Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice

Li, Ruidong; Zhang, Peng; Li, Chengguo; Yang, Wenchang; Yin, Yuping; Tao, Kaixiong

doi:10.7150/ijms.45842

Cited by 24 publications

(12 citation statements)

References 35 publications

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“…Nevertheless, cell damage occurs when cells encounter excessive oxidative stimulation that exceeds the capacity of the antioxidant defense system. The excessive oxidative stimulus will cause the oxidization of the cell's membrane and eventually destroy cells ( Li et al, 2020b ). It has been reported that the reduction of oxidative stress plays a pivotal role in diminishing hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

Yang

Yin

et al. 2021

Front. Pharmacol.

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The liver is an important metabolic organ, and acute liver injury (ALI) is potentially lethal. Itaconate, a metabolic intermediate from the tricarboxylic acid cycle, showed emerging anti-oxidative and anti-inflammation properties, and an accumulating protective effect in multiple diseases, but its role in ALI still needs to be further explored. Here we established an ALI model induced by carbon tetrachloride in mice. Our results showed that 4-Octyl itaconate (OI), a derivate of itaconate, mitigated hepatic damage by improving liver function, reducing histopathological damage, and decreasing the death of hepatocytes. Additionally, OI decreased myeloperoxidase and thiobarbituric acid reactive substances (TBARS) levels in the ALI model. OI also inhibited the inflammatory response by reducing pro-inflammatory cytokine secretion (IL-6, TNF-α, IL-1β, and MCP-1) and infiltration of macrophages and neutrophils in the ALI model. However, administration of ML385, a specified Nrf2 inhibitor, eliminated the protective properties of OI in the CCl4-induced liver injury model by increasing hepatic damage and oxidative stress. Furthermore, OI increased the expression and nuclear translocation of Nrf2 and elevated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1, while knockdown of Nrf2 eliminated these effects in murine hepatocyte NCTC 1469 under CCl4 treatment. Moreover, we found that OI reduced serum High-mobility group box 1 (HMGB1) levels in CCl4-treated mice. Finally, OI inhibited nuclear translocation of factor-kappa B (NF-𝜅B) and inflammatory cytokine production in murine macrophages. In conclusion, these results indicated that OI ameliorated CCl4-induced ALI by mitigating oxidative stress and the inflammatory response. The possible mechanism was associated with the elevation of Nrf2 nuclear translocation and inhibition of HMGB1 mediated the nuclear translocation of NF-𝜅B.

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Section: Discussionmentioning

confidence: 99%

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

Yang

Yin

et al. 2021

Front. Pharmacol.

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“…Acute liver failure (ALF) is a critical clinical syndrome that leads to high mortality in clinic [ 1 ]. Pathogenic factors such as viral infection, toxic chemicals, and hepatotoxic drugs can cause ALF [ 2 – 5 ]. Lipopolysaccharide (LPS) is a component of the outer cell wall of gram-negative bacteria, which can induce liver damage by activating inflammatory cytokine production [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Normally, hepatocytes are protected from oxidative injury by antioxidative enzymes in the liver. Many antioxidative genes are regulated by Nrf2, and activation of Nrf2 shows a protective effect in hepatic diseases [ 5 , 11 , 12 ]. Normally, Nrf2 is combined with Kelch-like ECH2-associated protein 1 (Keap1) in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Protective Role of 4‐Octyl Itaconate in Murine LPS/D‐GalN‐Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis

Yang

Yin

et al. 2021

Oxidative Medicine and Cellular Longevity

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Oxidative stress, inflammation, and apoptosis are crucial in the pathogenesis of acute liver failure (ALF). 4-Octyl itaconate (OI) showed antioxidative and anti-inflammatory properties in many disease models. However, its role in lipopolysaccharide- (LPS-)/D-galactosamine- (D-GalN-) induced ALF is still not investigated. Here, we established an ALF murine model induced by LPS/D-GalN administration. And we found that OI improved survival rate in the murine ALF model. Our results also showed that OI alleviated LPS/D-GalN-induced hepatic histopathological injury and reduced the serum activities of alanine transaminase and aspartate transaminase. Moreover, OI reduced serum levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factors-α, and interlukin-6. Additionally, OI mitigated oxidative stress and alleviated lipid peroxidation in a murine model of ALF. This was evaluated by a reduction of thiobarbituric acid reactive substances (TBARS) in liver tissues. In addition, OI increased the ratio of reduced glutathione/oxidized glutathione and the activities of antioxidant enzymes including catalase and superoxide dismutase. Moreover, the apoptosis of hepatocytes in the liver was inhibited by OI. Furthermore, we found that OI inhibited LPS-induced nuclear translocation and activation of factor-kappa B (NF-κB) p65 in macrophages which could be inhibited by OI-induced activation of nuclear factor erythroid-2-related factor (Nrf2) signaling. Additionally, D-GalN-induced reactive oxygen species (ROS) generation and apoptosis in hepatocytes were inhibited by OI-induced activation of Nrf2 signaling. Therefore, the underlying mechanism for OI’s protective effect in LPS/D-GalN-induced ALF may be associated with deactivation of NF-κB signaling in macrophages to reduce inflammation and inhibition of ROS-related hepatocyte apoptosis by activating Nrf2. In conclusion, OI showed a protective role in LPS/D-GalN-induced ALF by reducing inflammation, enhancing antioxidant capacity, and inhibiting cell apoptosis.

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“…Thus, if 5-CMF and its GSH conjugate are exported by different rates, then compounds that alter cytoplasmic GSH levels, for example, by conjugating to GSH, may influence the results of the CMFDA assay. Therefore, we used two compounds that have been reported to alter intracellular GSH levels, DLbuthionine-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase [28], the rate limiting enzyme in GSH synthesis, and the NRF2 activator tert-butylhydroquinone (TBHQ) [29]. Incubations with BSO and TBHQ were performed for 48 h prior to the CMFDA assay.…”

Section: No Influence Of Substances That Deplete or Induce Glutathione Levelsmentioning

confidence: 99%

The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds

Brecklinghaus¹,

Albrecht²,

Kappenberg³

et al. 2022

Chemico-Biological Interactions

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Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice

Cited by 24 publications

References 35 publications

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

Protective Role of 4‐Octyl Itaconate in Murine LPS/D‐GalN‐Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis

The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds

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