategy for glioblastoma therapy.

Hempseed Water-Soluble Protein Fraction and Its Hydrolysate Display Different Biological Features

Hempseeds, from the Cannabis sativa plant, and its derivates are a versatile food option for various dietary preferences. Due to their aminoacidic profile, researchers have studied the presence of bioactive peptides in hempseed proteins. In this study, the water-soluble fraction of hempseed protein was extracted, and the derived peptides were analyzed. The investigation focused on their biological function, particularly their antioxidant activity. Several biological functions have arisen, such as angiotensin-converting enzyme inhibition activity, dipeptidyl-peptidase IV, dipeptidyl-peptidase III inhibition, and ubiquitin-mediated proteolysis activation. The hydrolysates show greater 2,2-azinobis-[3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity compared to the proteins (97.95 ± 4.48 versus 81.04 ± 10.63). Furthermore, the impact of these proteins and peptides on the U937 cell line was evaluated to assess cell viability and their potential role in modulating inflammation associated with gastrointestinal autoimmune diseases. Protein treatment resulted in a significant reduction in cell viability, as opposed to hydrolysates, which did not affect it.

Radiosensitizing Capacity of Fenofibrate in Glioblastoma Cells Depends on Lipid Metabolism

Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average survival time <2 years). Altered lipid metabolism, which increases fatty acid synthesis and thereby contributes to radioresistance in GBM, is a hallmark of cancer. Therefore, we explored the radiosensitizing effect of the clinically approved, lipid-lowering drug fenofibrate (FF) in different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress and impairing mitochondrial membrane integrity, but radioprotects LN18 cells by reducing the production of reactive oxygen species (ROS) and stabilizing the mitochondrial membrane potential. A comparative protein and lipid analysis revealed striking differences in the two GBM cell lines: LN18 cells exhibited a significantly higher membrane expression density of the fatty acid (FA) cluster protein transporter CD36 than U87 cells, a higher expression of glycerol-3-phosphate acyltransferase 4 (GPAT4) which supports the production of large lipid droplets (LDs), and a lower expression of diacylglycerol O-acyltransferase 1 (DGAT1) which regulates the formation of small LDs. Consequently, large LDs are predominantly found in LN18 cells, whereas small LDs are found in U87 cells. After a combined treatment of FF and irradiation, the number of large LDs significantly increased in radioresistant LN18 cells, whereas the number of small LDs decreased in radiosensitive U87 cells. The radioprotective effect of FF in LN18 cells could be associated with the presence of large LDs, which act as a sink for the lipophilic drug FF. To prevent uptake of FF by large LDs and to ameliorate its function as a radiosensitizer, FF was encapsulated in biomimetic cell membrane extracellular lipid vesicles (CmEVs) which alter the intracellular trafficking of the drug. In contrast to the free drug, CmEV-encapsulated FF was predominantly enriched in the lysosomal compartment, causing necrosis by impairing lysosomal membrane integrity. Since the stability of plasma and lysosomal membranes is maintained by the presence of the stress-inducible heat shock protein 70 (Hsp70) which has a strong affinity to tumor-specific glycosphingolipids, necrosis occurs predominantly in LN18 cells having a lower membrane Hsp70 expression density than U87 cells.In summary, our findings indicate that the lipid metabolism of tumor cells can affect the radiosensitizing capacity of FF when encountered either as a free drug or as a drug loaded in biomimetic lipid vesicles.

Design, Synthesis, and Anti‐Glioma Activity Evaluation of Dehydroabietic Acid Derivatives

AbstractDehydroabietic acid (DHAA) is a common natural product with a broad range of biological activities. In previous research, our group identified a range of dehydroabietic acid derivatives with strong anti‐glioma activity. In order to search for better anti‐glioma drugs candidates, new chalcone derivatives A1‐A10 and B1‐B10 were designed and synthesized in this study. The antiproliferative activity of these derivatives against U87 glioma cells was tested by CCK‐8 assay, in which A10 has the best IC50 value of 11.39 µM. Scratch and cloning studies further confirmed that A10 strongly inhibited the proliferation and colony‐forming activity of U87 cells. The antiproliferative activity of A10 on U87 cells showed some concentration dependence manner and the pKa values of A10 were within the desirable range of anti‐gliomas drugs. In addition, molecular docking revealed hydrogen bonding interaction was formed between A10 and the target protein. These results suggest that A10 may be a promising DHAA‐derived lead compound that deserves further strategic optimization in search of the anticancer candidates against glioma.

