Mechanism of Salutary Effects of Astringinin on Rodent Hepatic Injury following Trauma-Hemorrhage: Akt-Dependent Hemeoxygenase-1 Signaling Pathways

Liu, Fu-Chao; Hwang, Tsong‐Long; Lau, Ying-Tung; Yu, Huang-Ping

doi:10.1371/journal.pone.0025907

Cited by 15 publications

(30 citation statements)

References 34 publications

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“…In this study, hepatic IL-6, TNF-α, and MIP-1α levels were significantly attenuated in the animals treated with tropisetron after trauma-hemorrhage. Tissue MPO activity is an important indicator of neutrophil infiltration, and it has been correlated with CINC-1 and CINC-3 expression after trauma-hemorrhage [12], [18]. Our results showed that trauma-hemorrhage results in a significant increase in hepatic cytokine/chemokine levels and ICAM-1 expression, which are accompanied by elevated hepatic MPO activity.…”

Section: Discussionsupporting

confidence: 49%

“…IL-6 is an important pro-inflammatory mediator in hepatic damage and is required for chemokine production and adhesion molecule expression. Liver injury or hypoxia causes marked increases in hepatic IL-6 expression [18], [26]. In this study, hepatic IL-6, TNF-α, and MIP-1α levels were significantly attenuated in the animals treated with tropisetron after trauma-hemorrhage.…”

Section: Discussionmentioning

confidence: 48%

“…Pro-inflammatory chemokines, such as cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), are potent chemoattractants for neutrophils [6], [15]. Intercellular adhesion molecule-1 (ICAM-1) is up-regulated after trauma-hemorrhage, and it enhances a firm adhesion of neutrophils to the vascular endothelium [12], [18]. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α) also play important role in neutrophil infiltration and hepatic inflammation following organ injury [6], [18], [19].…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

Liu

Hwang

et al. 2012

PLoS ONE

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Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35–40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury after trauma-hemorrhage is likely mediated through p38 MAPK-dependent HO-1 expression.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

Liu

Hwang

et al. 2012

PLoS ONE

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“…It serves as a protective factor by as it has anti-inflammatory, anti-apoptotic and anti-proliferative properties. These beneficial effects are due to the metabolites of HO-1 (CO, biliverdin and free iron) (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro

Wang

Xiong

Guo

et al. 2014

International Journal of Molecular Medicine

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Abstract. There is growing evidence indicating that autophagy plays a protective role in liver ischemia/reperfusion (IR) injury. Heme oxygenase-1 (HO-1) can also prevent liver IR injury by limiting inflammation and inducing an anti-apoptotic response. Autophagy also plays a crucial role in liver IR injury. The aim of the present study was to investigate the role of HO-1 in liver IR injury and the association between HO-1, autophagy and apoptotic pathways. IR simulation was performed using buffalo rat liver (BRL) cells, and HO-1 activity was either induced by hemin (HIR group) or inhibited by zinc protoporphyrin (ZnPP) (ZIR group). In the HIR and ZIR group, the expression of HO-1 and autophagy-related genes [light chain 3-Ⅱ (LC3-Ⅱ)] was assessed by RT-qPCR and the protein expression of caspases, autophagy-related genes and genes associated with apoptotic pathways (Bax) was detected by western blot anlaysis. The results of RT-PCR revealed the genetically decreased expression of HO-1 and autophagy-related genes in the ZIR group. Similar results were obtained by western blot analysis and immunofluorescence. An ultrastructural analysis revealed a lower number of autophagosomes in the ZIR group; in the HIR group, the number of autophagosomes was increased. The expression of Bax and cytosolic cytochrome c was increased, while that of Bcl-2 was decreased following treatment of the cells with ZnPP prior to IR simulation; the oppostie occurred in the HIR group. Cleaved caspase-3, caspase-9 and poly(ADPribose) polymerase (PARP) protein were activated in the IR and ZIR groups. The disruption of mitochondrial membrane potential was also observed in the ZIR group. In general, the downregulation of HO-1 reduced autophagy and activated the mitochondrial apoptotic pathway.

