Microenvironment-Responsive Hydrogel Reduces Seizures After Traumatic Brain Injury in Juvenile Rats by Reducing Oxidative Stress and Hippocampal Inflammation.

Traumatic brain injury (TBI) is the primary cause of child mortality and disability worldwide. It can result in severe complications that significantly impact children's quality of life, including post-traumatic epilepsy (PTE). An increasing number of studies suggest that TBI-induced oxidative stress and neuroinflammatory sequelae (especially, inflammation in the hippocampus region) may lead to the development of PTE. Due to the blood-brain barrier (BBB), typical systemic pharmacological therapy for TBI cannot deliver berberine (BBR) to the targeted location in the early stages of the injury, although BBR has strong anti-inflammatory properties. To break through this limitation, a microenvironment-responsive gelatin methacrylate (GM) hydrogel to deliver poly(propylene sulfide)60 (PPS60) and BBR (GM/PB) is developed for regulating neuroinflammatory reactions and removing reactive oxygen species (ROS) in the brain trauma microenvironment through PPS60. In situ injection of the GM/PB hydrogel efficiently bypasses the BBB and is administered directly to the surface of brain tissue. In post-traumatic brain injury models, GM/PB has the potential to mitigate oxidative stress and neuroinflammatory responses, facilitate functional recovery, and lessen seizing. These findings can lead to a new treatment for brain injuries, which minimizes complications and improves the quality of life.

Inhibition of chromosomal region maintenance 1 suppresses the migration and invasion of glioma cells via inactivation of the STAT3/MMP2 signaling pathway.

Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.

MALT1 is a potential therapeutic target in glioblastoma and plays a crucial role in EGFR-induced NF-κB activation.

Glioblastoma multiforme (GBM) is the most common malignant tumour in the adult brain and hard to treat. Nuclear factor κB (NF-κB) signalling has a crucial role in the tumorigenesis of GBM. EGFR signalling is an important driver of NF-κB activation in GBM; however, the correlation between EGFR and the NF-κB pathway remains unclear. In this study, we investigated the role of mucosa-associated lymphoma antigen 1 (MALT1) in glioma progression and evaluated the anti-tumour activity and effectiveness of MI-2, a MALT1 inhibitor in a pre-clinical GBM model. We identified a paracaspase MALT1 that is involved in EGFR-induced NF-kB activation in GBM. MALT1 deficiency or inhibition significantly affected the proliferation, survival, migration and invasion of GBM cells both in vitro and in vivo. Moreover, MALT1 inhibition caused G1 cell cycle arrest by regulating multiple cell cycle-associated proteins. Mechanistically, MALTI inhibition blocks the degradation of IκBα and prevents the nuclear accumulation of the NF-κB p65 subunit in GBM cells. This study found that MALT1, a key signal transduction cascade, can mediate EGFR-induced NF-kB activation in GBM and may be potentially used as a novel therapeutic target for GBM.

Palladium Catalysis for Aerobic Oxidation Systems Using Robust Metal-Organic Framework.

Described here is a new and viable approach to achieve Pd catalysis for aerobic oxidation systems (AOSs) by circumventing problems associated with both the oxidation and the catalysis through an all-in-one strategy, employing a robust metal-organic framework (MOF). The rational assembly of a PdII catalyst, phenanthroline ligand, and CuII species (electron-transfer mediator) into a MOF facilitates the fast regeneration of the PdII active species, through an enhanced electron transfer from in situ generated Pd0 to CuII , and then CuI to O2 , trapped in the framework, thus leading to a 10 times higher turnover number than that of the homogeneous counterpart for Pd-catalyzed desulfitative oxidative coupling reactions. Moreover, the MOF catalyst can be reused five times without losing activity. This work provides the first exploration of using a MOF as a promising platform for the development of Pd catalysis for AOSs with high efficiency, low catalyst loading, and reusability.