Dynole‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

AbstractDynamin plays a crucial role in mitosis, and dynamin inhibition broadly correlates with cytotoxicity. Dynole 34–2, dynamin inhibitor, is highly cytotoxic, but its poor drug‐like properties limit its in vivo development. Three focused libraries of dynole‐based dynamin inhibitors were synthesized enhance their druglike properties while maintaining their dynamin inhibition and cytotoxicity. Iterative modifications were undertaken to probe the effects of changes to the cyanoacrylamide linker amide, alkyl chain moieties, the N‐propyl‐N,N‐dimethylamino moiety and the indole core. These compounds were screened against: HT29 and SW480 (colon), SMA (spontaneous murine astrocytoma), MCF‐7 (breast), BE2‐C (glioblastoma), SJ‐G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines to reveal a good correlation between dynamin inhibition and cytotoxicity. High potency against brain cancer cell lines was observed. The most dynamin active compounds returned average GI50 values of 2.26 and 1.5 µM across the cell lines examined. The most active compound against 4 brain cancer cell lines averaged a GI50 value of 4.7 µM; 10‐fold improved over the gold standard for glioblastoma treatment; temozolomide. Importantly, this maintained a tPSA of 24.8Å2 and cLogP of 4.11; appropriate for blood brain barrier penetration. This active analogue in this series was (Z)‐2‐(3,4‐dichlorophenyl)‐3‐(1‐(3‐(dimethylamino)propyl)‐1H‐pyrrol‐3‐yl)acrylonitrile (34).

Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.

In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-κB subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry "fingerprinting", immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-κB activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-κB activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-κB inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2- and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL.

Hypoxia-Inducible Factor-1α Regulates BNIP3-Dependent Mitophagy and Mediates Metabolic Reprogramming Through Histone Lysine Lactylation Modification to Affect Glioma Proliferation and Invasion.

Gliomas are the predominant form of malignant brain tumors. We investigated the mechanism of hypoxia-inducible factor-1α (HIF-1α) affecting glioma metabolic reprogramming, proliferation and invasion. Human glioma cell U87 was cultured under hypoxia and treated with small interfering (si)HIF-1α, si-B cell lymphoma-2/adenovirus E1B 19-kDa interacting protein 3 (siBNIP3), si-YT521-B homology domain 2 (siYTHDF2), 3-methyladenine and 2-deoxyglucose, with exogenous sodium lactate-treated normally-cultured cells as a lactate-positive control. Cellular hexokinase 2, lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 enzyme activities, glucose uptake, and levels of lactic acid and adenosine triphosphate (ATP), and HIF-1α, glycolysis-related proteins, mitophagy-related proteins, histone H3 lysine 18 lactylation (H3K18la) and YTHDF2 were determined by ELISA, 2-NBDG, kits, and Western blot. Extracellular acidification rate (ECAR), and cell proliferation, invasion, apoptosis and mitophagy were evaluated by extracellular flux analysis, CCK-8, Transwell, flow cytometry, and immunofluorescence staining. H3K18la-YTHDF2 relationship and YTHDF2-BNIP3 interaction were assessed by ChIP and Co-IP assays. Hypoxia-induced highly-expressed HIF-1α in glioma cells increased glycolysis-related protein levels, glycolytic enzyme activities, glucose uptake, lactic acid production, ATP level and ECAR, thereby promoting metabolic reprogramming, invasion and proliferation. HIF-1α mediated metabolic reprogramming, proliferation and invasion through BNIP3-dependent mitophagy, which were partly negated by mitophagy inhibition. HIF-1α induced histone Kla modification to upregulate YTHDF2. YTHDF2 downregulation impeded YTHDF2-BNIP3 interaction and inhibited HIF-1α-induced BNIP3-dependent mitophagy, curbing glioma cell metabolic reprogramming, proliferation and invasion. Hypoxia-induced high HIF-1α expression upregulated YTHDF2 through hH3K18la modification, enhanced YTHDF2-BNIP3 interaction, and regulated BNIP3-dependent mitophagy-mediated metabolic reprogramming to affect glioma proliferation and invasion.

