Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells

Zhao, Mingyi; Chen, Jiajie; Zhu, Ping; Fujino, Masayuki; Takahara, Taro; Toyama, Sumika; Tomita, Amy; Zhao, Lingling; Yang, Zhangping; Hei, Mingyan; Liu, Zhong; Zhuang, Jian; Kimura, Shuichi; Li, Xiaokang

doi:10.1016/j.intimp.2015.04.032

Cited by 56 publications

(32 citation statements)

References 30 publications

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“…Subsequently, we showed that the administration of the CO‐releaser, CORM‐A1 determines an improvement in the clinical parameters, and it is able to modulate genes identified by the in silico analysis. Our data are in accordance with Zhao et al (), who showed that Dihydroquercetin (DHQ), through activation of Nrf2 and HO‐1 expression, is able to ameliorate ConA‐induced mouse liver injury by increasing survival, reducing serum transaminase levels, preventing histopathological features and decreasing pro‐inflammatory cytokine expression in the hepatic tissue.…”

Section: Discussionsupporting

confidence: 93%

Involvement of the Nrf2/HO‐1/CO axis and therapeutic intervention with the CO‐releasing molecule CORM‐A1, in a murine model of autoimmune hepatitis

Mangano

Cavalli

Mammana

et al. 2017

Journal Cellular Physiology

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Concanavalin A (ConA)-induced hepatitis is an experimental model of human autoimmune hepatitis induced in rodents by i.v. injection of Con A. The disease is characterized by increase in serum levels of transaminases and massive immune infiltration of the livers. Type 1, type 2, and type 17 cytokines play a pathogenic role in the development of ConA-induced hepatitis. To understand further the immunoregulatory mechanisms operating in the development and regulation of ConA-induced hepatitis, we have evaluated the role of the anti-inflammatory pathway Nrf2/HO-1/CO (Nuclear Factor E2-related Factor 2/Heme Oxygenase-1/Carbon Monoxide) in this condition and determined whether the in vivo administration of CO via the CO-releasing molecule (CORM) CORM-A1, influences serological and histological development of Con-A-induced hepatitis. We have firstly evaluated in silico the genes belonging to the Nrf2/HO-1/CO pathway that are involved in the pathogenesis of autoimmune hepatitis (AIH). The data obtained from the in silico study demonstrate that a significant number of genes modulated in the liver of ConA-challenged mice belong to the Nrf2 pathway; on the other hand, the administration of CORM-A1 determines an improvement in several sero-immunological and histological parameters, and it is able to modulate genes identified by the in silico analysis. Collectively, our data indicate that the Nrf2/HO-1/CO pathway is fundamental for the regulation of the immune responses, and that therapeutic intervention aimed at its modulation by CORM-A1 may represent a valuable strategy to be considered for the treatment of autoimmune hepatitis in humans.

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Section: Discussionsupporting

confidence: 93%

Involvement of the Nrf2/HO‐1/CO axis and therapeutic intervention with the CO‐releasing molecule CORM‐A1, in a murine model of autoimmune hepatitis

Mangano

Cavalli

Mammana

et al. 2017

Journal Cellular Physiology

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“…6a) [36]. Six hours after hydrogen peroxide (H 2 O 2 ) stimulation, Kupffer cell apoptosis was elevated in an H 2 O 2 dose-dependent manner compared with that in controls, whereas co-culture with MSCs protected Kupffer cells from apoptosis in the presence of low concentrations of H 2 O 2 (100 μM and 200 μM).…”

Section: Resultsmentioning

confidence: 99%

Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation

Tian

Wang

et al. 2016

Stem Cell Res Ther

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BackgroundLiver transplantation is the optimal treatment option for end-stage liver disease, but organ shortages dramatically restrict its application. Donation after cardiac death (DCD) is an alternative approach that may expand the donor pool, but it faces challenges such as graft dysfunction, early graft loss, and cholangiopathy. Moreover, DCD liver grafts are no longer eligible for transplantation after their warm ischaemic time exceeds 30 min. Mesenchymal stem cells (MSCs) have been proposed as a promising therapy for treatment of certain liver diseases, but the role of MSCs in DCD liver graft function remains elusive.MethodsIn this study, we established an arterialized mouse non-heart-beating (NHB) liver transplantation model, and compared survival rates, cytokine and chemokine expression, histology, and the results of in vitro co-culture experiments in animals with or without MSC infusion.ResultsMSCs markedly ameliorated NHB liver graft injury and improved survival post-transplantation. Additionally, MSCs suppressed Kupffer cell apoptosis, Th1/Th17 immune responses, chemokine expression, and inflammatory cell infiltration. In vitro, PGE2 secreted by MSCs inhibited Kupffer cell apoptosis via TLR4-ERK1/2-caspase3 pathway regulation.ConclusionOur study uncovers a protective role for MSCs and elucidates the underlying immunomodulatory mechanism in an NHB liver transplantation model. Our results suggest that MSCs are uniquely positioned for use in future clinical studies owing to their ability to protect DCD liver grafts, particularly in patients for whom DCD organs are not an option according to current criteria.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0416-y) contains supplementary material, which is available to authorized users.

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“…HO-1 exerts a protective effect by catalyzing the oxidative degradation of heme to carbon monoxide (CO), iron, and biliverdin-IXα, which scavenges endogenous injury factors to protect hepatocytes (11). Several studies have reported that HO-1 has a positive protective role in hepatitis and that the downregulation of HO-1 expression aggravated the severity of hepatic injury (44,45). Consistent with this, it was observed that FIGURE 8 | HO-1 mediated the suppression of MF on the LPS-induced inflammatory responses in KCs.…”

Section: Discussionmentioning

confidence: 99%

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells

et al. 2020

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Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl 3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.

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Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells

Cited by 56 publications

References 30 publications

Involvement of the Nrf2/HO‐1/CO axis and therapeutic intervention with the CO‐releasing molecule CORM‐A1, in a murine model of autoimmune hepatitis

Involvement of the Nrf2/HO‐1/CO axis and therapeutic intervention with the CO‐releasing molecule CORM‐A1, in a murine model of autoimmune hepatitis

Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells

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