Pirfenidone ameliorates concanavalin A-induced hepatitis in mice via modulation of reactive oxygen species/nuclear factor kappa B signalling pathways

El‐Agamy, Dina S.

doi:10.1111/jphp.12651

Cited by 24 publications

(26 citation statements)

References 36 publications

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“…Oxidative stress is an important manifestation of hepatocyte injury induced by Con A. In Con A-treated mice, there is an imbalance between the oxidant and antioxidant status in liver tissue [8]. In our study, at 24 h after injection of Con A, levels of MDA, MPO, and NO were statistically significantly upregulated and activities of SOD and GSH were downregulated in liver tissue.…”

Section: Effect Of Serotonin On Hepatic Oxidative Stress Injury Insupporting

confidence: 52%

“…Experimental Animals. Male wild-type (WT) C57BL/6 mice (purchased from Animal Feeding Center of Xi'an Jiaotong University Health Science Center, Xi'an, China) and male mice with TPH1 (critical rate-limiting enzyme for the synthesis of peripheral serotonin) knockout (TPH1−/−, which originated from C57BL/6 mice, kindly presented by Max Planck Institute for Molecular Genetics, Berlin, Germany, and the genotype was tested by PCR) were used (6)(7)(8) weeks old, 20-25 g). As previously described, the lack of peripheral serotonin is the only difference between TPH1 −/− and WT mice [26].…”

Section: Methodsmentioning

confidence: 99%

“…This model is accompanied by massive liver tissue necrosis, extensive inflammatory response, and prominent hepatocyte apoptosis [5]. In addition, remarkable oxidative stress injury, characterized by significant upregulation in contents of oxidative markers and significant downregulation in activities of antioxidative markers, is closely related to inflammation and Con A-mediated hepatocyte damage [5][6][7][8]. As easy operation, low cost, well repeatability, and close to the pathological process of human viral hepatitis, Con A-induced ALI is regarded as the best experimental model for ALI research [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…He et al showed elevated oxidative products (MDA and 8-hydroxy-2′-deoxyguanosine) and reduced activities of SOD and cata-lase in Con A-treated mice [7]. El-Agamy reported that the administration of Con A markedly increased hepatic MDA content and decreased hepatic levels of GSH and SOD compared to the control group [8]. The present study indicated that Con A injection caused a marked elevation of lipid peroxidation as presented by excessive accumulation of MDA, MPO, and NO in liver tissue.…”

mentioning

confidence: 99%

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The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Pang

Jin

et al. 2020

Oxidative Medicine and Cellular Longevity

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Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.

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Section: Effect Of Serotonin On Hepatic Oxidative Stress Injury Insupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Pang

Jin

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Recently, many reports elucidated the involvement of nuclear factor kappa-B (NF-κB) in the pathogenesis of Con A-induced AIH. Activation of NF-κB and subsequent up-regulation of downstream inflammatory cascades mediate the inflammatory response in Con A-associated hepatotoxicity (Xu et al, 2008 ; El-Agamy, 2016 ; Li et al, 2016 ). Apoptosis has a crucial role in Con A-induced hepatitis.…”

Section: Introductionmentioning

confidence: 99%

Pristimerin as a Novel Hepatoprotective Agent Against Experimental Autoimmune Hepatitis

et al. 2018

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Pristimerin (Pris) is bioactive natural quinonoid triterpene that has anti-inflammatory and anti-cancer activities. Meanwhile, its effect against hepatitis needs to be elucidated. This investigation aimed to evaluate the ability of Pris to protect against autoimmune hepatitis (AIH). A mouse model of AIH was established using single concanavalin A (Con A) intravenous injection. Mice were treated with Pris at two different doses (0.4 and 0.8 mg/kg) for 5 days prior to Con A challenge. Markers of hepatic injury, oxidative, inflammatory, and apoptotic damage were estimated. Results have revealed that Pris pretreatment ameliorated Con A-induced hepatic damage. There was decrease in the elevated serum indices of hepatic damage (ALT, AST, ALP, and LDH) and improvement of the histopathological picture of the liver. Pris effectively decreased Con A-induced neutrophil infiltration into the hepatic tissue as presented by amelioration of the level and immuno-expression of myeloperoxidase (MPO). Additionally, Pris attenuated Con A-induced increase in CD4+ T-cells in hepatic tissue. Lipid peroxidation was significantly depressed simultaneously with enhancement of the antioxidant capacity in Pris pretreated animals. Pris also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression and its binding capacity. In addition, Pris increased mRNA expression of heme-oxygenase-1 (HO-1) and restored its normal level. Furthermore, Pris decreased the level and immuno-expression of nuclear factor kappa-B (NF-κB) as well as the downstream inflammatory cascade (TNF-α, IL-6, and IL-1β). Finally, Pris showed inhibitory effect on Con A-induced apoptotic alteration in liver as it decreased the mRNA expression and levels the apoptotic markers (Bax and caspase-3) and increased mRNA expression and level of the anti-apoptotic protein (Bcl2). In conclusion, this study demonstrates the potent hepatoprotective efficacy of Pris against Con A-induced hepatitis which may be related to anti-oxidative, anti-inflammatory, and anti-apoptotic pathways. Pris could serve as a new candidate for the management of hepatitis.

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Pirfenidone alleviates smoke inhalation lung injury of rats via the NF‐κB signaling pathway

Lv,

Yang,

Wang

2024

Immunity Inflam & Disease

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ObjectiveSmoke inhalation lung injury (SILI) is a common complication in fires and wars, characterized by acute onset and severe condition. Pirfenidone (PFD), a new small‐molecule drug, has been shown to improve lung function and inhibit pulmonary fibrosis and inflammation. This study aimed to elucidate the effect and underlying mechanism of PFD on SILI in rats.Materials and MethodsSILI rats were constructed using a homemade smoking device, which was then treated with PFD. The blood was collected from the abdominal aorta, and the arterial blood gas was detected. The productions of oxidative stress markers and inflammatory cytokines in plasma were measured by enzyme linked immunosorbent assay assay. Moreover, the alveolar surface area, wet:dry weight ratio of the lung tissues, and bronchoalveolar lavage fluid (BALF) were determined as well. The pulmonary histopathology, cell apoptosis, and the related proteins of nuclear factor kappa B (NF‐κB) pathway were determined by hematoxylin‐eosin staining, TdT‐mediated dUTP‐biotin nick end labeling, and western blot assays, respectively.ResultsPFD had a significant protective effect on SILI via inhibiting oxidative stress, inflammation, and apoptosis. Mechanistically, PFD inhibited the activation of NF‐κB pathway in vivo. Moreover, activation of NF‐κB pathway attenuated the PFD‐mediated protective effect against SILI.ConclusionsThese data demonstrate that PFD alleviates SILI of rats via the NF‐κB signaling pathway, which provides an attractive therapeutic option for SILI treatment.

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Pirfenidone ameliorates concanavalin A-induced hepatitis in mice via modulation of reactive oxygen species/nuclear factor kappa B signalling pathways

Abstract: Pirfenidone hepatoprotective activity may be mediated through its antioxidant ability that suppresses NF-κB activation signalling pathways suggesting that PFD may be a new candidate for treatment of acute hepatitis.

Cited by 24 publications

References 36 publications

The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Pristimerin as a Novel Hepatoprotective Agent Against Experimental Autoimmune Hepatitis

Pirfenidone alleviates smoke inhalation lung injury of rats via the NF‐κB signaling pathway

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