Differential Effects of Sertraline and Penfluridol on EMT and ECM Remodeling in Glioblastoma Cell Lines

Background and Purpose: Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis due to rapid recurrence, chemoresistance, and limited efficacy of standard therapies. Epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling are critical processes in GBM progression and metastasis. The aim of this study is to examine the potential effects of sertraline and penfluridol on the EMT process and gelatinase activity in human glioblastoma cell lines. Methods: U87 and U251 human glioblastoma cells were treated with sertraline and penfluridol at previously identified IC50 doses. Protein levels of EMT markers, E-cadherin, vimentin, Snail, Slug, Twist1, phospho-Akt (p-Akt), and tissue inhibitor of metalloproteinases-2 (TIMP-2), were evaluated using Western blotting. Additionally, the impact of sertraline and penfluridol on the release and activity of MMP-2 and MMP-9 were assessed through gelatin zymography. Results: Both sertraline and penfluridol significantly reduced vimentin expression in U251 cells, indicating inhibition of the mesenchymal phenotype. Conversely, these drugs increased vimentin levels in U87 cells, highlighting cell line-specific differences. Sertraline and penfluridol also increased TIMP-2 levels in U251 cells but not in U87 cells. Neither drug altered MMP-2 or MMP-9 activity in either cell line, suggesting that their effects on ECM remodeling may be mediated through TIMP-2 upregulation rather than direct modulation of gelatinase activity. Conclusion: These findings suggest that sertraline and penfluridol potentially inhibit EMT and reduce ECM degradation in U251 cells but exert contrasting effects in U87 cells. This highlights the heterogeneity of GBM tumors and the importance of personalized therapeutic approaches.

Sophoricoside Inhibited Glioblastoma Cell Progression Through Activated AMP-Activated Protein Kinase (AMPK).

Glioblastoma (GBM) is the most common malignant primary brain tumor, with a mean survival of less than 2 years. Unique brain structures and the microenvironment, including blood-brain barriers, put great challenges on clinical drug development. Sophoricoside (Sop), an isoflavone glycoside isolated from seeds of Sophora japonica L., is one of the active constituents of traditional Chinese medicine and found to inhibit the bioactivity of cytokines (e.g., interleukin-5) and inflammatory responses, as well as to attenuate glucose and lipid metabolism in related diseases. However, the effects of Sop on cancer progression have not been systemically investigated. In this study, we performed a comprehensive investigation of Sop's function in GBM using colony formation and Transwell assays in vitro, along with subcutaneous xenograft tumor analysis in vivo. We employed RNA sequencing and bioinformatics analysis in conjunction with Western blotting (WB) and reverse transcription-quantitative polymerase chain reaction (RT-PCR) to explore the underlying mechanism. Our results demonstrated that Sop suppressed U251 cell proliferation and metastasis in vitro and inhibited the tumorigenic behavior of U251 cells in vivo. Further investigations revealed a positive correlation between the levels of activated AMP-activated protein kinase (AMPK) and Sop treatment; notably the application of the AMPK inhibitor, compound C (CC), abolished inhibitory effects of Sop on the malignant phenotype of U251 cells. These findings suggest the potential application of Sop in GBM treatment and highlight opportunities for the development of new therapeutic strategies.

Nanoparticle encapsulation enables systemic IGF-Trap delivery to inhibit intra-cerebral glioma growth.

Glioblastoma is an aggressive brain cancer with a 5-year survival rate of 5-10%. Current therapeutic options are limited, due in part to drug exclusion by the blood-brain barrier, restricting access of targeted drugs to the tumor. The receptor for the type 1 insulin-like growth factor (IGF-1R) was identified as a therapeutic target in glioblastoma. We previously reported that the intracerebral growth of glioma cells with reduced IGF-1R levels was inhibited. The objectives of this study were to evaluate the sensitivity of glioma cells to a novel IGF-axis inhibitor, the IGF-Trap, and optimize its delivery to the brain. We tested the effect of the IGF-Trap on the growth of the human glioma stem cells MES-1123 and U87 MG cells, and of murine GL261 cells in vivo, using subcutaneous and orthotopic implantation. We show that the growth of glioma cells implanted subcutaneously or orthotopically in the brain was inhibited by systemic and direct intracerebral administration of IGF-Trap, respectively, resulting in increased survival. To increase the efficiency of systemic delivery to the brain, we encapsulated the IGF-Trap in trimethyl chitosan (TRIOZAN™) nanoparticles prior to intravenous injection. We found that nanoparticle encapsulation increased the uptake and retention of the IGF-Trap in the brain and resulted in an improved therapeutic effect against intra-cerebrally growing tumors. Our results identify the IGF-Trap as a potent inhibitor of intracerebral glioma growth and show that encapsulation in nanoparticles can improve delivery of biologics such as the IGF-Trap to the brain, thereby enhancing the therapeutic response.

