Ethyl pyruvate alleviates pulmonary arterial hypertension via PI3K-Akt signaling.

Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome that is extremely difficult to manage, and there is currently no effective treatment. We want to elucidate the therapeutic effect of ethyl pyruvate (EP) on PAH and its possible mechanism. Pulmonary artery endothelial cells (PAECs) were cultured in conventional low-oxygen environments, and cellular proliferation was monitored after treatment with EP. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 was detected by Western blot. After hyperkinetic PAH rabbits' models were treated with EP, hemodynamic data were collected. Right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 protein was also detected after using autophagy inhibitor and agonists. We found that EP could inhibit PAECs proliferation. After EP treatment, expression of p-PI3K/Akt was upregulated in vitro and in vivo. LC3-II and Beclin-1 were inhibited and their expression was lower after autophagy inhibitor was given, while after administration of autophagy agonists, their expression was higher than that in the EP alone group. Besides, EP attenuated PAH, and right ventricular hypertrophy and pulmonary vascular remodeling were also reversed. EP can reduce PAH and reverse vascular remodeling which is associated with inhibition of autophagy in PAECs based on PI3K-Akt signaling pathway. The results of this study can provide surgical opportunities for patients with severe PAH caused by congenital heart disease in clinical cardiovascular surgery.

Ethyl pyruvate attenuates cisplatin-induced ovarian injury in rats via activating Nrf2 pathway.

Although cisplatin (CDDP) is an antineoplastic drug widely used for the treatment of various tumors, its toxicity on the reproductive system is a concern for patients. Ethyl pyruvate (EP) possesses potent antioxidant and anti-inflammatory activities. The objective of this study was to evaluate the therapeutic potential of EP on CDDP-mediated ovotoxicity for the first time. Rats were exposed to CDDP (5 mg/kg) and then treated with two doses of EP (20 and 40 mg/kg) for 3 days. Serum fertility hormone markers were evaluated using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers were also determined. In addition, how CDDP affects the nuclear factor erythroid 2-associated factor 2 (Nrf2) pathway and the effect of EP on this situation were also addressed. EP improved CDDP-induced histopathological findings and restored decreasing levels of fertility hormones. EP treatment also reduced the levels of CDDP-mediated OS, inflammation, ERS and apoptosis. In addition, EP attenuated CDDP-induced suppression in the levels of Nrf2 and its target genes, including heme oxygenase-1, NAD(P)H quinone dehydrogenase-1, superoxide dismutase and glutathione peroxidase. Histological and biochemical results showed that EP can have therapeutic effects against CDDP-induced ovotoxicity with antioxidant, anti-inflammatory and Nrf2 activator activities.

NRF2 Plays a Crucial Role in the Tolerogenic Effect of Ethyl Pyruvate on Dendritic Cells.

Ethyl pyruvate (EP) is a redox-active compound that has been previously shown to be effective in restraining immune hyperactivity in animal models of various autoimmune and chronic inflammatory diseases. Importantly, EP has also been proven to have a potent tolerogenic effect on dendritic cells (DCs). Here, the influence of EP on the signaling pathways in DCs relevant for their tolerogenicity, including anti-inflammatory NRF2 and pro-inflammatory NF-κB, was explored. Specifically, the effects of EP on DCs obtained by GM-CSF-directed differentiation of murine bone marrow precursor cells and matured under the influence of lipopolysaccharide (LPS) were examined via immunocytochemistry and RT-PCR. EP counteracted LPS-imposed morphological changes and down-regulated the LPS-induced expression of pro-inflammatory mediators in DCs. While it reduced the activation of NF-κB, EP potentiated NRF2 and downstream antioxidative molecules, thus implying the regulation of NRF2 signaling pathways as the major reason for the tolerizing effects of EP on DCs.

Ethyl Pyruvate Decreases Collagen Synthesis and Upregulates MMP Activity in Keloid Fibroblasts and Keloid Spheroids.

