Pyridoxine (vitamin B6) toxicity is a well-known model for peripheral neuropathy. GABA and glutamate are two neurotransmitters in neural pathways involved in the peripheral neuropathy. Cichorium intybus (Chicory) contains glycosides and triterpenoids, which inhibit glutamatergic transmission and enhance GABAergic transmission. The present study was aimed at studying the effect of chicory extract (CE) on the pyridoxine-induced peripheral neuropathy with a particular focus on glutamatergic and GABAergic systems. In this experimental study, a high dose of pyridoxine (800 mg/kg, i.p.) was injected for 14 days to induce neuropathy in male rats. To evaluate the behavioral symptoms, three tests including rotarod, hot plate, and foot fault were used. After the induction of neuropathy, CE (50 mg/kg i.p.) was injected intraperitoneally for 10 consecutive days. Morphologically, the sciatic nerve and the DRG neurons were evaluated in the control, neuropathy, and chicory groups by H&E staining. For evaluating the mechanism, picrotoxin (1 mg/kg) and MK-801 (0.1 mg/kg) were also individually injected 15 min before the extract administration. The concentration of TNF-α in rat sciatic nerve and DRG neurons were also measured by enzyme-linked-immunoassay (ELISA). Morphological and physiological changes occurred in the DRG and sciatic nerve following pyridoxine intoxication. The CE exerted an anti-neuropathic effect on the sciatic nerve and DRG neurons and also decreased reaction time in hot plate test (p < 0.05), increased balance time in rotarod test (p < 0.001), and improved foot fault performance (p < 0.01). Moreover, CE administration reduced TNF-α level in DRG (p < 0.001) and sciatica nerve (p < 0.001). Picrotoxin, unlike MK-801, showed a significant difference in all three behavioral tests and reduced TNF-α content in comparison with group received extraction alone (with p < 0.001 for all three tests). Our results showed beneficial effects of CE on pyridoxine-induced peripheral neuropathy. Modulating of the GABAergic system mediated by TNF-α may be involved in the anti-neurotoxic effect of CE.
Glioblastoma multiforme (GBM) is a complicated and heterogeneous brain tumor with short-term survival outcomes. Commercial therapies are not practical due to cell infiltration capacity, high proliferative rate, and blood-brain barrier. In this context, recognition of the molecular mechanism of tumor progression might help the development of new cancer therapeutics. Recently, more evidence has supported CD73 and downstream adenosine A2A/A2B receptor signaling playing a crucial role in glioblastoma pathogenesis; therefore, targeting CD73 in murine tumor models can reduce tumor development.CD73 is an ecto-enzyme inducing tumor metastasis, angiogenesis, and immune escape via the production of extracellular adenosine in the tumor microenvironment. In this review, we provided information about clinical characteristics as well as the therapeutic management of glioblastoma. Then, we focused on newly available experimental evidence distinguishing between the essential role of CD73 on this tumor growth and a new method for the treatment of GBM patients.
Despite the development of various therapeutic approaches over the past decades, the glioblastoma (GBM) treatment remains a major challenge. The extracellular adenosine-generating enzyme CD73 is involved in the pathogenesis and progression of GBM, and targeting CD73 may represent a novel approach to this cancer. This study characterized three-dimensional culture systems based on three compositions of hydrogel and chose an optimum type for local delivery of CD73 to target GBM cells as a possible therapeutic approach for this disease. Rheology measurements, Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), and cell proliferation assay were conducted to analyze the synthesized hydrogel and choose an optimal formula. The viability of tumor cells in the optimal hydrogel was assessed by histology and confocal microscopy imaging. Furthermore, tumor cells' sensitivity to CD73 inhibitor was investigated by cell proliferation assay and real-time PCR. The data demonstrated that the hydrogel with 5 w% gelatin and 5 w% sodium alginate had superior rheological properties and cell viability. Therefore, it could provide a more suitable environment for GBM cells and mimic the natural microenvironment more properly. CD73 inhibitor-treated GBM cells significantly decreased proliferation rate and expressions of VEGF and HIF1-α within the optimal hydrogel. Our current research revealed the great potential of CD73 inhibitor for clinical translation of cancer study by analyzing 3D tumor cell behavior and function, and therefore for more effective treatment protocols for GBM.
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