GOLPH3 inhibits glioma cell apoptosis through the JNK signaling pathway

BackgroundGlioma, a primary intracranial tumor, is marked by high rates of mortality and disability, making it a significant health concern. Understanding the molecular mechanisms underlying glioma initiation and progression and identifying potential therapeutic targets for gene therapy are crucial for improving patient outcomes. Golgi phosphoprotein 3 (GOLPH3), predominantly localized at the trans-Golgi network, has been implicated in the pathogenesis of various cancers. However, its precise role in glioma progression remains under active investigation.MethodsTo elucidate the function of GOLPH3, U87 glioma cells were transfected with GOLPH3-specific small interfering RNA (siRNA) to suppress its expression. An in vivo glioma model was generated by implanting GOLPH3-knockdown U87 cells into nude mice. Apoptosis was assessed using flow cytometry, immunofluorescence staining, TUNEL assays, and Western blotting. The activation of the JNK signaling pathway was evaluated by analyzing the phosphorylation levels of JNK and c-Jun through Western blotting.ResultsDownregulation of GOLPH3 in U87 glioma cells significantly enhanced apoptosis, as evidenced by increased levels of cleaved caspase-3 and higher apoptosis rates. Furthermore, GOLPH3 knockdown led to the activation of the JNK signaling pathway, as indicated by elevated phosphorylation of JNK and c-Jun. In vivo, suppression of GOLPH3 expression inhibited tumor growth and increased apoptosis within the tumor microenvironment.ConclusionThese findings suggest that GOLPH3 might play a pivotal role in regulating apoptosis in malignant glioma cells via the JNK signaling pathway. Thus, GOLPH3 may represent a promising therapeutic target for glioma treatment.

Screening and identification of host signaling pathways for alleviating influenza-induced production of pro-inflammatory cytokines, IP-10, IL-8, and MCP-1, using a U937 cell-based influenza model

Influenza virus infection initiates an exaggerated inflammatory response, which may culminate in a fatal cytokine storm characterized by the excessive production of pro-inflammatory cytokines. Prior research indicates that IP-10, IL-8, and MCP-1, primarily produced by monocytes and macrophages, play a crucial role in influenza-induced inflammation. The lung injury from influenza virus infection can be mitigated by suppressing or inhibiting these cytokines through knockout, knockdown, or targeted intervention approaches. To identify the key host signaling pathways responsible for producing pro-inflammatory cytokines, we utilized a U937 cell model that secretes IP-10, IL-8, and MCP-1 in response to influenza infection. This model has been previously validated in our laboratory as an appropriate system for screening anti-inflammatory agents and potential drug targets. We conducted a screening assay employing an inhibitor library consisting of 2,138 compounds that target various known pathways and host factors. Our findings indicated that inhibitors targeting protein tyrosine kinases and mitogen-activated protein kinases demonstrated superior efficacy in suppressing cytokine production induced by influenza A virus infection compared to inhibitors aimed at other host factors. Notably, a substantial proportion of the identified hits capable of inhibiting the expression of all three cytokines in the secondary screening were classified as tyrosine kinase inhibitors. Validation experiments further established that Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways, along with p38 MAPK and Raf–MEK–ERK pathways, are the principal regulators of pro-inflammatory cytokine expression in monocytes and macrophages. Moreover, our results suggest that TKIs present promising opportunities as novel therapeutic agents against influenza-induced pneumonia.