Keloids, marked by abnormal cellular proliferation and excessive extracellular matrix (ECM) accumulation, pose significant therapeutic challenges. Ethyl pyruvate (EP), an inhibitor of the high-mobility group box 1 (HMGB1) and TGF-ß1 pathways, has emerged as a potential anti-fibrotic agent. Our research evaluated EP's effects on keloid fibroblast (KF) proliferation and ECM production, employing both in vitro cell cultures and ex vivo patient-derived keloid spheroids. We also analyzed the expression levels of ECM components in keloid tissue spheroids treated with EP through immunohistochemistry. Findings revealed that EP treatment impedes the nuclear translocation of HMGB1 and diminishes KF proliferation. Additionally, EP significantly lowered mRNA and protein levels of collagen I and III by attenuating TGF-ß1 and pSmad2/3 complex expression in both human dermal fibroblasts and KFs. Moreover, metalloproteinase I (MMP-1) and MMP-3 mRNA levels saw a notable increase following EP administration. In keloid spheroids, EP induced a dose-dependent reduction in ECM component expression. Immunohistochemical and western blot analyses confirmed significant declines in collagen I, collagen III, fibronectin, elastin, TGF-ß, AKT, and ERK 1/2 expression levels. These outcomes underscore EP's antifibrotic potential, suggesting its viability as a therapeutic approach for keloids.

Ethyl pyruvate attenuates cellular adhesion and proliferation of diffuse large B-cell lymphoma by targeting c-Jun.

Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl pyruvate (EP) is a derivative of pyruvic acid and found to have potent anti-tumor properties. Despite its potential benefits, the impact of EP on DLBCL remains ambiguous. Our objective is to elucidate the role of EP in modulating the development of DLBCL. Analysis of cholecystokinin-8 (CCK-8) revealed that treatment with EP significantly diminished the viability of DLBCL cells. Furthermore, EP administration suppressed colony formation and hindered cell adhesion and invasion in DLBCL cells. Examination of cell cycle progression showed that EP treatment induced arrest at the G1 phase and subsequently reduced the S phase population in DLBCL cells. EP treatment consistently exhibited apoptosis-inducing properties in Annexin-V assays, and notably downregulated the expression of Bcl-2 while increasing levels of proapoptotic cleaved caspase 3 and BAX in DLBCL cells. Additionally, EP treatment decreased the overexpression of c-Jun in c-Jun-transfected DLBCL cells. Further, EP demonstrated DNA-damaging effects in TUNEL assays. In vivo, xenograft animal models revealed that EP treatment significantly mitigated DLBCL tumor growth and suppressed DLBCL cell adhesion to bone marrow stromal cells. In summary, these findings suggest that EP mitigates DLBCL progression by inducing apoptosis, inducing cell cycle arrest, and promoting DNA damage.

Ethyl pyruvate, a versatile protector in inflammation and autoimmunity.

Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years.

Effects of intravenous ethyl pyruvate on cardiopulmonary variables and quality of recovery from anesthesia in horses.

OBJECTIVE: To determine the effects of intravenous ethyl pyruvate, an anti-inflammatory with putative benefits in horses with endotoxemia, on cardiopulmonary variables during anesthesia and the quality of anesthetic recovery. STUDY DESIGN: Randomized, crossover, blinded experimental design. ANIMALS: A total of six healthy Standardbred geldings, aged 13 ± 3 years and weighing 507 ± 66 kg (mean ± standard deviation). METHODS: Horses were anesthetized for approximately 90 minutes on two occasions with a minimum of 2 weeks apart using xylazine for sedation, ketamine and diazepam for induction, and isoflurane in oxygen for maintenance. Lactated Ringer's solution (LRS; 10 mL kg-1 hour-1) was administered during anesthesia. Treatments were randomized and administered starting approximately 30 minutes after induction of anesthesia and infused over 60 minutes: LRS (1 L) or ethyl pyruvate (150 mg kg-1 in 1 L LRS). Invasive arterial pressures, heart rate, respiratory rate and end-tidal carbon dioxide tensions were recorded every 5 minutes for the duration of anesthesia. Arterial blood gases, glucose and lactate concentrations were measured every 20 minutes. Anesthetic recovery was video recorded, stored, and subsequently rated by two individuals blinded to treatments. Total recovery time, time to extubation, number of attempts and time to sternal recumbency, number of attempts to stand and time to stand were recorded. Quality of recovery was analyzed. Data between treatments and within a treatment were assessed using two-way repeated-measures anova and a Pearson correlation coefficient, significant at p < 0.05. RESULTS: All horses completed the study. No significant differences were detected between the ethyl pyruvate and LRS treatments for either the cardiopulmonary variables or quality of recovery from anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: The results suggest that intravenous ethyl pyruvate can be administered to healthy anesthetized horses with minimal impact on the cardiopulmonary variables studied or the quality of recovery from anesthesia.

