Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice

Jin, Jing; Xiong, Tingting; Hou, Xiang-Yu; Sun, Xiaozhe; Liao, JiaYi; Huang, Zhiying; Huang, Min; Zhao, Zhongxiang

doi:10.1016/j.fct.2014.08.009

Cited by 54 publications

(37 citation statements)

References 41 publications

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“…Histopathological results showed that SVP caused marked inflammation, steatosis, and necrosis which confirm the biochemical analysis. These outcomes were demonstrated in the earlier studies . The concurrent administration of agmatine nearly abolished the deleterious biochemical and histological changes induced by SVP.…”

Section: Discussionsupporting

confidence: 70%

“…Inflammation also plays a crucial role in the VPA‐induced toxicity as its evident by its ability to activate transcription factor NF‐κB, thus causing release of inflammatory cytokines . Apart from the direct activation of NF‐κB, oxidative stress can stimulate the activation of NF‐κB, thus upregulating the expression of cytokines like TNF‐α, IL‐1β, and IL‐6 .…”

Section: Discussionmentioning

confidence: 99%

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Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

Ahmed

Aljuhani

Al‐Hujaili

et al. 2018

J Biochem & Molecular Tox

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Valproate is a widely used drug against epilepsy and several other neurological disorders although it has deleterious hepatotoxic side effects. The current study was designed to test if agmatine as nitric oxide modulator has protective effects against valproate‐induced hepatic injury. Male Swiss albino mice were treated with sodium valproate (SVP) with or without agmatine for 7 days. Serum and liver samples were collected for analysis. Results have revealed that agmatine exerted hepatoprotective effects against SVP‐associated hepatic injury. Agmatine ameliorated SVP‐induced elevated serum biochemical markers of hepatic damage such as serum transaminases, alkaline phosphatase, γ‐glutamyl transferase, and lactate dehydrogenase. Histopathological examination of the liver showed improvement of hepatic lesions in case of agmatine treatment. Furthermore, agmatine attenuated oxidative stress and enhanced antioxidants in liver tissue. Agmatine inhibited the activation of nuclear factor‐κB and ameliorated the immunoexpression of inducible nitric oxide synthetase. This was accompanied by decrease in the level of inflammatory markers as nitrite/nitrate, tumor necrosis factor‐α, and interleukin‐6. These data provide new evidence of the hepatoprotective activity of agmatine against SVP‐induced hepatotoxic effects.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

Ahmed

Aljuhani

Al‐Hujaili

et al. 2018

J Biochem & Molecular Tox

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“…Adherent leukocytes indirectly damaged the microvessels by releasing proteases and peroxides, causing increased pulmonary microvascular permeability and lung edema, eventually leading to reduced lung compliance and functional impairment [11] . Our previous pharmacological studies have confirmed that diammonium glycyrrhizinate could reduce lung injury by reducing inflammation of the respiratory tract, inhibiting the protein and mRNA levels of inflammatory factors in the lung tissue, and mitigating the expression and activation of NF-κB, which was consistent with others [12,13] . The present study further confirmed that DGLL can dose-dependently inhibit LPS- In addition to indirectly damaging blood vessels through leukocyte hyperactivation, LPS can also directly damage the microvascular barrier function, resulting in increased microvascular permeability and pulmonary edema [14,15] .…”

Section: Discussionsupporting

confidence: 90%

Diammonium glycyrrhizinate lipid ligand ameliorates lipopolysaccharide-induced acute lung injury by modulating vascular endothelial barrier function