Radiosensitization of Rare-Earth Nanoparticles Based on the Consistency Between Its K-Edge and the X-Ray Bremsstrahlung Peak

Nanoparticle-based X-ray radiosensitization strategies have garnered significant attention in recent years. However, the underlying mechanisms of radiosensitization remain incompletely understood. In this work, we explore the influence of the K-edge effect in the X-ray absorption of nanomaterials on sensitization. Due to the alignment of the K-edge of thulium (Tm) with the Bremsstrahlung peak in the energy spectrum of medical X-ray accelerators, the following four different rare-earth nanomaterials with varying Tm percentages were designed: NaTmF4, NaTm0.6Lu0.4F4, NaTm0.4Lu0.6F4, and NaLuF4. We evaluated the X-ray absorption and the ability to generate secondary electrons and reactive oxygen species (ROS) of these nanoparticles. The radiosensitizing effect was evaluated through clonogenic assays. Our results showed that the K-edge effect affected secondary electron generation but did not significantly change ROS production. Nonetheless, NaTmF4 induced marginally more DNA damage in the U87 cells than the other cell types. NaTmF4 also exhibited superior radiosensitization efficacy against the U87 tumor cells. This shows that secondary electrons and ROS play pivotal roles in radiosensitization, which might be crucial to improving cancer treatment efficacy through enhanced radiation therapy outcomes.

Mogroside V ameliorates astrocyte inflammation induced by cerebral ischemia through suppressing TLR4/TRADD pathway.

Inflammation and oxidative stress are pivotal factors in the onset and progression of secondary injury following cerebral ischemia-reperfusion (I/R). Mogroside V (MV), a primary active compound of Siraitia grosvenorii, exhibits significant anti-inflammatory and antioxidant properties. However, its specific effects in cerebral ischemia remain unclear. In this study, we evaluated the neuroprotective effects of MV in a model of focal cerebral ischemia. Male C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) as an in vivo model of cerebral ischemia-reperfusion injury (CIRI), while U87 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate CIRI in vitro. MV administration was found to reduce mortality, infarct volume, cerebral edema, and alleviate neurological deficits in these I/R mice. Furthermore, MV mitigated cerebral I/R injury by decreasing oxidative stress markers, such as reactive oxygen species (ROS) and malondialdehyde (MDA), while enhancing superoxide dismutase (SOD) levels. Gene Set Enrichment Analysis (GSEA) of the KEGG pathway revealed that most differentially expressed genes (DEGs) were involved in the Toll-like receptor/NF-κB/TNF/apoptosis signaling pathway. These findings were confirmed by real-time PCR, western blotting, immunohistochemistry, and immunofluorescence co-localization which demonstrated that MV reduced astrocyte inflammatory responses by inhibiting cytokine secretion associated with the TLR4/TRADD pathway. Additionally, MV protected neurons from apoptosis, as supported by TUNEL, Nissl, and HE staining. In conclusion, MV attenuates astrocyte inflammation and exerts neuroprotective effects following cerebral I/R injury, likely through suppression of the TLR4/TRADD signaling pathway.

Glut-1 exerts anti-tumor activity in glioma by regulating AKT / mTOR signaling pathway

Objective Glioma is a common tumor in neurosurgery. Glut-1 is the main carrier of glucose uptake by cells and can provide energy through the glycolytic pathway. However, the role and related mechanisms of Glut-1 in glioma have not yet been elucidated. Methods Real time PCR and Western blot were done to assess Glut-1 level in glioma tumor tissues and adjacent tissues. Glioma U87 cells were separated into control group; Glut-1 negative control (NC group); and Glut-1 siRNA group followed by analysis of Glut-1 expression, cell proliferation by MTT assay, cell invasion, cell apoptosis and cycle by flow cytometry and AKT / mTOR signaling proteins level by Western blot. Results Glut-1 expression was significantly increased in the tissues of glioma patients (P &lt; 0.05) compared to adjacent tissues and its level was related to tumor size, pathological grade and survival. Down-regulating the expression of Glut-1 can significantly inhibit tumor cell proliferation and invasion, increase apoptosis and induce G0 phase of cell cycle arrest, and inhibit the expression of AKT / mTOR signaling proteins phosphorylation (P &lt; 0.05). Conclusions Glut-1 level in glioma tissues is significantly increased, which is related to the pathological features. Down-regulating Glut-1 can inhibit glioma by regulating the AKT / mTOR signaling pathway.

