Histone deacetylase inhibitors valproic acid and sodium butyrate enhance prostaglandins release in lipopolysaccharide-activated primary microglia

Neuroscience ◽  
2014 ◽  
Vol 265 ◽  
pp. 147-157 ◽  
Author(s):  
V. Singh ◽  
H.S. Bhatia ◽  
A. Kumar ◽  
A.C.P. de Oliveira ◽  
B.L. Fiebich
Plants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1164
Author(s):  
Óscar Martínez ◽  
Verónica Arjones ◽  
María Victoria González ◽  
Manuel Rey

The low induction rates of somatic embryogenesis are one of the main limitations in its routine application in the grapevine (Vitis vinifera L.). The use of an induction medium containing histone deacetylase inhibitors (trichostatin A and, mainly, sodium butyrate) resulted in an improvement of the embryogenic responses in grapevine (cv. Mencía) cotyledonary and recently germinated somatic embryos. The relative expression of several grapevine genes related to embryogenic competence or encoding histone deacetylase enzymes was studied in cotyledonary somatic embryos that were cultured in the presence of 0.5 mM sodium butyrate. The results showed a significant overexpression of the BBM and VvSERK2 genes after 24 h of culture, whereas the VvWOX2 gene was underexpressed less in treated versus untreated explants. The results suggest that the inhibitor may trigger a molecular response related to an increase in embryogenic competence and changes in the expression of associated genes. The treatment with sodium butyrate also produced significant variations in the expression of several histone deacetylase enzyme-encoding genes. These results may enhance the possibility of obtaining somatic embryos, reducing the seasonal constraints associated with the use of floral explants in grapevines.


2020 ◽  
Vol 8 (1) ◽  
pp. e000195 ◽  
Author(s):  
Johannes Laengle ◽  
Julijan Kabiljo ◽  
Leah Hunter ◽  
Jakob Homola ◽  
Sophie Prodinger ◽  
...  

BackgroundThe monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized.MethodsWe analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach.ResultsVPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the “do not eat me” signal CD47 on tumor cells.ConclusionsHDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.


2016 ◽  
Vol 5 (3) ◽  
pp. 859-870 ◽  
Author(s):  
Yue Luo ◽  
Hui Wang ◽  
Xipeng Zhao ◽  
Chao Dong ◽  
Fengmei Zhang ◽  
...  

Valproic acid (VPA) is one of the representative compounds of histone deacetylase inhibitors (HDACis) and is used widely for the clinical treatment of epilepsy and other convulsive diseases.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3808-3808
Author(s):  
Ryan J Castoro ◽  
Noel J Raynal ◽  
Xuelin Huang ◽  
Carlos E. Bueso-Ramos ◽  
Guillermo Garcia-Manero ◽  
...  

Abstract Abstract 3808 Poster Board III-744 DNA methylation is a common epigenetic mechanism of gene silencing in patients with the Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML). Epigenetic therapy with drugs which inhibit DNA methylation such as 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) have proven to be clinically potent in MDS and AML. In addition to DNA methylation inhibitors, histone deacetylase inhibitors (HDACi) have activity in leukemias, and at low doses show epigenetic synergy with DNA methylation inhibitors. To test this synergy in the clinic, we designed a phase II randomized study comparing decitabine alone (20 mg/m2 IV daily x 5 every 4 weeks) to decitabine (same dose) plus valproic acid (50 mg/kg PO daily for 7 days started at the same time as decitabine). We have previously reported interim results from this study, showing an overall response rate of 64% in MDS/CMML (CR in 39%) and 46% in AML (CR in 25%) with no significant differences in response or survival between the two arms. We now report on molecular analyses in this trial. We have studied DNA methylation of ALOX12, LINE1, MapK15, miR124a-1 and 3 and P15 using bisulfite-pyrosequencing, and expression of ATM, mi124a, p15 and p21 by qPCR at baseline and at days 5, 12 and 30 after initiation of therapy in 60 (32 for expression) patients treated on the study (33 received decitabine, 27 received decitabine + valproic acid, overall there were 31CRs or HI's and 28 NRs, 1 patient was inevaluable for response). Global methylation (measured by LINE1) decreased at day 5 by an average of 6.8 ±1.8% in the DAC arm and 3.5 ± 1.2% in the DAC/VPA arm (p=0.20). At day 12, the decrease (from baseline) was by 10.2 ± 2.2% in the DAC arm and 7.0 ± 1.5% in the DAC/VPA arm (p=0.32). At day 30 we observed a decrease of 6.4 ± 1.4% in the DAC arm and 4.8 ±2.2% in the DAC/VPA arm. We found no statistical differences between the two arms in any of the other genes studied for hypomethylation. By qPCR, expression of p15 at day 5 increased by 1.2±0.6 fold in the DAC arm and by 2.5±0.7 fold in the DAC/VPA arm (p=0.01). We found no differences in the other 3 genes studied between the two arms. We next asked about correlations between epigenetic modulation and response. There was no association between LINE1 methylation change at days 5, 12 or 30 and response. By contrast, sustained hypomethylation of miR124a1 correlated with response; at day 5, miR124a methylation had changed by -17.9 ± 3.7% in responders vs. -15.2 ± 5.8% in non-responders, while at day 30, methylation decreased further to -24±6.5%% in responders, but had already partially recovered to -5.3 ±5.8% of baseline in non-responders (p=0.029 for a comparison between responders and non-responders). Additionally we found that responders hypomethylated miR124a-3 faster by a change in methylation of -34.1 ± 6.3% at day 5 compared to non-responders who had -14.8 ± 6.3% at day 5 (p= 0.039). However there was no difference at day 30. By qPCR we studied the same genes as previously listed. We found that responders had a larger induction of p15 gene expression at day 5, 2.3 ± 0.75 fold compared to non-responders who had a 0.91 ± 0.66 fold increase (p=0.018). We also found a similar pattern in expression induction in the ATM gene, where responders at day 5 had a 1.92 ± 0.51 fold increase as compared to non-responders who had a 0.3 ± 0.64 fold increase (p=0.034). Similarly, for the mature miR124a locus, responders had a 2.91 ± 0.88 fold increase in expression at day 30 compared to non-responders who had 1.1 ± 0.24 fold change in gene expression (p=0.03). In conclusion, we found that adding Valproic acid to decitabine enhances activation of P15, but also shows trends for reducing hypomethylation induction, which is consistent with in-vitro studies. These opposing trends may explain why the response rate is not dramatically different in the two arms. We also found that sustained gene specific hypomethylation correlates with response, as does induction of expression of P15, miR124 and ATM, which confirms and extends our prior studies. Thus, modulation of DNA methylation and gene expression appears to be associated with response to decitabine, and testing whether histone deacetylase inhibitors enhance this response will require non-overlapping dosing regimens and, likely, more potent HDAC inhibitors. Disclosures: No relevant conflicts of interest to declare.


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