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Shi H, Sun J, Sun Y, Wu J, Jiang G, Xu Z, Shi X, Fang M. Intestinal Epithelial Cell-specific Knockout of METTL3 Aggravates Intestinal Inflammation in CLP Mice by Weakening the Intestinal Barrier. Curr Pharm Biotechnol 2025; 26:80-91. [PMID: 38482615 DOI: 10.2174/0113892010271970240202054245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/19/2023] [Accepted: 12/28/2023] [Indexed: 11/30/2024]
Abstract
BACKGROUND Many studies have demonstrated that the expression of methyltransferase- like 3 (METTL3) is altered in various inflammatory diseases. Its specific mechanistic role in the intestinal inflammatory response during sepsis remains limited and requires further investigation. OBJECTIVES Explore the potential mechanism of METTL3 in the intestinal inflammatory response during sepsis. MATERIALS AND METHODS Immunohistochemical analysis was utilized to detect the expression of METTL3 in the necrotic intestine of patients with intestinal necrosis and the small intestine of cecal ligation and puncture (CLP) mice. Mice were subjected to the CLP and Sham surgeries, intestine tissue was harvested and performed HE staining, and ELISA to examine intestinal inflammatory responses, while TUNEL staining was applied to detect intestinal cell apoptosis. Additionally, ELISA was used to detect diamine oxidase (DAO) and intestinal fatty acid binding protein (I-FABP) levels in intestinal tissue. Immunohistochemistry and RT-qPCR were also employed to examine the mRNA and protein expression levels of Zona Occludens 1 (ZO-1) and Claudin-1. Finally, transcriptomic sequencing was performed on the small intestine tissues of METTL3 Knock-out (KO) and Wild-type (WT) mice in response to sepsis. RESULTS METTL3 exhibited lower expression level in the necrotic intestine of patients and the small intestine of CLP mice. Loss of METTL3 in CLP mice triggered significantly higher expression of TNF-α and IL-18, down-regulated expression of ZO-1 and claudin-1, and decreased expression of DAO and I-FABP in the intestinal tissue. KEGG enrichment analysis showed that the differential genes were significantly enriched in immune-related pathways. CONCLUSION This study reveals a novel mechanism responsible for exacerbated intestinal inflammation orchestrated by METTL3. Particularly, METTL3 null mice displayed decreased ZO- 1 and Claudin-1 expression, which largely hampered intestinal epithelial barrier function, resulting in bacterial and toxin translocation and intestinal immune activation and inflammation against sepsis.
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Affiliation(s)
- Hongzhou Shi
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Jiahui Sun
- School of Public Health, Southeast University, Nanjing, 210000, China
| | - Yaya Sun
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Junjie Wu
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Guangqing Jiang
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Zhaiyue Xu
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Xin Shi
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Miao Fang
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
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Bakdemir M, Çetin E. Hepatoprotective effects of ethyl pyruvate against carbon tetrachloride-induced oxidative stress, biochemical and histological alterations in rats. Arch Physiol Biochem 2021; 127:359-366. [PMID: 31314597 DOI: 10.1080/13813455.2019.1640254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
This study investigated the protective effects of ethyl pyruvate (EP) against carbon tetrachloride (CCl4)-induced acute hepatic injury in rats. The administration of a single dose of CCl4 (1.6 g/kg body weight) significantly elevated the levels of malondialdehyde, nitric oxide, alanine transaminase, aspartate transaminase, and alkaline phosphatase, cholesterol, low-density lipoprotein cholesterol, and triglycerides. In addition, CCl4 was found to significantly suppress the activity of superoxide dismutase, catalase, and glutathione peroxidase. All of these parameters were restored to their normal levels by the administration of EP before and after the CCl4 injection. Moreover, the number of positive apoptotic hepatocytes had significantly increased in the CCl4 group but decreased in rats treated with EP along with CCl4. Histopathological changes induced by CCl4 were also ameliorated by EP treatment. These findings provided evidence that EP, because of its antioxidant and anti-apoptotic action, could protect rat liver against CCl4-induced acute liver injury.