The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a fatal brain tumor, lacking effective treatment. Epidermal growth factor receptor (EGFR) is recognized as an attractive target for GBM treatment. However, GBMs have very poor responses to the first- and second-generation EGFR inhibitors. The third-generation EGFR-targeted drug, AZD9291, is a novel and irreversible inhibitor. It is noteworthy that AZD9291 shows excellent blood-brain barrier penetration and has potential for the treatment of brain tumors. METHODS: In this study, we evaluated the anti-tumor activity and effectiveness of AZD9291 in a preclinical GBM model. RESULTS: AZD9291 showed dose-responsive growth inhibitory activity against six GBM cell lines. Importantly, AZD9291 inhibited GBM cell proliferation > 10 times more efficiently than the first-generation EGFR inhibitors. AZD9291 induced GBM cell cycle arrest and significantly inhibited colony formation, migration, and invasion of GBM cells. In an orthotopic GBM model, AZD9291 treatment significantly inhibited tumor survival and prolonged animal survival. The underlying anti-GBM mechanism of AZD9291 was shown to be different from that of the first-generation EGFR inhibitors. In contrast to erlotinib, AZD9291 continuously and efficiently inhibited the EGFR/ERK signaling in GBM cells. CONCLUSION: AZD9291 demonstrated an efficient preclinical activity in GBM in vitro and in vivo models. AZD9291 has been approved for the treatment of lung cancer with good safety and tolerability. Our results support the possibility of conducting clinical trials of anti-GBM therapy using AZD9291.

microRNA-4500 inhibits human glioma cell progression by targeting IGF2BP1.

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) overexpression promotes glioma cell progression. The aim of the current study is to silence IGF2BP1 in glioma cells by the microRNA (miRNA) strategy. The bio-informatic analyses identified that microRNA-4500 (miR-4500) putatively targets 3'-UTR (3'-untranslated region) of IGF2BP1. In A172 cells and primary human glioma cells ectopic overexpression of the wild-type miR-4500 (but not the mutant form) downregulated IGF2BP1 and its target genes (Gli1, IGF2 and c-Myc). Functional studies show that ectopic miR-4500 overexpression inhibited glioma cell growth, survival, proliferation, migration and invasion. Conversely, in A172 cells miR-4500 inhibition, by a lentiviral construct, increased expression of IGF2BP1 and its targets, promoting cell survival, proliferation and migration. Furthermore, IGF2BP1 knockout by the CRISPR/Cas9 method inhibited A172 cell progression. Significantly, miR-4500 overexpression or miR-4500 inhibition was ineffective in IGF2BP1 knockout A172 cells. At last, we show that miR-4500 levels are downregulated in human glioma tissues, correlating with IGF2BP1 upregulation. Together, we conclude that miR-4500 inhibits human glioma cell progression by targeting IGF2BP1.

Enhanced Activity and Enantioselectivity of Henry Reaction by the Postsynthetic Reduction Modification for a Chiral Cu(salen)-Based Metal-Organic Framework.

Metal-organic frameworks (MOFs) imbedded privileged molecular catalysts are of particular interest due to their higher catalytic activities derived from the MOFs pore/channel confinement effect, improved lifetime through eliminating intermolecular deactivation pathway, and the recyclability based on their heterogeneity. In this work, a 3D chiral metallosalen-based MOF [Cd2(Cu(salen))(DMF)3]·DMF·3H2O (1) with a 1D open channel was synthesized and characterized by single-crystal X-ray diffraction and other physicochemical methods. Upon postsynthetic reduction modification with NaBH4, the conversion from imino to amino group on salen cores of 1 generates the reduction product 2 with a more flexible chiral group and more alkaline backbone, meanwhile still maintaining the original porous framework. 2 can be used as an efficient heterogeneous catalyst for the asymmetric Henry reaction with broad substrate applicability and exhibits higher activity and enantioselectivity (ee up to 98%) compared with the unreduced 1. Note that 2 can accelerate the Henry reaction of pyridine-2-carboxaldehyde possessing a potential coordination atom with excellent ee value; however, the homogeneous counterpart does not. In addition, the bulky aldehydes show a decrease in activity but almost the same enantioselectivity with an increase in the molecular size of substrates as a result of the chiral confinement effect of 2, indicating the size-dependent selectivity. To the best of our knowledge, this is the highest enantioselectivity for asymmetric Henry reaction catalyzed by MOF-based catalysts.

Highly Stable Chiral Zirconium-Metallosalen Frameworks for CO2 Conversion and Asymmetric C-H Azidation.

