Pristimerin as a Novel Hepatoprotective Agent Against Experimental Autoimmune Hepatitis

Abstract

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.

Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways

“…Hence, levels of the related downstream inflammatory cytokines, NOx, TNF-α, and IL-6 were dramatically decreased. These data are consistent with previous studies showing the inhibitory activity of Pris on NF-kB activation and subsequent release of inflammatory cytokines 17,43. The ability of Pris to inhibit DOX-induced NF-kB activation partially explains the underlying cardioprotective mechanism of Pris in DOX-induced cardiotoxicity.…”

“…cDNA was obtained from RNA (1 µg) using a cDNA reverse transcription kit as described in the manufacturer’s protocol (Qiagen NV). Real-time quantitative PCR (SYBR Green PCR Master Mix Kit) was used to determine the mRNA expression of targeted genes as described previously 17. Sequences of the primers are listed in Table 1.…”

“…The anti-inflammatory activity of Pris was initially linked to suppression of the release of nitric oxide (NOx) via inhibition of inducible nitric oxide synthase (iNOS). More recently, Pris was shown to inhibit NF-kB and its inflammatory cascade 16,17. Based on these data, we hypothesized that Pris might have potential protective activities against DOX-induced myocardial damage.…”

Pristimerin Suppresses RANKL-Induced Osteoclastogenesis and Ameliorates Ovariectomy-Induced Bone Loss

“…One study reported that Pristimerin could protect against DOX-induced cardiotoxicity due to activation of Nrf2 and inhibition of MAPK signaling ( El-Agamy et al, 2019 ). Another study indicated that Pristimerin possessed protective effects against autoimmune hepatitis via the activation of Nrf2/HO-1 pathway, thus exerted its anti-oxidative, anti-inflammatory properties ( El-Agamy et al, 2018 ). In our study, Pristimerin effectively inhibited the generation of ROS induced by RANKL and increased the expression of Nrf2, HO-1, and NQO-1 in BMMs, this could also be one of the mechanisms by which Pristimerin inhibits osteoclastogenesis.…”

Methylprednisolone Decreases Mitochondria-Mediated Apoptosis and Autophagy Dysfunction in Hepatocytes of Experimental Autoimmune Hepatitis Model via the Akt/mTOR Signaling

“…Interventions that directly modulate apoptosis in AIH have not been studied in the clinic but have been shown to promote malignancy in animals. A number of potential drugs were shown to have protective effects in an AIH model partly through the inhibition of hepatocyte apoptosis (El-Agamy et al, 2018; Feng et al, 2018a; Kim et al, 2018; Yu et al, 2019). Most studies on AIH have found that the antiapoptotic effects of these drugs depend on cytokines secreted by inflammatory cells, including activated T cells and macrophages.…”