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Affiliation(s)
- Miraç Bakdemir
- Department of Veterinary Physiology, Institute of Health Sciences, Erciyes University, Kayseri, Turkey
| | - Ebru Çetin
- Department of Physiology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey
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Jung SM, Lee J, Baek SY, Lee J, Jang SG, Hong SM, Park JS, Cho ML, Park SH, Kwok SK. Ethyl pyruvate ameliorates inflammatory arthritis in mice. Int Immunopharmacol 2017; 52:333-341. [PMID: 28987932 DOI: 10.1016/j.intimp.2017.09.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 09/25/2017] [Accepted: 09/26/2017] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Ethyl pyruvate (EP) is the ethyl ester of pyruvate and has antioxidative and anti-inflammatory effects. This study aimed to evaluate the therapeutic effect of EP in inflammatory arthritis and to identify the underlying mechanisms. METHODS Mice with collagen-induced arthritis (CIA) were treated with the vehicle control or EP at 20mg/kg, and clinical and histological analyses were performed on the animals. The differentiation of murine CD4+ T cells into T helper 17 (Th17) cells in the presence of EP was investigated in vitro. The effects of EP on osteoclastogenesis were determined by staining for tartrate-resistant acid phosphatase, and measuring the mRNA levels of osteoclastogenesis-related genes. The expression of high-mobility group box 1 (HMGB1) was evaluated after EP therapy using immunohistochemical staining and Western blotting. RESULTS EP significantly improved the clinical and histological features of arthritis in CIA mice. EP suppressed the differentiation of CD4+ T cells into Th17 cells, and inhibited the expression of RORγt. The generation of osteoclasts and osteoclastogenic markers from murine and human monocytes was significantly reduced in the presence of EP. The expression of HMGB1 in the synovium was significantly lower in CIA mice treated with EP, compared to control CIA mice. During osteoclastogenesis, HMGB1 release from monocytes was inhibited in the presence of EP. CONCLUSIONS EP attenuated synovial inflammation and bone destruction in the experimental arthritis model through suppression of IL-17 and HMGB-1. The data suggests that EP could be a novel therapeutic agent for the treatment of inflammatory arthritis, such as rheumatoid arthritis.
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Affiliation(s)
- Seung Min Jung
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jaeseon Lee
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Ye Baek
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Juhyun Lee
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Se Gwang Jang
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung-Min Hong
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin-Sil Park
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Mi-La Cho
- Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung-Ki Kwok
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Rheumatism Research Center, Catholic Institutes of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SMM, McCormick JK, Mele T. A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes 2014; 7:233. [PMID: 24725742 PMCID: PMC4022086 DOI: 10.1186/1756-0500-7-233] [Citation(s) in RCA: 332] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 04/09/2014] [Indexed: 12/19/2022] Open
Abstract
Background The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis. Methods Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient. Results Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury. Conclusions The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.
