Proximate Composition, In vitro Antioxidant and Anti-inflammatory Properties of Adansonia digitata and Belanites aegyptiaca Seeds

This study evaluated the nutritional and medicinal properties of seeds from Adansonia digitata (BSF) and Balanite aegyptiaca (DDSF) plant. Proximate chemical composition, mineral elements composition, flavonoids, phenolics, antioxidant capacity, and anti-inflammatory properties were studied. Results obtained revealed that DDSF had the highest moisture, crude fat and crude protein content of 7.66 %, 42.80 %, 20.37 % respectively, whilst BSF gave the highest ash, crude fibre and carbohydrate content. Elemental analysis revealed BSF had the highest Mg content (313.65 mg/100g) and DDSF gave the highest Ca content (118.62 mg/100g). Additionally, DDSF gave the highest total phenolics (18.89 mg TAE/ 100 g), total flavonoids (8.80 mg QE/ 100 g) as well as the highest total antioxidant capacity of (19.62 mg AAE/ 100 g) dry of extract. Based on results obtained in this study, seeds obtained from the Adansonia digitata and Balanite aegyptiaca could be a potential source of functional food and antioxidant agents

let-7 microRNAs regulate microglial function and suppress glioma growth through Toll-like receptor 7

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma

Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

Glial cell line‐derived neurotrophic factor (GDNF) is released by glioma cells and promotes tumor growth. We have previously found that GDNF released from the tumor cells is a chemoattractant for microglial cells, the immune cells of the central nervous system. Here we show that GDNF increases matrix metalloproteinase (MMP) 9 and MMP14 expression in cultured microglial cells from mixed sexes of neonatal mice. The GDNF‐induced microglial MMP9 and MMP14 upregulation is mediated by GDNF family receptor alpha 1 receptors and dependent on p38 mitogen‐activated protein kinase signaling. In organotypic brain slices, GDNF promotes the growth of glioma and this effect depends on the presence of microglia. We also previously found that MMP9 and MMP14 upregulation can be mediated by Toll‐like receptor (TLR) 2 signaling and here we demonstrate that GDNF increases the expression of TLR1 and TLR2. In conclusion, GDNF promotes the pro‐tumorigenic phenotype of microglia

Down-regulation of Aquaporin-1 mediates a microglial phenotype switch affecting glioma growth

Aquaporin 1 (AQP1), a transmembrane protein that forms water channels, has previously been shown to facilitate growth and progression of many types of tumors by modulating tumor cell migration, proliferation and angiogenesis. Here, we determined the impact of AQP1 expression in the tumor environment on the progression of brain tumors. Primary microglia from wild type(WT) and AQP1 knockout(KO) mice were used to test AQP1 effect on microglia function by using Western blot, quantative PCR, in an experimental in vivo mouse glioma model and organotypic brain slice culture. Deletion of AQP1 in the host tissue significantly reduced the survival of the mice implanted with GL261 glioma cells. The density of glioma-associated microglia/macrophages was almost doubled in AQP1KO mice. We found that factors secreted from GL261 cells decrease microglial AQP1 expression via the MEK/ERK pathway, and that inhibition of this pathway with Trametinib reduced tumor growth and prolonged the survival of tumor bearing mice, an effect which required the presence of microglia. Deletion of AQP1 in cultured microglia resulted in an increase in migratory activity and a decrease in TLR4-dependent innate immune responses. Our study demonstrates a functional relevance of AQP1 expression in microglia and hints to AQP1 as a potential novel target for glioma therapy

Glioma-initiating cell-induced Interleukin-6 production is mediated by Toll-like receptor 4 in microglia

