rutin and 2-2--4-4--tetrabromodiphenyl-ether

Topics: Albumins; Animals; Carrier Proteins; Chemokine CXCL12; Creatinine; Cyclooxygenase 2; Halogenated Diphenyl Ethers; Hydroxyethylrutoside; Kidney; Male; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Protective Agents; Reactive Oxygen Species; Receptors, CXCR4; RNA Interference; RNA, Small Interfering; Signal Transduction; Thioredoxins

2,2,4,4-Tetrabromodiphenyl ether (BDE-47), one of the persistent organic pollutants, seriously influences the quality of life; however, its pathological mechanism remains unclear. Troxerutin is a flavonoid with pharmacological activity of antioxidation and anti-inflammation. In the present study, we investigated troxerutin against BDE-47-induced kidney cell apoptosis and explored the underlying mechanism. The results show that troxerutin reduced renal cell apoptosis and urinary protein secretion in BDE-47-treated mice. Western blot analysis shows that troxerutin supplement enhanced the ratio of Bcl-2/Bax; inhibited the release of cytochrome c from mitochondria, the activation of procaspase-9 and procaspase-3, and the cleavage of PARP; and reduced FAS, FASL, and caspase-8 levels induced by BDE-47. In addition, troxerutin decreased the production of reactive oxygen species (ROS) and increased the activities of antioxidative enzymes. Furthermore, troxerutin blunted Nrf2 ubiquitylation, enhanced the activity of Nrf2, decreased the activity of NOX2, and ameliorated kidney oxidant status of BDE-47-treated mice. Together, these results confirm that troxerutin could alleviate the cytotoxicity of BDE-47 through antioxidation and antiapoptosis, which suggests that its protective mechanism is involved in the inhibition of apoptosis via suppressing NOX2 activity and increasing Nrf2 signaling pathway.

Topics: Animals; Anticoagulants; Apoptosis; Halogenated Diphenyl Ethers; Hydroxyethylrutoside; Kidney; Kidney Diseases; Male; Mice; NF-E2-Related Factor 2

Emerging evidence indicates that 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD(+)-depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD(+)-depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-κB p65 and the acetylation of NF-κB p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced hepatotoxicity.

Topics: Animals; Antioxidants; Halogenated Diphenyl Ethers; Hazardous Substances; Hydroxyethylrutoside; Liver; Mice; NF-kappa B; Oxidative Stress

Proteasome dysfunction has been associated with the pathogeneses of a variety of diseases and with the neurotoxicities of environmental chemicals; however, whether proteasome dysfunction plays a role in the cellular toxicity of polybrominated diphenyl ethers (PBDEs) has not been investigated to date. Emerging evidence suggests that antioxidants exhibit evident beneficial effects on the cellular toxicity associated with PBDEs. In the present study, we investigated whether troxerutin attenuates BDE-47-induced hepatocyte apoptosis by restoring proteasome function and explored the mechanisms underlying this effect. Our results revealed that proteasome dysfunction was involved in the BDE-47-induced hepatocyte apoptosis in the mouse liver. Furthermore, our results revealed that troxerutin effectively inhibited hepatocyte apoptosis by restoring oxidative stress-mediated proteasome dysfunction in BDE-47-treated mice. Consequently, troxerutin markedly suppressed endoplasmic reticulum (ER) stress in the livers of the BDE-47-treated mice. The inhibitory effects of troxerutin on ER stress and apoptotic pathways were markedly blunted by treatment with epoxomicin (a selective inhibitor of proteasome). Ultimately, troxerutin dramatically blocked TRAF2-ASK1-JNK signaling and CHOP-mediated apoptosis signaling in the BDE-47-treated mouse livers. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be a candidate for the prevention of and therapy for BDE-47-induced hepatotoxicity.

Topics: Animals; Apoptosis; Endoplasmic Reticulum Stress; Halogenated Diphenyl Ethers; Hepatocytes; Hydroxyethylrutoside; Male; Mice; Mice, Inbred ICR; Oligopeptides; Oxidative Stress; Proteasome Endopeptidase Complex