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

Yang, Runkuan; Zhu, Shengtao; Tønnessen, Tor Inge

doi:10.1186/s12950-016-0144-1

Cited by 56 publications

(44 citation statements)

References 93 publications

(174 reference statements)

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“…To test this hypothesis, we investigated whether inhibition of HMGB1 secretion by the simple aliphatic ester of pyruvic acid, ethyl pyruvate (EP), decreases diabetes-related hepatocellular damage, suppresses activation of inflammatory cascades from TLR4, and modulates the inflammatory status. By virtue of its ability to ameliorate multiple acute inflammatory organ injuries in experimental animal models, EP acts as an anti-inflammatory agent [45]. More importantly, a part of its anti-inflammatory properties include it capability to downregulate HMGB1 release [37].…”

Section: Introductionmentioning

confidence: 99%

Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway

et al. 2018

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Chronic inflammation plays an essential role in the development of diabetic complications. Understanding the molecular mechanisms that support inflammation is a prerequisite for the design of novel anti-inflammatory therapies. These would take into consideration circulating levels of cytokines and damage-associated molecular patterns (DAMPs) that include the high mobility group box 1 (HMGB1) protein which, in part, promotes the inflammatory response through TLR4 signaling. The liver, as the source of circulating cytokines and acute-phase proteins, contributes to the control of systemic inflammation. We previously found that liver injury in streptozotocin-induced diabetic rats correlated with the level of oxidative stress, increased expression of HMGB1, and with the activation of TLR4-mediated cell death pathways. In the present work, we examined the effects of ethyl pyruvate (EP), an inhibitor of HMGB1 release/expression, on the modulation of activation of the HMGB1/TLR4 inflammatory cascade in diabetic liver. We observed that increased expression of inflammatory markers, TNF-α, IL-6, and haptoglobin in diabetic liver was associated with increased HMGB1/TLR4 interaction, activation of MAPK (p38, ERK, JNK)/NF-κB p65 and JAK1/STAT3 signaling pathways, and with decreased expression of Nrf2-regulated antioxidative enzymes. The reduction in HMGB1 expression as the result of EP administration reduced the pro-inflammatory activity of HMGB1 and exerted a protective effect on diabetic liver, which was observed as improved liver histology and antioxidant and inflammatory statuses. Our results suggest that prevention of HMGB1 release and blockage of the HMGB/TLR4 axis represents a potentially effective therapeutic strategy aimed at ameliorating diabetes-induced inflammation and ensuing liver injury.

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Section: Introductionmentioning

confidence: 99%

Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway

et al. 2018

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“…Our results imply that the concept of a strict dichotomy between glycolysis and oxidative phosphorylation as energy sources for effector T cells and Treg, respectively, may be over-simplistic and, therefore, targeting the glycolytic pathway for Treg expansion and suppressive function by EP could be beneficial. Thus far, EP has been shown to be safe when tested in both healthy human volunteers and heart surgery patients [ 2 , 38 ]. Our data suggest that the utilization of EP may be a promising supporting therapy for autoimmune and immunoinflammatory diseases in which the enhancement of Treg numbers and suppressive functions is expected to dampen disease activity and progression.…”

Section: Discussionmentioning

confidence: 99%

Ethyl Pyruvate Promotes Proliferation of Regulatory T Cells by Increasing Glycolysis

et al. 2020

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Ethyl pyruvate (EP), a stable form of pyruvate, has shown beneficial effects in animal models of shock, ischemia/reperfusion injury, and sepsis due to its potent anti-oxidant and anti-inflammatory properties. Our recent study demonstrated that EP application prevented the clinical manifestation of type 1 diabetes in mice by augmenting regulatory T cell (Treg) number and function. Our present study shows that EP increases Treg proliferation and suppressive function (perforin and IL-10 expression) during in vitro differentiation from conventional CD4+CD25− T cells. Enhanced expansion of Treg after EP treatment correlated with increased ATP levels and relied on increased glycolysis. Inhibition of oxidative phosphorylation did not attenuate EP stimulatory effects, suggesting that this metabolic pathway was not mandatory for EP-driven Treg proliferation. Moreover, EP lowered the expression of carnitine palmitoyltransferase I, an enzyme involved in fatty acid oxidation. Further, the stimulatory effect of EP on Treg proliferation was not mediated through inhibition of the mTOR signaling pathway. When given in vivo either intraperitoneally or orally to healthy C57BL/6 mice, EP increased the number of Treg within the peritoneal cavity or gut-associated lymphoid tissue, respectively. In conclusion, EP promotes in vitro Treg proliferation through increased glycolysis and enhances Treg proliferation when administered in vivo.

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“…While pyruvate is very effective for in vitro experiments in protecting acinar cells against L-Asparaginase-triggered damage [39], a simple derivative of pyruvic acid, namely, ethyl pyruvate has been found useful for treatment of bile-induced AP in a rat model [54]. Ethyl pyruvate is also known as a ROS scavenger and, in addition, has other anti-inflammatory effects [55]. The role of ROS in AP remains controversial [30,56,57,58], while a recent study has shown an important contribution of nitric oxide [31] in pancreatic pathology, justifying the use of NO synthase inhibitors as a potential AP treatment [59,60].…”

Section: How To Save Pacs From Ca 2+ Overload and Necrosis?mentioning

confidence: 99%

Ca2+ signalling underlying pancreatitis

et al. 2018

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In spite of significant scientific progress in recent years, acute pancreatitis (AP) is still a dangerous and in up to 5% of cases deadly disease with no specific cure. It is self-resolved in the majority of cases, but could result in chronic pancreatitis (CP) and increased risk of pancreatic cancer (PC). One of the early events in AP is premature activation of digestive pro-enzymes, including trypsinogen, inside pancreatic acinar cells (PACs) due to an excessive rise in the cytosolic Ca concentration, which is the result of Ca release from internal stores followed by Ca entry through the store operated Ca channels in the plasma membrane. The leading causes of AP are high alcohol intake and biliary disease with gallstones obstruction leading to bile reflux into the pancreatic duct. Recently attention in this area of research turned to another cause of AP - Asparaginase based drugs - which have been used quite successfully in treatments of childhood acute lymphoblastic leukaemia (ALL). Unfortunately, Asparaginase is implicated in triggering AP in 5-10% of cases as a side effect of the anti-cancer therapy. The main features of Asparaginase-elicited AP (AAP) were found to be remarkably similar to AP induced by alcohol metabolites and bile acids. Several potential therapeutic avenues in counteracting AAP have been suggested and could also be useful for dealing with AP induced by other causes. Another interesting development in this field includes recent research related to pancreatic stellate cells (PSCs) that are much less studied in their natural environment but nevertheless critically involved in AP, CP and PC. This review will attempt to evaluate developments, approaches and potential therapies for AP and discuss links to other relevant diseases.

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

Cited by 56 publications

References 93 publications

Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway

Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway

Ethyl Pyruvate Promotes Proliferation of Regulatory T Cells by Increasing Glycolysis

Ca2+ signalling underlying pancreatitis

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