Comparative analysis of isoform-specific and non-selective histone deacetylase inhibitors in attenuating the intestinal damage after hemorrhagic shock

Abstract

BackgroundIsoform-specific histone deacetylase inhibitors (HDACIs) MC1568 and ACY1083 are comparable to the non-selective HDACI valproic acid (VPA) in improving survival in rodents undergoing lethal hemorrhage. However, the organ-specific properties of isoform-specific HDACIs have not been fully evaluated. Also, whether they can act synergistically is not known. We hypothesized that isoform-specific HDACIs are superior to VPA in attenuating intestinal injury and act synergistically when coadministered.MethodsSprague Dawley rats were hemorrhaged (40% of total blood volume) and randomized to receive (n=4 per group) (1) MC1568 (5 mg/kg), (2) ACY1083 (30 mg/kg), (3) MC1568+ACY1083 (combination: 5 mg/kg + 30 mg/kg, respectively), (4) VPA (250 mg/kg), or (5) normal saline (NS; vehicle; 250 μL). Animals were observed for 3 hours, after which blood samples were collected and samples of the ileum were harvested. Expression of interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) was assessed in the tissues using enzyme-linked immunosorbent assay. Intestinal cleaved caspase 3 (c-caspase 3) levels were assessed as a marker of apoptosis, and histologic sections of the ileum were examined for signs of bowel injury. Levels of IL-1β and TNF-α were also measured in the serum as global markers of inflammation.ResultsTreatments with MC1568, ACY1083, MC1568+ACY1083, and VPA were associated with decreased IL-1β levels in the intestine and serum compared with NS. IL-1β and TNF-α levels were significantly lower in the ACY1083 group compared with the VPA group. CINC-1 levels were significantly lower in the isoform-specific HDACI groups compared with the NS; however, no significant differences were seen with VPA. All treatment groups had a lower expression of intestinal c-caspase 3 compared with NS. Furthermore, MC1568 and ACY1083 groups had lower apoptosis compared with the VPA group. Bowel injury scores were significantly lower in the isoform-specific HDACI groups compared with the NS group; however, the attenuation in the VPA-treated animals did not reach statistical significance.DiscussionIsoform-specific HDACIs provide superior intestinal protection compared with VPA in a rodent model of hemorrhagic shock.Level of evidencePreclinical study.

Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2+ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression

“…Relevant to the latter, various groups have focused on developing cofactor analogs to modulate activities of epigenetic enzymes overexpressed in tumors (15). These studies have identified several promising cellpermeable small molecule inhibitors of histone-modifying enzymes, such as DOT1Li, EPZ004777, LSD1i, and GSK690 (18)(19)(20)(21)(22). However, some cell-permeable inhibitors with high potency in vitro have shown little or no biological activity in vivo (23,24).…”

Dualistic Saha Dose-Dependent Effects on Glial-Inflammatory Response

“…Several studies showed that class I HDACi MS275 reduces neuroinflammation in a mouse model of Alzheimer’s disease [55][56][57] and suppresses cytokine expression in murine microglia activated with LPS [43]. Although several pieces of evidence reported the MC1568 ability to modulate inflammation according to the cell types [58][59][60], to the best of our knowledge, other than our data, there is no evidence of MC1568’s ability to modulate the glial inflammatory response.…”

A Comparative Analysis to Determine the Optimum Histone Deacetylase Inhibitors and Administration Route for Improving Survival and Organ Injury in Rats After Hemorrhagic Shock

“…Despite the small samples, differences in survival were found, although the differences among sirtinol, MS-275, LMK-235, tubastatin A, and TSA treatments were not significant. Second, only male rats were used in this study, but this was because there is gender dimorphism in trauma patients (5,9,34), and female sex hormones are considered protective in shock. Future research will need to validate the effect of various HDACIs in female animals.…”

“…Histone deacetylases (HDACs) are involved in epigenetic regulation and lead to gene transcription repression. However, HDAC inhibitors (HDACIs) can improve the acetylation of histones to induce transcriptional activation, resulting in the production of proteins (4,5). Acetylation affects the function of several cytoplasmic proteins and leads to a "prosurvival phenotype" (6).…”

“…So far, 18 human HDACs have been identified and grouped into the following 4 classes: class I, class II (class IIa and class IIb), class III, and class IV (4,5,7,8). Recent studies have revealed that HDACIs play an important role in HS models.…”