Organic dust exposure induces stress response and mitochondrial dysfunction in monocytic cells.

Exposure to airborne organic dust (OD), rich in microbial pathogen-associated molecular patterns (PAMPs), is shown to induce lung inflammation. A common manifestation in lung inflammation is altered mitochondrial structure and bioenergetics that regulate mitochondrial ROS (mROS) and feed a vicious cycle of mitochondrial dysfunction. The role of mitochondrial dysfunction in other airway diseases is well known. However, whether OD exposure induces mitochondrial dysfunction remains elusive. Therefore, we tested a hypothesis that organic dust extract (ODE) exposure induces mitochondrial stress using a human monocytic cell line (THP1). We examined whether co-exposure to ethyl pyruvate (EP) or mitoapocynin (MA) could rescue ODE exposure induced mitochondrial changes. Transmission electron micrographs showed significant differences in cellular and organelle morphology upon ODE exposure. ODE exposure with and without EP co-treatment increased the mtDNA leakage into the cytosol. Next, ODE exposure increased PINK1, Parkin, cytoplasmic cytochrome c levels, and reduced mitochondrial mass and cell viability, indicating mitophagy. MA treatment was partially protective by decreasing Parkin expression, mtDNA and cytochrome c release and increasing cell viability.

Ethyl pyruvate: A newly discovered compound against ischemia-reperfusion injury in multiple organs.

Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention.

Ethyl pyruvate ameliorates heat stroke-induced multiple organ dysfunction and inflammatory responses by induction of stress proteins and activation of autophagy in rats.

Objective: Heat stroke (HS) elicits the systemic inflammatory responses that result in multiple organ dysfunction (MOD). Heat shock response and autophagy are activated during heat stress for removal of damaged organelles and proteins, emerging as a major regulator of cellular homeostasis. Ethyl pyruvate (EP) is a derivative of pyruvic acid and possesses antioxidant and anti-inflammatory effects. This study aims to investigate the effects of EP on MOD in HS rats and explore the possible mechanisms.Method: Anesthetized rats were placed in a heating chamber (42 °C) to elevate the core body temperature attaining to 42.9 °C. Rats were then moved to room temperature and monitored for 6 h. EP (60 mg/kg, i.v.) was administered 30 min prior to heat exposure.Results: Results showed that EP significantly reduced HS-induced increases in plasma levels of LDH, CPK, GPT and CK-MB, reversed the decrease of platelet counts, and alleviated intestinal mucosal and pulmonary damage. Moreover, EP reduced pro-inflammatory protein, including TNF-α, IL-6, IL-1ß, HMGB1 and iNOS, and induced stress proteins, heme oxygenase-1 (HO-1), heat shock protein (HSP) 70 and HSP90 in the liver of HS rats. The levels of HS-activated autophagy-regulatory proteins were affected by EP, in which the phosphorylated mTOR and AKT were reduced, and the phosphorylated AMPK increased, accompanied with upregulation in ULK1, Atg7, Atg12 and LC3II, and downregulation of p62.Conclusion: In conclusion, EP ameliorated HS-induced inflammatory responses and MOD, and the underlying mechanism is associated with the induction of the stress proteins HO-1 and HSP70 as well as restorage of autophagy.

The Role of HMGB1 in Invasive Candida albicans Infection.