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“…The inhibition of IL-10 has been shown to promote the expression of inflammatory cytokines, reduce insulin signaling and activate gluconeogenic and lipidogenic pathways in an animal model of diet-induced fatty liver disease (19). In addition, the upregulation of HO-1 has been shown to induce a reduction in the levels of cytokines, adhesion molecules, chemokines and neutrophil accumulation, and to ameliorate organ injury in a state of shock (20)(21)(22). As previously demonstrated, the induction of HO-1 reduces hepatic ischemia reperfusion injury (23), hepatic injury after trauma hemorrhage (24) and renal oxidative stress in diabetic SHRs (25).…”

Section: Cdaa Diet --------------------------------------------------mentioning

confidence: 99%

Hypertension exacerbates liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined diet in rats

Arima

Uto

Ibusuki

et al. 2013

International Journal of Molecular Medicine

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Abstract. The effect of hypertension on non-alcoholic fatty liver disease (NAFLD) remains unclear at the molecular level. In this study, we investigated the effects of hypertension on the degree of hepatic steatosis, liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined (CDAA) diet in spontaneously hypertensive rats (SHRs). Seven-week-old male SHRs were fed standard chow with high or normal salt concentrations for 7 weeks, followed by a CDAA diet containing high or normal salt for an additional 8 or 24 weeks. Hepatic steatosis was assessed using hepatic triglyceride levels and Oil red O staining. Hepatic fibrosis was evaluated using Sirius red and Azan staining. Systolic blood pressure (SBP) gradually increased with a high-salt diet and was significantly higher after 7 weeks of feeding with highsalt vs. normal-salt chow. After 8 weeks on the CDAA diet, the degree of hepatic steatosis did not differ between the high-salt and normal-salt groups; however, alanine aminotransferase and fasting blood glucose levels were significantly higher and hepatic mRNA levels for interleukin (IL)-10 and heme oxygenase (HO)-1 were significantly lower in the high-salt group compared with the normal-salt group. After 24 weeks on the CDAA diet, the high-salt group had significantly more severe hepatic fibrosis and a higher hepatic mRNA expression of α-smooth muscle actin and lower hepatic IL-10 and HO-1 mRNA levels compared with the normal-salt group. In conclusion, our results indicate that hypertension is a potential risk factor for liver injury and hepatic fibrosis through glucose intolerance and decreased IL-10-mediated or HO-1-induced anti-inflammatory mechanisms. IntroductionNon-alcoholic fatty liver disease (NAFLD) includes nonalcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and NASH may lead to hepatic cirrhosis or hepatocellular carcinoma (HCC) (1,2). NAFLD/NASH can be viewed as a metabolic syndrome phenotype involving the liver, and the incidence of NAFLD has increased with corresponding increases in risk factors for metabolic syndrome, such as obesity, diabetes and hypertension. Such metabolic risk factors may promote the pathological progression of NAFLD/NASH, and NAFLD advances more rapidly in patients with a greater number of metabolic risk factors (3,4).The incidence of hypertension is significantly higher in patients with NAFLD compared with the general population (5). Furthermore, a higher incidence of NASH has been observed in patients with NAFLD who also have hypertension and these patients are likely to progress to advanced hepatic fibrosis (6), which suggests that hypertension may promote the onset or progression of hepatitis and hepatic fibrosis. However, the possible association between hypertension and the pathological progression of NAFLD has not been fully established.Rats fed a choline-deficient L-amino acid-defined (CDAA) diet initially develop fatty liver and hepatitis, and may subsequently progress to hepatic fibrosis and HCC (7). These findings indic...

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Mechanism of Salutary Effects of Astringinin on Rodent Hepatic Injury following Trauma-Hemorrhage: Akt-Dependent Hemeoxygenase-1 Signaling Pathways

Cited by 15 publications

References 34 publications

Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

Protective Effect of Tropisetron on Rodent Hepatic Injury after Trauma-Hemorrhagic Shock through P38 MAPK-Dependent Hemeoxygenase-1 Expression

ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro

Hypertension exacerbates liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined diet in rats

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