Liu

Zhou

et al. 2020

Preprint

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Background: The present study investigated the attenuating effect of diammonium glycyrrhizinate lipid ligand (DGLL) on acute lung injury (ALI) and pulmonary edema induced by lipopolysaccharide (LPS) in rats.Methods: Rat ALI model was established by LPS (10 mg/kg) intraperitoneal injection, and DGLL (30, 60, 120 mg/kg) was administrated orall 1 hour before LPS infusion. Six hours after LPS stimulation, lung injury was evaluated by histological staining. Pulmonary edema was evaluated by lung wet-dry weight ratio, the protein concentration of bronchoalveolar lavage fluid (BALF), and the evans blue (EB) extravasation in lung tissues. The expression of cytokines and adhesion molecules in lung tissues were detected by ELISA method. The myeloperoxidase (MPO) expression was detected by immunohistochemical staining. Western blot was used to detect the expression changes of the proteins associated with pulmonary inflammation and microvascular permeability.Results: DGLL significantly inhibited LPS induced ALI, manifested as attenuation of MPO positive cells and TNF-α, IL-6, ICAM-1 expression in rat lung tissue. In addition, DGLL abrogated LPS-induced pulmonary edema, decreased the protein concentration in BALF and EB extravasation. Meanwhile, DGLL inhibited the degradation of vascular endothelial cadherin (VE-Cadherin) and tight junction protein, including ZO-1, Occludin, and JAM-1.Conclusions: DGLL has an inhibitory effect on LPS-induced rat ALI, which is related to the inhibition of inflammatory cell infiltration and microvascular barrier disruption. These results provide a theoretical basis for DGLL in the potential clinical treatment of ALI.

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“…Nrf2 has emerged as an indispensable regulator of both constitutive and inducible expression of phase II detoxifying and antioxidant enzyme genes in various cells (Jin et al . ). Nrf2 facilitates the induction of target genes responsible for cell survival (Klaassen & Reisman ).…”

Section: Discussionmentioning

confidence: 97%

“…However, Nrf2 activated by ROS limits the capacity of cells to escape from injury, because they also stimulate cell death signaling (Jin et al . ). SOD is an antioxidant enzyme involved in the scavenging of superoxide radicals and we found AFB1‐treated PBHs resulted in decreased activity of SOD, which was consistent with previous reports (Cao & Wang ).…”

Section: Discussionmentioning

confidence: 97%

Aflatoxin B1 impairs mitochondrial functions, activates ROS generation, induces apoptosis and involves Nrf2 signal pathway in primary broiler hepatocytes

Liu

Wang

2016

Animal Science Journal

121

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Aflatoxin B1 (AFB1) is known as a mycotoxin that causes various health problems in animals, but the precise mechanism of AFB1 on mitochondrial functions and apoptosis in primary broiler hepatocytes (PBHs) is not clear. The objective of this study was to investigate the effects of AFB1 on the mitochondrial functions, reactive oxygen species (ROS) generation, apoptosis and nuclear factor erythroid 2-like factor 2 (Nrf2)-related signal pathway in PBHs. Here, the mitochondrial membrane potential (MMP), ROS generation, antioxidative genes and apoptosis in PBHs induced by AFB1 were investigated. The results showed that AFB1 evoked mitochondrial ROS generation, decreased MMP and induced apoptosis in PBHs. AFB1 increased the percentage of apoptotic cells, and expression of caspase-9 and caspase-3, upregulated messenger RNA (mRNA) expression of Nrf2 and downregulated mRNA expressions of NAD(P)H: quinine oxidoreductase 1, superoxide dismutase and Heme oxygenase 1 in PBHs. The expression of Bax was also observed in cytoplasm. These findings suggested AFB1 results in a significant impairment of mitochondrial functions, activates ROS generation, induces apoptosis, and is involved in Nrf2 signal pathway through mitochondria ROS-dependent signal pathways in PBHs.

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Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice

Cited by 54 publications

References 41 publications

Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

Diammonium glycyrrhizinate lipid ligand ameliorates lipopolysaccharide-induced acute lung injury by modulating vascular endothelial barrier function

Aflatoxin B1 impairs mitochondrial functions, activates ROS generation, induces apoptosis and involves Nrf2 signal pathway in primary broiler hepatocytes

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