The engineering of highly stable metal-organic frameworks (MOFs) will unveil the intrinsic potential of these materials for practical applications, especially for heterogeneous catalyzes. However, it is fairly challenging to rationally design robust MOFs serving as highly effective and reusable heterogeneous catalysts. Here, for the first time, we report the construction of four robust UiO-type chiral zirconium-metallosalen frameworks, denoted ZSF-1-4. Single-crystal X-ray-diffraction reveals that the frameworks consist of twelve-connected Zr6O8 clusters with privileged chiral metallosalen ligands anchored at ideal positions, generating confined chiral cages that enable synergistic activation. Unlike UiO-68 that is highly sensitive to aqueous solutions, ZSF-1-4 exhibit excellent chemical stability in aqueous solutions with a wide range of pH owing to the abundant hydrophobic groups within metallosalen ligands. These features render ZSF-1 and ZSF-2 to be excellent recycled heterogeneous catalysts for the conversion of imitated industrial CO2 with epoxides into cyclic carbonates with the highest reported turnover numbers in Zr-MOFs. With regard to asymmetric catalysis, ZSF-3 and ZSF-4 can effectively catalyze C-H azidation reaction in water medium with ee value up to 94%. Moreover, these robust ZSFs can be further extended to other analogues with various metal centers through demetallization-remetallization strategy, which renders them to be an excellent platform for broader fields.

FoxR2 promotes glioma proliferation by suppression of the p27 pathway.

FoxR2 plays an important role in the development of many human tumors. However, the effects of FoxR2 on tumorigenicity of human glioma remain unclear. In this study, we investigated the roles of FoxR2 in cell proliferation and invasion of glioma. We found that overexpression of FoxR2 promoted the proliferation, migration and invasion of glioma cells. Knockout of FoxR2 induced G1 arrest by decreasing the expression levels of cyclin D1, cyclin E and p-Rb. Mechanistically, upregulation of FoxR2 increased the level and activity of MMP-2 and decreased the expression of p27. Furthermore, overexpression of FoxR2 decreased the nuclear accumulation of p27. Taken together, these results indicate that upregulation of FoxR2 may confer enhanced tumorigenicity in glioma cells.

High expression of Bruton's tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma.

BACKGROUND: Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed. METHODS: In this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo. RESULTS: Our data demonstrate that high expression of BTK is a novel prognostic marker for poor survival in patients with glioma. BTK-specific inhibitor ibrutinib effectively inhibits the proliferation, migration and invasion ability of glioma cells. Furthermore, ibrutinib can induce G1 cell-cycle arrest by regulating multiple cell cycle-associated proteins. More importantly, we found that BTK inhibition significantly blocks the degradation of IκBα and prevents the nuclear accumulation of NF-κB p65 subunit induced by EGF in glioma cells. CONCLUSIONS: Taken together, our study suggests that BTK is a novel prognostic marker and molecular therapeutic target for glioma. BTK is required for EGFR-induced NF-κB activation in glioma cells. These findings provide the basis for future clinical studies of ibrutinib for the treatment of glioma.

Smoothened is a poor prognosis factor and a potential therapeutic target in glioma.

Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome. Our data suggest that GDC-0449 significantly inhibits the proliferation of glioma cells by inducing cell cycle arrest at the G1 phase. Our results demonstrate that GDC-0449 can effectively inhibit the migration and invasion of glioma cells. Furthermore, GDC-0449 treatment significantly suppressed glioma cell xenograft tumorigenesis. Mechanistically, GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli1 and Gli2). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. Taken together, our study suggests that smoothened could be used as a prognostic marker and molecular therapeutic target for glioma.

CRM1/XPO1 is associated with clinical outcome in glioma and represents a therapeutic target by perturbing multiple core pathways.

BACKGROUND: Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative. METHODS: In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model. RESULTS: We found that high expression of CRM1 in glioma is a predictor of short overall survival and poor patient outcome. Our data demonstrate that S109 significantly inhibits the proliferation of human glioma cells by inducing cell cycle arrest at the G1 phase. Notably, we observed that high-grade glioma cells are more sensitive to S109 treatment compared with low-grade glioma cells. In an intracranial mouse model, S109 significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Mechanistically, S109 treatment simultaneously perturbed the three core pathways (the RTK/AKT/Foxos signaling pathway and the p53 and Rb1 tumor-suppressor pathways) implicated in human glioma cells by promoting the nuclear retention of multiple tumor-suppressor proteins. CONCLUSIONS: Taken together, our study highlights the potential role of CRM1 as an attractive molecular target for the treatment of human glioma and indicates that CRM1 inhibition by S109 might represent a novel treatment approach.