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Affiliation(s)
| | | | | | | | | | | | - Tina Mele
- Division of General Surgery, Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
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Ethyl pyruvate prevents inflammatory factors release and decreases intestinal permeability in rats with D-galactosamine-induced acute liver failure. Hepatobiliary Pancreat Dis Int 2013; 12:180-8. [PMID: 23558073 DOI: 10.1016/s1499-3872(13)60029-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The pathogenesis and progression of acute liver failure (ALF) are closely associated with intestinal endotoxemia because of the high permeability of the intestinal wall. Treatment with ethyl pyruvate (EP) has been shown to protect liver failure effectively. The current study aimed to explore the relationship between proinflammatory cytokines and intestinal permeability, and to investigate whether EP administration might prevent the release of multiple proinflammatory cytokines and decrease intestinal permeability and therefore, protect the liver from injury. METHODS The ALF model was induced by D-galactosamine in rats. The rats were randomly divided into control (saline, i.p.), model (D-galactosamine, 1.2 g/kg, i.p.), prevention [EP injection (40 mg/kg) 2 hours ahead of D-galactosamine] and treatment groups (EP injection 2 hours after D-galactosamine). Samples were obtained at 12 and 24 hours after ALF induction, respectively. The histology of liver and intestinal tissue was assessed. Serum alanine aminotransferase, endotoxin, D(-)-lactate, diamine oxidase (DAO), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and high mobility group box-1 (HMGB1) were evaluated. The survival of rats was also recorded. RESULTS The rats in model group showed severe damage to liver tissue and intestinal mucosa 12 and 24 hours after ALF induction. EP significantly improved liver or intestinal injury. In addition, serum endotoxin, D(-)-lactate, DAO, TNF-alpha, IFN-gamma and HMGB1 levels were significantly increased in the model group compared with the control group. There was a positive correlation between intestinal permeability and proinflammatory cytokines. EP significantly reduced serum endotoxin, D(-)-lactate, DAO, TNF-alpha, IFN-gamma and HMGB1 levels. The median survival time was significantly prolonged in both prevention and treatment groups (126 and 120 hours compared with 54 hours in the model group). CONCLUSIONS EP has protective and therapeutic effects on intestinal mucosa. EP decreases intestinal permeability, and inhibits the release of multiple proinflammatory cytokines in rats with ALF.
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Wang Y, Yin P, Huang S, Wang J, Sun R. Ethyl pyruvate protects against lipopolysaccharide-induced white matter injury in the developing rat brain. Int J Dev Neurosci 2012; 31:181-8. [PMID: 23280059 DOI: 10.1016/j.ijdevneu.2012.12.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Revised: 12/17/2012] [Accepted: 12/20/2012] [Indexed: 10/27/2022] Open
Abstract
The neuroprotective effects of ethyl pyruvate (EP) have been proved in several brain injury models, yet very little is known about its action on neonatal white matter injury. To investigate the effect of EP on white matte damage, a stereotactic intracerebral injection of lipopolysaccharide (LPS, 1mg/kg) was performed on postnatal day 5 Sprague-Dawley rat pups, and EP was administrated intraperitoneally at a dose of 40mg/kg immediately, 1h and 12h after LPS exposure. Significantly, treatment with EP reduced LPS-induced ventricle dilation, loss of O4+ and O1+ oligodendrocytes, apoptosis of oligodendrocytes, and hypomyelination. The protective effect of EP was associated with suppressed inflammatory responses, indicated by the inhibition of activation of microglia and astrocytes, as well as the decreased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) in rat brains. Also, EP prevented the elevation of cleaved caspase-3 in periventricular white matter tissue after LPS insult. Taken together, these results suggest that EP confers potent protection against LPS-induced white matter injury via its anti-inflammatory and anti-apoptotic properties.
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Affiliation(s)
- Yingyan Wang
- Pediatric Department of Qilu Hospital, Shandong University, Jinan, Shandong Province, China
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Wang LW, Wang LK, Chen H, Fan C, Li X, He CM, Gong ZJ. Ethyl pyruvate protects against experimental acute-on-chronic liver failure in rats. World J Gastroenterol 2012; 18:5709-18. [PMID: 23155311 PMCID: PMC3484339 DOI: 10.3748/wjg.v18.i40.5709] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 05/21/2012] [Accepted: 07/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective effects of ethyl pyruvate (EP) on acute-on-chronic liver failure (ACLF) in rats.
METHODS: An ACLF model was established in rats, and animals were randomly divided into normal, model and EP treatment groups. The rats in EP treatment group received EP (40 mg/kg) at 3 h, 6 h, 12 h and 24 h after induction of ACLF. Serum endotoxin, high mobility group box-1 (HMGB1), alanine transaminase (ALT), tumor necrosis factor-α (TNF-α), interferon-α (IFN-γ), interleukin (IL)-10 and IL-18 levels, changes of liver histology and HMGB1 expressions in liver tissues were detected at 48 h after induction of ACLF. The effects of EP on the survival of ACLF rats were also observed.
