Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100 mg/kg) 24 h after administration of 4 mg/kg mercuric chloride (HgCl2). The results showed that luteolin ameliorated HgCl2 induced anemia and hepatotoxicity, regulating radical oxygen species (ROS) production and hepatocyte viability in vitro and oxidative stress and apoptosis in vivo. Furthermore, luteolin reversed the changes in levels of inflammation- and apoptosis-related proteins involving NF-κB, TNF-α, Sirt1, mTOR, Bax, p53, and Bcl-2, and inhibited p38 MAPK activation. Luteolin enhanced antioxidant defense system based on Keap1, Nrf2, HO-1, NQO1, and KLF9. Moreover, luteolin did not affect miRNA-146a expression. Collectively, our findings, for the first time, elucidate a precise mechanism for attenuation of HgCl2-induced liver dysfunction by dietary luteolin via regulating Sirt1/Nrf2/TNF-α signaling pathway, and provide a foundation for further study of luteolin as a novel therapeutic agent against inorganic mercury poisoning.

As a kind of potent stimulus, lipopolysaccharide (LPS) has the ability to cause cell damage by activating toll-like receptor(TLR)4, then nuclear factor kappa B (NF-κB) translocates into the nucleus and changes the expression of related inflammatory genes. Baicalin is extracted from Radix Scutellariae, which possesses anti-inflammation, antioxidant and antibacterial properties. However, the effects of it on LPS-induced liver inflammation have not been fully elucidated. This study aims to investigate the anti-inflammatory effects of Baicalin on the LPS-induced liver inflammation and its underlying molecular mechanisms in chicken. The results of histopathological changes, serum biochemical analysis, NO levels and myeloperoxidase activity showed that Baicalin pretreatment ameliorated LPS-induced liver inflammation. ELISA and qPCR assays showed that Baicalin dose-dependently suppressed the production of IL-1β, IL-6, and TNF-α. Furthermore, the mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were significantly decreased by Baicalin. TLR4 is an important sensor in LPS infection. Molecular studies showed that the expression of TLR4 was inhibited by Baicalin pretreatment. In addition, Baicalin pretreatment inhibited NF-kB signaling pathway activation. All results demonstrated the protective effects of Baicalin pretreatment against LPS-induced liver inflammation in chicken via negative regulation of inflammatory mediators through the down-regulation of TLR4 expression and the inhibition of NF-kB activation.

Mercury exposure is a common cause of metal poisoning which is biotransformed to highly toxic metabolites thus eliciting biochemical alterations and oxidative stress. Luteolin, a phenolic compound found in many natural products, has multiple biological functions. Our study was aimed to explore the biological effects of luteolin in a liver injury model induced in rats by mercuric chloride (HgCl2). Criteria for injury included liver enzyme, glutathione and malondialdehyde levels, histopathology, TUNEL assay, hepatocyte viability and reactive oxygen species levels. The results showed that luteolin protected against HgCl2-induced liver injury. Luteolin increased total nuclear factor-erythroid-2-related factor 2 (Nrf2) levels in the presence of HgCl2. Upregulation of its downstream factors, heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1, was also observed. This suggested that protection by luteolin against HgCl2-induced liver injury involved Nrf2 pathway activation. Luteolin also decreased expression of nuclear factor-κB (NF-κB) and P53. HgCl2 exposure led to increased Bcl-associated X protein (Bax), and decreased Bcl-2-related protein long form of Bcl-x (Bcl-xL) and B-cell leukemia/lymphoma-2 (Bcl-2) expression, leading to an increased Bax/Bcl-2 ratio. Taken together, our data suggested that decreasing oxidative stress is a protective mechanism of luteolin against development of HgCl2-induced liver injury, through the Nrf2/NF-κB/P53 signaling pathway in rats.

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Lead (Pb) is a global environmental health hazard that leads to nephrotoxicity. However, the effective treatment of Pb-induced nephrotoxicity remains elusive. Grape seed procyanidin extract (GSPE) has beneficial properties for multiple biological functions. Therefore, the present study investigated whether GSPE reduced Pb-induced nephrotoxicity as well as the protective mechanism of GSPE in a well-established 35-day Pb induced nephrotoxicity rat model. The results showed that GSPE normalized Pb-induced oxidative stress, histological damage, inflammatory, apoptosis, and changes of miR153 and glycogen synthase kinase 3β (GSK-3β) levels in rat kidney. Moreover, GSPE enhanced the induction of phase II detoxifying enzymes (heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1) by increasing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. This study identifies for the first time that Pb-induced oxidative stress in rat kidney is attenuated by GSPE treatment via activating Nrf2 signaling pathway and suppressing miR153 and GSK-3β. Nrf2 signaling provides a new therapeutic target for renal injury induced by Pb, and GSPE could be a potential natural agent to protect against Pb-induced nephrotoxicity.

Lead (Pb) is one of the most relevant heavy metals contaminants which cause oxidative stress and threaten human health. The lung is one of the organs most severely damaged by Pb. In this study, we investigated the protective effect of grape seed procyanidin extract (GSPE) on Pb-induced lung injury in rats. We found that GSPE alleviated Pb-induced lung injury by relieving oxidative stress, reducing release of inflammatory factors, and inhibiting apoptosis. Furthermore, GSPE enhanced the antioxidant defense systems by activating the nuclear factor-erythroid-2-related factor (Nrf2) signaling pathway to promote downstream expression of heme oxygenase 1 and NAD(P)H quinone oxidoreductase 1. The subsequent ubiquitin-binding protein p62 (sequestosome 1), a downstream target of Nrf2, formed a positive feedback loop with Nrf2 during oxidative stress responses. GSPE treatment resulted in activation of adenosine monophosphate-activated protein kinase (AMPK), which was highly involved in Nrf2 activation. Overall, our findings demonstrate that theprotective effect of GSPE on Pb-induced lung injury arises from activation of the AMPK/Nrf2/p62 signaling pathway, thus providing a new approach for treatment of Pb intoxication.

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Arsenic trioxide (AsO) is both the most prevalent, naturally occurring inorganic arsenical threatening human health and an efficient therapeutic for acute promyelocytic leukemia. Regretfully, AsO-treated cancer patients often suffer from hepatotoxicity. While effective antioxidant and anticarcinogenic actions of allicin have previously been demonstrated, studies indicating how allicin affects AsO-induced hepatotoxicity and arsenic accumulation are lacking. Our study, for the first time, elaborates potential details of the hepatoprotective mechanisms of allicin against AsO-induced liver injury. Wistar rats were administrated allicin (30 mg/kg) 1 h before AsO (3 mg/kg) by daily gavage for 2 weeks. Our results indicate that allicin ameliorated AsO-induced liver dysfunction, oxidative stress, and arsenic accumulation in the liver. Meanwhile, allicin decreased NF-κB level and upregulated expression of proteins reduced by AsO including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1, and Krüppel-like factor 9 (KLF9). In addition, allicin promoted B cell lymphoma-extra large expression and suppressed B cell lymphoma-2-associated X protein levels regulated by AsO. However, neither allicin nor AsO affected cytochrome P450 2E1 mRNA expression. In conclusion, allicin attenuated AsO-induced hepatotoxicity by activating the Nrf2 signaling pathway involving KLF9 to inhibit oxidative stress and apoptosis. Our findings elucidate a detailed mechanism by which allicin provides protection against AsO-induced liver injury and support its potential role as an adjunctive therapy for patients suffering from chronic arsenic exposure.