Ethyl Pyruvate Inhibits HMGB1 Phosphorylation and Release by Chelating Calcium

Shin, Jong-Gye; Kim, Il Doo; Kim, Seung-Woo; Lee, Hye Kyung; Jin, Young–Joo; Park, Ju Hun; Kim, Tae Kyung; Suh, Chang Kook; Kwak, Jooyoung; Lee, Keun Hyeung; Han, Pyung Lim; Lee, Ja Kyeong

doi:10.2119/molmed.2014.00039

Cited by 45 publications

(45 citation statements)

References 36 publications

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“…HMGB1 can undergo multiple PTMs, including cysteine oxidation, (41,(118)(119)(120)(121) lysine N-acetylation, (41,(122)(123)(124)(125)(126)(127)(128)(129)(130) serine phosphorylation , (41,125,(131)(132)(133)(134) lysine methylation, (135,136) serine adenosine diphosphate ribosylation, (137) and asparagine, threonine, and lysine glycation. (138) Prediction analysis suggests that HMGB1 may also undergo ubiquitination in lysines 146 and 147; however, this has not been experimentally confirmed.…”

Section: Posttranslational Modificationsmentioning

confidence: 99%

High‐Mobility Group Box‐1 and Liver Disease

Gaskell

Nieto

2018

Hepatology Communications

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High‐mobility group box‐1 (HMGB1) is a ubiquitous protein. While initially thought to be simply an architectural protein due to its DNA‐binding ability, evidence from the last decade suggests that HMGB1 is a key protein participating in the pathogenesis of acute liver injury and chronic liver disease. When it is passively released or actively secreted after injury, HMGB1 acts as a damage‐associated molecular pattern that communicates injury and inflammation to neighboring cells by the receptor for advanced glycation end products or toll‐like receptor 4, among others. In the setting of acute liver injury, HMGB1 participates in ischemia/reperfusion, sepsis, and drug‐induced liver injury. In the context of chronic liver disease, it has been implicated in alcoholic liver disease, liver fibrosis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Recently, specific posttranslational modifications have been identified that could condition the effects of the protein in the liver. Here, we provide a detailed review of how HMGB1 signaling participates in acute liver injury and chronic liver disease.

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Section: Posttranslational Modificationsmentioning

confidence: 99%

High‐Mobility Group Box‐1 and Liver Disease

Gaskell

Nieto

2018

Hepatology Communications

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“…EP not only prevents nuclear-to-cytoplasmic translocation of HMGB1 [95], but also inhibits cytoplasmic HMGB1 to be released extracellularly [12]. Moreover, EP inhibits HMGB1 release from primary microglial cells via direct intracellular Ca (2+) chelation [97], and EP also regulates inflammation and exerts a neuroprotective effect via dual functions, chelating intracellular Zn (2+) and promoting NAD replenishment [98]. …”

Section: Molecular Mechanisms Responsible For the Anti-inflammatory Ementioning

confidence: 99%

Ethyl pyruvate is a novel anti-inflammatory agent to treat multiple inflammatory organ injuries

2016

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Ethyl pyruvate (EP) is a simple derivative of pyruvic acid, which is an important endogenous metabolite that can scavenge reactive oxygen species (ROS). Treatment with EP is able to ameliorate systemic inflammation and multiple organ dysfunctions in multiple animal models, such as acute pancreatitis, alcoholic liver injury, acute respiratory distress syndrome (ARDS), acute viral myocarditis, acute kidney injury and sepsis. Recent studies have demonstrated that prolonged treatment with EP can ameliorate experimental ulcerative colitis and slow multiple tumor growth. It has become evident that EP has pharmacological anti-inflammatory effect to inhibit multiple early inflammatory cytokines and the late inflammatory cytokine HMGB1 release, and the anti-tumor activity is likely associated with its anti-inflammatory effect. EP has been tested in human volunteers and in a clinical trial of patients undergoing cardiac surgery in USA and shown to be safe at clinical relevant doses, even though EP fails to improve outcome of the heart surgery, EP is still a promising agent to treat patients with multiple inflammatory organ injuries and the other clinical trials are on the way. This review focuses on how EP is able to ameliorate multiple organ injuries and summarize recently published EP investigations. Graphical AbstractThe targets of the anti-inflammatory agent EP

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“…For example, EP has been reported to reduce mortality in lethal models of hemorrhagic shock and sepsis [1,2], to significantly mitigate acute pancreatitis-induced damage [3], and to reduce infarct volumes and improve motor function scores in an animal model of ischemic stroke [4]. The protective effects of EP have been reported to be due to its antiinflammatory, anti-oxidative, anti-apoptotic, and ionchelating effects [5][6][7][8]. Various molecular mechanisms have been proposed to explain its anti-inflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Neuroprotective Effects of DIPOPA (N,N-Diisopropyl-2-Oxopropanamide), an Ethyl Pyruvate Bioisoster, in the Postischemic Brain

et al. 2019

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Ethyl pyruvate (EP) is a simple aliphatic ester of pyruvic acid and has been shown to have protective properties, which have been attributed to its anti-inflammatory, anti-oxidative, and anti-apoptotic functions. In an effort to develop better derivatives of EP, we previously synthesized DEOPA (N,N-diethyl-2-oxopropanamide, a novel isoster of EP) which has greater neuroprotective effects than EP, probably due to its anti-inflammatory and anti-excitotoxic effects. In the present study, we synthesized 3 DEOPA derivatives, in which its diethylamino group was substituted with diisopropylamino, dipropylamino, or diisobutylamino groups. Among them, DIPOPA (N,N-diisopropyl-2-oxopropanamide) containing diisopropylamino group had a greater neuroprotective effect than DEOPA or EP when administered intravenously to a rat middle cerebral artery occlusion (MCAO) model at 9 h after MCAO. Furthermore, DIPOPA had a wider therapeutic window than DEOPA and a marked reduction of infarct volume was accompanied by greater neurological and behavioral improvements. In particular, DIPOPA exerted robust anti-inflammatory effects, as evidenced by marked suppressions of microglia activation and neutrophil infiltration in the MCAO model, in microglial cells, and in neutrophil-endothelial cocultures at lower concentration, and did so more effectively than DEOPA. In particular, DIPOPA remarkably suppressed neutrophil infiltration into brain parenchyma, and this effect was attributed to the expressional inhibitions of cell adhesion molecules in neutrophils of brain parenchyma and in circulating neutrophils via NF-κB inhibition. Together, these results indicate the robust neuroprotective effects of DIPOPA are attributable to its anti-inflammatory effects and suggest that DIPOPA offers a potential therapeutic means of ameliorating cerebral ischemic injury and other inflammation-related pathologies.

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Ethyl Pyruvate Inhibits HMGB1 Phosphorylation and Release by Chelating Calcium

Cited by 45 publications

References 36 publications

High‐Mobility Group Box‐1 and Liver Disease

High‐Mobility Group Box‐1 and Liver Disease

Ethyl pyruvate is a novel anti-inflammatory agent to treat multiple inflammatory organ injuries

Anti-Inflammatory and Neuroprotective Effects of DIPOPA (N,N-Diisopropyl-2-Oxopropanamide), an Ethyl Pyruvate Bioisoster, in the Postischemic Brain

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