INTRODUCTION: High mobility group box 1 (HMGB1) is an important "late" inflammatory mediator in bacterial sepsis. Ethyl pyruvate (EP), an inhibitor of HMGB1, can prevent bacterial sepsis by decreasing HMGB1 levels. However, the role of HMGB1 in fungal sepsis is still unclear. Therefore, we investigated the role of HMGB1 and EP in invasive C. albicans infection. METHODS: We measured serum HMGB1 levels in patients with sepsis with C. albicans infection and without fungal infection, and control subjects. We collected clinical indices to estimate correlations between HMGB1 levels and disease severity. Furthermore, we experimentally stimulated mice with C. albicans and C. albicans + EP. Then, we examined HMGB1 levels from serum and tissue, investigated serum levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), determined pathological changes in tissues, and assessed mortality. RESULTS: Serum HMGB1 levels in patients with severe sepsis with C. albicans infection were elevated. Increased HMGB1 levels were correlated with procalcitonin (PCT), C-reactive protein (CRP), 1,3-ß-D-Glucan (BDG) and C. albicans sepsis severity. HMGB1 levels in serum and tissues were significantly increased within 7 days after mice were infected with C. albicans. The administration of EP inhibited HMGB1 levels, decreased tissue damage, increased survival rates and inhibited the release of TNF-α and IL-6. CONCLUSIONS: HMGB1 levels were significantly increased in invasive C. albicans infections. EP prevented C. albicans lethality by decreasing HMGB1 expression and release. HMGB1 may provide an effective diagnostic and therapeutic target for invasive C. albicans infections.

Ethyl pyruvate protects against sepsis-associated encephalopathy through inhibiting the NLRP3 inflammasome.

BACKGROUND: With the advance of antibiotics and life support therapy, the mortality of sepsis has been decreasing in recent years. However, the incidence of sepsis-associated encephalopathy (SAE), a common complication of sepsis, is still high. There are few effective therapies to treat clinical SAE. We previously found that ethyl pyruvate (EP), a metabolite derivative, is able to effectively inhibit the NLRP3 inflammasome activation. Administration of ethyl pyruvate protects mice against polymicrobial sepsis in cecal ligation and puncture (CLP) model. The aim of present study is to investigate if ethyl pyruvate is able to attenuate SAE. METHODS: After CLP, C57BL/6 mice were intraperitoneally or intrathecally injected with saline or ethyl pyruvate using the sham-operated mice as control. New Object Recognition (NOR) and Morris Water Maze (MWM) were conducted to determine the cognitive function. Brain pathology was assessed via immunohistochemistry. To investigate the mechanisms by which ethyl pyruvate prevent SAE, the activation of NLRP3 in the hippocampus and the microglia were determined using western blotting, and cognitive function, microglia activation, and neurogenesis were assessed using WT, Nlrp3-/- and Asc-/- mice in the sublethal CLP model. In addition, Nlrp3-/- and Asc-/- mice treated with saline or ethyl pyruvate were subjected to CLP. RESULTS: Ethyl pyruvate treatment significantly attenuated CLP-induced cognitive decline, microglia activation, and impaired neurogenesis. In addition, EP significantly decreased the NLRP3 level in the hippocampus of the CLP mice, and inhibited the cleavage of IL-1ß induced by NLRP3 inflammsome in microglia. NLRP3 and ASC deficiency demonstrated similar protective effects against SAE. Nlrp3-/- and Asc-/- mice significantly improved cognitive function and brain pathology when compared with WT mice in the CLP models. Moreover, ethyl pyruvate did not have additional effects against SAE in Nlrp3-/- and Asc-/- mice. CONCLUSION: The results demonstrated that ethyl pyruvate confers protection against SAE through inhibiting the NLRP3 inflammasome.

Pyruvic acid/ethyl pyruvate inhibits melanogenesis in B16F10 melanoma cells through PI3K/AKT, GSK3ß, and ROS-ERK signaling pathways.