RESULTS: Serum levels of endotoxin (0.394 ± 0.066 EU/mL vs 0.086 ± 0.017 EU/mL, P < 0.001), HMGB1 (35.42 ± 10.86 μg/L vs 2.14 ± 0.27 μg/L, P < 0.001), ALT (8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L, P < 0.001), TNF-α (190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L, P < 0.001), IFN-γ (715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L, P < 0.001), IL-10 (6.85 ± 0.64 ng/L vs 3.49 ± 0.24 ng/L, P < 0.001) and IL-18 (85.19 ± 3.49 ng/L vs 55.38 ± 1.25 ng/L, P < 0.001) were significantly increased, and liver tissues presented severe pathological injury in the model group compared with the normal group. However, EP administration significantly improved hepatic histopathology and reduced the serum levels of endotoxin (0.155 ± 0.045 EU/mL vs 0.394 ± 0.066 EU/mL, P < 0.001) and inflammatory cytokines (11.13 ± 2.58 μg/L vs 35.42 ± 10.86 μg/L for HMGB1, 3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT, 128.55 ± 5.76 ng/L vs 190.77 ± 12.34 ng/L for TNF-α, 438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-γ, 3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10, and 60.35 ± 1.63 ng/L vs 85.19 ± 3.49 ng/L for IL-18, respectively, P < 0.001), and the levels of HMGB1 in liver tissues regardless of treatment time after induction of ACLF. EP treatment at the four time points prolonged the median survival time of ACLF rats (60 h) to 162 h, 120 h, 102 h and 78 h, respectively (χ2 = 41.17, P < 0.0001).
CONCLUSION: EP administration can protect against ACLF in rats, and is a potential and novel therapeutic agent for severe liver injury.
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Addition of polydextrose and galactooligosaccharide to formula does not affect bacterial translocation in the neonatal piglet. J Pediatr Gastroenterol Nutr 2011; 52:210-6. [PMID: 21240011 DOI: 10.1097/mpg.0b013e3181ffcaee] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES The aim of the study was to determine the effect of polydextrose (PDX) and galactooligosaccharide (GOS) on bacterial translocation (BT) in neonatal piglets. MATERIALS AND METHODS Piglets (n = 36) were randomized 12 hours after birth to receive total enteral nutrition (TEN) as formula; TEN + GOS (4 g/L), TEN + PDX (4 g/L), or TEN + GOS + PDX (2 g/L each) for 7 days or were supported by total parenteral nutrition (TPN) as a positive control for BT (n = 8). Blood, spleen, liver, and mesenteric lymph node (MLN) samples were cultured for aerobic and anaerobic bacteria. Colon microbiota 16S rDNA was measured by polymerase chain reaction. Myeloperoxidase activity and tumor necrosis factor-α expression were measured in ileum and ascending colon. RESULTS Among the enterally fed groups, no difference was seen in the Lactobacillus and Bacteroides 16S rDNA copies per gram of colonic contents, yet total bacterial levels were lower (P < 0.05) in the TEN + GOS group compared with TEN alone. Bacteria were detected in the blood, liver spleen, and MLN of TPN piglets. In contrast, bacterial counts were predominantly detected in the MLN of TEN piglets, at much lower levels than in TPN, and levels were not affected by GOS and PDX addition. TPN piglets had elevated (P < 0.05) ileal myeloperoxidase activity and a trend in elevated ascending colon tumor necrosis factor-α expression (P = 0.1). CONCLUSIONS PDX and GOS added to formula do not induce BT in healthy piglets. Low levels of bacteria in MLN of healthy neonatal piglets may reflect mucosal sampling rather than pathological BT.