Cinnamaldehyde impacts key cellular signaling pathways for induction of programmed cell death in high-grade and low-grade human glioma cells

ObjectivePrimary tumors of the brain and a large percent of malignant brain tumors are gliomas. Gliomas comprise high-grade gliomas like glioblastoma multiforme (GBMs), many of which have mutation in the tumor suppressor p53 gene and low-grade gliomas (LGGs). LGGs can progress to GBMs due to various factors. The available treatment options for GBMs and LGGs include surgical resection, radiation and chemotherapy. The chemotherapeutic drug available in the clinic is temozolomide (TMZ). However, TMZ can cause damage to DNA if taken for prolonged period. This warrants the discovery of drugs that would potentially elicit less adverse side effects while maintaining anticancer activity. To this end, we evaluated the impact of cinnamaldehyde (CA), a single, purified component of the natural product cinnamon.ResultsThe elucidation of the mechanism of action revealed the impact of CA on reactive oxygen species (ROS) levels. Moreover, its effect on the extrinsic programmed cell death pathway resulted in the increase of apoptotic cell populations, invoking multicaspase. Notably, the cell survival/death pivotal molecule Bcl-2 was impacted. These effects were observed in both the types of brain tumor cells studied: GBMs, represented by U251 cells (p53 mutated cell line) and LGGs represented by H4 cells. Results from the current study suggest potential for CA as a therapeutic option as it is expected to have fewer adverse side effects due to it being a component of a natural product and possibly deter the progression of LGGs to GBMs.

The Synthesis, Crystal Structure, Modification, and Cytotoxic Activity of α-Hydroxy-Alkylphosphonates.

A series of α-hydroxy-alkylphosphonates and α-hydroxy-alkylphosphine oxides were synthesized by the Pudovik reaction of acetaldehyde and acetone with dialkyl phosphites or diarylphosphine oxides. The additions were performed in three different ways: in liquid phase using triethylamine as the catalyst (1), on the surface of Al2O3/KF solid catalyst (2), or by a MW-assisted Na2CO3-catalyzed procedure (3). In most of the cases, our methods were more efficient and more robust than those applied in the literature. Two of the α-hydroxy-alkylphosphonates were subjected to single-crystal X-ray analysis, suggesting a dimeric and a chain supramolecular buildup in their respective crystals. Four α-hydroxy-alkylphosphonates and one α-hydroxy-ethylphosphine oxide were reacted with different acid chlorides to afford ten α-acyloxyphosphonates. Diethyl α-hydroxy-ethylphosphonate was transformed to the methanesulfonyloxy derivative that was useful in the Michaelis-Arbuzov reaction with triethyl phosphite and ethyl diphenylphosphinite to afford tetraethyl ethylidenebisphosphonate and diethyl α-(diphenylphosphinoyl)-ethylphosphonate, respectively. The α-hydroxyphosphonates and α-hydroxyphosphine oxides prepared were subjected to bioactivity studies, and the compounds tested exhibited limited cytotoxic effects on U266 cells with modest reductions in viability at a concentration of 100 μM.

Targeting JAK/STAT3 in glioblastoma cells using an alginate-PNIPAm molecularly imprinted hydrogel for the sustained release of ruxolitinib.

Glioblastoma (GBM) is a notoriously aggressive primary brain tumor characterized by elevated recurrence rates and poor overall survival despite multimodal treatment. Local treatment strategies for GBM are safer and more effective alternatives to systemic chemotherapy, directly tackling residual cancer cells in the resection cavity by circumventing the blood-brain barrier. Molecularly imprinted polymers (MIPs) are promising drug delivery systems due to their high-affinity binding cavities that enable tailored release kinetics. This study reports the development of a semi-synthetic polysaccharide MIP-based hydrogel intended for the post-surgical management of GBM. The biodegradable implant, made of calcium-crosslinked alginate-poly(N-isopropylacrylamide) graft copolymer, was designed for the sustained release of ruxolitinib (RUX) in the resection cavity, targeting the Janus kinase/Signal Transducer and Activator of Transcription-3 signaling pathway. The molecularly imprinted hydrogel demonstrated thermo-thickening and shear-thinning behavior, high entrapment efficiency of RUX (84.59±0.73%), and sustained release over 14days, underscoring the advantages that molecular imprinting of the alginate matrix provides compared to conventional MIPs. The dose-dependent inhibitory effects of the imprinted hydrogel against U251 and A172 GBM cells were demonstrated by increased apoptosis, reduced confluence, colony formation, and delayed wound healing, whereas the non-imprinted hydrogel was biocompatible. The MIP hydrogel could be a safe and effective GBM treatment.

Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma

Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment.Graphical