Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis

Abstract

Signals from stressed cells and the enteric microbiota activate macrophages and dendritic cells and mediate intestinal inflammation. HMGB1 serves as an immunogenic stimuli causing release of inflammatory cytokines by myeloid cells. Ethyl pyruvate inhibits secretion of HMGB1 and improves survival in models of endotoxemia and hemorrhagic shock. We reasoned that ethyl pyruvate may be protective in colitis, which involves similar inflammatory pathways. In IL-10(-/-) mice with established chronic colitis, ethyl pyruvate administration ameliorated colitis and reduced intestinal cytokine production. IL-10(-/-) mice demonstrated increased intestinal HMGB1 expression and decreased expression of RAGE compared with wild-type mice. Fecal HMGB1 levels were decreased in ethyl pyruvate-treated mice. Furthermore, ethyl pyruvate induced HO-1 expression in intestinal tissue. In TNBS-induced colitis, intrarectal administration of ethyl pyruvate resulted in amelioration of colitis and reduced intestinal cytokine production. In LPS-activated murine macrophages, ethyl pyruvate decreased expression of IL-12 p40 and NO production but did not affect IL-10 levels. Ethyl pyruvate did not inhibit nuclear translocation of NF-kappaB family members but attenuated NF-kappaB DNA binding. Additionally, ethyl pyruvate induced HO-1 mRNA and protein expression and HO-1 promoter activation. Moreover, ethyl pyruvate prevented nuclear-to-cytoplasmic translocation of HMGB1. In conclusion, the HMGB1/RAGE pathway has pathophysiologic and diagnostic significance in experimental colitis. Ethyl pyruvate and other strategies to inhibit HMGB1 release and function represent promising interventions in chronic inflammatory diseases.

Inhibitory effects of ethyl pyruvate administration on human gastric cancer growth via regulation of the HMGB1-RAGE and Akt pathways in vitro and in vivo

“…EP treatment of septic mice decreases circulating levels of HMGB1. Pretreatment with EP also prevents endotoxin lethality, inhibits the release of TNF and HMGB1 and ameliorates murine colitis and renal ischemia and reperfusion injury by decreasing HMGB1 release (19)(20)(21). Delayed treatment with EP also suppresses tumor growth significantly, although to a lesser extent.…”

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

“…TNBS-induced colitis in BALB/c mice: BALB/c mice (n = 5-8/group) were used to evaluate the antiinflammatory effects of plecanatide on TNBS-induced colitis by previously described procedures [27,28] . Briefly, colitis was induced in 2-4 mo old female BALB/c mice by administering 2.5 mg TNBS in 50% ethanol into the lumen of the colon (injection volume 100 μL).…”

“…Colon tissues were removed and weighed. Distal sections were fixed, stained with H and E, and evaluated for histopathology and visual severity scores [27,28] . Scoring of the H and E-stained tissue sections employed the following criteria: Normalappearing crypts (score 0); abnormal crypt pathology without ulceration (score 1); depleted crypts with some ulceration/ inflammation (score 2); 20%-70% depleted crypts and increased ulceration/inflammation (score 3); > 70% depleted crypts with substantial ulceration/ inflammation (score 4); and totally ulcerated/inflamed colon with no crypts remaining (score 5).…”

Enhancing the Therapeutic Effects of Ethyl Pyruvate on Gastric Cancer through Knockdown of YAP1 Expression

“…Pretreatment with EP can prevent endotoxin lethality and inhibit the release of TNF and HMGBI (12). It also ameliorates colitis and renal ischemia and reperfusion injury by decreasing HMGB I release (13,14). More importantly, treatment with EP significantly suppresses tumor growth, although to a slight extent, and decreases innate and adaptive immune cell infiltrates and serum IL-6 and HMGB 1 levels in the liver (15).…”