scholarly journals The Effect of Valproic Acid on the Transcriptional Activity of Ngf and Bdnf Genes of in Vitro Cultured Neurons Under Oxidative Stress Conditions

Author(s):  
A. D. Filev ◽  
E. S. Ershova ◽  
E.A. Savinova ◽  
A. M. Кalakov ◽  
N. N. Veiko ◽  
...  

Brain-derived neurotrophic factor (BDNF) is a secretory molecule that promotes peripheral neurons synaptic transmission and plasticity by TrkB receptor activation. This is shown in cultured central nervous system (CNS) neurons, including hippocampal and cortical cholinergic, dopaminergic and serotonergic neurons. Hypotheses suggesting that BDNF may play a potential role in the pathophysiology of schizophrenia are based on the key role of BDNF in the synaptic plasticity and, consequently, regulation of cognitive functions. In the schizophrenia treatment valproic acid is used in complex combined therapy regimens. Treatment of schizophrenia patients with valproate increases the BDNF level. Since it is not yet clear whether the BDNF protein levels measured in serum samples and in the brain correlate, we investigated valproate effects on the cultured neurons Bdnf transcription level. The primary neuron-glia culture was obtained from the cerebellum of 8-9-day-old Wistar rats. Valproic acid was added to the neurons (at a concentration of 50 µg/ml), oxidative stress was stimulated by 40 µMof H2O2, and injury was caused by mechanical damage to the neuron culture. It was shown that valproic acid in 3-24 hours increases the transcriptional activity of the Bdnf and Ngf (nerve growth factor) genes 2–2.5-fold (p<0.01) and approximately 1.5-fold (p<0.01), respectively. Mechanical trauma, unlike oxidative stress, activates the transcriptional activity of the Ngf and Bdnf genes (p<0.01). However, under oxidative stress and mechanical damage to neurons, the effect of valproic acid on the Ngf and Bdnf genes expression was insignificant. Fluorescence microscopy analysis using specific antibodies to neurons (anti-Map-2) showed that in the presence of valproic acid, the number of neuronal processes and contacts between them significantly increased. Evidently, valproate addition to antipsychotics can be effective for the overall clinical response. Relatively little research has been done on the signaling pathways in neurons that are activated by the valproic acid. However, we have obtained evidence of activation of the Ngf and Bdnf genes transcription in cultured neurons in vitro. We also found that in the presence of valproic acid, the number of neuronal processes and contacts between them significantly increased. However, we have also found that the oxidative stress accompanying the schizophrenia can significantly reduce the valproic acid effect on the Ngf and Bdnf genes expression. The results of the study may be potentially useful for new schizophrenia therapy strategies development.

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 533
Author(s):  
Man-Hong Leung ◽  
Ho Tsoi ◽  
Chun Gong ◽  
Ellen PS Man ◽  
Stefania Zona ◽  
...  

Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.


2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Akio Monji ◽  
Yasuko K Bando ◽  
Toko Mitsui ◽  
Morihiko Aoyama ◽  
Hiroya Kawase ◽  
...  

