A5102900205- Histone Deacetylase Inhibitors Research
- Chemical Synthesis and Analysis
- Protein Structure and Dynamics
- Heat shock proteins research
- Analytical Chemistry and Chromatography
- Molecular spectroscopy and chirality
- Enzyme Structure and Function
- Adenosine and Purinergic Signaling
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Botanical Research and Chemistry
- Signaling Pathways in Disease
- Lipid Membrane Structure and Behavior
- HIV Research and Treatment
- Viral Infections and Immunology Research
- Toxin Mechanisms and Immunotoxins
- Immune Cell Function and Interaction
- Synthesis and Biological Evaluation
- Click Chemistry and Applications
- Electron Spin Resonance Studies
- Advanced NMR Techniques and Applications
- Biochemical and Structural Characterization
- Acute Myeloid Leukemia Research
Italfarmaco (Italy)
2008-2019
University of Colorado Denver
2006-2012
The Medical Center of Aurora
2012
Children's Hospital Colorado
2009
University of Colorado Health
2002
University of Brescia
2002
Chemi (Italy)
1995-1999
St George's Hospital
1995-1997
Howard Hughes Medical Institute
1997
The University of Texas Southwestern Medical Center
1997
Suberoylanilide hydroxamic acid (SAHA) is a acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors deacetylase, exhibits antitumor effects by increasing expression genes regulating tumor survival, we found that reduces production proinflammatory cytokines in vivo vitro. A single oral administration mice dose-dependently reduced circulating TNF-alpha, IL-1-beta, IL-6, IFN-gamma induced...
We studied inhibition of histone deacetylases (HDACs), which results in the unraveling chromatin, facilitating increased gene expression. ITF2357, an orally active, synthetic inhibitor HDACs, was evaluated as anti-inflammatory agent. In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduced by 50% release tumor necrosis factor-α (TNFα) at 10 to 22 nM, intracellular interleukin (IL-1α 12 secretion IL-1β 12.5 25 and production...
Abstract Inhibitors of histone deacetylases (HDAC) are being studied for their antiproliferative effects in preclinical cancer trials. Recent studies suggest an anti-inflammatory role this class compounds. Because inflammatory bowel disease is associated with increased risk malignancies, agents and properties would be therapeutic interest. HDAC inhibitors from various classes were selected evaluated vitro capacity to suppress cytokine production induce apoptosis acetylation. Valproic acid...
Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions not known. We investigated action 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment DCs with significantly reduced TLR-induced secretion proinflammatory cytokines, suppressed expression CD40 CD80, in vitro vivo allostimulatory responses induced by DCs. In addition, injection...
Pharmacological manipulation of gene expression is considered a promising avenue to reduce postischemic brain damage. Histone deacetylases (HDACs) play central role in epigenetic regulation transcription, and inhibitors HDACs are emerging as neuroprotective agents. In this study, we investigated the effect HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on histone acetylation control ischemic mouse brain. We report that H3 was constitutively present at specific lysine residues neurons...
Based on fast atom bombardment mass spectrometry and proton nuclear magnetic resonance studies, this substance is an acylated metabolite of glucosamine 1-phosphate.Lipid X E. coli has a M, = 71 1.87 as the free acid (Cs.r&sNOlzP) contains two 8-hydroxymyristate moieties, one attached amide at 2 position other ester 3 sugar.It hydroxyl groups 4 6 positions, anomeric configuration CY.The structure lipid from E.coli closely resembles reducing end subunit A, it might represent very early...
The monophosphoryl lipid A (MLA) obtained from the lipopolysaccharides of ~~m o n e ~~a minne~ota R695 was fractionated on a silicic acid column to yield heptaacyl, hexaacyl, and pentaacyl MLA.Each these MLAs methylated with diazomethane dimethyl derivative purified homogeneity by reverse-phase high performance liquid chromatography.The molecular ions positive ion fast atom bombardment mass spectrometry heptaacyl MLA allowed us establish formula M, C112H211N2023P 1983.3,respectively.Cleavage...
This issue of Molecular Medicine contains 14 original research reports and state-of-the-art reviews on histone deacetylase inhibitors (HDACi's), which are being studied in models a broad range diseases not related to the proapoptotic properties used treat cancer. The spectrum these responsive HDACi's is for most part due several antiinflammatory properties, often observed vitro but importantly also animal models. One unifying property reduction cytokine production as well inhibition...
