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Protective Effects of Crocetin on Arsenic Trioxide-Induced Hepatic Injury: Involvement of Suppression in Oxidative Stress and Inflammation Through Activation of Nrf2 Signaling Pathway in Rats.

ABSTRACT: PurposeArsenic trioxide (ATO) has been shown to induce hepatic injury. Crocetin is a primary constituent of saffron, which has been verified to have antioxidant and anti-inflammatory effects. In the current experiment, we evaluated the efficacy of crocetin against ATO-induced hepatic injury and explored the potential molecular mechanisms in rats.MethodsRats were pretreated with 25 or 50 mg/kg crocetin 6 h prior to treating with 5 mg/kg ATO to induce hepatic injury daily for 7 days.ResultsTreatment with crocetin attenuated ATO-induced body weight loss, decreases in food and water consumption, and improved ATO-induced hepatic pathological damage. Crocetin significantly inhibited ATO-induced alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) increases. Crocetin prevented ATO-induced liver malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Crocetin abrogated the ATO-induced decrease of catalase (CAT) and superoxide dismutase (SOD) activity. Crocetin was found to significantly restore the protein levels of interleukin 6 (IL-6), interleukin 1? (IL-1?), and tumor necrosis factor-alpha (TNF-?). Furthermore, crocetin promoted the expression of nuclear factor erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADP(H): quinone oxidoreductase 1 (NQO1).ConclusionThese findings suggest that crocetin ameliorates ATO-induced hepatic injury in rats. In addition, the effect of crocetin might be related to its role in antioxidant stress, as an anti-inflammatory agent, and in regulating the Nrf2 signaling pathway.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7245440 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out.Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI50 data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested in vitro for the ability to influence tumor susceptibility to arsenic trioxide.A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down.In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.

Project description:Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the "shock-and-kill" strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the "shock-and-kill" strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.

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Protective Effects of Crocetin on Arsenic Trioxide-Induced Hepatic Injury: Involvement of Suppression in Oxidative Stress and Inflammation Through Activation of Nrf2 Signaling Pathway in Rats.

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