Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver

Sun, Fang; Hamagawa, Eri; Tsutsui, Chihiro; Ono, Yukiko; Ogiri, Yukako; Kojo, Shosuke

doi:10.1016/s0925-4439(00)00098-3

Cited by 146 publications

(115 citation statements)

References 37 publications

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“…In chemically induced liver damage models, toxicity is induced by proinflammatory cytokines such as TNF-a, IL-1, and IL-6 from KCs (Badger et al, 1996). These cytokines activate NFkB, leading to necrosis and apoptosis of liver cells (Sun et al, 2001). In our study, CCl 4 treatment increased the levels of TNF-a, IL-1, and IL-6.…”

Section: Discussionmentioning

confidence: 99%

Salvia miltiorrhizacompounds protect the liver from acute injury by regulation of p38 and NFκB signaling in Kupffer cells

Yue

Wang

et al. 2014

Pharmaceutical Biology

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Context: Salvia miltiorrhiza Bunge is a traditional Asian medicine used to treat cerebral and cardiac ischemia. However, the effects of the active compounds of S. miltiorrhiza on liver damage are unclear. Objective: In this study, we tested the effects on acute liver injury of crude S. miltiorrhiza extracts from roots as well as neotanshinone B, dehydromiltirone, tanshinol A, tanshinone I, dihydrotanshinono I, neotanshinone A, cryptanshinono, tanshinone II A, and salvianolie acid B from purified S. miltiorrhiza extracts. Materials and methods: Various compounds or ethanol extract of S. miltiorrhiza (50, 100, and 200 mg/kg, p.o.) were administered to rats for five consecutive days. After acute carbon tetrachloride (CCl 4 )-induced liver injury by treatment of rats with a single dose of CCl 4 (0.75 mL/kg, p.o), rat liver function was tested by measuring serum biochemical parameters. Serum cytokine concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). Expression of p38 and NFkB was evaluated by western blot. Results: All S. miltiorrhiza components showed their effects on liver function from the dose from 50 to 200 mg/kg. At the dose of 200 mg/kg, they reduced serum levels of alkaline phosphatase (ALP) by 34-77%, alanine aminotransferase (ALT) by 30-57%, aspartate aminotransferase (AST) by 43-72%, creatine total bilirubin (BIL-T) by 33-81%, albumin (ALB) by 37-67%, indicating that S. miltiorrhiza extracts protected liver from CCl 4 -induced damage. Moreover, S. miltiorrhiza extracts at 200 mg/kg reduced the increase in the proinflammatory cytokines tumor necrosis factor-a (TNF-a) by 25-82%, interleukin-1 (IL-1) by 42-74% and interleukin-6 (IL-6) by 67-83%, indicating an effect on alleviating liver inflammation. Furthermore, in vitro, S. miltiorrhiza extracts inhibited p38 and NFkB signaling in Kupffer cells. This effect could be a main mechanism by which S. miltiorrhiza protects against acute liver toxicity. Discussion and conclusion: Active compounds of S. miltiorrhiza protected the liver from CCl 4 -induced injury. Protection might have been due to inhibition of p38 and NFkB signaling in Kupffer cells, which subsequently reduced inflammation in the liver.

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Section: Discussionmentioning

confidence: 99%

Salvia miltiorrhizacompounds protect the liver from acute injury by regulation of p38 and NFκB signaling in Kupffer cells

Yue

Wang

et al. 2014

Pharmaceutical Biology

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“…CC14 is long known to cause hepatic centrilobular necrosis, although a recent report indicates that the hepatotoxin induces not only necrosis but also apoptosis in the liver of rats [32]. The hepatotoxicity of CCl4 requires the hepatic cytochrome P450-mediated metabolism of CC14 to trichloromethyl radical (`CC13) and involves the formation of free radicals such as 'CC13 and its 02 adduct ('CC1300) and lipid peroxidation initiated by CC14-derived free radicals [33].…”

Section: Discussionmentioning

confidence: 99%

Contribution of Xanthine Oxidase-Derived Oxygen Free Radicals to the Development of Carbon Tetrachloride-Induced Acute Liver Injury in Rats

Ohta

Kongo-Nishimura

Imai

et al. 2003

J. Clin. Biochem. Nutr.

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Summary We examined how oxygen free radicals derived from xanthine oxidase (XOD) contribute to the development of carbon tetrachloride (CCl4)-induced acute liver injury in rats. In rats treated with CCl4 (1 ml/kg), liver injury appeared 3 h after the treatment and developed by 24 h, judged from the serum levels of transaminases. Hepatic and serum XOD activities and serum uric acid concentration did not change 6 h after CCl4 treatment, but they all increased at 12 h and further increased at 24 h. An increase in the concentration of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and decreases in reduced glutathione concentration and Cu,Zn-superoxide dismutase (SOD) activity, but not Mn-SOD activity, were observed in the liver at b h after CCl4 treatment and these changes were further enhanced at 24h. When allopurinol (50 mg/kg), an XOD inhibitor, was administered to CCl4-treated rats 6 h after CCl4 treatment, liver injury progression was prevented with attenuation of increased hepatic and serum XOD activities, serum uric acid concentration, and hepatic TBARS concentration and decreased hepatic reduced glutathione concentration and Cu,Zn-SOD activity at 24 h after CCl4 treatment. These results indicate that XOD-derived oxygen free radicals contribute to the progression of CCl4-induced acute liver injury in rats both by stimulating hepatic lipid peroxidation and by disrupting hepatic antioxidant defense system.

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“…We used CCl 4 , a chemical that, in the short term, induces hepatocyte apoptosis (9), which is followed by secondary necrosis (10,11). When administered repetitively, CCl 4 induces liver fibrosis (12).…”

mentioning

confidence: 99%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

128

119

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Edited by Jeffrey PessinFibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl 4 administration to WT and IRF3-, Toll/ Interleukin-1R (TIR) domain-containing adapter-inducing interferon-␤ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl 4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl 4 . Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl 4 . In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the proapoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.

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Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver

Cited by 146 publications

References 37 publications

Salvia miltiorrhizacompounds protect the liver from acute injury by regulation of p38 and NFκB signaling in Kupffer cells

Salvia miltiorrhizacompounds protect the liver from acute injury by regulation of p38 and NFκB signaling in Kupffer cells

Contribution of Xanthine Oxidase-Derived Oxygen Free Radicals to the Development of Carbon Tetrachloride-Induced Acute Liver Injury in Rats

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

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