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Pyruvate: immunonutritional effects on neutrophil intracellular amino or alpha-keto acid profiles and reactive oxygen species production. Amino Acids 2010; 40:1077-90. [PMID: 20839016 PMCID: PMC3061003 DOI: 10.1007/s00726-010-0731-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 08/23/2010] [Indexed: 01/19/2023]
Abstract
For the first time the immunonutritional role of pyruvate on neutrophils (PMN), free α-keto and amino acid profiles, important reactive oxygen species (ROS) produced [superoxide anion (O(2) (-)), hydrogen peroxide (H(2)O(2))] as well as released myeloperoxidase (MPO) acitivity has been investigated. Exogenous pyruvate significantly increased PMN pyruvate, α-ketoglutarate, asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, glycine and serine in a dose as well as duration of exposure dependent manner. Moreover, increases in O(2) (-) formation, H(2)O(2)-generation and MPO acitivity in parallel with intracellular pyruvate changes have also been detected. Regarding the interesting findings presented here we believe, that pyruvate fulfils considerably the criteria for a potent immunonutritional molecule in the regulation of the PMN dynamic α-keto and amino acid pools. Moreover it also plays an important role in parallel modulation of the granulocyte-dependent innate immune regulation. Although further research is necessary to clarify pyruvate's sole therapeutical role in critically ill patients' immunonutrition, the first scientific successes seem to be very promising.
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Kim SY, Choi JS, Park C, Jeong JW. Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle. Cancer Lett 2010; 295:236-41. [PMID: 20338685 DOI: 10.1016/j.canlet.2010.03.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 03/03/2010] [Accepted: 03/04/2010] [Indexed: 10/19/2022]
Abstract
Ethyl pyruvate is a simple derivative of the endogenous metabolite pyruvate. Pyruvate is the starting substrate for the tricarboxylic acid (TCA) cycle and plays a central role in intermediary metabolism. The present study was to determine whether ethyl pyruvate affects the expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and to explore the mechanism of HIF-1alpha regulation. We found that ethyl pyruvate increased HIF-1alpha stability via inhibition of pVHL-mediated degradation. Furthermore, ethyl pyruvate enhanced the reactive oxygen species (ROS) generated through the TCA cycle in mitochondria. Taken together, our results support a novel role for ethyl pyruvate in HIF-1alpha stabilization by which high rates of the TCA cycle can promote ROS production.
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Affiliation(s)
- Seon-Ye Kim
- Department of Anatomy and Neurobiology, Biomedical Science Institute, Kyung Hee University, Seoul, Republic of Korea
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Shen H, Hu X, Liu C, Wang S, Zhang W, Gao H, Stetler RA, Gao Y, Chen J. Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms. Neurobiol Dis 2009; 37:711-22. [PMID: 20026271 DOI: 10.1016/j.nbd.2009.12.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Revised: 12/02/2009] [Accepted: 12/08/2009] [Indexed: 10/20/2022] Open
Abstract
Ethyl pyruvate (EP) is protective in experimental models of many illnesses. This study investigates whether EP can protect against neonatal hypoxic-ischemic (H-I) brain injury. Pre-treatment with EP significantly reduced brain damage at 7 days post-H-I, with 50 mg/kg EP achieving over 50% recovery in tissue loss compared to vehicle-treated animals. Delayed treatment with EP until 30 min after H-I was still neuroprotective. EP-afforded brain protection, together with neurological function improvement, was observed up to 2 months after H-I. We further demonstrated an inhibitory effect of EP on cell death, both in an in vivo model of H-I and in in vitro neuronal cultures subjected to OGD, by reducing calpain activation and calcium dysregulation. Moreover, EP exerted an anti-inflammatory effect in microglia by inhibiting NF-kappaB activation and subsequent release of inflammatory mediators. Taken together, our results suggest that EP confers potent neuroprotection against neonatal H-I brain injury via its anti-cell death and anti-inflammatory actions. EP is a potential novel therapeutic agent for neonatal H-I brain injury.
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Affiliation(s)
- Hongxia Shen
- State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences Fudan University, Shanghai 200032, China
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