Erythropoietin Increases Survival and Attenuates Fulminant Hepatic Failure Injury Induced by d-Galactosamine/Lipopolysaccharide in Mice

Ben‐Ari, Ziv; Zilbermints, Veacheslav; Pappo, Orit; Avlas, Orna; Sharon, Eran; Greif, Franklin; Cheporko, Yelena; Ravid, Amiram; Shapiro, Rivka; Hochhauser, Edith

doi:10.1097/tp.0b013e31821cdea5

Cited by 17 publications

(5 citation statements)

References 33 publications

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“…37 In the present study, 5′-AMP could not inhibit LPS-induced nuclear translocation of NF- κ B p65, but suppressed transactivation activity of NF- κ B. It is known that histone methylation could modulate NF- κ B downstream genes.…”

Section: Discussioncontrasting

confidence: 52%

Adenosine 5′-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice

et al. 2014

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D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced lethality and acute liver failure is dependent on endogenously produced inflammatory cytokines. Adenosine has been proven to be a central role in the regulation of inflammatory response. It is not entirely clear that which adenosine action is actually crucial to limiting inflammatory tissue destruction. Here we showed that GalN/LPS challenge elevated hepatic adenosine and induced lethality in adenosine receptor-deficient mice with equal efficiency as wild-type mice. In GalN/LPS-treated mice, pretreatment with adenosine 5′-monophosphate (5′-AMP) significantly elevated hepatic adenosine level and reduced mortality through decreasing cytokine and chemokine production. In RAW264.7 cells, 5′-AMP treatment inhibited the production of inflammatory cytokines, which is not mediated through adenosine receptors. 5′-AMP failed to attenuate LPS-induced nuclear factor-κB (NF-κB) p65 nuclear translocation, but reduced LPS-induced recruitment of NF-κB p65 to inflammatory gene promoters and decreased LPS-induced enrichment of H3K4 dimethylation at the tumor necrosis factor-α (TNF-α) promoter, which was involved in 5′-AMP-induced elevation of cellular adenosine and a decline of methylation potential. In vitro biochemical analysis revealed that adenosine directly attenuated recruitment of NF-κB to the TNF-α and interleukin-6 promoters. Our findings demonstrate that 5′-AMP-inhibiting inflammatory response is not mediated by adenosine receptors and it may represent a potential protective agent for amelioration of LPS-induced liver injury.

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Section: Discussioncontrasting

confidence: 52%

Adenosine 5′-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice

et al. 2014

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“…We and others found that ischemia alone can activate this pathway [6,50]. Moreover, the role of JNK in myocardial ischemia/reperfusion (I/R) remains controversial, since equally robust studies have reported dichotomous results suggesting both cardioprotective [51][52][53] and detrimental effects [6,49,54]. In contrast to our previous report, we have found a significant reduction in the expression of phospho-cJun in wild type (WT) mice pretreated with UTP compared to MI alone (p<0.05).…”

Section: Discussionmentioning

confidence: 99%

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Hochhauser

Cohen

Waldman

et al. 2013

Purinergic Signalling

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Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y 2 and P2Y 4 (UTP-activated), P2Y 6 , and P2Y 14 . Previously, we showed that uridine 5′-triphosphate (UTP) activating P2Y 2 R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y 2 R in vitro and in vivo following MI using uridine-5′-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y 2 R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y 2 R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5H-dibenzo [a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0±3.1 % vs. 33.4±2.7 %, p < 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage (p<0.05) and c-Jun phosphorylation increased. Thus, P2Y 2 R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo.

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“…The toll like receptor 4 (TLR4) recognizes endogenous free fat acid and exogenous pathogens [20], [21] and engagement of TLR4 activates the nuclear factor κB (NF-κB) [22] and mitogen-activated protein kinase (MAPK) subfamily members [23], including the extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38 MAPK, as well ascytokines [24], and stimulates the production of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, contributing to glucose intolerance and insulin resistance. Given that EPO treatment inhibits the NF-κB, ERK and JNK activation, and TNF-α and IL-6 production in animal models of hepatic injury [25]–[28], we hypothesize that EPO may also inhibit the HFD-induced chronic inflammation, contributing to the improvement of glucose intolerance and insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Inhibits Gluconeogenesis and Inflammation in the Liver and Improves Glucose Intolerance in High-Fat Diet-Fed Mice

Wang

Zhu

et al. 2013

PLoS ONE

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Erythropoietin (EPO) has multiple biological functions, including the modulation of glucose metabolism. However, the mechanisms underlying the action of EPO are still obscure. This study is aimed at investigating the potential mechanisms by which EPO improves glucose tolerance in an animal model of type 2 diabetes. Male C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks and then treated with EPO (HFD-EPO) or vehicle saline (HFD-Con) for two week. The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. Therefore, our data indicated that EPO treatment improved glucose intolerance by inhibiting gluconeogenesis and inflammation in the livers of HFD-fed mice.

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Erythropoietin Increases Survival and Attenuates Fulminant Hepatic Failure Injury Induced by d-Galactosamine/Lipopolysaccharide in Mice

Abstract: The administration of rhEPO brought about increased survival and attenuation of the hepatic injury. This was associated with decreased hepatic NF-κB and JNK activation and thus TNF-α and IL-1β levels. These findings have important implications for the potential use of rhEPO in FHF.

Cited by 17 publications

References 33 publications

Adenosine 5′-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice

Adenosine 5′-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Erythropoietin Inhibits Gluconeogenesis and Inflammation in the Liver and Improves Glucose Intolerance in High-Fat Diet-Fed Mice

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