Biology subjects

Schonfeld, M.

Publications and source records attributed to Schonfeld, M..

3 recordsLinked to original sources

bioRxiv2021

Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformins effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformins effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder, but warrant caution given the potential for metformins effects to generalize to a natural reward in female rats.

neuroscience↗

bioRxiv2018

Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice

ObjectivesWe previously revealed a role for EZH2 in inducing pro-inflammatory epigenetic changes in lupus CD4+ T cells. In this study, we sought to determine if inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.\n\nMethodsEZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and mRNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by DZNep intraperitoneal administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-dsDNA antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.\n\nResultsEZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy.\n\nLymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep treated mice. Concentrations of circulating cytokines and chemokines, including TNF, IFN-{gamma}, CCL2, RANTES/CCL5, IL-10, KC/CXCL1, IL-12, IL-12p40 and MIP-1{beta}/CCL4 were decreased in DZNep treated mice.\n\nConclusionsZH2 is upregulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option in lupus patients.

immunology↗

bioRxiv2018

Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

ObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.\n\nMethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.\n\nResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFN upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFN. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFN in lupus CD8+ T cells, but not healthy controls. Co-incubation of naive CD4+ T cells with IFN-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.\n\nConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFN in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

immunology↗