The histone deacetylase inhibitor ITF2357 (givinostat) prevents diastolic dysfunction by enhancing cardiac myofibril relaxation.
Abstract Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions target HDACs (that is, HDAC inhibitors) are potential therapeutic interest for treatment muscular dystrophies. In this study, we explored effectiveness long-term with different doses inhibitor givinostat mdx mice—the mouse model Duchenne dystrophy (DMD). This study identified an...
Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both vitro and vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution specific class I IIb HDACs to inflammatory gene expression RA fibroblast-like synoviocytes (FLS).RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i HDAC8i. Alternatively, transfected HDAC3, HDAC6 interferon (IFN)-α/β receptor alpha...
Abstract The α‐amino acids with long alkyl side chains, the so‐called lipidic amino 1a – e , and their homo‐oligomers, peptides 1p aj represent a class of compounds which combine structural properties proteins characteristics lipids membranes. were synthesised from appropriate bromide diethyl acetamidomalonate. Resolution was made chemically, by forming diastereomers acid esters an optically pure α‐pinene derivative. protected homooligomers in solution assistance water‐soluble carbodiimide...
A highly purified monophosphoryl lipid A, TLC-3 fraction obtained from the lipopolysaccharides of heptoseless mutant Salmonella typhimurium C3OfC2 1 was converted to dimethyl pentatrimethylsilyl derivative and analyzed by proton NMR spectroscopy at 400 MHz.Substantial downfield shifts remnances for protons 3-and 3"carbons glucosamine disaccharide 5.06 5.15 ppm, respectively, occurred normal range 3.5-4.1 indicating that these two positions on sugar rings were acylated.Significant shift...
Abstract Histone deacetylase (HDAC) inhibition modulates dendritic cell (DC) functions and regulates experimental graft-vs-host disease other immune-mediated diseases. The mechanisms by which HDAC immune responses remain largely unknown. STAT-3 is a transcription factor shown to negatively regulate DC functions. In this study we report that acetylates activates STAT-3, DCs promoting the of IDO. These findings demonstrate novel functional role for posttranslational modification through...
Hepatocellular carcinoma (HCC) displays a striking resistance to chemotherapeutic drugs or innovative tumor cell apoptosis–inducing agents such as necrosis factor–related apoptosis-inducing ligand (TRAIL). Recently, we found 2 histone deacetylase inhibitors (HDAC-I), valproic acid and ITF2357, exhibiting inherent therapeutic activity against HCC. In TRAIL-sensitive cancer cells, the mechanism of HDAC-I–induced death has been identified be TRAIL-dependent by inducing apoptosis in an autocrine...
ITF2357 (givinostat) is a histone deacetylase inhibitor with antiinflammatory properties at low nanomolar concentrations. We report here phase I safety and pharmacokinetics trial in healthy males administered 50, 100, 200, 400 or 600 mg orally. After 50 mg, mean maximal plasma concentrations reached 104 nmol/L 2 h after dosing, half-life of 6.9 h. 100 concentration 199 2.1 6.0 Repeat doses for 7 consecutive days 200 resulted nearly the same kinetics. There were no serious adverse effects...
In type 1 diabetes, inflammatory and immunocompetent cells enter the islet produce proinflammatory cytokines such as interleukin-1 β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) interferon-γ (IFNγ); each contribute to β-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly humans but also possess antiinflammatory cytokine-suppressing properties. Here we show that oral administration HDAC inhibitor ITF2357 mice normalized...
<h3>ABSTRACT</h3> The field of cross-linking mass spectrometry has matured to a frequently used tool for the investigation protein structures as well interactome studies up system wide level. growing community generated broad spectrum applications, linker types, acquisition strategies and specialized data analysis tools, which makes it challenging, especially newcomers, decide an appropriate workflow. Therefore, we here present large flexible synthetic peptide library reliable instrument...
Inhibition of histone deacetylases (HDAC) has been shown to modulate gene expression and cytokine production after stimulation with several stimuli. In the present study, antiinflammatory effect a potent HDACi, ITF2357, was explored in different experimental models arthritis. addition, bone protective ITF2357 investigated invitro. Treatment acute arthritis (Streptococcus pyogenes cell wall (SCW) arthritis) showed that joint swelling influx into cavity were reduced. Furthermore, chondrocyte...