PURPOSE: Glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex4) is a remedy for type 2 diabetes mellitus (T2DM). Ex4 ameliorates cardiac dysfunction in preclinical and clinical settings. However, it remains unclear whether the impact of Ex4 on cardiac remodeling in diabetic cardiomyopathy (DMC), of which primary characteristics are microvasculopathy and mitochondrial damage. Methods and Results: Diet-induced T2DM (DIO) mice and age- and gender-matched lean control mice were allocated into EX4 (24 nmole/kg/day for 40 days; DIO-Ex4 and LEAN-Ex4) and vehicle groups (DIO-veh and LEAN-veh). We first confirmed the GLP-1R expression in every single chamber of mouse heart by immunoblotting and PCR. Ex4 treatment ameliorated both systemic and cardiac insulin resistance without affecting body weight in DIO. Cardiac capillary density of DIO-veh was reduced compared to those LEAN-veh, which were reversed by Ex4 treatment. Tube formation assay and immunoblot analysis using culture endothelial cells revealed that Ex4 directly enhanced in vitro angiogenesis in a PKA/eNOS-dependent fashion. Systolic and diastolic left-ventricular (LV) dysfunctions observed in DIO-veh were restored by Ex4 with decline in LV wall thickening. Myocardial fibrosis detected using sirius-red staining and tissue oxidative stress detected by a fluorescence indicator DHE were attenuated in DIO-Ex4. Of note, analyses using transmission electron microscopy and a fluorescence indicator for damaged mitochondria (mitotracker red) revealed that Ex4 treatment reversed cardiac mitochondrial remodeling and increased healthy mitochondria. Ex4 treatment modulated cardiac oxidative stress balance by upregulating antioxidative molecules (SOD, thioredoxin, glutathione peroxidase) and reduction of NOX4 level; whereas it had no influence on NOX2 level. Conclusions: Ex4 enhances cardiac angiogenesis via GLP-1R-mediated activation of PKA/eNOS axis and accelerates reverses remodeling of myocardial mitochondria, at least in part, via its facilitating effects on antioxidative defense.


2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Youguang Pu ◽  
Yiao Tan ◽  
Chunbao Zang ◽  
Fangfang Zhao ◽  
Cifeng Cai ◽  
...  

AbstractLong-noncoding RNAs (lncRNAs) play roles in regulating cellular functions. High-throughput sequencing analysis identified a new lncRNA, termed LAMTOR5-AS1, the expression of which was much higher in the chemosensitive osteosarcoma (OS) cell line G-292 than in the chemoresistant cell line SJSA-1. Further investigations revealed that LAMTOR5-AS1 significantly inhibits the proliferation and multidrug resistance of OS cells. In vitro assays demonstrated that LAMTOR5-AS1 mediates the interaction between nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2) and kelch-like ECH-associated protein 1 (KEAP1), which regulate the oxidative stress. Further mechanistic studies revealed that LAMTOR5-AS1 inhibited the ubiquitination degradation pathway of NRF2, resulting in a higher level of NRF2 but a loss of NRF2 transcriptional activity. High level of NRF2 in return upregulated the downstream gene heme oxygenase 1 (HO-1). Moreover, NRF2 controls its own activity by promoting LAMTOR5-AS1 expression, whereas the feedback regulation is weakened in drug-resistant cells due to high antioxidant activity. Overall, we propose that LAMTOR5-AS1 globally regulates chemotherapy-induced cellular oxidative stress by controlling the expression and activity of NRF2.


2006 ◽  
Vol 175 (4S) ◽  
pp. 257-257
Author(s):  
Jennifer Sung ◽  
Qinghua Xia ◽  
Wasim Chowdhury ◽  
Shabana Shabbeer ◽  
Michael Carducci ◽  
...  

2019 ◽  
Vol 56 (3) ◽  
pp. 529-533
Author(s):  
Mihaela Pantea ◽  
Diana Andreea Ighigeanu ◽  
Alexandra Totan ◽  
Maria Greabu ◽  
Daniela Miricescu ◽  
...  

This in vitro study analyses the biochemical interaction between saliva and three types of dental composite resins (a direct resin, an indirect resin and a dual-cure resin used for cementation of indirect dental restorations). The resin samples were obtained following a specific protocol and in line with the producers� recommendations; the resin samples were incubated with saliva samples collected from 19 healthy volunteers. The obtained results showed that the tested composite resins did not produce significant changes in oxidative stress parameters that were analysed (albumin, uric acid, GGT / gamma glutamyl transferase, OXSR-1 / oxidative stress responsive kinase 1) and do not influence the inflammatory salivary status reflected by the levels of IL-6 - an inflammatory marker.


2007 ◽  
Vol 12 (4) ◽  
pp. 191-196 ◽  
Author(s):  
Mi-Jung So ◽  
Boh-Kyung Kim ◽  
Mi-Jin Choi ◽  
Kun-Young Park ◽  
Sook-Hee Rhee ◽  
...  

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.


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