Melanin is the main product of human melanocytes and functions to protect skin from ultraviolet (UV) radiation while conferring color to skin and hair. Tyrosinase is the rate-limiting enzyme for melanin synthesis along with tyrosinase-related protein (TRP)-1 and TRP-2. Microphthalmia-associated transcription factor regulates tyrosinase gene expression and is in turn regulated by extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/AKT, and glycogen synthase kinase (GSK)3ß signaling pathways. Pyruvic acid (PA) is an energy source for ATP synthesis in the tricarboxylic acid cycle that also acts as a reactive oxygen species (ROS) scavenger. As UV irradiation induces melanin synthesis and ROS generation, we speculated that PA or ethyl pyruvate (EP), a stable form of pyruvate, regulates melanogenesis. B16F10 melanoma cells served as a melanin synthesis model. Treatment with PA or EP suppressed melanin synthesis while increasing intracellular ROS levels, which was accompanied by increased ERK phosphorylation in the case of EP treatment. PA and EP induced GSK3ß phosphorylation and activated PI3K/AKT signaling, leading to decreased melanin synthesis. These results indicate that PA and EP inhibit melanogenesis via PI3K/AKT and GSK3ß signaling and targeting the ERK and GSK3ß pathways, respectively. Thus, PA and EP can potentially be used for treatment of hyperpigmentation disorders.

Ethyl Pyruvate Promotes Proliferation of Regulatory T Cells by Increasing Glycolysis.

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.

Ringer's ethyl pyruvate solution attenuates hypoperfusion and renal injury after multivisceral ischemia-reperfusion in rabbits.

Ringer's ethyl pyruvate solution (REPS) has been protective against experimental renal, intestinal, and spinal ischemia and may be useful for organ protection in major vascular surgery. The purpose of this study was to investigate whether REPS attenuates organ injury in a rabbit model of supraceliac aortic cross-clamp that simulates thoracoabdominal aortic surgery. Following the Institutional Animal Care and Use Committee's approval, 20 rabbits were undergone cross-clamping of the supraceliac thoracic aorta for 30 min, and observed for 180 min after reperfusion. Either REPS (33 mg/kg/h of ethyl pyruvate) or Ringer's lactate solution were infused throughout the study period. Arterial pressure and aortic blood flow were continuously monitored. Blood lactate concentration, serum transaminase levels, neutrophil activation, and urinary N-acetyl-beta-glucosaminidase (NAG) activity were evaluated. After reperfusion, supraceliac aortic blood flow was significantly higher, and urinary NAG was significantly lower in animals that received REPS, while the other parameters were not significantly different. In conclusion, REPS attenuated the reduction of aortic blood flow and urinary NAG elevation after the cross-clamp of supraceliac aorta.

Ethyl pyruvate attenuates ventilation-induced diaphragm dysfunction through high-mobility group box-1 in a murine endotoxaemia model.

Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator-induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high-mobility group box-1 (HMGB1) levels are associated with patients requiring long-term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti-HMGB1 antibody could attenuate sepsis-exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti-HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor-1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti-HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin-enhanced VIDD by inhibiting HMGB1 signalling pathway.

Ethyl pyruvate reduces organic dust-induced airway inflammation by targeting HMGB1-RAGE signaling.

BACKGROUND: Animal production workers are persistently exposed to organic dust and can suffer from a variety of respiratory disease symptoms and annual decline in lung function. The role of high mobility group box-1 (HMGB1) in inflammatory airway diseases is emerging. Hence, we tested a hypothesis that organic dust exposure of airway epithelial cells induces nucleocytoplasmic translocation of HMGB1 and blocking this translocation dampens organic dust-induced lung inflammation. METHODS: Rats were exposed to either ambient air or swine barn (8 h/day for either 1, 5, or 20 days) and lung tissues were processed for immunohistochemistry. Swine barn dust was collected and organic dust extract (ODE) was prepared and sterilized. Human airway epithelial cell line (BEAS-2B) was exposed to either media or organic dust extract followed by treatment with media or ethyl pyruvate (EP) or anti-HMGB1 antibody. Immunoblotting, ELISA and other assays were performed at 0 (control), 6, 24 and 48 h. Data (as mean ± SEM) was analyzed using one or two-way ANOVA followed by Bonferroni's post hoc comparison test. A p value of less than 0.05 was considered significant. RESULTS: Compared to controls, barn exposed rats showed an increase in the expression of HMGB1 in the lungs. Compared to controls, ODE exposed BEAS-2B cells showed nucleocytoplasmic translocation of HMGB1, co-localization of HMGB1 and RAGE, reactive species and pro-inflammatory cytokine production. EP treatment reduced the ODE induced nucleocytoplasmic translocation of HMGB1, HMGB1 expression in the cytoplasmic fraction, GM-CSF and IL-1ß production and augmented the production of TGF-ß1 and IL-10. Anti-HMGB1 treatment reduced ODE-induced NF-κB p65 expression, IL-6, ROS and RNS but augmented TGF-ß1 and IL-10 levels. CONCLUSIONS: HMGB1-RAGE signaling is an attractive target to abrogate OD-induced lung inflammation.

