Therapeutic Treatment With Ethyl Pyruvate Attenuates the Severity of Liver Injury in Rats With Severe Acute Pancreatitis

Luan, Zhenggang; Zhang, Hao; Ma, Xiaochun; Zhang, Cheng; Guo, Ren-Xuan

doi:10.1097/mpa.0b013e31823cd3ef

Cited by 17 publications

(26 citation statements)

References 54 publications

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“…In patients and animals with AP, serum levels of HMGB1 are significantly elevated and positively correlate with the severity of this disease (Kocsis et al, 2009; Yasuda et al, 2007; Yasuda et al, 2006). Importantly, inhibiting the release or cytokine activity of HMGB1 (e.g., HMGB1 neutralizing antibody, ethyl pyruvate, danaparoid sodium, cisplatin, A box, antithrombin III, and pyrrolidine dithiocarbamate) confers protection against experimental AP (Cheng et al, 2007; Hagiwara et al, 2009g; Jo et al, 2013; Luan et al, 2013a; Luan et al, 2012; Luan et al, 2013b; Sawa et al, 2006; Weng et al, 2012; Yan et al, 2012a; Yang et al, 2009b; Yang et al, 2008; Yuan et al, 2009; Zhang et al, 2010). However, intracellular HMGB1 in the pancreas protects against acute pancreatitis (Kang et al, 2013b).…”

Section: Hmgb1 and Diseasementioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

801

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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Section: Hmgb1 and Diseasementioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

801

828

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“…Concerning the lungs, EtP has been shown to protect against ventilation-induced neutrophil infiltration and the accompanying deleterious oxidative stress (25). Hepatic injury in animals with severe acute pancreatitis, but also sepsisor hemorrhage-induced organ injuries in vivo, were prevented by EtP (26)(27)(28)(29). Collectively, these results suggest that due to its stability, lack of adverse effects, wide therapeutic window and apparently no signs of intoxication, EtP will be useful in a clinical setting for the treatment of acute inflammation.…”

Section: Introductionmentioning

confidence: 99%

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Relja

Omid

Wagner

et al. 2015

International Journal of Molecular Medicine

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Abstract. Increases in pro-inflammatory cytokine levels and tissue-infiltrating leukocytes have been closely linked to increased systemic and local inflammation, which result in organ injury. Previously, we demonstrated the beneficial and hepatoprotective anti-inflammatory effects of acute ethanol (EtOH) ingestion in an in vivo model of acute inflammation. Due to its undesirable side-effects, however, EtOH does not represent a therapeutic option for treatment of acute inflammation. Therefore, in this study, we compared the effects of acute EtOH exposure with ethyl pyruvate (EtP) as an alternative anti-inflammatory drug in an in vitro model of hepatic and pulmonary inflammation. Human hepatocellular carcinoma cells Huh7 and alveolar epithelial cells A549 were stimulated with either interleukin (IL) IL-1β (1 ng/ml, 24 h) or tumor necrosis factor (TNF) (10 ng/ml, 4 h), and then treated with EtP (2.5-10 mM), sodium pyruvate (NaP, 10 mM) or EtOH (85-170 mM) for 1 h. IL-6 or IL-8 release from Huh7 or A549 cells, respectively, was measured by an enzyme-linked immunosorbent assay. Neutrophil adhesion to cell monolayers and CD54 expression were also analyzed. Bcl-2 and Bax gene expression was determined by RT-qPCR, and western blot analysis was performed to determine the mechanisms involved. Treating A549 cells with either EtOH or EtP significantly reduced the IL-1β-or TNF-induced IL-8 release, whereas treating Huh7 cells did not significantly alter IL-6 release. Similarly, neutrophil adhesion to stimulated A549 cells was significantly reduced by EtOH or EtP, whereas for Huh7 cells the tendency for reduced neutrophil adhesion rates by EtOH or EtP was not significant. CD54 expression was noticeably reduced in A549 cells, but this was not the case in Huh7 cells after treatment. The Bax/ Bcl-2 ratio was dose-dependently decreased by EtOH and by high-dose EtP in A549 cells, indicating a reduction in apoptosis, whereas this effect was not observed in Huh7 cells. The underlying mechanisms involve reduced phosphorylation of Akt and nuclear factor-κB (NF-κB) p65. We noted that as with EtP, EtOH reduced the inflammatory response in lung epithelial cells under acute inflammatory conditions. However, due to the low impact which EtP and EtOH had on the hepatocellular cells, our data suggest that both substances exerted different effects depending on the cellular entity. The possible underlying mechanisms involved the downregulation of Akt and the transcription factor NF-κB, but further research on this subject is required.

