Hepatoprotective effect of apolipoprotein A4 against carbon tetrachloride induced acute liver injury through mediating hepatic antioxidant and inflammation response in mice

Li, Xiaoming; Liu, Xiaohuan; Zhang, Yupeng; Cheng, Cheng; Fan, Jingna; Zhou, Jiarong; Garstka, Malgorzata; Li, Zong-Fang

doi:10.1016/j.bbrc.2020.11.024

Cited by 20 publications

(15 citation statements)

References 28 publications

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“…It is well known that CCl4 is a potent hepatotoxin and used to induce acute liver injury in experimental animal models by mechanisms involving oxidative stress, lipid peroxidation in the hepatocyte membrane, inflammatory responses, and hepatocyte apoptosis and necrosis [ 37 ]. The present study results revealed the CCl 4 induction of the oxidative stress status through the altered cellular redox balance in both testicular and thyroid tissues.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Potential of Parsley Leaf (Petroselinum crispum) Essential Oil on Hypothyroidism and Testicular Injury in Mice Intoxicated by Carbon Tetrachloride

Badr

Algefare

Alfwuaires

2021

BioMed Research International

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The aim of the present study was to investigate the ameliorative potential of parsley (Petroselinum crispum) leaf essential oil (PO) against the detrimental effects of carbon tetrachloride (CCl4) on the thyroid gland and testes of mice. Twenty-four adult male mice were divided into four groups and treated for 4 weeks. The 1st control group received 3 mL/kg olive oil intraperitoneally, twice a week followed by 0.5 mL/kg saline intragastrically daily. The 2nd CCl4 group received CCl4 (3 mL/kg intraperitoneally, twice a week). The 3rd PO group received PO (0.5 mL/kg intragastrically daily), while the 4th CCl4+PO group received CCl4 coadministrated with PO at the aforementioned doses. CCl4 group recorded significant ( p < 0.05 ) reduction in the activities of antioxidant enzyme catalase (CAT) and superoxide dismutase (SOD) and significant ( p < 0.05 ) increase in the lipid peroxidation end product’s level malondialdehyde (MDA) in the testes and thyroid glands. Meanwhile, serum levels of testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid hormones (thyroid-stimulating hormone (TSH), total triiodothyronine (T3), free triiodothyronine (fT3), total thyroxine (T4), and free thyroxine (fT4)) significantly decreased. Also, histopathologically, the testicular tissue showed hypospermatogenesis within irregular-shaped seminiferous tubules with prominent edema in the interstitial spaces confirming the aforementioned biochemical alterations. Treatment with PO significantly reduced the testicular and thyroid oxidative stress ( p < 0.05 ) and elevated the testosterone (73.47%), FSH (92.11%), LH (33.33%), T3 (23.47%), fT3 (39.13%), T4 (27.91%), and fT4 (75%) as compared to that of CCl4-treated group corresponding values. The PO GC/MS analysis indicated bioactive monoterpenes (major component is 1,3,8-mentha triene 34.48%) and phenylpropenes (major component is myristicin 21.04%). Results suggested the ameliorative effect of PO against CCl4-induced hypogonadism in mice by suppressing oxidative stress and maintaining thyroid gland function.

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Section: Discussionmentioning

confidence: 99%

Antioxidant Potential of Parsley Leaf (Petroselinum crispum) Essential Oil on Hypothyroidism and Testicular Injury in Mice Intoxicated by Carbon Tetrachloride

Badr

Algefare

Alfwuaires

2021

BioMed Research International

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“…CCl4 is transformed into the highly reactive free radical trichloromethyl radical (•CCl3) and trichloromethyl peroxy radical (•OOCCl3) in the liver tissue by cytochrome p450, which leads to lipid peroxidation and cellar injury ( Unsal et al, 2020 ). These free radicals also probably initiate the hepatic inflammatory response by activating macrophages to produce tumor necrosis factor-α (TNF-α) and other pro-inflammatory cytokines ( Li X. et al, 2021 ). Hence, increasing the antioxidant pathway could represent a pivotal mechanism in protecting the liver during acute oxidative stress.…”

Section: Introductionmentioning

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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“…Here, we primarily identified APOA4, one of the downstream molecules of HGF-c-Met signaling, to be a soluble PD marker of rh-HGF. Interestingly, it has been demonstrated that APOA4 is not just a constituent of high-density lipoprotein but it exerts anti-oxidant and anti-inflammatory effects to protect liver damage in mice [ 10 , 11 ]. Notably, serum APOA4 seemed to increase in murine ALF over normal mice without exogenous rh-HGF ( Figure 4 A; rh-HGF, 0 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

“…Among those, APOA4, which has been previously known as one of the apolipoproteins, was found to be a soluble PD marker and can be secreted into the blood as a result of HGF-c-Met signaling. Recently, it was reported that APOA4 is not just a constituent of high-density lipoprotein, but it also exerts anti-oxidant and anti-inflammatory effects to protect from liver damage in mice [ 10 , 11 ]. Therefore, validation of the utility of APOA4 as a PD marker of rh-HGF in clinical trials would help pharmacodynamic evaluation of rh-HGF, and furthermore, may give clues to elucidate its mechanism of action in humans, not just by direct effect on hepatocytes but also via APOA4 protein.…”

Section: Introductionmentioning

confidence: 99%

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

Motoi

Uesugi

Obara

et al. 2021

IJMS

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Background: Hepatocyte growth factor (HGF) is an endogenously induced bioactive molecule that has strong anti-apoptotic and tissue repair activities. In this research, we identified APOA4 as a novel pharmacodynamic (PD) marker of the recombinant human HGF (rh-HGF), E3112. Methods: rh-HGF was administered to mice, and their livers were investigated for the PD marker. Candidates were identified from soluble proteins and validated by using human hepatocytes in vitro and an animal disease model in vivo, in which its c-Met dependency was also ensured. Results: Among the genes induced or highly enhanced after rh-HGF exposure in vivo, a soluble apolipoprotein, Apoa4, was found to be induced by rh-HGF in the murine liver. By using primary cultured human hepatocytes, the significant induction of human APOA4 was observed at the mRNA and protein levels, and it was inhibited in the presence of a c-Met inhibitor. Although mice constitutively expressed Apoa4 mRNA in the small intestine and the liver, the liver was the primary organ affected by administered rh-HGF to strongly induce APOA4 in a dose- and c-Met-dependent manner. Serum APOA4 levels were increased after rh-HGF administration, not only in normal mice but also in anti-Fas-induced murine acute liver failure (ALF), which confirmed the pharmacodynamic nature of APOA4. Conclusions: APOA4 was identified as a soluble PD marker of rh-HGF with c-Met dependency. It should be worthwhile to clinically validate its utility through clinical trials with healthy subjects and ALF patients.

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Hepatoprotective effect of apolipoprotein A4 against carbon tetrachloride induced acute liver injury through mediating hepatic antioxidant and inflammation response in mice

Cited by 20 publications

References 28 publications

Antioxidant Potential of Parsley Leaf (Petroselinum crispum) Essential Oil on Hypothyroidism and Testicular Injury in Mice Intoxicated by Carbon Tetrachloride

Antioxidant Potential of Parsley Leaf (Petroselinum crispum) Essential Oil on Hypothyroidism and Testicular Injury in Mice Intoxicated by Carbon Tetrachloride

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

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

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