Ethyl pyruvate and analogs as potential treatments for acute pancreatitis: A review of in vitro and in vivo studies.

Ethyl pyruvate (EP) has been shown to improve outcomes from multiple organ dysfunction syndrome (MODS) in experimental animal models of critical illness. This review aimed to summarise in vitro and in vivo effects of EP analogs on acute pancreatitis (AP) with the objective of proposing medicinal chemistry modifications of EP for future research. In vitro studies showed that both sodium pyruvate and EP significantly reduced pancreatic acinar necrotic cell death pathway activation induced by multiple pancreatic toxins. In vivo studies using different murine AP models showed that EP (usually at a dose of 40 mg/kg every 6 h) consistently reduced pain, markers of pancreatic injury, systemic inflammation and MODS. There was also a significant increase in survival rate, even when EP was administered 12 h after disease induction (compared with untreated groups or those treated with Ringer's lactate solution). Experimental studies suggest that EP and analogs are promising drug candidates for treating AP. EP or analogs can undergo medicinal chemistry modifications to improve its stability and deliverability. EP or analogs could be evaluated as a supplement to intravenous fluid therapy in AP.

Inhibition of Neuronal Nitric Oxide Synthase by Ethyl Pyruvate in Schwann Cells Protects Against Peripheral Nerve Degeneration.

Schwann cells are essential glial cells in the peripheral nervous system (PNS), and dysfunction of Schwann cells can induce various peripheral neurodegenerative diseases. Oxidative stress has been implicated as a causative factor in degenerative nerve diseases; however, there no effective molecules are available to inhibit nerve degeneration in peripheral neurodegenerative diseases. Ethyl pyruvate (EP) is a candidate regulator of oxidative stress, targeting Schwann cells during peripheral nerve degeneration. Here, we investigated the effects of EP on axonal degradation, demyelination, transcriptional regulation, and macrophage recruitment during Wallerian degeneration of the sciatic nerve, ex vivo and in vivo. EP prevented the expression of neuronal nitric oxide synthase (NOS1), but not that of inducible nitric oxide synthase (NOS2), during Wallerian degeneration. These results suggest that effect of EP on Schwann cells may protect against peripheral nerve degeneration through its NOS1-specific regulation.

Ethyl pyruvate (EP) suppressed post-harvest blue mold of sweet cherry fruit by inhibiting the growth of Penicillium oxalicum.

BACKGROUND: The shelf-life of fresh sweet cherry is relatively short due to fungal decay during post-harvest storage. To investigate the effect and the mechanism of action of ethyl pyruvate (EP) against blue mold of sweet cherry fruit caused by Penicillium oxalicum, the spores were treated with 25 mg L-1 EP. The spore germination rate of P. oxalicum, the integrities of the cell wall and plasma membrane, reactive oxygen species (ROS) and malondialdehyde (MDA) were evaluated. RESULTS: EP treatment significantly suppressed post-harvest blue mold of sweet cherry fruit. We found that the treatment of 25 mg L-1 EP significantly suppressed blue mold of post-harvest sweet cherry fruit by directly inhibiting germination and the mycelial growth of P. oxalicum. After co-inoculation with EP for 30 min, the spore germination rate of P. oxalicum was reduced by 83.5%. In addition, the pH of the EP solution was found to affect its antimicrobial activity. After treatment with EP, the cell surface structures of the spores of P. oxalicum were much more incomplete, and higher ROS and MDA values were recorded in the spores. CONCLUSIONS: The results suggested that EP treatment destroyed the integrities of the cell surface structures and caused oxidative damage of the spores of P. oxalicum. © 2019 Society of Chemical Industry.