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“…The anti-inflammatory effects of pyruvate have been implicated in several pathologies, such as severe acute pancreatitis, 22 liver injury in diabetic rats, 23 cataracts 24 down-regulation of oxidative stress, albuminuria and glomerular injury in animal models of nephropathy. 2,25 The anti-inflammatory activities of pyruvate have been associated with i) the inhibition of cellular adhesion to the endothelium, 3 ii) the inhibition of NADPH-oxidase in kidney lesion, 2 iii) the association between the up-regulation of HO-1 and the inhibition of nitric oxide synthase expression associated with high-mobility group box 1 (HMGB-1) release in RAW 264.7 cells, 7 and iv) the down-regulation of oxidative stress and HMGB-1 expression during lung injury in C57BL/mice.…”

Section: Discussionmentioning

confidence: 99%

Absence of pyruvate anti-oxidant effect on granulocytes stimulated toll-like receptors

Chamon

Fagundes-Netto

Gonzaga

et al. 2013

Free Radicals and Antioxidants

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a b s t r a c tAim & background: Pyruvate is considered as an anti-inflammatory and anti-oxidant produced from glucose metabolism. We examined the effects of sodium pyruvate on reactive oxygen species (ROS) production induced by opsonized particles in phagocytosing or toll-like receptor 4 (TLR4)-stimulated granulocytes obtained from type 2 diabetic (T2DM) patients compared with those from healthy individuals. Methods: Luminol-dependent chemiluminescence was used to quantify the ROS generated. The phagocytosis by granulocytes obtained from T2DM patients or healthy individuals was evaluated in the absence of stimulation and in the presence of opsonized particles (zymosan complex recovered using the complement fragment C3b, ZC3b) or LPS as a TLR4 activator. Pyruvate (10 À4 M) markedly inhibited ROS generation in unstimulated and ZC3b-stimulated granulocytes from T2DM patients and healthy individuals. Results: Our results showed 370.0% and 199.0% activation of ROS generation during phagocytosis in healthy subjects and T2DM patients, respectively. In the presence of pyruvate, these percentages were reduced to 81.0% and 80.0%, respectively. Thus, pyruvate exhibited similar suppressive activity during granulocyte phagocytosis in healthy individuals and T2DM patients (p > 0.05). In contrast, pyruvate did not inhibit or down-regulate ROS generation in granulocytes stimulated with LPS. LPS-induced ROS production in granulocytes from healthy subjects (309%) and T2DM patients (62.5%). In the presence of pyruvate, the ROS generation in LPS-stimulated granulocytes was greater (64.0%) in the cells obtained from T2DM patients compared with cells obtained from healthy individuals (38.0%) (p < 0.05; chi-square test). Conclusion:The dual effect of pyruvate might be associated with a metabolic signaling pathway that depends on the oxidizing profile of the target cell. However, the effects of pyruvate must be further studied before using this compound as an anti-inflammatory or anti-oxidant therapeutic resource.

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Therapeutic Treatment With Ethyl Pyruvate Attenuates the Severity of Liver Injury in Rats With Severe Acute Pancreatitis

Abstract: Our results demonstrate that EP might play a therapeutic role in liver inflammation in this SAP model, and these beneficial effects of EP are because of the modulation of high-mobility group box 1 and other inflammatory cytokine responses.

Cited by 17 publications

References 54 publications

HMGB1 in health and disease

HMGB1 in health and disease

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Absence of pyruvate anti-oxidant effect on granulocytes stimulated toll-like receptors

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