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    Additive cell protective and oxidative stress reducing effects of combined treatment with cromolyn sodium and masitinib on MPTP-induced toxicity in SH-SY5Y neuroblastoma cells
    (2022) Göksu Erol, Azize Yasemin; Koçancı, Fatma Gonca; Demir Dora, Devrim; Uysal, Hilmi
    The suppression of oxidative-stress induced neurotoxicity by antioxidants serves as a potential preventive strategy for neurodegenerative diseases. In this study, we aimed to investigate the cell protective and antioxidant effects of masitinib and cromolyn sodium against toxin-induced neurodegeneration. First, human neuroblastoma SH-SY5Y cells were differentiated into neuron-like (d)-SH-SY5Y cells. The differentiated cells were confirmed by immuno-staining with anti-PGP9.5 antibody, a neuronal marker. Cell culture groups were formed, and a neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) was applied on cells followed by masitinib and/or cromolyn sodium treatments. Survival rate of cells were detected by MTT assay. Anti-inflammatory Transforming Growth Factor-?1 (TGF-?1) and nitric oxide (NO) levels and total oxidant and antioxidant capacities (TOC and TAC) in cell conditioned media (CM) were measured. Morphological analysis and apoptotic nuclear assessment of cells were also noted. When (d)-SH-SY5Y cells were exposed to neurotoxin, cell viability rates of these cells were found to be decreased in a concentration-dependent manner. CM of toxin applied group displayed higher levels of TOC/TAC ratios and NO levels compared to control (p < 0.01). Both masitinib and cromolyn sodium protected cells from toxin-induced cell death as revealed by ameliorated rates of viability, reversed toxin-induced elevation of TOC/ TAC ratios, and decreased NO levels in their CM (p < 0.01). Combined treatment significantly reduced TOC/TAC ratios and NO levels more effectively compared to mono-treatments. Both drugs also increased TGF-?1 levels significantly in cell CM. When these agents were tested for therapeutic effects against toxin-induced cell degeneration, better viability results were obtained by both masitinib and cromolyn sodium treatment, with significantly better amelioration provided by combined application of these drugs (p < 0.01). This study demonstrated new findings that combined treatment with cromolyn sodium, an FDA-approved drug of asthma, and masitinib, an orally administered drug with a low toxicity, exert neuroprotective and additive therapeutic effects. We propose that combination therapy of masitinib and cromolyn sodium may represent an innovative treatment in neurodegenerative diseases. Combination therapy may be more advantageous that it enables combined application of lower doses of both drugs, providing less side effects.
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    Combination Treatment with Cromolyn Sodium and Masitinib Displays Cell-Protective Effect and Shows Additive Anti-Oxidative Actions on an in vitro Neurodegenerative Model
    (Springer/Plenum Publishers, 2021) Erol, A. Yasemin Goksu; Kocanci, Fatma Gonca; Demir-Dora, Devrim; Uysal, Hilmi
    [Abstract Not Available]
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    Microglia cells treated with synthetic vasoactive intestinal peptide or transduced with LentiVIP protect neuronal cells against degeneration
    (Wiley, 2024) Goksu, Azize Yasemin; Kocanci, Fatma Gonca; Akinci, Ersin; Demir-Dora, Devrim; Erendor, Fulya; Sanlioglu, Salih; Uysal, Hilmi
    A common pathological hallmark of neurodegenerative disorders is neuronal cell death, accompanied by neuroinflammation and oxidative stress. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. The gene therapy field shows long-term promise for treating a wide range of neurodegenerative diseases (ND). In this study, we aimed to investigate the in vitro efficacy of transduction of microglia using lentiviral gene therapy vectors encoding VIP (LentiVIP). Additionally, we tested the protective effects of the secretome derived from LentiVIP-infected immortalized human microglia HMC3 cells, and cells treated with Synthetic VIP (SynVIP), against toxin-induced neurodegeneration. First, LentiVIP, which stably expresses VIP, was generated and purified. VIP secretion in microglial conditioned media (MG CM) for LentiVIP-infected HMC3 microglia cells was confirmed. Microglia cells were activated with lipopolysaccharide, and groups were formed as follows: 1) Control, 2) SynVIP-treated, or 3) LentiVIP-transduced. These MG CM were applied on an in vitro neurodegenerative model formed by differentiated (d)-SH-SY5Y cells. Then, cell survival analysis and apoptotic nuclear staining, besides measurement of oxidative/inflammatory parameters in CM of cells were performed. Activated MG CM reduced survival rates of both control and toxin-applied (d)-SH-SY5Y cells, whereas LentiVIP-infected MG CM and SynVIP-treated ones exhibited better survival rates. These findings were supported by apoptotic nuclear evaluations of (d)-SH-SY5Y cells, alongside oxidative/inflammatory parameters in their CM. LentiVIP seems worthy of further studies for the treatment of ND because of the potential of gene therapy to treat diseases effectively with a single injection. Cultured microglial cells were activated with LPS, and then grouped as: 1) Control, 2) SynVIP-treated, or 3) LentiVIP-transduced microglia. Subsequently, conditioned media of microglial groups were applied on differentiated-SH-SY5Y cells that were exposed to MPTP (a neurotoxin) or not. Several analysis and tests were performed to investigate the protective effects of SynVIP or LentiVIP against toxicity of MPTP or microglial secretome. image