Activation of the GPX4/TLR4 Signaling Pathway Participates in the Alleviation of Selenium Yeast on Deltamethrin-Provoked Cerebrum Injury in Quails.

Deltamethrin (DLM) is a member of pyrethroid pesticide widely applied for agriculture and aquaculture, and its residue in the environment seriously threatens the bio-safety. The cerebrum might be vulnerable to pesticide-triggered oxidative stress. However, there is no specific antidote for treating DLM-triggered cerebral injury. Selenium (Se) is an essential trace element functionally forming selenoprotein glutathione peroxidase (GPX) in antioxidant defense. Se yeast (SY) is a common and effective organic form of Se supplement with high selenomethionine content. Accordingly, this study focused on investigating the therapeutic potential of SY on DLM-induced cerebral injury in quails after chronically exposing to DLM and exploring the underlying mechanisms. Quails were treated with/without SY (0.4 mg kg-1 SY added in standard diet) in the presence/absence of DLM (45 mg kg-1 body weight intragastrically) for 12 weeks. The results showed SY supplementation ameliorated DLM-induced cerebral toxicity. Concretely, SY elevated the content of Se and increased GPX4 level in DLM-treated quail cerebrum. Furthermore, SY enhanced antioxidant defense system by upregulating nuclear factor-erythroid-2-related factor 2 (Nrf2) associated members. Inversely, SY diminished the changes of apoptosis- and inflammation-associated proteins and genes including toll-like receptor 4 (TLR4). Collectively, our results suggest that dietary SY protects against DLM-induced cerebral toxicity in quails via positively regulating the GPX4/TLR4 signaling pathway. GPX4 may be a potential therapeutic target for insecticide-induced biotoxicity.

Inflammation response after the cessation of chronic arsenic exposure and post-treatment of natural astaxanthin in liver: potential role of cytokine-mediated cell-cell interactions.

Ongoing groundwater arsenic contamination throughout China was first recognized in the 1960s. Groundwater arsenic contamination is a high risk for human and animal health worldwide. Apart from drinking water, diet is the second pathway for arsenic to enter the human body and eventually cause liver injury. Natural astaxanthin extracted from the green algae Haematococcus pluvialis has dominated the nutraceutical market for potential health benefits. Nevertheless, the molecular mechanism underlying the protective effect post astaxanthin against arsenic-induced hepatotoxicity remains largely obscure. In this study, we investigate the effect of natural astaxanthin (derived from Haemotococcus pluvialis) on oxidative stress and liver inflammatory response in rats after the cessation of chronic arsenic exposure. Wistar rats were given astaxanthin (250 mg kg-1) daily for 2 weeks after the cessation of exposure to sodium arsenite (300 µg L-1, drinking water, 24 weeks) by intragastric administration. The results showed that post treatment with astaxanthin attenuated liver injury induced by long-term exposure to arsenic in rats. Most importantly, post treatment with astaxanthin decreased the increasing of inflammatory cytokine NF-κB, tumor necrosis factor-α, interleukin-1ß, oxidative stress level, and total arsenic content in livers of rats exposed to arsenic. In addition, post treatment with astaxanthin reversed the increasing of protein levels of alpha-smooth muscle actin and collagen Iα1, which are the activation markers of hepatic stellate cells (HSCs). Collectively, these data demonstrate that post astaxanthin treatment attenuates inflammation response in the liver after the cessation of chronic arsenic exposure via inhibition of cytokine-mediated cell-cell interactions. Daily ingestion of natural astaxanthin might be a potential and beneficial candidate for the treatment of liver damage after the cessation of chronic exposure to sodium arsenite.

Dietary melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway.

Exposure to chromium (Cr) causes a number of respiratory diseases, including lung cancer and pulmonary fibrosis. However, there is currently no safe treatment for Cr-induced lung damage. Here, we used in vivo and in vitro approaches to examine the protective effects of melatonin (MEL) on Cr-induced lung injury and to identify the underlying molecular mechanisms. We found that treatment of rats or a mouse lung epithelial cell MLE-12 with MEL attenuated K2Cr2O7-induced lung injury by reducing the production of oxidative stress and inflammatory mediators and inhibiting cell apoptosis. MEL treatment upregulated the expression of silent information regulator 1 (Sirt1), which deacetylated the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α). In turn, this increased the expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and key anti-oxidant target genes. These results suggest that melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway. Dietary MEL supplement may be a potential new strategy for the treatment of Cr poisoning.

Grape seed procyanidin extract protects against Pb-induced lung toxicity by activating the AMPK/Nrf2/p62 signaling axis.

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.

Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARα signaling pathway.

Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead-induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT-PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARα signaling pathway, and suggests that dietary GSPE may be a protector against lead-induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure.

Grape seed procyanidin extract ameliorates lead-induced liver injury via miRNA153 and AKT/GSK-3ß/Fyn-mediated Nrf2 activation.

Lead-induced hepatotoxicity is characterized by an extensive oxidative stress. Grape seed procyanidin extract (GSPE) possesses abundant biological activities. Herein, we investigated the protective role of GSPE against lead-induced liver injury and determined the potential molecular mechanisms. In vivo, rats were treated with/without lead acetate (PbAc) (0.05%, w/v) in the presence/absence of GSPE (200 mg/kg). In vitro, hepatocytes were pretreated with/without GSPE (100 µg/ml) in the presence/absence of PbAc (100 µM). PbAc administration to rats resulted in anemia, liver dysfunction, lead accumulation in the bone and liver, oxidative stress, DNA damage and apoptosis. GSPE significantly attenuated these adverse effects, except lead accumulation in liver. GSPE also decreased the expression of miRNA153 and increased the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and levels of its downstream protein, and protein kinase B (AKT) phosphorylation in PbAc-induced liver injury. In primary hepatocytes treated with PbAc, GSPE increased hepatocyte viability and decreased lactate dehydrogenase release and reactive oxygen species levels. Dietary GSPE attenuated PbAc-induced liver injury in rats via an integrated mechanism associated with the miRNA153 and AKT/glycogen synthase kinase 3 beta/Fyn-mediated Nrf2 activation.