OBJECTIVE: Malignant gliomas are the most frequent primary tumours of the brain with poor clinical prognosis. Infiltrating peripheral macrophages and resident microglia that constitute the dominant tumour-[[Unsupported Character - Codename ­]]-infiltrating cells in glioblastoma are induced by the glioma cells to become immunosuppressive and tumour supportive. Glioma-[[Unsupported Character - Codename ­]]-initiating cells (GIC) could potentially promote this pro-[[Unsupported Character - Codename ­]]-tumorigenic phenotype. Exploring the interaction between GIC and glioma associated microglia/macrophages (GAM) may offer us an opportunity to further understand the cellular and molecular features of the GIC niche. We here investigate the potential of GIC versus bulk cells to induce a pro-[[Unsupported Character - Codename ­]]- tumorigenic microglial cytokine profile. METHODS: In the present study we stimulated primary cultured microglia with glioma conditioned medium (GCM) from GICs enriched or depleted GL261 cells and cytokine levels were determined by FlowCytomix. RESULTS: An almost 4-[[Unsupported Character - Codename ­]]-fold upregulation in microglial IL-[[Unsupported Character - Codename ­]]-6 secretion was observed using GCM from GICs while the secretion was unchanged with GCM from GICs depleted GL261 cells. Since Toll-[[Unsupported Character - Codename ­]]-like receptors are pattern recognition receptors that are responsible for pro-[[Unsupported Character - Codename ­]]-inflammatory cytokines release, we screened through all the TLRs and identified TLR4 as the main TLR controlling microglial IL-[[Unsupported Character - Codename ­]]-6 secretion. IL-[[Unsupported Character - Codename ­]]-6R and gp130 are highly expressed in GICs but not in microglial cells. The implantation of GL261-[[Unsupported Character - Codename ­]]-EGFP cells into IL-[[Unsupported Character - Codename ­]]-6 -[[Unsupported Character - Codename ­]]-/-[[Unsupported Character - Codename ­]]- mice resulted in significantly smaller tumours as compared to wild-[[Unsupported Character - Codename ­]]- type control mice. IL-[[Unsupported Character - Codename ­]]-6 and IL-[[Unsupported Character - Codename ­]]-6R are also expressed in human gliomas (which contain up to 30% microglia/macrophages) and inversely correlates with patient survival. CONCLUSIONS: Our results show that GICs, but not the bulk glioma cells initiate microglial IL-[[Unsupported Character - Codename ­]]-6 secretion. IL-[[Unsupported Character - Codename ­]]-6 in turn promotes glioma cell growth and invasion

Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

Glial cell line‐derived neurotrophic factor (GDNF) is released by glioma cells and promotes tumor growth. We have previously found that GDNF released from the tumor cells is a chemoattractant for microglial cells, the immune cells of the central nervous system. Here we show that GDNF increases matrix metalloproteinase (MMP) 9 and MMP14 expression in cultured microglial cells from mixed sexes of neonatal mice. The GDNF‐induced microglial MMP9 and MMP14 upregulation is mediated by GDNF family receptor alpha 1 receptors and dependent on p38 mitogen‐activated protein kinase signaling. In organotypic brain slices, GDNF promotes the growth of glioma and this effect depends on the presence of microglia. We also previously found that MMP9 and MMP14 upregulation can be mediated by Toll‐like receptor (TLR) 2 signaling and here we demonstrate that GDNF increases the expression of TLR1 and TLR2. In conclusion, GDNF promotes the pro‐tumorigenic phenotype of microglia

Velocity-Selective Arterial Spin Labeling Perfusion in Monitoring High Grade Gliomas Following Therapy: Clinical Feasibility at 1.5T and Comparison with Dynamic Susceptibility Contrast Perfusion

MR perfusion imaging is important in the clinical evaluation of primary brain tumors, particularly in differentiating between true progression and treatment-induced change. The utility of velocity-selective ASL (VSASL) compared to the more commonly utilized DSC perfusion technique was assessed in routine clinical surveillance MR exams of 28 patients with high-grade gliomas at 1.5T. Using RANO criteria, patients were assigned to two groups, one with detectable residual/recurrent tumor (“RT”, n = 9), and the other with no detectable residual/recurrent tumor (“NRT”, n = 19). An ROI was drawn to encompass the largest dimension of the lesion with measures normalized against normal gray matter to yield rCBF and tSNR from VSASL, as well as rCBF and leakage-corrected relative CBV (lc-rCBV) from DSC. VSASL (rCBF and tSNR) and DSC (rCBF and lc-rCBV) metrics were significantly higher in the RT group than the NRT group allowing adequate discrimination (p p = 0.002; Pearson’s correlation). These results suggest that VSASL is clinically feasible at 1.5T and has the potential to offer a noninvasive alternative to DSC perfusion in monitoring high-grade gliomas following therapy

Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling

BACKGROUND: Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2). METHODS: Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices. RESULTS: The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo. CONCLUSIONS: Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies.Feng Hu, Omar Dildar a Dzaye, Alexander Hahn, Yong Yu, Rick Joey Scavetta, Gunnar Dittmar, Adrian Kamil Kaczmarek, Kylie R. Dunning, Carmela Ricciardelli, Jan L. Rinnenthal, Frank L. Heppner, Seija Lehnardt, Michael Synowitz, Susanne A. Wolf, and Helmut Kettenman